Hematology News

The Department of Health & Human Services is proposing an overhaul of HIPAA that will make it easier to access patients’ personal health information, including the health records of patients with mental illness. The proposal would also do away with the requirement that all patients sign a notice of privacy practices.

The changes are contained in a 357-page proposed rule, which was unveiled by federal officials Dec. 10. Roger Severino, director of HHS’ Office for Civil Rights, said in a briefing that the sweeping proposal would empower patients, reduce the administrative burden for health care providers, and pave the way to better-coordinated care.

HHS estimated that the rule could save $3.2 billion over 5 years, but it’s not clear how much of that would accrue to clinical practices.

The most obvious cost-saving aspect for medical and dental practices is the proposal that practitioners would no longer have to provide and collect signed notifications of privacy practices.

“This has been a tremendous waste of time and effort and has caused massive confusion,” said Mr. Severino. He said some patients thought they were waiving privacy rights and that, in some cases, physicians refused to administer care unless patients signed the notices. “That was never the intent.”

Requiring that patients sign the form and that practices keep copies for 6 years is an “unnecessary burden,” said Mr. Severino. “We’ve lost whole forests from this regulation.”

Under the new proposal, health care providers would merely have to let patients know where to find their privacy policies.
 

Sharing mental health info

The rule would also ease the standard for sharing information about a patient who is in a mental health crisis, such as an exacerbation of a serious mental illness or a crisis related to a substance use disorder, including an overdose.

Currently, clinicians can choose to disclose protected health information – to a family member, a caregiver, a law enforcement official, a doctor, or an insurer – if they believe that doing so is advisable in their “professional judgment.” The rule proposes to ease that to a “good faith” belief that a disclosure would be in the best interest of the patient. In both instances, the patient can still object and block the disclosure.

As an example, HHS said that, in the case of a young adult who had experienced an overdose of opioids, a licensed health care professional could make the determination to “disclose relevant information to a parent who is involved in the patient’s treatment and who the young adult would expect, based on their relationship, to participate in or be involved with the patient’s recovery from the overdose.”

HHS is also proposing to let clinicians disclose information in cases in which an individual might be a threat to himself or others, provided the harm is “serious and reasonably foreseeable.”

Currently, information can only be disclosed if it appears there is a “serious and imminent” threat to health or safety. If an individual experienced suicidal ideation, for instance, a health care professional could notify family that the individual is at risk.
 

Fast, no-cost access

The rule also aims to make it easier for patients to get access to their own health care information quickly – within 15 days of a request – instead of the 30 days currently allowed, and sometimes at no cost.

The 30-day time frame is “a relic of a pre-Internet age that should be dispensed with,” said Mr. Severino.

Patients can also request that a treating physician get his or her records from a clinician who had previously treated the individual. The request would be fulfilled within 15 days, although extensions might be possible.

“That takes away the burden of coordination from the patient and puts it on those parties that are responsible for the actual provision of care and that are better positioned to do that coordination,” Mr. Severino said.

Health care professionals will also have to share with patients a fee schedule for records requests. However, if records are shared through a patient portal with view, download, and transmit capabilities, the provider can’t charge the patient for the time it took to upload the information into the system.

“We do not believe a patient’s personal medical record should be profit centers for providers,” Mr. Severino said.

Patients will be allowed to take photos with a smartphone of personal health information – such as an x-ray or sonogram – while receiving care.

The rule is open for public comment until mid-February. After that, it will become final in 180 days. The agency said it would not begin enforcement until 240 days after the final rule was published.

A version of this article originally appeared on Medscape.com.

The Department of Health & Human Services is proposing an overhaul of HIPAA that will make it easier to access patients’ personal health information, including the health records of patients with mental illness. The proposal would also do away with the requirement that all patients sign a notice of privacy practices.

The changes are contained in a 357-page proposed rule, which was unveiled by federal officials Dec. 10. Roger Severino, director of HHS’ Office for Civil Rights, said in a briefing that the sweeping proposal would empower patients, reduce the administrative burden for health care providers, and pave the way to better-coordinated care.

HHS estimated that the rule could save $3.2 billion over 5 years, but it’s not clear how much of that would accrue to clinical practices.

The most obvious cost-saving aspect for medical and dental practices is the proposal that practitioners would no longer have to provide and collect signed notifications of privacy practices.

“This has been a tremendous waste of time and effort and has caused massive confusion,” said Mr. Severino. He said some patients thought they were waiving privacy rights and that, in some cases, physicians refused to administer care unless patients signed the notices. “That was never the intent.”

Requiring that patients sign the form and that practices keep copies for 6 years is an “unnecessary burden,” said Mr. Severino. “We’ve lost whole forests from this regulation.”

Under the new proposal, health care providers would merely have to let patients know where to find their privacy policies.
 

Sharing mental health info

The rule would also ease the standard for sharing information about a patient who is in a mental health crisis, such as an exacerbation of a serious mental illness or a crisis related to a substance use disorder, including an overdose.

Currently, clinicians can choose to disclose protected health information – to a family member, a caregiver, a law enforcement official, a doctor, or an insurer – if they believe that doing so is advisable in their “professional judgment.” The rule proposes to ease that to a “good faith” belief that a disclosure would be in the best interest of the patient. In both instances, the patient can still object and block the disclosure.

As an example, HHS said that, in the case of a young adult who had experienced an overdose of opioids, a licensed health care professional could make the determination to “disclose relevant information to a parent who is involved in the patient’s treatment and who the young adult would expect, based on their relationship, to participate in or be involved with the patient’s recovery from the overdose.”

HHS is also proposing to let clinicians disclose information in cases in which an individual might be a threat to himself or others, provided the harm is “serious and reasonably foreseeable.”

Currently, information can only be disclosed if it appears there is a “serious and imminent” threat to health or safety. If an individual experienced suicidal ideation, for instance, a health care professional could notify family that the individual is at risk.
 

Fast, no-cost access

The rule also aims to make it easier for patients to get access to their own health care information quickly – within 15 days of a request – instead of the 30 days currently allowed, and sometimes at no cost.

The 30-day time frame is “a relic of a pre-Internet age that should be dispensed with,” said Mr. Severino.

Patients can also request that a treating physician get his or her records from a clinician who had previously treated the individual. The request would be fulfilled within 15 days, although extensions might be possible.

“That takes away the burden of coordination from the patient and puts it on those parties that are responsible for the actual provision of care and that are better positioned to do that coordination,” Mr. Severino said.

Health care professionals will also have to share with patients a fee schedule for records requests. However, if records are shared through a patient portal with view, download, and transmit capabilities, the provider can’t charge the patient for the time it took to upload the information into the system.

“We do not believe a patient’s personal medical record should be profit centers for providers,” Mr. Severino said.

Patients will be allowed to take photos with a smartphone of personal health information – such as an x-ray or sonogram – while receiving care.

The rule is open for public comment until mid-February. After that, it will become final in 180 days. The agency said it would not begin enforcement until 240 days after the final rule was published.

A version of this article originally appeared on Medscape.com.

The Department of Health & Human Services is proposing an overhaul of HIPAA that will make it easier to access patients’ personal health information, including the health records of patients with mental illness. The proposal would also do away with the requirement that all patients sign a notice of privacy practices.

The changes are contained in a 357-page proposed rule, which was unveiled by federal officials Dec. 10. Roger Severino, director of HHS’ Office for Civil Rights, said in a briefing that the sweeping proposal would empower patients, reduce the administrative burden for health care providers, and pave the way to better-coordinated care.

HHS estimated that the rule could save $3.2 billion over 5 years, but it’s not clear how much of that would accrue to clinical practices.

The most obvious cost-saving aspect for medical and dental practices is the proposal that practitioners would no longer have to provide and collect signed notifications of privacy practices.

“This has been a tremendous waste of time and effort and has caused massive confusion,” said Mr. Severino. He said some patients thought they were waiving privacy rights and that, in some cases, physicians refused to administer care unless patients signed the notices. “That was never the intent.”

Requiring that patients sign the form and that practices keep copies for 6 years is an “unnecessary burden,” said Mr. Severino. “We’ve lost whole forests from this regulation.”

Under the new proposal, health care providers would merely have to let patients know where to find their privacy policies.
 

Sharing mental health info

The rule would also ease the standard for sharing information about a patient who is in a mental health crisis, such as an exacerbation of a serious mental illness or a crisis related to a substance use disorder, including an overdose.

Currently, clinicians can choose to disclose protected health information – to a family member, a caregiver, a law enforcement official, a doctor, or an insurer – if they believe that doing so is advisable in their “professional judgment.” The rule proposes to ease that to a “good faith” belief that a disclosure would be in the best interest of the patient. In both instances, the patient can still object and block the disclosure.

As an example, HHS said that, in the case of a young adult who had experienced an overdose of opioids, a licensed health care professional could make the determination to “disclose relevant information to a parent who is involved in the patient’s treatment and who the young adult would expect, based on their relationship, to participate in or be involved with the patient’s recovery from the overdose.”

HHS is also proposing to let clinicians disclose information in cases in which an individual might be a threat to himself or others, provided the harm is “serious and reasonably foreseeable.”

Currently, information can only be disclosed if it appears there is a “serious and imminent” threat to health or safety. If an individual experienced suicidal ideation, for instance, a health care professional could notify family that the individual is at risk.
 

Fast, no-cost access

The rule also aims to make it easier for patients to get access to their own health care information quickly – within 15 days of a request – instead of the 30 days currently allowed, and sometimes at no cost.

The 30-day time frame is “a relic of a pre-Internet age that should be dispensed with,” said Mr. Severino.

Patients can also request that a treating physician get his or her records from a clinician who had previously treated the individual. The request would be fulfilled within 15 days, although extensions might be possible.

“That takes away the burden of coordination from the patient and puts it on those parties that are responsible for the actual provision of care and that are better positioned to do that coordination,” Mr. Severino said.

Health care professionals will also have to share with patients a fee schedule for records requests. However, if records are shared through a patient portal with view, download, and transmit capabilities, the provider can’t charge the patient for the time it took to upload the information into the system.

“We do not believe a patient’s personal medical record should be profit centers for providers,” Mr. Severino said.

Patients will be allowed to take photos with a smartphone of personal health information – such as an x-ray or sonogram – while receiving care.

The rule is open for public comment until mid-February. After that, it will become final in 180 days. The agency said it would not begin enforcement until 240 days after the final rule was published.

A version of this article originally appeared on Medscape.com.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

An investigational chimeric antigen receptor T-cell (CAR T-cell) construct targeting two antigens on multiple myeloma cells showed promise in a first-in-humans trial, investigators said.

Among 16 patients with relapsed/refractory, heavily pretreated multiple myeloma who received the dual-targeting construct GC012F, the overall response rate was 93.8%, and all of six patients who received the cells at the highest of three dose levels had stringent complete responses (sCR) and were negative for minimal residual disease (MRD) at 6 months follow-up, reported Weijun Fu, MD, PhD, from Shanghai (China) Changzheng Hospital in an oral abstract presented during the virtual American Society of Hematology annual meeting.

GC012F is a novel CAR-T cell platform targeting both the B-cell maturation antigen (BCMA), which is universally expressed on malignant plasma cells, and CD19, which is expressed on both multiple myeloma cells and progenitors, Dr. Fu said.

“Targeting CD19 can trigger elimination of malignant cells by CAR T. Our preclinical work demonstrated more effective elimination of multiple myeloma clone-forming cells by BCMA and CD19 dual CAR T, so targeting both BCMA and CD19 antigens could improve efficacy and reduce relapse,” he said.

The construct is created using the FasTCAR platform that, according to manufacturer Gracell Biotechnologies (Shanghai), allows for cell culturing and expansion within 24-36 hours, rather than 2-3 weeks required for other CAR T-cell products.
 

Investigator-initiated trial

In a phase 1 investigator-initiated trial, 16 patients with a median age of 56 (range 27-71) years were enrolled. The patients all had relapsed or refractory multiple myeloma according to 2016 International Myeloma Working Group criteria, with a life expectancy of at least 3 months and adequate organ function.

The median time since diagnosis was 3 years (range 1-10). All but one of the 16 patients had high-risk disease, 3 had double-hit disease (the presence of two deletions, gain of function, or p53 mutation), and 5 patients had one or more extramedullary plasmacytomas. Four of the patients had received therapy with an anti-CD38 monoclonal antibody.

Following lymphodepletion with fludarabine and cyclophosphamide, the patients received the CAR T cells in a single infusion at dose levels of either 1, 2, or 3 times 10⁵ cells/kg.

As of the cutoff date in July 2020, 15 of the 16 patients had a clinical response, including 9 with a CR or sCR, and 6 with a very good partial response (VGPR). As noted before, all of the six patients treated at the highest dose level had a sCR. At the median follow-up of 7.3 months, the median duration of response had not been reached.

Among all patients evaluable for response at month 1 (14 patients), 11 were MRD negative by flow cytometry. At month 3 all 11 evaluable patients were MRD negative, and all of 10 patients evaluable at 6 months were also MRD negative.

As with other CAR T-cell constructs, all patients developed the cytokine-release syndrome (CRS), with grade 1 or 2 severity in 14 patients, and grade 3 in 2 patients. The median time to onset of CRS was 6 days (range 2-10), and the median duration was 4 days (range 1-8 days).

No cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were observed.

One patient treated at the middle dose level presented with fever and died shortly after day 78 of an unknown cause during the COVID-19 pandemic. Two patients died of extramedullary disease; each had achieved MRD negativity.

Investigators continue to follow the patients and are enrolling new patients in the ongoing study.
 

‘Interesting approach’

Sandy W. Wong, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, who was not involved in the study, said in an interview that the dual-targeted approach is interesting, in light of a case report presented at ASH 2020 of a patient with multiple myeloma who had a partial response to CAR T-cell therapy with a different construct and who developed a subsequent biallelic loss of BCMA that resulted in resistance to CAR T-cell therapy.

“This raises the idea that, if we perhaps had a dual-targeted CAR T, perhaps we will prolong progression-free survival, in order to avoid antigen escape. So I do think the concept is very interesting and does deserve further study,” she said.

CD19 is thought to be expressed on myeloma stem cells, “so the question is: Are patients not being cured because there is a reservoir of myeloma cells, and targeting CD19 is thought to get at this putative myeloma stem cell? but that remains to be seen,” she added.

Dr. Wong comoderated the session where Dr. Fu presented the data.

The study was supported by participating medical centers and Gracell Biotechnologies. Dr. Fu and Dr. Wong reported no relevant conflicts of interest to disclose.

SOURCE: Jiang H et al. ASH 2020, Abstract 178.

More than 40 value-based payment models – from direct contracting to bundled payments – have been introduced into the Medicare program in the past 10 years, with the goal of improving care while lowering costs. Hopes were high that they would be successful.

But despite the new alternative payment models, costs have not declined. If this continues, Medicare won’t have sufficient funds to cover benefit costs after 2024. Physicians could suffer a huge blow to their income.

Many of the value-based care models simply did not work as expected, said Seema Verma, head of the Centers for Medicare & Medicaid Services, at a recent HLTH Conference. “They are not producing the types of savings the taxpayers deserve,” Ms. Verma said.

The Medicare Payment Advisory Commission (MedPac) concluded that, while dozens of payment models were tested, most failed to generate net savings for Medicare. Even the most successful of the models produced only modest savings. MedPac elaborated: “The track record raises the question of whether changes to particular models or CMMI’s [Center for Medicare & Medicaid Innovation’s] broader strategies might be warranted.”

What will happen now, as government officials admit that their value-based programs haven’t worked? The value-based programs could become more stringent. Here’s what physicians will have to contend with.

More risk. Experts agree that risk – financial risk – will be a component of future programs. Two-sided risk is likely to be the norm. This means that both parties – the provider and the insurer – are at financial risk for the patients covered by the program.

For example, a plan with 50,000 beneficiary patients would estimate the cost of caring for those patients on the basis of multiple variables. If the actual cost is lower than anticipated, both parties share in the savings. However, both share in the loss if the cost of caring for their patient population exceeds expectations.

This may compel physicians to enhance efficiency and potentially limit the services provided to patients. Typically, however, the strategy is to make efforts to prevent services like ED visits and admissions by focusing on health maintenance.

In contrast to most current value-based models, which feature little to no downside risk for physicians, double-sided risk means physicians could lose money. The loss may incorporate a cap – 5%, for example – but programs may differ. Experts concur that double-sided risk will be a hallmark of future programs.

Better data. The majority of health care services are rendered via fee-for-service: Patients receive services and physicians are paid, yet little or no information about outcomes is exchanged between insurers and physicians.

Penny Noyes, president of Health Business Navigators and contract negotiator for physicians, is not a fan of the current crop of value-based programs and feels that data transparency is positive. Sound metrics can lead to improvement, she said, adding: “It’s not money that drives physicians to make decisions; it’s what’s in the best interest of their patients and their patients’ long-term care.”

Value-based programs can work but only if applicable data are developed and given to physicians so that they can better understand their current performance and how to improve.

Mandated participation. Participation in value-based programs has been voluntary, but that may have skewed the results, which were better than what typical practice would have shown. Acknowledging this may lead CMS to call for mandated participation as a component of future programs. Physicians may be brought into programs, if only to determine whether the models really work. To date, participation in the programs has been voluntary, but that may change in the future.

Innovation. The private insurance market may end up as a key player. Over the past 6 months, health insurers have either consolidated partnerships with telemedicine companies to provide no-cost care to beneficiaries or have launched their own initiatives.

Others are focused on bringing together patients and providers operating outside of the traditional health care system, such as Aetna’s merger with CVS which now offers retail-based acute care (MinuteClinic) and chronic care (HealthHUB). Still other payers are gambling with physician practice ownership, as in the case of United Healthcare’s OptumHealth, which now boasts around 50,000 physicians throughout the country.

New practice models are emerging in private practices as well. Physicians are embracing remote care, proactively managing care transitions, and seeking out more methods to keep patients healthy and at home.
 

Not much was expected from value-based plans 

Many are not surprised that the value-based models did not produce impressive results. Ms. Noyes doubted that positive outcomes will be achieved for physicians in comparison with what could have been attained under fee-for-service arrangements with lower administrative costs.

While the Affordable Care Act attempted to encourage alternative reimbursement, it limits the maximum medical loss ratio (MLR) a payer could achieve. For many plans, that maximum was 85%. Simply put, at least $0.85 of each premium collected had to be paid in claims; the remaining $0.15 went to margin, claims, and other administrative costs. A payer with an 82% MLR then would have to rebate the 3% difference to enrollees.

But that’s not what occurred, according to Ms. Noyes. Because value-based payments to providers are considered a claims expense, an MLR ratio of 82% allowed the payer to distribute the 3% difference to providers as value-based payments. Ms. Noyes said: “That may sound good for the provider, but the result was essentially a freeze on the provider’s fee-for-service reimbursement with the prospect of getting value-based payments like ‘shared savings.’ 

“When the providers tried to increase their base fee-for-service rates just to match inflation, payers often advised that any future raises had to be earned through value-based programs,” Ms. Noyes added. The value-based formulas confuse providers because payments are often made for periods as far back as 18 months, and providers do not have data systems to reconcile their payer report cards retrospectively. The result is that providers tended to accept whatever amount the payer distributed.

Executives at Lumeris, a company that helps health systems participate successfully in value-based care, see potential in a newer approach to alternative payments, such as CMS’ Direct Contracting initiative. This voluntary payment model offers options tailored to several types of organizations that aim to reduce costs while preserving or enhancing the quality of care for Medicare fee-for-service beneficiaries.

Jeff Smith, chief commercial officer for population health at Lumeris, explained that the Direct Contracting initiative can provide physicians with a more attractive option than prior value-based models because it adjusts for the complexity and fragility of patients with complex and chronic conditions. By allowing providers to participate in the savings generated, the initiative stands in stark contrast to what Mr. Smith described as the “shared savings to nothingness” experienced by providers in earlier-stage alternative payment models.

Physicians engaged with value-based programs like Direct Contracting are investing in nurses to aid with initiatives regarding health promotion and transitions of care. When a patient is discharged, for example, the nurse contacts the patient to discuss medications, schedule follow-up appointments, and so forth – tasks typically left to the patient (or caregiver) to navigate in the traditional system.

The initiative recognizes the importance of managing high-risk patients, those whom physicians identify as having an extraordinary number of ED visits and admissions. These patients, as well as so-called “rising-risk” patients, are targeted by nurses who proactively communicate with patients (and caregivers) to address patient’s needs, including social determinants of health.

Physicians who have a large load of patients in value-based programs are hiring social workers, pharmacists, and behavioral health experts to help. Of course, these personnel are costly, but that’s what the value-based programs aim to reimburse.

Still, the road ahead to value based is rocky and may not gain momentum for some time. Johns Hopkins University’s Doug Hough, PhD, an economist, recounts a government research study that sought to assess the university’s health system participation in a value-based payment program. While there were positive impacts on the program’s target population, Hough and his team discovered that the returns achieved by the optional model didn’t justify the health system’s financial support for it. The increasingly indebted health system ultimately decided to drop the optional program.

Dr. Hough indicated that the health system – Johns Hopkins Medicine – likely would have  continued its support for the program had the government at least allowed it to break even. Although the payment program under study was a 3-year project, the bigger challenge, declared Dr. Hough, is that “we can’t turn an aircraft carrier that quickly.”

“Three years won’t show whether value-based care is really working,” Dr. Hough said.

Robert Zipper, MD, a hospitalist and senior policy advisor for Sound Physicians, a company that works to improve outcomes in acute care, agreed with Dr. Hough that performance tends to improve with time. Yet, Dr. Zipper doesn’t see much change in the near term, because “after all, there is nothing to replace them [the programs].”

The problem gets even stickier for private payers because patients may be on an insurance panel for as little as a year or 2. Thanks to this rapid churn of beneficiaries, even the best-designed value-based program will have little time to prove its worth.

Dr. Zipper is among the many who don’t expect significant changes in the near term, asserting that “President Biden will want to get a few policy wins first, and health care is not the easiest place to start.”

But it’s likely that payers and others will want to see more emphasis on value-based programs despite these programs’ possible value to patients, physicians, and health systems alike.

A version of this article originally appeared on Medscape.com.

More than 40 value-based payment models – from direct contracting to bundled payments – have been introduced into the Medicare program in the past 10 years, with the goal of improving care while lowering costs. Hopes were high that they would be successful.

But despite the new alternative payment models, costs have not declined. If this continues, Medicare won’t have sufficient funds to cover benefit costs after 2024. Physicians could suffer a huge blow to their income.

Many of the value-based care models simply did not work as expected, said Seema Verma, head of the Centers for Medicare & Medicaid Services, at a recent HLTH Conference. “They are not producing the types of savings the taxpayers deserve,” Ms. Verma said.

The Medicare Payment Advisory Commission (MedPac) concluded that, while dozens of payment models were tested, most failed to generate net savings for Medicare. Even the most successful of the models produced only modest savings. MedPac elaborated: “The track record raises the question of whether changes to particular models or CMMI’s [Center for Medicare & Medicaid Innovation’s] broader strategies might be warranted.”

What will happen now, as government officials admit that their value-based programs haven’t worked? The value-based programs could become more stringent. Here’s what physicians will have to contend with.

More risk. Experts agree that risk – financial risk – will be a component of future programs. Two-sided risk is likely to be the norm. This means that both parties – the provider and the insurer – are at financial risk for the patients covered by the program.

For example, a plan with 50,000 beneficiary patients would estimate the cost of caring for those patients on the basis of multiple variables. If the actual cost is lower than anticipated, both parties share in the savings. However, both share in the loss if the cost of caring for their patient population exceeds expectations.

This may compel physicians to enhance efficiency and potentially limit the services provided to patients. Typically, however, the strategy is to make efforts to prevent services like ED visits and admissions by focusing on health maintenance.

In contrast to most current value-based models, which feature little to no downside risk for physicians, double-sided risk means physicians could lose money. The loss may incorporate a cap – 5%, for example – but programs may differ. Experts concur that double-sided risk will be a hallmark of future programs.

Better data. The majority of health care services are rendered via fee-for-service: Patients receive services and physicians are paid, yet little or no information about outcomes is exchanged between insurers and physicians.

Penny Noyes, president of Health Business Navigators and contract negotiator for physicians, is not a fan of the current crop of value-based programs and feels that data transparency is positive. Sound metrics can lead to improvement, she said, adding: “It’s not money that drives physicians to make decisions; it’s what’s in the best interest of their patients and their patients’ long-term care.”

Value-based programs can work but only if applicable data are developed and given to physicians so that they can better understand their current performance and how to improve.

Mandated participation. Participation in value-based programs has been voluntary, but that may have skewed the results, which were better than what typical practice would have shown. Acknowledging this may lead CMS to call for mandated participation as a component of future programs. Physicians may be brought into programs, if only to determine whether the models really work. To date, participation in the programs has been voluntary, but that may change in the future.

Innovation. The private insurance market may end up as a key player. Over the past 6 months, health insurers have either consolidated partnerships with telemedicine companies to provide no-cost care to beneficiaries or have launched their own initiatives.

Others are focused on bringing together patients and providers operating outside of the traditional health care system, such as Aetna’s merger with CVS which now offers retail-based acute care (MinuteClinic) and chronic care (HealthHUB). Still other payers are gambling with physician practice ownership, as in the case of United Healthcare’s OptumHealth, which now boasts around 50,000 physicians throughout the country.

New practice models are emerging in private practices as well. Physicians are embracing remote care, proactively managing care transitions, and seeking out more methods to keep patients healthy and at home.
 

Not much was expected from value-based plans 

Many are not surprised that the value-based models did not produce impressive results. Ms. Noyes doubted that positive outcomes will be achieved for physicians in comparison with what could have been attained under fee-for-service arrangements with lower administrative costs.

While the Affordable Care Act attempted to encourage alternative reimbursement, it limits the maximum medical loss ratio (MLR) a payer could achieve. For many plans, that maximum was 85%. Simply put, at least $0.85 of each premium collected had to be paid in claims; the remaining $0.15 went to margin, claims, and other administrative costs. A payer with an 82% MLR then would have to rebate the 3% difference to enrollees.

But that’s not what occurred, according to Ms. Noyes. Because value-based payments to providers are considered a claims expense, an MLR ratio of 82% allowed the payer to distribute the 3% difference to providers as value-based payments. Ms. Noyes said: “That may sound good for the provider, but the result was essentially a freeze on the provider’s fee-for-service reimbursement with the prospect of getting value-based payments like ‘shared savings.’ 

“When the providers tried to increase their base fee-for-service rates just to match inflation, payers often advised that any future raises had to be earned through value-based programs,” Ms. Noyes added. The value-based formulas confuse providers because payments are often made for periods as far back as 18 months, and providers do not have data systems to reconcile their payer report cards retrospectively. The result is that providers tended to accept whatever amount the payer distributed.

Executives at Lumeris, a company that helps health systems participate successfully in value-based care, see potential in a newer approach to alternative payments, such as CMS’ Direct Contracting initiative. This voluntary payment model offers options tailored to several types of organizations that aim to reduce costs while preserving or enhancing the quality of care for Medicare fee-for-service beneficiaries.

Jeff Smith, chief commercial officer for population health at Lumeris, explained that the Direct Contracting initiative can provide physicians with a more attractive option than prior value-based models because it adjusts for the complexity and fragility of patients with complex and chronic conditions. By allowing providers to participate in the savings generated, the initiative stands in stark contrast to what Mr. Smith described as the “shared savings to nothingness” experienced by providers in earlier-stage alternative payment models.

Physicians engaged with value-based programs like Direct Contracting are investing in nurses to aid with initiatives regarding health promotion and transitions of care. When a patient is discharged, for example, the nurse contacts the patient to discuss medications, schedule follow-up appointments, and so forth – tasks typically left to the patient (or caregiver) to navigate in the traditional system.

The initiative recognizes the importance of managing high-risk patients, those whom physicians identify as having an extraordinary number of ED visits and admissions. These patients, as well as so-called “rising-risk” patients, are targeted by nurses who proactively communicate with patients (and caregivers) to address patient’s needs, including social determinants of health.

Physicians who have a large load of patients in value-based programs are hiring social workers, pharmacists, and behavioral health experts to help. Of course, these personnel are costly, but that’s what the value-based programs aim to reimburse.

Still, the road ahead to value based is rocky and may not gain momentum for some time. Johns Hopkins University’s Doug Hough, PhD, an economist, recounts a government research study that sought to assess the university’s health system participation in a value-based payment program. While there were positive impacts on the program’s target population, Hough and his team discovered that the returns achieved by the optional model didn’t justify the health system’s financial support for it. The increasingly indebted health system ultimately decided to drop the optional program.

Dr. Hough indicated that the health system – Johns Hopkins Medicine – likely would have  continued its support for the program had the government at least allowed it to break even. Although the payment program under study was a 3-year project, the bigger challenge, declared Dr. Hough, is that “we can’t turn an aircraft carrier that quickly.”

“Three years won’t show whether value-based care is really working,” Dr. Hough said.

Robert Zipper, MD, a hospitalist and senior policy advisor for Sound Physicians, a company that works to improve outcomes in acute care, agreed with Dr. Hough that performance tends to improve with time. Yet, Dr. Zipper doesn’t see much change in the near term, because “after all, there is nothing to replace them [the programs].”

The problem gets even stickier for private payers because patients may be on an insurance panel for as little as a year or 2. Thanks to this rapid churn of beneficiaries, even the best-designed value-based program will have little time to prove its worth.

Dr. Zipper is among the many who don’t expect significant changes in the near term, asserting that “President Biden will want to get a few policy wins first, and health care is not the easiest place to start.”

But it’s likely that payers and others will want to see more emphasis on value-based programs despite these programs’ possible value to patients, physicians, and health systems alike.

A version of this article originally appeared on Medscape.com.

More than 40 value-based payment models – from direct contracting to bundled payments – have been introduced into the Medicare program in the past 10 years, with the goal of improving care while lowering costs. Hopes were high that they would be successful.

But despite the new alternative payment models, costs have not declined. If this continues, Medicare won’t have sufficient funds to cover benefit costs after 2024. Physicians could suffer a huge blow to their income.

Many of the value-based care models simply did not work as expected, said Seema Verma, head of the Centers for Medicare & Medicaid Services, at a recent HLTH Conference. “They are not producing the types of savings the taxpayers deserve,” Ms. Verma said.

The Medicare Payment Advisory Commission (MedPac) concluded that, while dozens of payment models were tested, most failed to generate net savings for Medicare. Even the most successful of the models produced only modest savings. MedPac elaborated: “The track record raises the question of whether changes to particular models or CMMI’s [Center for Medicare & Medicaid Innovation’s] broader strategies might be warranted.”

What will happen now, as government officials admit that their value-based programs haven’t worked? The value-based programs could become more stringent. Here’s what physicians will have to contend with.

More risk. Experts agree that risk – financial risk – will be a component of future programs. Two-sided risk is likely to be the norm. This means that both parties – the provider and the insurer – are at financial risk for the patients covered by the program.

For example, a plan with 50,000 beneficiary patients would estimate the cost of caring for those patients on the basis of multiple variables. If the actual cost is lower than anticipated, both parties share in the savings. However, both share in the loss if the cost of caring for their patient population exceeds expectations.

This may compel physicians to enhance efficiency and potentially limit the services provided to patients. Typically, however, the strategy is to make efforts to prevent services like ED visits and admissions by focusing on health maintenance.

In contrast to most current value-based models, which feature little to no downside risk for physicians, double-sided risk means physicians could lose money. The loss may incorporate a cap – 5%, for example – but programs may differ. Experts concur that double-sided risk will be a hallmark of future programs.

Better data. The majority of health care services are rendered via fee-for-service: Patients receive services and physicians are paid, yet little or no information about outcomes is exchanged between insurers and physicians.

Penny Noyes, president of Health Business Navigators and contract negotiator for physicians, is not a fan of the current crop of value-based programs and feels that data transparency is positive. Sound metrics can lead to improvement, she said, adding: “It’s not money that drives physicians to make decisions; it’s what’s in the best interest of their patients and their patients’ long-term care.”

Value-based programs can work but only if applicable data are developed and given to physicians so that they can better understand their current performance and how to improve.

Mandated participation. Participation in value-based programs has been voluntary, but that may have skewed the results, which were better than what typical practice would have shown. Acknowledging this may lead CMS to call for mandated participation as a component of future programs. Physicians may be brought into programs, if only to determine whether the models really work. To date, participation in the programs has been voluntary, but that may change in the future.

Innovation. The private insurance market may end up as a key player. Over the past 6 months, health insurers have either consolidated partnerships with telemedicine companies to provide no-cost care to beneficiaries or have launched their own initiatives.

Others are focused on bringing together patients and providers operating outside of the traditional health care system, such as Aetna’s merger with CVS which now offers retail-based acute care (MinuteClinic) and chronic care (HealthHUB). Still other payers are gambling with physician practice ownership, as in the case of United Healthcare’s OptumHealth, which now boasts around 50,000 physicians throughout the country.

New practice models are emerging in private practices as well. Physicians are embracing remote care, proactively managing care transitions, and seeking out more methods to keep patients healthy and at home.
 

Not much was expected from value-based plans 

Many are not surprised that the value-based models did not produce impressive results. Ms. Noyes doubted that positive outcomes will be achieved for physicians in comparison with what could have been attained under fee-for-service arrangements with lower administrative costs.

While the Affordable Care Act attempted to encourage alternative reimbursement, it limits the maximum medical loss ratio (MLR) a payer could achieve. For many plans, that maximum was 85%. Simply put, at least $0.85 of each premium collected had to be paid in claims; the remaining $0.15 went to margin, claims, and other administrative costs. A payer with an 82% MLR then would have to rebate the 3% difference to enrollees.

But that’s not what occurred, according to Ms. Noyes. Because value-based payments to providers are considered a claims expense, an MLR ratio of 82% allowed the payer to distribute the 3% difference to providers as value-based payments. Ms. Noyes said: “That may sound good for the provider, but the result was essentially a freeze on the provider’s fee-for-service reimbursement with the prospect of getting value-based payments like ‘shared savings.’ 

“When the providers tried to increase their base fee-for-service rates just to match inflation, payers often advised that any future raises had to be earned through value-based programs,” Ms. Noyes added. The value-based formulas confuse providers because payments are often made for periods as far back as 18 months, and providers do not have data systems to reconcile their payer report cards retrospectively. The result is that providers tended to accept whatever amount the payer distributed.

Executives at Lumeris, a company that helps health systems participate successfully in value-based care, see potential in a newer approach to alternative payments, such as CMS’ Direct Contracting initiative. This voluntary payment model offers options tailored to several types of organizations that aim to reduce costs while preserving or enhancing the quality of care for Medicare fee-for-service beneficiaries.

Jeff Smith, chief commercial officer for population health at Lumeris, explained that the Direct Contracting initiative can provide physicians with a more attractive option than prior value-based models because it adjusts for the complexity and fragility of patients with complex and chronic conditions. By allowing providers to participate in the savings generated, the initiative stands in stark contrast to what Mr. Smith described as the “shared savings to nothingness” experienced by providers in earlier-stage alternative payment models.

Physicians engaged with value-based programs like Direct Contracting are investing in nurses to aid with initiatives regarding health promotion and transitions of care. When a patient is discharged, for example, the nurse contacts the patient to discuss medications, schedule follow-up appointments, and so forth – tasks typically left to the patient (or caregiver) to navigate in the traditional system.

The initiative recognizes the importance of managing high-risk patients, those whom physicians identify as having an extraordinary number of ED visits and admissions. These patients, as well as so-called “rising-risk” patients, are targeted by nurses who proactively communicate with patients (and caregivers) to address patient’s needs, including social determinants of health.

Physicians who have a large load of patients in value-based programs are hiring social workers, pharmacists, and behavioral health experts to help. Of course, these personnel are costly, but that’s what the value-based programs aim to reimburse.

Still, the road ahead to value based is rocky and may not gain momentum for some time. Johns Hopkins University’s Doug Hough, PhD, an economist, recounts a government research study that sought to assess the university’s health system participation in a value-based payment program. While there were positive impacts on the program’s target population, Hough and his team discovered that the returns achieved by the optional model didn’t justify the health system’s financial support for it. The increasingly indebted health system ultimately decided to drop the optional program.

Dr. Hough indicated that the health system – Johns Hopkins Medicine – likely would have  continued its support for the program had the government at least allowed it to break even. Although the payment program under study was a 3-year project, the bigger challenge, declared Dr. Hough, is that “we can’t turn an aircraft carrier that quickly.”

“Three years won’t show whether value-based care is really working,” Dr. Hough said.

Robert Zipper, MD, a hospitalist and senior policy advisor for Sound Physicians, a company that works to improve outcomes in acute care, agreed with Dr. Hough that performance tends to improve with time. Yet, Dr. Zipper doesn’t see much change in the near term, because “after all, there is nothing to replace them [the programs].”

The problem gets even stickier for private payers because patients may be on an insurance panel for as little as a year or 2. Thanks to this rapid churn of beneficiaries, even the best-designed value-based program will have little time to prove its worth.

Dr. Zipper is among the many who don’t expect significant changes in the near term, asserting that “President Biden will want to get a few policy wins first, and health care is not the easiest place to start.”

But it’s likely that payers and others will want to see more emphasis on value-based programs despite these programs’ possible value to patients, physicians, and health systems alike.

A version of this article originally appeared on Medscape.com.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.

A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
 

Remission can be improved

While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.

The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.

The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m² per day) and cyclophosphamide (250mg/m² per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
 

100% MRD negative

On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.

Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.

Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 10⁴ copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
 

STAR holds promise

Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.

Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”

Dr. Lu reported that she had no relevant disclosures.

SOURCE: Lu P et al. ASH 2020, Abstract 270.

In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.

These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.¹ Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. mRNA vaccines work differently. They do not contain antigens. Instead, they contain a blueprint for the antigen in the form of genetic material, mRNA. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.

The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.²

A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”³ Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
 

Early efficacy results have been surprising

Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.

Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.

Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
 

Could mRNA COVID-19 vaccines be dangerous in the long term?

These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.^4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.

What about availability?

Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.

Timelines and testing other vaccines

Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.

Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.

AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.

Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.

Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.

Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.

After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.

Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.

However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at [email protected].

References

1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.

2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.

3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).

4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.

5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.

6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.

In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.

These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.¹ Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. mRNA vaccines work differently. They do not contain antigens. Instead, they contain a blueprint for the antigen in the form of genetic material, mRNA. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.

The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.²

A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”³ Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
 

Early efficacy results have been surprising

Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.

Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.

Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
 

Could mRNA COVID-19 vaccines be dangerous in the long term?

These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.^4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.

What about availability?

Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.

Timelines and testing other vaccines

Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.

Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.

AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.

Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.

Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.

Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.

After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.

Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.

However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at [email protected].

References

1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.

2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.

3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).

4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.

5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.

6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.

In mid-November, Pfizer/BioNTech were the first with surprising positive protection interim data for their coronavirus vaccine, BNT162b2. A week later, Moderna released interim efficacy results showing its coronavirus vaccine, mRNA-1273, also protected patients from developing SARS-CoV-2 infections. Both studies included mostly healthy adults. A diverse ethnic and racial vaccinated population was included. A reasonable number of persons aged over 65 years, and persons with stable compromising medical conditions were included. Adolescents aged 16 years and over were included. Younger adolescents have been vaccinated or such studies are in the planning or early implementation stage as 2020 came to a close.

These are new and revolutionary vaccines, although the ability to inject mRNA into animals dates back to 1990, technological advances today make it a reality.¹ Traditional vaccines typically involve injection with antigens such as purified proteins or polysaccharides or inactivated/attenuated viruses. mRNA vaccines work differently. They do not contain antigens. Instead, they contain a blueprint for the antigen in the form of genetic material, mRNA. In the case of Pfizer’s and Moderna’s vaccines, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary lipid nanoparticles to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. (The properties of the respective lipid nanoparticle packaging may be the factor that impacts storage requirements discussed below.) When injected into muscle (myocyte), the lipid nanoparticles containing the mRNA inside are taken into muscle cells, where the cytoplasmic ribosomes detect and decode the mRNA resulting in the production of the spike protein antigen. It should be noted that the mRNA does not enter the nucleus, where the genetic information (DNA) of a cell is located, and can’t be reproduced or integrated into the DNA. The antigen is exported to the myocyte cell surface where the immune system’s antigen presenting cells detect the protein, ingest it, and take it to regional lymph nodes where interactions with T cells and B cells results in antibodies, T cell–mediated immunity, and generation of immune memory T cells and B cells. A particular subset of T cells – cytotoxic or killer T cells – destroy cells that have been infected by a pathogen. The SARS-CoV-2 mRNA vaccine from Pfizer was reported to induce powerful cytotoxic T-cell responses. Results for Moderna’s vaccine had not been reported at the time this column was prepared, but I anticipate the same positive results.

The revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced. This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab – and it can be done incredibly fast. It is reported that the mRNA code for the vaccine by Moderna was made in 2 days and production development was completed in about 2 months.²

A 2007 World Health Organization report noted that infectious diseases are emerging at “the historically unprecedented rate of one per year.”³ Severe acute respiratory syndrome (SARS), Zika, Ebola, and avian and swine flu are recent examples. For most vaccines against emerging diseases, the challenge is about speed: developing and manufacturing a vaccine and getting it to persons who need it as quickly as possible. The current seasonal flu vaccine takes about 6 months to develop; it takes years for most of the traditional vaccines. That’s why once the infrastructure is in place, mRNA vaccines may prove to offer a big advantage as vaccines against emerging pathogens.
 

Early efficacy results have been surprising

Both vaccines were reported to produce about 95% efficacy in the final analysis. That was unexpectedly high because most vaccines for respiratory illness achieve efficacy of 60%-80%, e.g., flu vaccines. However, the efficacy rate may drop as time goes by because stimulation of short-term immunity would be in the earliest reported results.

Preventing SARS-CoV-2 cases is an important aspect of a coronavirus vaccine, but preventing severe illness is especially important considering that severe cases can result in prolonged intubation/artificial ventilation, prolonged disability and death. Pfizer/BioNTech had not released any data on the breakdown of severe cases as this column was finalized. In Moderna’s clinical trial, a secondary endpoint analyzed severe cases of COVID-19 and included 30 severe cases (as defined in the study protocol) in this analysis. All 30 cases occurred in the placebo group and none in the mRNA-1273–vaccinated group. In the Pfizer/BioNTech trial there were too few cases of severe illness to calculate efficacy.

Duration of immunity and need to revaccinate after initial primary vaccination are unknowns. Study of induction of B- and T-cell memory and levels of long-term protection have not been reported thus far.
 

Could mRNA COVID-19 vaccines be dangerous in the long term?

These will be the first-ever mRNA vaccines brought to market for humans. In order to receive Food and Drug Administration approval, the companies had to prove there were no immediate or short-term negative adverse effects from the vaccines. The companies reported that their independent data-monitoring committees hadn’t “reported any serious safety concerns.” However, fairly significant local reactions at the site of injection, fever, malaise, and fatigue occur with modest frequency following vaccinations with these products, reportedly in 10%-15% of vaccinees. Overall, the immediate reaction profile appears to be more severe than what occurs following seasonal influenza vaccination. When mass inoculations with these completely new and revolutionary vaccines begins, we will know virtually nothing about their long-term side effects. The possibility of systemic inflammatory responses that could lead to autoimmune conditions, persistence of the induced immunogen expression, development of autoreactive antibodies, and toxic effects of delivery components have been raised as theoretical concerns.^4-6 None of these theoretical risks have been observed to date and postmarketing phase 4 safety monitoring studies are in place from the Centers for Disease Control and Prevention and the companies that produce the vaccines. This is a risk public health authorities are willing to take because the risk to benefit calculation strongly favors taking theoretical risks, compared with clear benefits in preventing severe illnesses and death.

What about availability?

Pfizer/BioNTech expects to be able to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. Moderna expects to produce 20 million doses by the end of 2020, and 500 million to 1 billion doses in 2021. Storage requirements are inherent to the composition of the vaccines with their differing lipid nanoparticle delivery systems. Pfizer/BioNTech’s BNT162b2 has to be stored and transported at –80° C, which requires specialized freezers, which most doctors’ offices and pharmacies are unlikely to have on site, or dry ice containers. Once the vaccine is thawed, it can only remain in the refrigerator for 24 hours. Moderna’s mRNA-1273 will be much easier to distribute. The vaccine is stable in a standard freezer at –20° C for up to 6 months, in a refrigerator for up to 30 days within that 6-month shelf life, and at room temperature for up to 12 hours.

Timelines and testing other vaccines

Strong efficacy data from the two leading SARS-CoV-2 vaccines and emergency-use authorization Food and Drug Administration approval suggest the window for testing additional vaccine candidates in the United States could soon start to close. Of the more than 200 vaccines in development for SARS-CoV-2, at least 7 have a chance of gathering pivotal data before the front-runners become broadly available.

Testing diverse vaccine candidates, based on different technologies, is important for ensuring sufficient supply and could lead to products with tolerability and safety profiles that make them better suited, or more attractive, to subsets of the population. Different vaccine antigens and technologies also may yield different durations of protection, a question that will not be answered until long after the first products are on the market.

AstraZeneca enrolled about 23,000 subjects into its two phase 3 trials of AZD1222 (ChAdOx1 nCoV-19): a 40,000-subject U.S. trial and a 10,000-subject study in Brazil. AstraZeneca’s AZD1222, developed with the University of Oxford (England), uses a replication defective simian adenovirus vector called ChAdOx1.AZD1222 which encodes the SARS-CoV-2 spike protein. After injection, the viral vector delivers recombinant DNA that is decoded to mRNA, followed by mRNA decoding to become a protein. A serendipitous manufacturing error for the first 3,000 doses resulted in a half dose for those subjects before the error was discovered. Full doses were given to those subjects on second injections and those subjects showed 90% efficacy. Subjects who received 2 full doses showed 62% efficacy. A vaccine cannot be licensed based on 3,000 subjects so AstraZeneca has started a new phase 3 trial involving many more subjects to receive the combination lower dose followed by the full dose.

Johnson and Johnson (J&J) started its phase 3 trial evaluating a single dose of JNJ-78436735 in September. Phase 3 data may be reported by the end of2020. In November, J&J announced it was starting a second phase 3 trial to test two doses of the candidate. J&J’s JNJ-78436735 encodes the SARS-CoV-2 spike protein in an adenovirus serotype 26 (Ad26) vector, which is one of the two adenovirus vectors used in Sputnik V, the Russian vaccine reported to have 90% efficacy at an early interim analysis.

Sanofi and Novavax are both developing protein-based vaccines, a proven modality. Sanofi, in partnership with GlaxoSmithKline started a phase 1/2 clinical trial in the Fall 2020 with plans to commence a phase 3 trial in late December. Sanofi developed the protein ingredients and GlaxoSmithKline added one of their novel adjuvants. Novavax expects data from a U.K. phase 3 trial of NVX-CoV2373 in early 2021 and began a U.S. phase 3 study in late November. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike protein and contains Novavax’s patented saponin-based Matrix-M adjuvant.

Inovio Pharmaceuticals was gearing up to start a U.S. phase 2/3 trial of DNA vaccine INO-4800 by the end of 2020.

After Moderna and Pfizer-BioNTech, CureVac has the next most advanced mRNA vaccine. It was planned that a phase 2b/3 trial of CVnCoV would be conducted in Europe, Latin America, Africa, and Asia. Sanofi is also developing a mRNA vaccine as a second product in addition to its protein vaccine.

Vaxxinity planned to begin phase 3 testing of UB-612, a multitope peptide–based vaccine, in Brazil by the end of 2020.

However, emergency-use authorizations for the Pfizer and Moderna vaccines could hinder trial recruitment in at least two ways. Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials to give subjects the opportunity to switch to a vaccine proven to be effective. Even if unblinding doesn’t occur, as the two authorized vaccines start to become widely available, volunteering for clinical trials may become less attractive.
 

Dr. Pichichero is a specialist in pediatric infectious diseases, and director of the Research Institute at Rochester (N.Y.) General Hospital. He said he has no relevant financial disclosures. Email Dr. Pichichero at [email protected].

References

1. Wolff JA et al. Science. 1990 Mar 23. doi: 10.1126/science.1690918.

2. Jackson LA et al. N Engl J Med. 2020 Nov 12. doi: 10.1056/NEJMoa2022483.

3. Prentice T and Reinders LT. The world health report 2007. (Geneva Switzerland: World Health Organization, 2007).

4. Peck KM and Lauring AS. J Virol. 2018. doi: 10.1128/JVI.01031-17.

5. Pepini T et al. J Immunol. 2017 May 15. doi: 10.4049/jimmunol.1601877.

6. Theofilopoulos AN et al. Annu Rev Immunol. 2005. doi: 10.1146/annurev.immunol.23.021704.115843.

Among people hospitalized with COVID-19, a combination of baricitinib and remdesivir reduces the median time to recovery, compared with remdesivir plus placebo, according to trial results published Dec. 11 in the New England Journal of Medicine.

Median time to recovery was 7 days for patients who received baricitinib versus 8 days for patients who received placebo.

The difference was greater in patients who required high-flow oxygen or noninvasive ventilation during their hospitalization. In this group, baricitinib shortened median time to recovery from 18 days to 10 days.

“Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or noninvasive mechanical ventilation,” reported Andre C. Kalil, MD, MPH, from the University of Nebraska Medical Center, Omaha, and colleagues. In addition, the combination was associated with fewer adverse events.

The study details data from the ACTT-2 trial that the Food and Drug Administration used to issue an emergency-use authorization for baricitinib in combination with remdesivir on Nov. 19.

Under the emergency-use authorization, baricitinib (Olumiant, Eli Lilly), a Janus kinase inhibitor approved for the treatment of rheumatoid arthritis, may be used in combination with remdesivir (Veklury, Gilead), an antiviral, for treating hospitalized adults and children aged at least 2 years with suspected or confirmed COVID-19.

The combination is intended for patients who need supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation.
 

Combo treatment favored

It is unclear how baricitinib compares with dexamethasone, which improved survival and led to a 1-day shorter hospital stay in another trial. There are differences between the drugs and trial designs, and only a “head-to-head comparison ... will allow the efficacy and safety differences between these two approaches to be fully understood,” Dr. Kalil and coauthors wrote.

“Dexamethasone has a long half-life, acts on glucocorticoid receptors, and reduces inflammation through a broad-pathway approach that has been associated with immunosuppression, hospital-acquired infections, gastrointestinal bleeding, hyperglycemia, and neuromuscular weakness, even with short courses,” they wrote. “Baricitinib has a short half-life, acts on targeted critical pathways to reduce inflammation while minimizing biologic redundancy with less immunosuppression, and may have antiviral activity.”

The ACTT-2 trial started in May and enrolled 1,033 patients in eight countries. Participants were randomly assigned to receive oral baricitinib tablets plus intravenous remdesivir or oral placebo tablets plus remdesivir. 

Participants who received both drugs had significantly improved clinical status at day 15. Patients who received both treatments also had fewer serious adverse events.

“Although ACTT-2 was not powered to detect a difference in mortality between the two groups, both the survival rate and the time-to-death analyses favored combination treatment,” the researchers wrote.

The trial was sponsored by the National Institute of Allergy and Infectious Diseases. Some of the authors disclosed funding from government grants and financial ties to Eli Lilly, Gilead, and other companies.

A version of this article originally appeared on Medscape.com.

Among people hospitalized with COVID-19, a combination of baricitinib and remdesivir reduces the median time to recovery, compared with remdesivir plus placebo, according to trial results published Dec. 11 in the New England Journal of Medicine.

Median time to recovery was 7 days for patients who received baricitinib versus 8 days for patients who received placebo.

The difference was greater in patients who required high-flow oxygen or noninvasive ventilation during their hospitalization. In this group, baricitinib shortened median time to recovery from 18 days to 10 days.

“Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or noninvasive mechanical ventilation,” reported Andre C. Kalil, MD, MPH, from the University of Nebraska Medical Center, Omaha, and colleagues. In addition, the combination was associated with fewer adverse events.

The study details data from the ACTT-2 trial that the Food and Drug Administration used to issue an emergency-use authorization for baricitinib in combination with remdesivir on Nov. 19.

Under the emergency-use authorization, baricitinib (Olumiant, Eli Lilly), a Janus kinase inhibitor approved for the treatment of rheumatoid arthritis, may be used in combination with remdesivir (Veklury, Gilead), an antiviral, for treating hospitalized adults and children aged at least 2 years with suspected or confirmed COVID-19.

The combination is intended for patients who need supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation.
 

Combo treatment favored

It is unclear how baricitinib compares with dexamethasone, which improved survival and led to a 1-day shorter hospital stay in another trial. There are differences between the drugs and trial designs, and only a “head-to-head comparison ... will allow the efficacy and safety differences between these two approaches to be fully understood,” Dr. Kalil and coauthors wrote.

“Dexamethasone has a long half-life, acts on glucocorticoid receptors, and reduces inflammation through a broad-pathway approach that has been associated with immunosuppression, hospital-acquired infections, gastrointestinal bleeding, hyperglycemia, and neuromuscular weakness, even with short courses,” they wrote. “Baricitinib has a short half-life, acts on targeted critical pathways to reduce inflammation while minimizing biologic redundancy with less immunosuppression, and may have antiviral activity.”

The ACTT-2 trial started in May and enrolled 1,033 patients in eight countries. Participants were randomly assigned to receive oral baricitinib tablets plus intravenous remdesivir or oral placebo tablets plus remdesivir. 

Participants who received both drugs had significantly improved clinical status at day 15. Patients who received both treatments also had fewer serious adverse events.

“Although ACTT-2 was not powered to detect a difference in mortality between the two groups, both the survival rate and the time-to-death analyses favored combination treatment,” the researchers wrote.

The trial was sponsored by the National Institute of Allergy and Infectious Diseases. Some of the authors disclosed funding from government grants and financial ties to Eli Lilly, Gilead, and other companies.

A version of this article originally appeared on Medscape.com.

Among people hospitalized with COVID-19, a combination of baricitinib and remdesivir reduces the median time to recovery, compared with remdesivir plus placebo, according to trial results published Dec. 11 in the New England Journal of Medicine.

Median time to recovery was 7 days for patients who received baricitinib versus 8 days for patients who received placebo.

The difference was greater in patients who required high-flow oxygen or noninvasive ventilation during their hospitalization. In this group, baricitinib shortened median time to recovery from 18 days to 10 days.

“Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or noninvasive mechanical ventilation,” reported Andre C. Kalil, MD, MPH, from the University of Nebraska Medical Center, Omaha, and colleagues. In addition, the combination was associated with fewer adverse events.

The study details data from the ACTT-2 trial that the Food and Drug Administration used to issue an emergency-use authorization for baricitinib in combination with remdesivir on Nov. 19.

Under the emergency-use authorization, baricitinib (Olumiant, Eli Lilly), a Janus kinase inhibitor approved for the treatment of rheumatoid arthritis, may be used in combination with remdesivir (Veklury, Gilead), an antiviral, for treating hospitalized adults and children aged at least 2 years with suspected or confirmed COVID-19.

The combination is intended for patients who need supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation.
 

Combo treatment favored

It is unclear how baricitinib compares with dexamethasone, which improved survival and led to a 1-day shorter hospital stay in another trial. There are differences between the drugs and trial designs, and only a “head-to-head comparison ... will allow the efficacy and safety differences between these two approaches to be fully understood,” Dr. Kalil and coauthors wrote.

“Dexamethasone has a long half-life, acts on glucocorticoid receptors, and reduces inflammation through a broad-pathway approach that has been associated with immunosuppression, hospital-acquired infections, gastrointestinal bleeding, hyperglycemia, and neuromuscular weakness, even with short courses,” they wrote. “Baricitinib has a short half-life, acts on targeted critical pathways to reduce inflammation while minimizing biologic redundancy with less immunosuppression, and may have antiviral activity.”

The ACTT-2 trial started in May and enrolled 1,033 patients in eight countries. Participants were randomly assigned to receive oral baricitinib tablets plus intravenous remdesivir or oral placebo tablets plus remdesivir. 

Participants who received both drugs had significantly improved clinical status at day 15. Patients who received both treatments also had fewer serious adverse events.

“Although ACTT-2 was not powered to detect a difference in mortality between the two groups, both the survival rate and the time-to-death analyses favored combination treatment,” the researchers wrote.

The trial was sponsored by the National Institute of Allergy and Infectious Diseases. Some of the authors disclosed funding from government grants and financial ties to Eli Lilly, Gilead, and other companies.

A version of this article originally appeared on Medscape.com.

The Centers for Disease Control and Prevention (CDC) advisory committee recommended on December 12 the recently authorized Pfizer-BioNTech COVID-19 vaccine for people age 16 and over in the United States, stating they found it was safe and effective.

The agency said it will quickly issue guidance to clinicians so they can determine when and when not to give the vaccine, and to help them communicate the risks and benefits to patients.

CDC staff gave a preview of those clinical considerations at the agency’s Advisory Committee on Immunization Practices (ACIP) meeting on December 12 and said it would be holding calls with clinicians on December 13 and 14.

The CDC will also issue guidance December 13 on how organizations can handle the workforce problems that might arise as health care workers experience side effects from vaccination.

ACIP voted 11-0, with three recusals, to recommend use of the Pfizer-BioNTech mRNA vaccine in individuals 16 years or older according to the guidelines of the Food and Drug Administration’s (FDA’s) emergency use authorization issued December 11.

The panel also voted unanimously to include the vaccine in 2021 immunization schedules. All panel members said the recommendation should go hand-in-hand with ACIP’s previous recommendation on December 1 that allocation of the vaccine be phased-in, with health care workers and residents and staff of long-term care facilities in phase 1a.

Allergies, pregnant women?

ACIP panelists said clinicians need more guidance on whether to use the vaccine in pregnant or breastfeeding women, the immunocompromised, or those who have a history of allergies.

The FDA health care provider information sheet said there is not enough data to recommend vaccinating those women or the immunocompromised, and also advises against giving the vaccine to individuals who have a history of serious allergic reaction to any component of the vaccine.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research (CBER) clarified this in a briefing on December 12, noting that women who are pregnant or lactating can make the decision in consultation with their physician. And, he said, patients with any other history of allergy should be able to safely get the vaccine.

The CDC — in its soon-to-be-released guidance — will make the same recommendations. For any woman considering vaccination, she should consider the level of COVID-19 in the community, her personal risk of contracting the virus, the risks to her or her fetus of developing the disease, and the vaccine’s known side effects, Sarah Mbaeyi, MD, MPH, a medical officer at the agency, said during the panel meeting December 12.

She added that the CDC will also urge physicians to advise women to take acetaminophen if they develop a fever after vaccination — to protect the developing fetus from fever.

Sandra Fryhofer, MD, representing the American Medical Association, commended the CDC for these recommendations. But she also called on Pfizer, the FDA, and the CDC to make data from the developmental and reproductive toxicity (DART) studies public as soon as possible.

“We really need to put those results on warp speed and get them out there to give our physicians and pregnant women more information,” said Fryhofer, an adjunct associate professor of medicine at Emory University School of Medicine in Atlanta, Georgia.

The American College of Obstetricians and Gynecologists (ACOG) will also soon release guidance for vaccinating pregnant and breastfeeding women, said Linda Eckert, MD, FACOG, an ACOG representative on the panel.

ACOG and the CDC met the morning of December 12 to discuss risks and benefits with experts in immunology, placental pathology, and vaccine kinetics, she said.

“The overall complete consensus was that we don’t see biological plausibility at this time for placental transfer of the mRNA and that we see that direct fetal exposure or the possibility of fetal inflammatory response is extremely unlikely,” said Eckert, professor of obstetrics and gynecology at the University of Washington, Seattle. “Clearly we are waiting on the data.”

A Pfizer official told the ACIP panel that preliminary data “show no indication of either developmental or reproductive toxicity,” and that the company plans to send the final DART data to the FDA at the end of December.

On the potential for allergic reactions, the CDC concurred with the FDA that the vaccine should not be given to people with a history of serious reactions. The agency added that the category should include anyone who has had a reaction to any vaccine or injectable drug product because injectables may contain the same ingredients as the Pfizer vaccine, said Mbaeyi.

The CDC will also urge clinicians to observe patients with a history of anaphylaxis for 30 minutes after vaccination and all patients for at least 15 minutes afterward.

Should teens be a special population?

At least one ACIP panel member — Henry Bernstein, DO, MHCM, FAAP — said he was concerned that backing use of the vaccine in 16- and 17-year-olds was a leap of faith, given that Pfizer had extremely limited data on this cohort.

Bernstein, professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, also said that systemic reactions were more common in that age group.

He argued for making the 16- and 17-year-olds a “special population” that would get specific attention and guidance for vaccination from the federal agencies and professional societies.

Bernstein said he did not want to sow any more doubts in parents’ minds about vaccination, noting that hesitancy was a growing concern. “A successful pediatric vaccination program depends on creating and sustaining parental confidence in both the safety and effectiveness of this vaccine,” he said.

Many panelists, however, noted that there has been no evidence to suggest that the vaccine is not safe or less effective in that younger age group.

Yvonne Maldonado, MD, the American Academy of Pediatrics representative on the panel, said that this age group should not be denied the vaccine as they often have essential or front-line jobs that put them at higher risk for infection.

“I am very concerned about this message being sent out that this vaccine will not be safe in children,” said Maldonado, professor of pediatrics and health research and policy at Stanford University School of Medicine in California.

“We currently have no evidence that that is the case,” she said, adding there is also no indication younger children are biologically or physiologically different in their response or safety risk than 18-year-olds.

Vaccine = hope

Committee members breathed a sigh of relief at the end of the 2-day meeting, saying that although the Pfizer vaccine is not perfect, it represents a scientific milestone and a significant advance against the continuing march of the SARS-CoV-2 pandemic.

“This vaccine and future vaccines do provide a promise for a lot of progress in the future,” said panelist Beth P. Bell, MD, MPH, clinical professor of global health at the University of Washington School of Public Health in Seattle.

Peter Szilagyi, MD, MPH, executive vice-chair and vice-chair for research at the University of California, Los Angeles pediatrics department, said, “I’m really hopeful that this is the beginning of the end of the coronavirus pandemic.”

“The need for this vaccine is profound,” said Veronica McNally, president and CEO of the Franny Strong Foundation in West Bloomfield, Michigan.

The ACIP panel also made the argument that while the at least $10 billion spent on vaccine development by the federal government’s Operation Warp Speed alone has been a good investment, more spending is needed to actually get Americans vaccinated.

The imbalance between the two is “shocking and needs to be corrected,” said Bell. “We are not going to be able to protect the American public if we don’t have a way to deliver the vaccine to them.”

This article first appeared on Medscape.com.

The Centers for Disease Control and Prevention (CDC) advisory committee recommended on December 12 the recently authorized Pfizer-BioNTech COVID-19 vaccine for people age 16 and over in the United States, stating they found it was safe and effective.

The agency said it will quickly issue guidance to clinicians so they can determine when and when not to give the vaccine, and to help them communicate the risks and benefits to patients.

CDC staff gave a preview of those clinical considerations at the agency’s Advisory Committee on Immunization Practices (ACIP) meeting on December 12 and said it would be holding calls with clinicians on December 13 and 14.

The CDC will also issue guidance December 13 on how organizations can handle the workforce problems that might arise as health care workers experience side effects from vaccination.

ACIP voted 11-0, with three recusals, to recommend use of the Pfizer-BioNTech mRNA vaccine in individuals 16 years or older according to the guidelines of the Food and Drug Administration’s (FDA’s) emergency use authorization issued December 11.

The panel also voted unanimously to include the vaccine in 2021 immunization schedules. All panel members said the recommendation should go hand-in-hand with ACIP’s previous recommendation on December 1 that allocation of the vaccine be phased-in, with health care workers and residents and staff of long-term care facilities in phase 1a.

Allergies, pregnant women?

ACIP panelists said clinicians need more guidance on whether to use the vaccine in pregnant or breastfeeding women, the immunocompromised, or those who have a history of allergies.

The FDA health care provider information sheet said there is not enough data to recommend vaccinating those women or the immunocompromised, and also advises against giving the vaccine to individuals who have a history of serious allergic reaction to any component of the vaccine.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research (CBER) clarified this in a briefing on December 12, noting that women who are pregnant or lactating can make the decision in consultation with their physician. And, he said, patients with any other history of allergy should be able to safely get the vaccine.

The CDC — in its soon-to-be-released guidance — will make the same recommendations. For any woman considering vaccination, she should consider the level of COVID-19 in the community, her personal risk of contracting the virus, the risks to her or her fetus of developing the disease, and the vaccine’s known side effects, Sarah Mbaeyi, MD, MPH, a medical officer at the agency, said during the panel meeting December 12.

She added that the CDC will also urge physicians to advise women to take acetaminophen if they develop a fever after vaccination — to protect the developing fetus from fever.

Sandra Fryhofer, MD, representing the American Medical Association, commended the CDC for these recommendations. But she also called on Pfizer, the FDA, and the CDC to make data from the developmental and reproductive toxicity (DART) studies public as soon as possible.

“We really need to put those results on warp speed and get them out there to give our physicians and pregnant women more information,” said Fryhofer, an adjunct associate professor of medicine at Emory University School of Medicine in Atlanta, Georgia.

The American College of Obstetricians and Gynecologists (ACOG) will also soon release guidance for vaccinating pregnant and breastfeeding women, said Linda Eckert, MD, FACOG, an ACOG representative on the panel.

ACOG and the CDC met the morning of December 12 to discuss risks and benefits with experts in immunology, placental pathology, and vaccine kinetics, she said.

“The overall complete consensus was that we don’t see biological plausibility at this time for placental transfer of the mRNA and that we see that direct fetal exposure or the possibility of fetal inflammatory response is extremely unlikely,” said Eckert, professor of obstetrics and gynecology at the University of Washington, Seattle. “Clearly we are waiting on the data.”

A Pfizer official told the ACIP panel that preliminary data “show no indication of either developmental or reproductive toxicity,” and that the company plans to send the final DART data to the FDA at the end of December.

On the potential for allergic reactions, the CDC concurred with the FDA that the vaccine should not be given to people with a history of serious reactions. The agency added that the category should include anyone who has had a reaction to any vaccine or injectable drug product because injectables may contain the same ingredients as the Pfizer vaccine, said Mbaeyi.

The CDC will also urge clinicians to observe patients with a history of anaphylaxis for 30 minutes after vaccination and all patients for at least 15 minutes afterward.

Should teens be a special population?

At least one ACIP panel member — Henry Bernstein, DO, MHCM, FAAP — said he was concerned that backing use of the vaccine in 16- and 17-year-olds was a leap of faith, given that Pfizer had extremely limited data on this cohort.

Bernstein, professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, also said that systemic reactions were more common in that age group.

He argued for making the 16- and 17-year-olds a “special population” that would get specific attention and guidance for vaccination from the federal agencies and professional societies.

Bernstein said he did not want to sow any more doubts in parents’ minds about vaccination, noting that hesitancy was a growing concern. “A successful pediatric vaccination program depends on creating and sustaining parental confidence in both the safety and effectiveness of this vaccine,” he said.

Many panelists, however, noted that there has been no evidence to suggest that the vaccine is not safe or less effective in that younger age group.

Yvonne Maldonado, MD, the American Academy of Pediatrics representative on the panel, said that this age group should not be denied the vaccine as they often have essential or front-line jobs that put them at higher risk for infection.

“I am very concerned about this message being sent out that this vaccine will not be safe in children,” said Maldonado, professor of pediatrics and health research and policy at Stanford University School of Medicine in California.

“We currently have no evidence that that is the case,” she said, adding there is also no indication younger children are biologically or physiologically different in their response or safety risk than 18-year-olds.

Vaccine = hope

Committee members breathed a sigh of relief at the end of the 2-day meeting, saying that although the Pfizer vaccine is not perfect, it represents a scientific milestone and a significant advance against the continuing march of the SARS-CoV-2 pandemic.

“This vaccine and future vaccines do provide a promise for a lot of progress in the future,” said panelist Beth P. Bell, MD, MPH, clinical professor of global health at the University of Washington School of Public Health in Seattle.

Peter Szilagyi, MD, MPH, executive vice-chair and vice-chair for research at the University of California, Los Angeles pediatrics department, said, “I’m really hopeful that this is the beginning of the end of the coronavirus pandemic.”

“The need for this vaccine is profound,” said Veronica McNally, president and CEO of the Franny Strong Foundation in West Bloomfield, Michigan.

The ACIP panel also made the argument that while the at least $10 billion spent on vaccine development by the federal government’s Operation Warp Speed alone has been a good investment, more spending is needed to actually get Americans vaccinated.

The imbalance between the two is “shocking and needs to be corrected,” said Bell. “We are not going to be able to protect the American public if we don’t have a way to deliver the vaccine to them.”

This article first appeared on Medscape.com.

The Centers for Disease Control and Prevention (CDC) advisory committee recommended on December 12 the recently authorized Pfizer-BioNTech COVID-19 vaccine for people age 16 and over in the United States, stating they found it was safe and effective.

The agency said it will quickly issue guidance to clinicians so they can determine when and when not to give the vaccine, and to help them communicate the risks and benefits to patients.

CDC staff gave a preview of those clinical considerations at the agency’s Advisory Committee on Immunization Practices (ACIP) meeting on December 12 and said it would be holding calls with clinicians on December 13 and 14.

The CDC will also issue guidance December 13 on how organizations can handle the workforce problems that might arise as health care workers experience side effects from vaccination.

ACIP voted 11-0, with three recusals, to recommend use of the Pfizer-BioNTech mRNA vaccine in individuals 16 years or older according to the guidelines of the Food and Drug Administration’s (FDA’s) emergency use authorization issued December 11.

The panel also voted unanimously to include the vaccine in 2021 immunization schedules. All panel members said the recommendation should go hand-in-hand with ACIP’s previous recommendation on December 1 that allocation of the vaccine be phased-in, with health care workers and residents and staff of long-term care facilities in phase 1a.

Allergies, pregnant women?

ACIP panelists said clinicians need more guidance on whether to use the vaccine in pregnant or breastfeeding women, the immunocompromised, or those who have a history of allergies.

The FDA health care provider information sheet said there is not enough data to recommend vaccinating those women or the immunocompromised, and also advises against giving the vaccine to individuals who have a history of serious allergic reaction to any component of the vaccine.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologic Evaluation and Research (CBER) clarified this in a briefing on December 12, noting that women who are pregnant or lactating can make the decision in consultation with their physician. And, he said, patients with any other history of allergy should be able to safely get the vaccine.

The CDC — in its soon-to-be-released guidance — will make the same recommendations. For any woman considering vaccination, she should consider the level of COVID-19 in the community, her personal risk of contracting the virus, the risks to her or her fetus of developing the disease, and the vaccine’s known side effects, Sarah Mbaeyi, MD, MPH, a medical officer at the agency, said during the panel meeting December 12.

She added that the CDC will also urge physicians to advise women to take acetaminophen if they develop a fever after vaccination — to protect the developing fetus from fever.

Sandra Fryhofer, MD, representing the American Medical Association, commended the CDC for these recommendations. But she also called on Pfizer, the FDA, and the CDC to make data from the developmental and reproductive toxicity (DART) studies public as soon as possible.

“We really need to put those results on warp speed and get them out there to give our physicians and pregnant women more information,” said Fryhofer, an adjunct associate professor of medicine at Emory University School of Medicine in Atlanta, Georgia.

The American College of Obstetricians and Gynecologists (ACOG) will also soon release guidance for vaccinating pregnant and breastfeeding women, said Linda Eckert, MD, FACOG, an ACOG representative on the panel.

ACOG and the CDC met the morning of December 12 to discuss risks and benefits with experts in immunology, placental pathology, and vaccine kinetics, she said.

“The overall complete consensus was that we don’t see biological plausibility at this time for placental transfer of the mRNA and that we see that direct fetal exposure or the possibility of fetal inflammatory response is extremely unlikely,” said Eckert, professor of obstetrics and gynecology at the University of Washington, Seattle. “Clearly we are waiting on the data.”

A Pfizer official told the ACIP panel that preliminary data “show no indication of either developmental or reproductive toxicity,” and that the company plans to send the final DART data to the FDA at the end of December.

On the potential for allergic reactions, the CDC concurred with the FDA that the vaccine should not be given to people with a history of serious reactions. The agency added that the category should include anyone who has had a reaction to any vaccine or injectable drug product because injectables may contain the same ingredients as the Pfizer vaccine, said Mbaeyi.

The CDC will also urge clinicians to observe patients with a history of anaphylaxis for 30 minutes after vaccination and all patients for at least 15 minutes afterward.

Should teens be a special population?

At least one ACIP panel member — Henry Bernstein, DO, MHCM, FAAP — said he was concerned that backing use of the vaccine in 16- and 17-year-olds was a leap of faith, given that Pfizer had extremely limited data on this cohort.

Bernstein, professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, also said that systemic reactions were more common in that age group.

He argued for making the 16- and 17-year-olds a “special population” that would get specific attention and guidance for vaccination from the federal agencies and professional societies.

Bernstein said he did not want to sow any more doubts in parents’ minds about vaccination, noting that hesitancy was a growing concern. “A successful pediatric vaccination program depends on creating and sustaining parental confidence in both the safety and effectiveness of this vaccine,” he said.

Many panelists, however, noted that there has been no evidence to suggest that the vaccine is not safe or less effective in that younger age group.

Yvonne Maldonado, MD, the American Academy of Pediatrics representative on the panel, said that this age group should not be denied the vaccine as they often have essential or front-line jobs that put them at higher risk for infection.

“I am very concerned about this message being sent out that this vaccine will not be safe in children,” said Maldonado, professor of pediatrics and health research and policy at Stanford University School of Medicine in California.

“We currently have no evidence that that is the case,” she said, adding there is also no indication younger children are biologically or physiologically different in their response or safety risk than 18-year-olds.

Vaccine = hope

Committee members breathed a sigh of relief at the end of the 2-day meeting, saying that although the Pfizer vaccine is not perfect, it represents a scientific milestone and a significant advance against the continuing march of the SARS-CoV-2 pandemic.

“This vaccine and future vaccines do provide a promise for a lot of progress in the future,” said panelist Beth P. Bell, MD, MPH, clinical professor of global health at the University of Washington School of Public Health in Seattle.

Peter Szilagyi, MD, MPH, executive vice-chair and vice-chair for research at the University of California, Los Angeles pediatrics department, said, “I’m really hopeful that this is the beginning of the end of the coronavirus pandemic.”

“The need for this vaccine is profound,” said Veronica McNally, president and CEO of the Franny Strong Foundation in West Bloomfield, Michigan.

The ACIP panel also made the argument that while the at least $10 billion spent on vaccine development by the federal government’s Operation Warp Speed alone has been a good investment, more spending is needed to actually get Americans vaccinated.

The imbalance between the two is “shocking and needs to be corrected,” said Bell. “We are not going to be able to protect the American public if we don’t have a way to deliver the vaccine to them.”

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has authorized Pfizer/BioNTech’s COVID-19 vaccine for emergency use in people 16 years of age and older. 

The much-anticipated emergency use authorization (EUA) of this vaccine — the first such approval in the United States — was greeted with optimism by infectious disease and pulmonary experts, although unanswered questions remain regarding use in people with allergic hypersensitivity, safety in pregnant women, and how smooth distribution will be.

“I am delighted. This is a first, firm step on a long path to getting this COVID pandemic under control,” William Schaffner, MD, professor of infectious diseases at the Vanderbilt University School of Medicine in Nashville, Tennessee, said in an interview.

The FDA gave the green light after the December 10 recommendation from the agency’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting. The committee voted 17-4 in favor of the emergency authorization.

Allergic reactions reported in the UK

After vaccinations with the Pfizer vaccine began in the UK on December 8, reports surfaced of two healthcare workers who experienced allergic reactions. They have since recovered, but officials warned that people with a history of severe allergic reactions should not receive the Pfizer vaccine at this time.

“For the moment, they are asking people who have had notable allergic reactions to step aside while this is investigated. It shows you that the system is working,” Schaffner said.

Both vaccine recipients who experienced anaphylaxis carried EpiPens, as they were at high risk for allergic reactions, Hewlett said. Also, if other COVID-19 vaccines are approved for use in the future, people allergic to the Pfizer vaccine might have another option, he added.

Reassuring role models

Schaffner supports the CDC Advisory Committee on Immunization Practices (ACIP) decision to start vaccinations with healthcare workers and residents of long-term care facilities.

“Vaccinating healthcare workers, in particular, will be a model for the general public,” said Schaffner, who is also a former member of the IDSA board of directors. “If they see those of us in white coats and blue scrubs lining up for the vaccine, that will provide confidence.”

To further increase acceptance of the COVID-19 vaccine, public health officials need to provide information and reassure the general public, Schaffner said.

Hewlett agreed. “I know there are a lot of people in the population who are very hesitant about vaccines. As infection disease specialists and people in public health, we are trying to allay a lot of concerns people have.”

Reassurance will be especially important in minority communities. “They have been disproportionately affected by the virus, and they have a traditional history of not being optimally vaccinated,” Schaffner said. “We need to reach them in particular with good information and reassurance…so they can make good decisions for themselves and their families.”

No vaccine is 100% effective or completely free of side effects. “There is always a chance there can be adverse reactions, but we think for the most part this is going to be a safe and effective vaccine,” said Hewlett, medical director at the Division of Disease Control and deputy to commissioner of health at the Westchester County Department of Health in White Plains, New York.

Distribution: Smooth or full of strife?

In addition to the concern that some people will not take advantage of vaccination against COVID-19, there could be vaccine supply issues down the road, Schaffner said.

Culver agreed. “In the early phases, I expect that there will be some kinks to work out, but because the numbers are relatively small, this should be okay,” he said.

“I think when we start to get into larger-scale vaccination programs — the supply chain, transport, and storage will be a Herculean undertaking,” Culver added. “It will take careful coordination between healthcare providers, distributors, suppliers, and public health officials to pull this off.”

Planning and distribution also should focus beyond US borders. Any issues in vaccine distribution or administration in the United States “will only be multiplied in several other parts of the world,” Culver said. Because COVID-19 is a pandemic, “we need to think about vaccinating globally.”

Investigating adverse events

Adverse events common to vaccinations in general — injection site pain, headaches, and fever — would not be unexpected with the COVID-19 vaccines. However, experts remain concerned that other, unrelated adverse events might be erroneously attributed to vaccination. For example, if a fall, heart attack, or death occurs within days of immunization, some might immediately blame the vaccine product.

“It’s important to remember that any new, highly touted medical therapy like this will receive a lot of scrutiny, so it would be unusual not to hear about something happening to somebody,” Culver said. Vaccine companies and health agencies will be carefully evaluating any reported adverse events to ensure no safety signal was missed in the trials.

“Fortunately, there are systems in place to investigate these events immediately,” Schaffner said.

Pregnancy recommendations pending

One question still looms: Is the COVID-19 vaccination safe for pregnant women? This isn’t just a question for the general public, either, Schaffner said. He estimated that about 70 percent of healthcare workers are women, and data suggests about 300,000 of these healthcare workers are pregnant.

“The CDC’s Advisory Committee on Immunization Practices will speak to that just as soon as the EUA is issued,” he added.

Patients are asking Culver about the priority order for vaccination. He said it’s difficult to provide firm guidance at this point.

People also have “lingering skepticism” about whether vaccine development was done in a prudent way, Culver said. Some people question whether the Pfizer vaccine and others were rushed to market. “So we try to spend time with the patients, reassuring them that all the usual safety evaluations were carefully done,” he said.

Another concern is whether mRNA vaccines can interact with human DNA. “The quick, short, and definitive answer is no,” Schaffner said. The m stands for messenger — the vaccines transmit information. "Once it gets into a cell, the mRNA does not go anywhere near the DNA, and once it transmits its information to the cell appropriately, it gets metabolized, and we excrete all the remnants."

Hewlett pointed out that investigations and surveillance will continue. Because this is an EUA and not full approval, “that essentially means they will still be obligated to collect a lot more data than they would ordinarily,” he said.

How long immunoprotection will last also remains an unknown. “The big question left on the table now is the durability,” Culver said. “Of course, we won’t know the answer to that for quite some time.”

Schaffner and Culver have disclosed no relevant financial relationships. Hewlett was an employee of Pfizer until mid-2019. His previous work as Pfizer’s senior medical director of global medical product evaluation was not associated with development of the COVID-19 vaccine.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has authorized Pfizer/BioNTech’s COVID-19 vaccine for emergency use in people 16 years of age and older. 

The much-anticipated emergency use authorization (EUA) of this vaccine — the first such approval in the United States — was greeted with optimism by infectious disease and pulmonary experts, although unanswered questions remain regarding use in people with allergic hypersensitivity, safety in pregnant women, and how smooth distribution will be.

“I am delighted. This is a first, firm step on a long path to getting this COVID pandemic under control,” William Schaffner, MD, professor of infectious diseases at the Vanderbilt University School of Medicine in Nashville, Tennessee, said in an interview.

The FDA gave the green light after the December 10 recommendation from the agency’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting. The committee voted 17-4 in favor of the emergency authorization.

Allergic reactions reported in the UK

After vaccinations with the Pfizer vaccine began in the UK on December 8, reports surfaced of two healthcare workers who experienced allergic reactions. They have since recovered, but officials warned that people with a history of severe allergic reactions should not receive the Pfizer vaccine at this time.

“For the moment, they are asking people who have had notable allergic reactions to step aside while this is investigated. It shows you that the system is working,” Schaffner said.

Both vaccine recipients who experienced anaphylaxis carried EpiPens, as they were at high risk for allergic reactions, Hewlett said. Also, if other COVID-19 vaccines are approved for use in the future, people allergic to the Pfizer vaccine might have another option, he added.

Reassuring role models

Schaffner supports the CDC Advisory Committee on Immunization Practices (ACIP) decision to start vaccinations with healthcare workers and residents of long-term care facilities.

“Vaccinating healthcare workers, in particular, will be a model for the general public,” said Schaffner, who is also a former member of the IDSA board of directors. “If they see those of us in white coats and blue scrubs lining up for the vaccine, that will provide confidence.”

To further increase acceptance of the COVID-19 vaccine, public health officials need to provide information and reassure the general public, Schaffner said.

Hewlett agreed. “I know there are a lot of people in the population who are very hesitant about vaccines. As infection disease specialists and people in public health, we are trying to allay a lot of concerns people have.”

Reassurance will be especially important in minority communities. “They have been disproportionately affected by the virus, and they have a traditional history of not being optimally vaccinated,” Schaffner said. “We need to reach them in particular with good information and reassurance…so they can make good decisions for themselves and their families.”

No vaccine is 100% effective or completely free of side effects. “There is always a chance there can be adverse reactions, but we think for the most part this is going to be a safe and effective vaccine,” said Hewlett, medical director at the Division of Disease Control and deputy to commissioner of health at the Westchester County Department of Health in White Plains, New York.

Distribution: Smooth or full of strife?

In addition to the concern that some people will not take advantage of vaccination against COVID-19, there could be vaccine supply issues down the road, Schaffner said.

Culver agreed. “In the early phases, I expect that there will be some kinks to work out, but because the numbers are relatively small, this should be okay,” he said.

“I think when we start to get into larger-scale vaccination programs — the supply chain, transport, and storage will be a Herculean undertaking,” Culver added. “It will take careful coordination between healthcare providers, distributors, suppliers, and public health officials to pull this off.”

Planning and distribution also should focus beyond US borders. Any issues in vaccine distribution or administration in the United States “will only be multiplied in several other parts of the world,” Culver said. Because COVID-19 is a pandemic, “we need to think about vaccinating globally.”

Investigating adverse events

Adverse events common to vaccinations in general — injection site pain, headaches, and fever — would not be unexpected with the COVID-19 vaccines. However, experts remain concerned that other, unrelated adverse events might be erroneously attributed to vaccination. For example, if a fall, heart attack, or death occurs within days of immunization, some might immediately blame the vaccine product.

“It’s important to remember that any new, highly touted medical therapy like this will receive a lot of scrutiny, so it would be unusual not to hear about something happening to somebody,” Culver said. Vaccine companies and health agencies will be carefully evaluating any reported adverse events to ensure no safety signal was missed in the trials.

“Fortunately, there are systems in place to investigate these events immediately,” Schaffner said.

Pregnancy recommendations pending

One question still looms: Is the COVID-19 vaccination safe for pregnant women? This isn’t just a question for the general public, either, Schaffner said. He estimated that about 70 percent of healthcare workers are women, and data suggests about 300,000 of these healthcare workers are pregnant.

“The CDC’s Advisory Committee on Immunization Practices will speak to that just as soon as the EUA is issued,” he added.

Patients are asking Culver about the priority order for vaccination. He said it’s difficult to provide firm guidance at this point.

People also have “lingering skepticism” about whether vaccine development was done in a prudent way, Culver said. Some people question whether the Pfizer vaccine and others were rushed to market. “So we try to spend time with the patients, reassuring them that all the usual safety evaluations were carefully done,” he said.

Another concern is whether mRNA vaccines can interact with human DNA. “The quick, short, and definitive answer is no,” Schaffner said. The m stands for messenger — the vaccines transmit information. "Once it gets into a cell, the mRNA does not go anywhere near the DNA, and once it transmits its information to the cell appropriately, it gets metabolized, and we excrete all the remnants."

Hewlett pointed out that investigations and surveillance will continue. Because this is an EUA and not full approval, “that essentially means they will still be obligated to collect a lot more data than they would ordinarily,” he said.

How long immunoprotection will last also remains an unknown. “The big question left on the table now is the durability,” Culver said. “Of course, we won’t know the answer to that for quite some time.”

Schaffner and Culver have disclosed no relevant financial relationships. Hewlett was an employee of Pfizer until mid-2019. His previous work as Pfizer’s senior medical director of global medical product evaluation was not associated with development of the COVID-19 vaccine.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has authorized Pfizer/BioNTech’s COVID-19 vaccine for emergency use in people 16 years of age and older. 

The much-anticipated emergency use authorization (EUA) of this vaccine — the first such approval in the United States — was greeted with optimism by infectious disease and pulmonary experts, although unanswered questions remain regarding use in people with allergic hypersensitivity, safety in pregnant women, and how smooth distribution will be.

“I am delighted. This is a first, firm step on a long path to getting this COVID pandemic under control,” William Schaffner, MD, professor of infectious diseases at the Vanderbilt University School of Medicine in Nashville, Tennessee, said in an interview.

The FDA gave the green light after the December 10 recommendation from the agency’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting. The committee voted 17-4 in favor of the emergency authorization.

Allergic reactions reported in the UK

After vaccinations with the Pfizer vaccine began in the UK on December 8, reports surfaced of two healthcare workers who experienced allergic reactions. They have since recovered, but officials warned that people with a history of severe allergic reactions should not receive the Pfizer vaccine at this time.

“For the moment, they are asking people who have had notable allergic reactions to step aside while this is investigated. It shows you that the system is working,” Schaffner said.

Both vaccine recipients who experienced anaphylaxis carried EpiPens, as they were at high risk for allergic reactions, Hewlett said. Also, if other COVID-19 vaccines are approved for use in the future, people allergic to the Pfizer vaccine might have another option, he added.

Reassuring role models

Schaffner supports the CDC Advisory Committee on Immunization Practices (ACIP) decision to start vaccinations with healthcare workers and residents of long-term care facilities.

“Vaccinating healthcare workers, in particular, will be a model for the general public,” said Schaffner, who is also a former member of the IDSA board of directors. “If they see those of us in white coats and blue scrubs lining up for the vaccine, that will provide confidence.”

To further increase acceptance of the COVID-19 vaccine, public health officials need to provide information and reassure the general public, Schaffner said.

Hewlett agreed. “I know there are a lot of people in the population who are very hesitant about vaccines. As infection disease specialists and people in public health, we are trying to allay a lot of concerns people have.”

Reassurance will be especially important in minority communities. “They have been disproportionately affected by the virus, and they have a traditional history of not being optimally vaccinated,” Schaffner said. “We need to reach them in particular with good information and reassurance…so they can make good decisions for themselves and their families.”

No vaccine is 100% effective or completely free of side effects. “There is always a chance there can be adverse reactions, but we think for the most part this is going to be a safe and effective vaccine,” said Hewlett, medical director at the Division of Disease Control and deputy to commissioner of health at the Westchester County Department of Health in White Plains, New York.

Distribution: Smooth or full of strife?

In addition to the concern that some people will not take advantage of vaccination against COVID-19, there could be vaccine supply issues down the road, Schaffner said.

Culver agreed. “In the early phases, I expect that there will be some kinks to work out, but because the numbers are relatively small, this should be okay,” he said.

“I think when we start to get into larger-scale vaccination programs — the supply chain, transport, and storage will be a Herculean undertaking,” Culver added. “It will take careful coordination between healthcare providers, distributors, suppliers, and public health officials to pull this off.”

Planning and distribution also should focus beyond US borders. Any issues in vaccine distribution or administration in the United States “will only be multiplied in several other parts of the world,” Culver said. Because COVID-19 is a pandemic, “we need to think about vaccinating globally.”

Investigating adverse events

Adverse events common to vaccinations in general — injection site pain, headaches, and fever — would not be unexpected with the COVID-19 vaccines. However, experts remain concerned that other, unrelated adverse events might be erroneously attributed to vaccination. For example, if a fall, heart attack, or death occurs within days of immunization, some might immediately blame the vaccine product.

“It’s important to remember that any new, highly touted medical therapy like this will receive a lot of scrutiny, so it would be unusual not to hear about something happening to somebody,” Culver said. Vaccine companies and health agencies will be carefully evaluating any reported adverse events to ensure no safety signal was missed in the trials.

“Fortunately, there are systems in place to investigate these events immediately,” Schaffner said.

Pregnancy recommendations pending

One question still looms: Is the COVID-19 vaccination safe for pregnant women? This isn’t just a question for the general public, either, Schaffner said. He estimated that about 70 percent of healthcare workers are women, and data suggests about 300,000 of these healthcare workers are pregnant.

“The CDC’s Advisory Committee on Immunization Practices will speak to that just as soon as the EUA is issued,” he added.

Patients are asking Culver about the priority order for vaccination. He said it’s difficult to provide firm guidance at this point.

People also have “lingering skepticism” about whether vaccine development was done in a prudent way, Culver said. Some people question whether the Pfizer vaccine and others were rushed to market. “So we try to spend time with the patients, reassuring them that all the usual safety evaluations were carefully done,” he said.

Another concern is whether mRNA vaccines can interact with human DNA. “The quick, short, and definitive answer is no,” Schaffner said. The m stands for messenger — the vaccines transmit information. "Once it gets into a cell, the mRNA does not go anywhere near the DNA, and once it transmits its information to the cell appropriately, it gets metabolized, and we excrete all the remnants."

Hewlett pointed out that investigations and surveillance will continue. Because this is an EUA and not full approval, “that essentially means they will still be obligated to collect a lot more data than they would ordinarily,” he said.

How long immunoprotection will last also remains an unknown. “The big question left on the table now is the durability,” Culver said. “Of course, we won’t know the answer to that for quite some time.”

Schaffner and Culver have disclosed no relevant financial relationships. Hewlett was an employee of Pfizer until mid-2019. His previous work as Pfizer’s senior medical director of global medical product evaluation was not associated with development of the COVID-19 vaccine.

This article first appeared on Medscape.com.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

Vitamin D deficiency on admission to hospital was associated with a 3.7-fold increase in the odds of dying from COVID-19, according to an observational study looking back at data from the first wave of the pandemic.

Nearly 60% of patients with COVID-19 were vitamin D deficient upon hospitalization, with men in the advanced stages of COVID-19 pneumonia showing the greatest deficit.

Importantly, the results were independent of comorbidities known to be affected by vitamin D deficiency, wrote the authors, led by Dieter De Smet, MD, from AZ Delta General Hospital, Roeselare, Belgium.

“[The findings] highlight the need for randomized, controlled trials specifically targeting vitamin D–deficient patients at intake, and make a call for general avoidance of vitamin D deficiency as a safe and inexpensive possible mitigation of the SARS-CoV-2 pandemic,” Dr. De Smet and colleagues wrote in their article, published online Nov. 25 in the American Journal of Clinical Pathology.

A search of ClinicalTrials.gov reveals there are currently close to 40 ongoing intervention trials with vitamin D in COVID-19 around the world for varying purposes, including prevention, and varying forms of treatment.
 

Consider vitamin D to prevent COVID-19 infection

With regard to the potential role in prevention, “Numerous observational studies have shown that low vitamin D levels are a major predictor for poor COVID outcomes,” noted Jacob Teitelbaum, MD, an internist who specializes in treating chronic fatigue syndrome and fibromyalgia who also has an interest in COVID-19.

“This study shows how severe a problem this is,” Dr. Teitelbaum said in an interview. “A 3.7-fold increase in death rate if someone’s vitamin D level was below 20 [ng/mL] is staggering. It is arguably one of the most important risk factors to consider.”

“What is not clear is whether vitamin D levels are acting as an acute-phase reactant, dropping because of the infection, with larger drops indicating more severe disease, or whether vitamin D deficiency is causing worse outcomes,” added Dr. Teitelbaum, who is director of the Center for Effective CFIDS/Fibromyalgia Therapies, Kailua-Kona, Hawaii.

Also asked to comment, Andrea Giustina, MD, president of the European Society of Endocrinology, said: “The paper by De Smet et al confirms what we already hypothesized in BMJ last March: that patients with low vitamin D levels are at high risk of hospitalization for COVID-19 and developing severe and lethal disease. This is likely due to the loss in the protective action of vitamin D on the immune system and against the SARS-CoV-2–induced cytokine storm.”

He said it is particularly interesting that the authors of the new study had reported more prevalent vitamin D deficiency among men than women, most likely because women are more often treated with vitamin D for osteoporosis.

The new study should prompt all clinicians and health authorities to seriously consider vitamin D supplementation as an additional tool in the fight against COVID-19, particularly for the prevention of infection in those at high risk of both COVID-19 and hypovitaminosis D, such the elderly, urged Dr. Giustina, of San Raffaele Vita-Salute University, Milan.
 

Results adjusted for multiple confounders

Dr. De Smet and colleagues looked at serum 25-hydroxyvitamin D (25[OH]D) levels in 186 patients hospitalized for severe COVID-19 infection as a function of radiologic stage of COVID-19 pneumonia as well as the association between vitamin D status on admission and COVID-19 mortality.

Cognizant of the potential for confounding by multiple factors, they adjusted for age, sex, and known vitamin D–affected comorbidities such as diabetes, chronic lung disease, and coronary artery disease.

Patients were hospitalized from March 1 to April 7, 2020 (the peak of the first wave of the pandemic) at their institution, AZ Delta General Hospital, a tertiary network hospital.

The mean age of patients was 69 years, 41% were women, and 59% had coronary artery disease. Upon admission to hospital, median vitamin D level was 18 ng/mL (women, 20.7 ng/mL; men, 17.6 ng/mL).

A remarkably high percentage (59%, 109/186) of patients with COVID-19 were vitamin D deficient (25[OH]D <20 ng/mL) when admitted (47% of women and 67% of men), wrote the authors.

“What surprises me,” said Dr. Teitelbaum, is that almost 60% “of these patients had 25(OH)D under 20 ng/mL but most clinicians consider under 50 to be low.”

All patients had a chest CT scan to determine the radiologic stage of COVID-19 pneumonia and serum vitamin D measurement on admission. Radiologic stage of pneumonia was used as a proxy for immunologic phase of COVID-19.
 

Vitamin D deficiency correlated with worsening pneumonia

Among men, rates of vitamin D deficiency increased with advancing disease, with rates of 55% in stage 1, 67% in stage 2, and up to 74% in stage 3 pneumonia.

There is therefore “a clear correlation between 25(OH)D level and temporal stages of viral pneumonia, particularly in male patients,” the authors wrote.

“Vitamin D dampens excessive inflammation,” said Dr. Teitelbaum. “In these patients with acute respiratory distress syndrome, the immune system has gone wild.”

“The study was carried out in Belgium, so there’s less sunlight there than some other places, but even here in Hawaii, with plenty of sunshine, we have vitamin D deficiency,” he added.

“More studies are needed, but I think there are enough data to suggest a multivitamin should be used to aid prophylaxis, and this is reflected in [some] infectious disease recommendations,” he noted.

A version of this article originally appeared on Medscape.com.

Vitamin D deficiency on admission to hospital was associated with a 3.7-fold increase in the odds of dying from COVID-19, according to an observational study looking back at data from the first wave of the pandemic.

Nearly 60% of patients with COVID-19 were vitamin D deficient upon hospitalization, with men in the advanced stages of COVID-19 pneumonia showing the greatest deficit.

Importantly, the results were independent of comorbidities known to be affected by vitamin D deficiency, wrote the authors, led by Dieter De Smet, MD, from AZ Delta General Hospital, Roeselare, Belgium.

“[The findings] highlight the need for randomized, controlled trials specifically targeting vitamin D–deficient patients at intake, and make a call for general avoidance of vitamin D deficiency as a safe and inexpensive possible mitigation of the SARS-CoV-2 pandemic,” Dr. De Smet and colleagues wrote in their article, published online Nov. 25 in the American Journal of Clinical Pathology.

A search of ClinicalTrials.gov reveals there are currently close to 40 ongoing intervention trials with vitamin D in COVID-19 around the world for varying purposes, including prevention, and varying forms of treatment.
 

Consider vitamin D to prevent COVID-19 infection

With regard to the potential role in prevention, “Numerous observational studies have shown that low vitamin D levels are a major predictor for poor COVID outcomes,” noted Jacob Teitelbaum, MD, an internist who specializes in treating chronic fatigue syndrome and fibromyalgia who also has an interest in COVID-19.

“This study shows how severe a problem this is,” Dr. Teitelbaum said in an interview. “A 3.7-fold increase in death rate if someone’s vitamin D level was below 20 [ng/mL] is staggering. It is arguably one of the most important risk factors to consider.”

“What is not clear is whether vitamin D levels are acting as an acute-phase reactant, dropping because of the infection, with larger drops indicating more severe disease, or whether vitamin D deficiency is causing worse outcomes,” added Dr. Teitelbaum, who is director of the Center for Effective CFIDS/Fibromyalgia Therapies, Kailua-Kona, Hawaii.

Also asked to comment, Andrea Giustina, MD, president of the European Society of Endocrinology, said: “The paper by De Smet et al confirms what we already hypothesized in BMJ last March: that patients with low vitamin D levels are at high risk of hospitalization for COVID-19 and developing severe and lethal disease. This is likely due to the loss in the protective action of vitamin D on the immune system and against the SARS-CoV-2–induced cytokine storm.”

He said it is particularly interesting that the authors of the new study had reported more prevalent vitamin D deficiency among men than women, most likely because women are more often treated with vitamin D for osteoporosis.

The new study should prompt all clinicians and health authorities to seriously consider vitamin D supplementation as an additional tool in the fight against COVID-19, particularly for the prevention of infection in those at high risk of both COVID-19 and hypovitaminosis D, such the elderly, urged Dr. Giustina, of San Raffaele Vita-Salute University, Milan.
 

Results adjusted for multiple confounders

Dr. De Smet and colleagues looked at serum 25-hydroxyvitamin D (25[OH]D) levels in 186 patients hospitalized for severe COVID-19 infection as a function of radiologic stage of COVID-19 pneumonia as well as the association between vitamin D status on admission and COVID-19 mortality.

Cognizant of the potential for confounding by multiple factors, they adjusted for age, sex, and known vitamin D–affected comorbidities such as diabetes, chronic lung disease, and coronary artery disease.

Patients were hospitalized from March 1 to April 7, 2020 (the peak of the first wave of the pandemic) at their institution, AZ Delta General Hospital, a tertiary network hospital.

The mean age of patients was 69 years, 41% were women, and 59% had coronary artery disease. Upon admission to hospital, median vitamin D level was 18 ng/mL (women, 20.7 ng/mL; men, 17.6 ng/mL).

A remarkably high percentage (59%, 109/186) of patients with COVID-19 were vitamin D deficient (25[OH]D <20 ng/mL) when admitted (47% of women and 67% of men), wrote the authors.

“What surprises me,” said Dr. Teitelbaum, is that almost 60% “of these patients had 25(OH)D under 20 ng/mL but most clinicians consider under 50 to be low.”

All patients had a chest CT scan to determine the radiologic stage of COVID-19 pneumonia and serum vitamin D measurement on admission. Radiologic stage of pneumonia was used as a proxy for immunologic phase of COVID-19.
 

Vitamin D deficiency correlated with worsening pneumonia

Among men, rates of vitamin D deficiency increased with advancing disease, with rates of 55% in stage 1, 67% in stage 2, and up to 74% in stage 3 pneumonia.

There is therefore “a clear correlation between 25(OH)D level and temporal stages of viral pneumonia, particularly in male patients,” the authors wrote.

“Vitamin D dampens excessive inflammation,” said Dr. Teitelbaum. “In these patients with acute respiratory distress syndrome, the immune system has gone wild.”

“The study was carried out in Belgium, so there’s less sunlight there than some other places, but even here in Hawaii, with plenty of sunshine, we have vitamin D deficiency,” he added.

“More studies are needed, but I think there are enough data to suggest a multivitamin should be used to aid prophylaxis, and this is reflected in [some] infectious disease recommendations,” he noted.

A version of this article originally appeared on Medscape.com.

Vitamin D deficiency on admission to hospital was associated with a 3.7-fold increase in the odds of dying from COVID-19, according to an observational study looking back at data from the first wave of the pandemic.

Nearly 60% of patients with COVID-19 were vitamin D deficient upon hospitalization, with men in the advanced stages of COVID-19 pneumonia showing the greatest deficit.

Importantly, the results were independent of comorbidities known to be affected by vitamin D deficiency, wrote the authors, led by Dieter De Smet, MD, from AZ Delta General Hospital, Roeselare, Belgium.

“[The findings] highlight the need for randomized, controlled trials specifically targeting vitamin D–deficient patients at intake, and make a call for general avoidance of vitamin D deficiency as a safe and inexpensive possible mitigation of the SARS-CoV-2 pandemic,” Dr. De Smet and colleagues wrote in their article, published online Nov. 25 in the American Journal of Clinical Pathology.

A search of ClinicalTrials.gov reveals there are currently close to 40 ongoing intervention trials with vitamin D in COVID-19 around the world for varying purposes, including prevention, and varying forms of treatment.
 

Consider vitamin D to prevent COVID-19 infection

With regard to the potential role in prevention, “Numerous observational studies have shown that low vitamin D levels are a major predictor for poor COVID outcomes,” noted Jacob Teitelbaum, MD, an internist who specializes in treating chronic fatigue syndrome and fibromyalgia who also has an interest in COVID-19.

“This study shows how severe a problem this is,” Dr. Teitelbaum said in an interview. “A 3.7-fold increase in death rate if someone’s vitamin D level was below 20 [ng/mL] is staggering. It is arguably one of the most important risk factors to consider.”

“What is not clear is whether vitamin D levels are acting as an acute-phase reactant, dropping because of the infection, with larger drops indicating more severe disease, or whether vitamin D deficiency is causing worse outcomes,” added Dr. Teitelbaum, who is director of the Center for Effective CFIDS/Fibromyalgia Therapies, Kailua-Kona, Hawaii.

Also asked to comment, Andrea Giustina, MD, president of the European Society of Endocrinology, said: “The paper by De Smet et al confirms what we already hypothesized in BMJ last March: that patients with low vitamin D levels are at high risk of hospitalization for COVID-19 and developing severe and lethal disease. This is likely due to the loss in the protective action of vitamin D on the immune system and against the SARS-CoV-2–induced cytokine storm.”

He said it is particularly interesting that the authors of the new study had reported more prevalent vitamin D deficiency among men than women, most likely because women are more often treated with vitamin D for osteoporosis.

The new study should prompt all clinicians and health authorities to seriously consider vitamin D supplementation as an additional tool in the fight against COVID-19, particularly for the prevention of infection in those at high risk of both COVID-19 and hypovitaminosis D, such the elderly, urged Dr. Giustina, of San Raffaele Vita-Salute University, Milan.
 

Results adjusted for multiple confounders

Dr. De Smet and colleagues looked at serum 25-hydroxyvitamin D (25[OH]D) levels in 186 patients hospitalized for severe COVID-19 infection as a function of radiologic stage of COVID-19 pneumonia as well as the association between vitamin D status on admission and COVID-19 mortality.

Cognizant of the potential for confounding by multiple factors, they adjusted for age, sex, and known vitamin D–affected comorbidities such as diabetes, chronic lung disease, and coronary artery disease.

Patients were hospitalized from March 1 to April 7, 2020 (the peak of the first wave of the pandemic) at their institution, AZ Delta General Hospital, a tertiary network hospital.

The mean age of patients was 69 years, 41% were women, and 59% had coronary artery disease. Upon admission to hospital, median vitamin D level was 18 ng/mL (women, 20.7 ng/mL; men, 17.6 ng/mL).

A remarkably high percentage (59%, 109/186) of patients with COVID-19 were vitamin D deficient (25[OH]D <20 ng/mL) when admitted (47% of women and 67% of men), wrote the authors.

“What surprises me,” said Dr. Teitelbaum, is that almost 60% “of these patients had 25(OH)D under 20 ng/mL but most clinicians consider under 50 to be low.”

All patients had a chest CT scan to determine the radiologic stage of COVID-19 pneumonia and serum vitamin D measurement on admission. Radiologic stage of pneumonia was used as a proxy for immunologic phase of COVID-19.
 

Vitamin D deficiency correlated with worsening pneumonia

Among men, rates of vitamin D deficiency increased with advancing disease, with rates of 55% in stage 1, 67% in stage 2, and up to 74% in stage 3 pneumonia.

There is therefore “a clear correlation between 25(OH)D level and temporal stages of viral pneumonia, particularly in male patients,” the authors wrote.

“Vitamin D dampens excessive inflammation,” said Dr. Teitelbaum. “In these patients with acute respiratory distress syndrome, the immune system has gone wild.”

“The study was carried out in Belgium, so there’s less sunlight there than some other places, but even here in Hawaii, with plenty of sunshine, we have vitamin D deficiency,” he added.

“More studies are needed, but I think there are enough data to suggest a multivitamin should be used to aid prophylaxis, and this is reflected in [some] infectious disease recommendations,” he noted.

A version of this article originally appeared on Medscape.com.