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Fewer transplants for MM with quadruplet therapy?
“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.
They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).
“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.
“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
Study details
The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.
These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.
All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.
“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.
Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.
Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.
For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy.
Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.
Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.
The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.
“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.
“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”
To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.
“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
Randomized trial anticipated to clarify benefit
In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.
Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.
However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.
The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.
In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.
Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.
“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.
The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.
A version of this article first appeared on Medscape.com.
“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.
They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).
“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.
“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
Study details
The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.
These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.
All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.
“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.
Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.
Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.
For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy.
Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.
Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.
The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.
“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.
“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”
To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.
“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
Randomized trial anticipated to clarify benefit
In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.
Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.
However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.
The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.
In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.
Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.
“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.
The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.
A version of this article first appeared on Medscape.com.
“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.
They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).
“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.
“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
Study details
The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.
These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.
All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.
“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.
Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.
Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.
For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy.
Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.
Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.
The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.
“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.
“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”
To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.
“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
Randomized trial anticipated to clarify benefit
In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.
Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.
However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.
The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.
In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.
Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.
“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.
The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.
A version of this article first appeared on Medscape.com.
FROM JAMA ONCOLOGY
Evusheld for COVID-19: Lifesaving and free, but still few takers
Evusheld (AstraZeneca), a medication used to prevent SARS-CoV-2 infection in patients at high risk, has problems: Namely, that supplies of the potentially lifesaving drug outweigh demand.
At least 7 million people who are immunocompromised could benefit from it, as could many others who are undergoing cancer treatment, have received a transplant, or who are allergic to the COVID-19 vaccines. The medication has laboratory-produced antibodies against SARS-CoV-2 and helps the body protect itself. It can slash the chances of becoming infected by 77%, according to the U.S. Food and Drug Administration.
And it’s free to eligible patients (although there may be an out-of-pocket administrative fee in some cases).
To meet demand, the Biden administration secured 1.7 million doses of the medicine, which was granted emergency use authorization by the FDA in December 2021. As of July 25, however, 793,348 doses have been ordered by the administration sites, and only 398,181 doses have been reported as used, a spokesperson for the Department of Health & Human Services tells this news organization.
Each week, a certain amount of doses from the 1.7 million dose stockpile is made available to state and territorial health departments. States have not been asking for their full allotment, the spokesperson said July 28.
Now, HHS and AstraZeneca have taken a number of steps to increase awareness of the medication and access to it.
- On July 27, HHS announced that individual providers and smaller sites of care that don’t currently receive Evusheld through the federal distribution process via the HHS Health Partner Order Portal can now order up to three patient courses of the medicine. These can be
- Health care providers can use the HHS’s COVID-19 Therapeutics Locator to find Evusheld in their area.
- AstraZeneca has launched a new website with educational materials and says it is working closely with patient and professional groups to inform patients and health care providers.
- A direct-to-consumer ad launched on June 22 and will run in the United States online and on TV (Yahoo, Fox, CBS Sports, MSN, ESPN) and be amplified on social and digital channels through year’s end, an AstraZeneca spokesperson said in an interview.
- AstraZeneca set up a toll-free number for providers: 1-833-EVUSHLD.
Evusheld includes two monoclonal antibodies, tixagevimab and cilgavimab. The medication is given as two consecutive intramuscular injections during a single visit to a doctor’s office, infusion center, or other health care facility. The antibodies bind to the SARS-CoV-2 spike protein and prevent the virus from getting into human cells and infecting them. It’s authorized for use in children and adults aged 12 years and older who weigh at least 88 pounds.
Studies have found that the medication decreases the risk of getting COVID-19 for up to 6 months after it is given. The FDA recommends repeat dosing every 6 months with the doses of 300 mg of each monoclonal antibody. In clinical trials, Evusheld reduced the incidence of COVID-19 symptomatic illness by 77%, compared with placebo.
Physicians monitor patients for an hour after administering Evusheld for allergic reactions. Other possible side effects include cardiac events, but they are not common.
Doctors and patients weigh in
Physicians – and patients – from the United States to the United Kingdom and beyond are questioning why the medication is underused while lauding the recent efforts to expand access and increase awareness.
The U.S. federal government may have underestimated the amount of communication needed to increase awareness of the medication and its applications, said infectious disease specialist William Schaffner, MD, professor of preventive medicine at Vanderbilt University School of Medicine, Nashville, Tenn.
“HHS hasn’t made a major educational effort to promote it,” he said in an interview.
Many physicians who need to know about it, such as transplant doctors and rheumatologists, are outside the typical public health communications loop, he said.
Eric Topol, MD, director of the Scripps Research Transational Institute and editor-in-chief of Medscape, has taken to social media to bemoan the lack of awareness.
Another infectious disease expert agrees. “In my experience, the awareness of Evusheld is low amongst many patients as well as many providers,” said Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security, Baltimore.
“Initially, there were scarce supplies of the drug, and certain hospital systems tiered eligibility based on degrees of immunosuppression, and only the most immunosuppressed were proactively approached for treatment.”
“Also, many community hospitals never initially ordered Evusheld – they may have been crowded out by academic centers who treat many more immunosuppressed patients and may not currently see it as a priority,” Dr. Adalja said in an interview. “As such, many immunosuppressed patients would have to seek treatment at academic medical centers, where the drug is more likely to be available.”
A version of this article first appeared on Medscape.com.
Evusheld (AstraZeneca), a medication used to prevent SARS-CoV-2 infection in patients at high risk, has problems: Namely, that supplies of the potentially lifesaving drug outweigh demand.
At least 7 million people who are immunocompromised could benefit from it, as could many others who are undergoing cancer treatment, have received a transplant, or who are allergic to the COVID-19 vaccines. The medication has laboratory-produced antibodies against SARS-CoV-2 and helps the body protect itself. It can slash the chances of becoming infected by 77%, according to the U.S. Food and Drug Administration.
And it’s free to eligible patients (although there may be an out-of-pocket administrative fee in some cases).
To meet demand, the Biden administration secured 1.7 million doses of the medicine, which was granted emergency use authorization by the FDA in December 2021. As of July 25, however, 793,348 doses have been ordered by the administration sites, and only 398,181 doses have been reported as used, a spokesperson for the Department of Health & Human Services tells this news organization.
Each week, a certain amount of doses from the 1.7 million dose stockpile is made available to state and territorial health departments. States have not been asking for their full allotment, the spokesperson said July 28.
Now, HHS and AstraZeneca have taken a number of steps to increase awareness of the medication and access to it.
- On July 27, HHS announced that individual providers and smaller sites of care that don’t currently receive Evusheld through the federal distribution process via the HHS Health Partner Order Portal can now order up to three patient courses of the medicine. These can be
- Health care providers can use the HHS’s COVID-19 Therapeutics Locator to find Evusheld in their area.
- AstraZeneca has launched a new website with educational materials and says it is working closely with patient and professional groups to inform patients and health care providers.
- A direct-to-consumer ad launched on June 22 and will run in the United States online and on TV (Yahoo, Fox, CBS Sports, MSN, ESPN) and be amplified on social and digital channels through year’s end, an AstraZeneca spokesperson said in an interview.
- AstraZeneca set up a toll-free number for providers: 1-833-EVUSHLD.
Evusheld includes two monoclonal antibodies, tixagevimab and cilgavimab. The medication is given as two consecutive intramuscular injections during a single visit to a doctor’s office, infusion center, or other health care facility. The antibodies bind to the SARS-CoV-2 spike protein and prevent the virus from getting into human cells and infecting them. It’s authorized for use in children and adults aged 12 years and older who weigh at least 88 pounds.
Studies have found that the medication decreases the risk of getting COVID-19 for up to 6 months after it is given. The FDA recommends repeat dosing every 6 months with the doses of 300 mg of each monoclonal antibody. In clinical trials, Evusheld reduced the incidence of COVID-19 symptomatic illness by 77%, compared with placebo.
Physicians monitor patients for an hour after administering Evusheld for allergic reactions. Other possible side effects include cardiac events, but they are not common.
Doctors and patients weigh in
Physicians – and patients – from the United States to the United Kingdom and beyond are questioning why the medication is underused while lauding the recent efforts to expand access and increase awareness.
The U.S. federal government may have underestimated the amount of communication needed to increase awareness of the medication and its applications, said infectious disease specialist William Schaffner, MD, professor of preventive medicine at Vanderbilt University School of Medicine, Nashville, Tenn.
“HHS hasn’t made a major educational effort to promote it,” he said in an interview.
Many physicians who need to know about it, such as transplant doctors and rheumatologists, are outside the typical public health communications loop, he said.
Eric Topol, MD, director of the Scripps Research Transational Institute and editor-in-chief of Medscape, has taken to social media to bemoan the lack of awareness.
Another infectious disease expert agrees. “In my experience, the awareness of Evusheld is low amongst many patients as well as many providers,” said Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security, Baltimore.
“Initially, there were scarce supplies of the drug, and certain hospital systems tiered eligibility based on degrees of immunosuppression, and only the most immunosuppressed were proactively approached for treatment.”
“Also, many community hospitals never initially ordered Evusheld – they may have been crowded out by academic centers who treat many more immunosuppressed patients and may not currently see it as a priority,” Dr. Adalja said in an interview. “As such, many immunosuppressed patients would have to seek treatment at academic medical centers, where the drug is more likely to be available.”
A version of this article first appeared on Medscape.com.
Evusheld (AstraZeneca), a medication used to prevent SARS-CoV-2 infection in patients at high risk, has problems: Namely, that supplies of the potentially lifesaving drug outweigh demand.
At least 7 million people who are immunocompromised could benefit from it, as could many others who are undergoing cancer treatment, have received a transplant, or who are allergic to the COVID-19 vaccines. The medication has laboratory-produced antibodies against SARS-CoV-2 and helps the body protect itself. It can slash the chances of becoming infected by 77%, according to the U.S. Food and Drug Administration.
And it’s free to eligible patients (although there may be an out-of-pocket administrative fee in some cases).
To meet demand, the Biden administration secured 1.7 million doses of the medicine, which was granted emergency use authorization by the FDA in December 2021. As of July 25, however, 793,348 doses have been ordered by the administration sites, and only 398,181 doses have been reported as used, a spokesperson for the Department of Health & Human Services tells this news organization.
Each week, a certain amount of doses from the 1.7 million dose stockpile is made available to state and territorial health departments. States have not been asking for their full allotment, the spokesperson said July 28.
Now, HHS and AstraZeneca have taken a number of steps to increase awareness of the medication and access to it.
- On July 27, HHS announced that individual providers and smaller sites of care that don’t currently receive Evusheld through the federal distribution process via the HHS Health Partner Order Portal can now order up to three patient courses of the medicine. These can be
- Health care providers can use the HHS’s COVID-19 Therapeutics Locator to find Evusheld in their area.
- AstraZeneca has launched a new website with educational materials and says it is working closely with patient and professional groups to inform patients and health care providers.
- A direct-to-consumer ad launched on June 22 and will run in the United States online and on TV (Yahoo, Fox, CBS Sports, MSN, ESPN) and be amplified on social and digital channels through year’s end, an AstraZeneca spokesperson said in an interview.
- AstraZeneca set up a toll-free number for providers: 1-833-EVUSHLD.
Evusheld includes two monoclonal antibodies, tixagevimab and cilgavimab. The medication is given as two consecutive intramuscular injections during a single visit to a doctor’s office, infusion center, or other health care facility. The antibodies bind to the SARS-CoV-2 spike protein and prevent the virus from getting into human cells and infecting them. It’s authorized for use in children and adults aged 12 years and older who weigh at least 88 pounds.
Studies have found that the medication decreases the risk of getting COVID-19 for up to 6 months after it is given. The FDA recommends repeat dosing every 6 months with the doses of 300 mg of each monoclonal antibody. In clinical trials, Evusheld reduced the incidence of COVID-19 symptomatic illness by 77%, compared with placebo.
Physicians monitor patients for an hour after administering Evusheld for allergic reactions. Other possible side effects include cardiac events, but they are not common.
Doctors and patients weigh in
Physicians – and patients – from the United States to the United Kingdom and beyond are questioning why the medication is underused while lauding the recent efforts to expand access and increase awareness.
The U.S. federal government may have underestimated the amount of communication needed to increase awareness of the medication and its applications, said infectious disease specialist William Schaffner, MD, professor of preventive medicine at Vanderbilt University School of Medicine, Nashville, Tenn.
“HHS hasn’t made a major educational effort to promote it,” he said in an interview.
Many physicians who need to know about it, such as transplant doctors and rheumatologists, are outside the typical public health communications loop, he said.
Eric Topol, MD, director of the Scripps Research Transational Institute and editor-in-chief of Medscape, has taken to social media to bemoan the lack of awareness.
Another infectious disease expert agrees. “In my experience, the awareness of Evusheld is low amongst many patients as well as many providers,” said Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security, Baltimore.
“Initially, there were scarce supplies of the drug, and certain hospital systems tiered eligibility based on degrees of immunosuppression, and only the most immunosuppressed were proactively approached for treatment.”
“Also, many community hospitals never initially ordered Evusheld – they may have been crowded out by academic centers who treat many more immunosuppressed patients and may not currently see it as a priority,” Dr. Adalja said in an interview. “As such, many immunosuppressed patients would have to seek treatment at academic medical centers, where the drug is more likely to be available.”
A version of this article first appeared on Medscape.com.
Fourth patient cleared of HIV after stem cell transplant for blood cancer
MONTREAL – from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.
The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.
Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.
She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.
Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.
“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”
“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.
“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.
Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.
The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.
Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.
A version of this article first appeared on Medscape.com.
MONTREAL – from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.
The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.
Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.
She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.
Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.
“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”
“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.
“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.
Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.
The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.
Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.
A version of this article first appeared on Medscape.com.
MONTREAL – from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.
The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.
Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.
She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.
Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.
“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”
“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.
“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.
Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.
The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.
Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.
A version of this article first appeared on Medscape.com.
AT AIDS 2022
Coming to a pill near you: The exercise molecule
Exercise in a pill? Sign us up
You just got home from a long shift and you know you should go to the gym, but the bed is calling and you just answered. We know sometimes we have to make sacrifices in the name of fitness, but there just aren’t enough hours in the day. Unless our prayers have been answered. There could be a pill that has the benefits of working out without having to work out.
In a study published in Nature, investigators reported that they have identified a molecule made during exercise and used it on mice, which took in less food after being given the pill, which may open doors to understanding how exercise affects hunger.
In the first part of the study, the researchers found the molecule, known as Lac-Phe – which is synthesized from lactate and phenylalanine – in the blood plasma of mice after they had run on a treadmill.
The investigators then gave a Lac-Phe supplement to mice on high-fat diets and found that their food intake was about 50% of what other mice were eating. The supplement also improved their glucose tolerance.
Because the research also found Lac-Phe in humans who exercised, they hope that this pill will be in our future. “Our next steps include finding more details about how Lac-Phe mediates its effects in the body, including the brain,” Yong Xu, MD, of Baylor College of Medicine, Houston, said in a written statement. “Our goal is to learn to modulate this exercise pathway for therapeutic interventions.”
As always, we are rooting for you, science!
Gonorrhea and grandparents: A match made in prehistoric heaven
*Editorial note: LOTME takes no responsibility for any unfortunate imagery the reader may have experienced from the above headline.
Old people are the greatest. Back pains, cognitive decline, aches in all the diodes down your left side, there’s nothing quite like your golden years. Notably, however, humans are one of the few animals who experience true old age, as most creatures are adapted to maximize reproductive potential. As such, living past menopause is rare in the animal kingdom.
This is where the “grandmother hypothesis” comes in: Back in Ye Olde Stone Age, women who lived into old age could provide child care for younger women, because human babies require a lot more time and attention than other animal offspring. But how did humans end up living so long? Enter a group of Californian researchers, who believe they have an answer. It was gonorrhea.
When compared with the chimpanzee genome (as well as with Neanderthals and Denisovans, our closest ancestors), humans have a unique mutated version of the CD33 gene that lacks a sugar-binding site; the standard version uses the sugar-binding site to protect against autoimmune response in the body, but that same site actually suppresses the brain’s ability to clear away damaged brain cells and amyloid, which eventually leads to diseases like dementia. The mutated version allows microglia (brain immune cells) to attack and clear out this unwanted material. People with higher levels of this mutated CD33 variant actually have higher protection against Alzheimer’s.
Interestingly, gonorrhea bacteria are coated in the same sugar that standard CD33 receptors bind to, thus allowing them to bypass the body’s immune system. According to the researchers, the mutated CD33 version likely emerged as a protection against gonorrhea, depriving the bacteria of their “molecular mimicry” abilities. In one of life’s happy accidents, it turned out this mutation also protects against age-related diseases, thus allowing humans with the mutation to live longer. Obviously, this was a good thing, and we ran with it until the modern day. Now we have senior citizens climbing Everest, and all our politicians keep on politicking into their 70s and 80s ... well, everything has its drawbacks.
Parents raise a glass to children’s food addiction
There can be something pretty addicting about processed foods. Have you ever eaten just one french fry? Or taken just one cookie? If so, your willpower is incredible. For many of us, it can be a struggle to stop.
A recent study from the University of Michigan, which considered the existence of an eating phenotype, suggests our parents’ habits could be to blame.
By administering a series of questionnaires that inquired about food addiction, alcohol use disorders, cannabis use disorder, nicotine/e-cigarette dependence, and their family tree, investigators found that participants with a “paternal history of problematic alcohol use” had higher risk of food addiction but not obesity.
Apparently about one in five people display a clinically significant addiction to highly processed foods. It was noted that foods like ice cream, pizza, and french fries have high amounts of refined carbs and fats, which could trigger an addictive response.
Lindzey Hoover, a graduate student at the university who was the study’s lead author, noted that living in an environment where these foods are cheap and accessible can be really challenging for those with a family history of addiction. The investigators suggested that public health approaches, like restriction of other substances and marketing to kids, should be put in place for highly processed foods.
Maybe french fries should come with a warning label.
A prescription for America’s traffic problems
Nostalgia is a funny thing. Do you ever feel nostalgic about things that really weren’t very pleasant in the first place? Take, for instance, the morning commute. Here in the Washington area, more than 2 years into the COVID era, the traffic is still not what it used to be … and we kind of miss it.
Nah, not really. That was just a way to get everyone thinking about driving, because AAA has something of an explanation for the situation out there on the highways and byways of America. It’s drugs. No, not those kinds of drugs. This time it’s prescription drugs that are the problem. Well, part of the problem, anyway.
AAA did a survey last summer and found that nearly 50% of drivers “used one or more potentially impairing medications in the past 30 days. … The proportion of those choosing to drive is higher among those taking multiple medications.” How much higher? More than 63% of those with two or more prescriptions were driving within 2 hours of taking at least one of those meds, as were 71% of those taking three or more.
The 2,657 respondents also were asked about the types of potentially impairing drugs they were taking: 61% of those using antidepressants had been on the road within 2 hours of use at least once in the past 30 days, as had 73% of those taking an amphetamine, AAA said.
So there you have it. That guy in the BMW who’s been tailgating you for the last 3 miles? He may be a jerk, but there’s a good chance he’s a jerk with a prescription … or two … or three.
Exercise in a pill? Sign us up
You just got home from a long shift and you know you should go to the gym, but the bed is calling and you just answered. We know sometimes we have to make sacrifices in the name of fitness, but there just aren’t enough hours in the day. Unless our prayers have been answered. There could be a pill that has the benefits of working out without having to work out.
In a study published in Nature, investigators reported that they have identified a molecule made during exercise and used it on mice, which took in less food after being given the pill, which may open doors to understanding how exercise affects hunger.
In the first part of the study, the researchers found the molecule, known as Lac-Phe – which is synthesized from lactate and phenylalanine – in the blood plasma of mice after they had run on a treadmill.
The investigators then gave a Lac-Phe supplement to mice on high-fat diets and found that their food intake was about 50% of what other mice were eating. The supplement also improved their glucose tolerance.
Because the research also found Lac-Phe in humans who exercised, they hope that this pill will be in our future. “Our next steps include finding more details about how Lac-Phe mediates its effects in the body, including the brain,” Yong Xu, MD, of Baylor College of Medicine, Houston, said in a written statement. “Our goal is to learn to modulate this exercise pathway for therapeutic interventions.”
As always, we are rooting for you, science!
Gonorrhea and grandparents: A match made in prehistoric heaven
*Editorial note: LOTME takes no responsibility for any unfortunate imagery the reader may have experienced from the above headline.
Old people are the greatest. Back pains, cognitive decline, aches in all the diodes down your left side, there’s nothing quite like your golden years. Notably, however, humans are one of the few animals who experience true old age, as most creatures are adapted to maximize reproductive potential. As such, living past menopause is rare in the animal kingdom.
This is where the “grandmother hypothesis” comes in: Back in Ye Olde Stone Age, women who lived into old age could provide child care for younger women, because human babies require a lot more time and attention than other animal offspring. But how did humans end up living so long? Enter a group of Californian researchers, who believe they have an answer. It was gonorrhea.
When compared with the chimpanzee genome (as well as with Neanderthals and Denisovans, our closest ancestors), humans have a unique mutated version of the CD33 gene that lacks a sugar-binding site; the standard version uses the sugar-binding site to protect against autoimmune response in the body, but that same site actually suppresses the brain’s ability to clear away damaged brain cells and amyloid, which eventually leads to diseases like dementia. The mutated version allows microglia (brain immune cells) to attack and clear out this unwanted material. People with higher levels of this mutated CD33 variant actually have higher protection against Alzheimer’s.
Interestingly, gonorrhea bacteria are coated in the same sugar that standard CD33 receptors bind to, thus allowing them to bypass the body’s immune system. According to the researchers, the mutated CD33 version likely emerged as a protection against gonorrhea, depriving the bacteria of their “molecular mimicry” abilities. In one of life’s happy accidents, it turned out this mutation also protects against age-related diseases, thus allowing humans with the mutation to live longer. Obviously, this was a good thing, and we ran with it until the modern day. Now we have senior citizens climbing Everest, and all our politicians keep on politicking into their 70s and 80s ... well, everything has its drawbacks.
Parents raise a glass to children’s food addiction
There can be something pretty addicting about processed foods. Have you ever eaten just one french fry? Or taken just one cookie? If so, your willpower is incredible. For many of us, it can be a struggle to stop.
A recent study from the University of Michigan, which considered the existence of an eating phenotype, suggests our parents’ habits could be to blame.
By administering a series of questionnaires that inquired about food addiction, alcohol use disorders, cannabis use disorder, nicotine/e-cigarette dependence, and their family tree, investigators found that participants with a “paternal history of problematic alcohol use” had higher risk of food addiction but not obesity.
Apparently about one in five people display a clinically significant addiction to highly processed foods. It was noted that foods like ice cream, pizza, and french fries have high amounts of refined carbs and fats, which could trigger an addictive response.
Lindzey Hoover, a graduate student at the university who was the study’s lead author, noted that living in an environment where these foods are cheap and accessible can be really challenging for those with a family history of addiction. The investigators suggested that public health approaches, like restriction of other substances and marketing to kids, should be put in place for highly processed foods.
Maybe french fries should come with a warning label.
A prescription for America’s traffic problems
Nostalgia is a funny thing. Do you ever feel nostalgic about things that really weren’t very pleasant in the first place? Take, for instance, the morning commute. Here in the Washington area, more than 2 years into the COVID era, the traffic is still not what it used to be … and we kind of miss it.
Nah, not really. That was just a way to get everyone thinking about driving, because AAA has something of an explanation for the situation out there on the highways and byways of America. It’s drugs. No, not those kinds of drugs. This time it’s prescription drugs that are the problem. Well, part of the problem, anyway.
AAA did a survey last summer and found that nearly 50% of drivers “used one or more potentially impairing medications in the past 30 days. … The proportion of those choosing to drive is higher among those taking multiple medications.” How much higher? More than 63% of those with two or more prescriptions were driving within 2 hours of taking at least one of those meds, as were 71% of those taking three or more.
The 2,657 respondents also were asked about the types of potentially impairing drugs they were taking: 61% of those using antidepressants had been on the road within 2 hours of use at least once in the past 30 days, as had 73% of those taking an amphetamine, AAA said.
So there you have it. That guy in the BMW who’s been tailgating you for the last 3 miles? He may be a jerk, but there’s a good chance he’s a jerk with a prescription … or two … or three.
Exercise in a pill? Sign us up
You just got home from a long shift and you know you should go to the gym, but the bed is calling and you just answered. We know sometimes we have to make sacrifices in the name of fitness, but there just aren’t enough hours in the day. Unless our prayers have been answered. There could be a pill that has the benefits of working out without having to work out.
In a study published in Nature, investigators reported that they have identified a molecule made during exercise and used it on mice, which took in less food after being given the pill, which may open doors to understanding how exercise affects hunger.
In the first part of the study, the researchers found the molecule, known as Lac-Phe – which is synthesized from lactate and phenylalanine – in the blood plasma of mice after they had run on a treadmill.
The investigators then gave a Lac-Phe supplement to mice on high-fat diets and found that their food intake was about 50% of what other mice were eating. The supplement also improved their glucose tolerance.
Because the research also found Lac-Phe in humans who exercised, they hope that this pill will be in our future. “Our next steps include finding more details about how Lac-Phe mediates its effects in the body, including the brain,” Yong Xu, MD, of Baylor College of Medicine, Houston, said in a written statement. “Our goal is to learn to modulate this exercise pathway for therapeutic interventions.”
As always, we are rooting for you, science!
Gonorrhea and grandparents: A match made in prehistoric heaven
*Editorial note: LOTME takes no responsibility for any unfortunate imagery the reader may have experienced from the above headline.
Old people are the greatest. Back pains, cognitive decline, aches in all the diodes down your left side, there’s nothing quite like your golden years. Notably, however, humans are one of the few animals who experience true old age, as most creatures are adapted to maximize reproductive potential. As such, living past menopause is rare in the animal kingdom.
This is where the “grandmother hypothesis” comes in: Back in Ye Olde Stone Age, women who lived into old age could provide child care for younger women, because human babies require a lot more time and attention than other animal offspring. But how did humans end up living so long? Enter a group of Californian researchers, who believe they have an answer. It was gonorrhea.
When compared with the chimpanzee genome (as well as with Neanderthals and Denisovans, our closest ancestors), humans have a unique mutated version of the CD33 gene that lacks a sugar-binding site; the standard version uses the sugar-binding site to protect against autoimmune response in the body, but that same site actually suppresses the brain’s ability to clear away damaged brain cells and amyloid, which eventually leads to diseases like dementia. The mutated version allows microglia (brain immune cells) to attack and clear out this unwanted material. People with higher levels of this mutated CD33 variant actually have higher protection against Alzheimer’s.
Interestingly, gonorrhea bacteria are coated in the same sugar that standard CD33 receptors bind to, thus allowing them to bypass the body’s immune system. According to the researchers, the mutated CD33 version likely emerged as a protection against gonorrhea, depriving the bacteria of their “molecular mimicry” abilities. In one of life’s happy accidents, it turned out this mutation also protects against age-related diseases, thus allowing humans with the mutation to live longer. Obviously, this was a good thing, and we ran with it until the modern day. Now we have senior citizens climbing Everest, and all our politicians keep on politicking into their 70s and 80s ... well, everything has its drawbacks.
Parents raise a glass to children’s food addiction
There can be something pretty addicting about processed foods. Have you ever eaten just one french fry? Or taken just one cookie? If so, your willpower is incredible. For many of us, it can be a struggle to stop.
A recent study from the University of Michigan, which considered the existence of an eating phenotype, suggests our parents’ habits could be to blame.
By administering a series of questionnaires that inquired about food addiction, alcohol use disorders, cannabis use disorder, nicotine/e-cigarette dependence, and their family tree, investigators found that participants with a “paternal history of problematic alcohol use” had higher risk of food addiction but not obesity.
Apparently about one in five people display a clinically significant addiction to highly processed foods. It was noted that foods like ice cream, pizza, and french fries have high amounts of refined carbs and fats, which could trigger an addictive response.
Lindzey Hoover, a graduate student at the university who was the study’s lead author, noted that living in an environment where these foods are cheap and accessible can be really challenging for those with a family history of addiction. The investigators suggested that public health approaches, like restriction of other substances and marketing to kids, should be put in place for highly processed foods.
Maybe french fries should come with a warning label.
A prescription for America’s traffic problems
Nostalgia is a funny thing. Do you ever feel nostalgic about things that really weren’t very pleasant in the first place? Take, for instance, the morning commute. Here in the Washington area, more than 2 years into the COVID era, the traffic is still not what it used to be … and we kind of miss it.
Nah, not really. That was just a way to get everyone thinking about driving, because AAA has something of an explanation for the situation out there on the highways and byways of America. It’s drugs. No, not those kinds of drugs. This time it’s prescription drugs that are the problem. Well, part of the problem, anyway.
AAA did a survey last summer and found that nearly 50% of drivers “used one or more potentially impairing medications in the past 30 days. … The proportion of those choosing to drive is higher among those taking multiple medications.” How much higher? More than 63% of those with two or more prescriptions were driving within 2 hours of taking at least one of those meds, as were 71% of those taking three or more.
The 2,657 respondents also were asked about the types of potentially impairing drugs they were taking: 61% of those using antidepressants had been on the road within 2 hours of use at least once in the past 30 days, as had 73% of those taking an amphetamine, AAA said.
So there you have it. That guy in the BMW who’s been tailgating you for the last 3 miles? He may be a jerk, but there’s a good chance he’s a jerk with a prescription … or two … or three.
U.S. News issues top hospitals list, now with expanded health equity measures
For the seventh consecutive year, the Mayo Clinic in Rochester, Minn., took the top spot in the annual honor roll of best hospitals, published July 26 by U.S. News & World Report.
The 2022 rankings, which marks the 33rd edition, showcase several methodology changes, including new ratings for ovarian, prostate, and uterine cancer surgeries that “provide patients ... with previously unavailable information to assist them in making a critical health care decision,” a news release from the publication explains.
said the release. Finally, a new metric called “home time” determines how successfully each hospital helps patients return home.
Mayo Clinic remains No. 1
For the 2022-2023 rankings and ratings, U.S. News compared more than 4,500 medical centers across the country in 15 specialties and 20 procedures and conditions. Of these, 493 were recognized as Best Regional Hospitals as a result of their overall strong performance.
The list was then narrowed to the top 20 hospitals, outlined in the honor roll below, that deliver “exceptional treatment across multiple areas of care.”
Following Mayo Clinic in the annual ranking’s top spot, Cedars-Sinai Medical Center in Los Angeles rises from No. 6 to No. 2, and New York University Langone Hospitals finish third, up from eighth in 2021.
Cleveland Clinic in Ohio holds the No. 4 spot, down two from 2021, while Johns Hopkins Hospital in Baltimore and UCLA Medical Center in Los Angeles tie for fifth place. Rounding out the top 10, in order, are: New York–Presbyterian Hospital–Columbia and Cornell, New York; Massachusetts General Hospital, Boston; Northwestern Memorial Hospital, Chicago; Stanford (Calif.) Health Care–Stanford Hospital.
The following hospitals complete the top 20 in the United States:
- 11. Barnes-Jewish Hospital, St. Louis
- 12. UCSF Medical Center, San Francisco
- 13. Hospitals of the University of Pennsylvania–Penn Presbyterian, Philadelphia
- 14. Brigham and Women’s Hospital, Boston
- 15. Houston Methodist Hospital
- 16. Mount Sinai Hospital, New York
- 17. University of Michigan Health–Michigan Medicine, Ann Arbor
- 18. Mayo Clinic–Phoenix
- 19. Vanderbilt University Medical Center, Nashville, Tenn.
- 20. Rush University Medical Center, Chicago
For the specialty rankings, the University of Texas MD Anderson Cancer Center, Houston, remains No. 1 in cancer care, the Cleveland Clinic is No. 1 in cardiology and heart surgery, and the Hospital for Special Surgery in New York is No. 1 in orthopedics.
Top five for cancer
- 1. University of Texas MD Anderson Cancer Center, Houston
- 2. Memorial Sloan Kettering Cancer Center, New York
- 3. Mayo Clinic, Rochester, Minn.
- 4. Dana-Farber/Brigham and Women’s Cancer Center, Boston
- 5. UCLA Medical Center, Los Angeles
Top five for cardiology and heart surgery
- 1. Cleveland Clinic
- 2. Mayo Clinic, Rochester, Minn.
- 3. Cedars-Sinai Medical Center, Los Angeles
- 4. New York–Presbyterian Hospital–Columbia and Cornell, New York
- 5. New York University Langone Hospitals
Top five for orthopedics
- 1. Hospital for Special Surgery, New York
- 2. Mayo Clinic, Rochester, Minn.
- 3. Cedars-Sinai Medical Center, Los Angeles
- 4. New York University Langone Hospitals
- 5. (tie) Rush University Medical Center, Chicago
- 5. (tie) UCLA Medical Center, Los Angeles
According to the news release, the procedures and conditions ratings are based entirely on objective patient care measures like survival rates, patient experience, home time, and level of nursing care. The Best Hospitals rankings consider a variety of data provided by the Centers for Medicare & Medicaid Services, American Hospital Association, professional organizations, and medical specialists.
The full report is available online.
A version of this article first appeared on Medscape.com.
For the seventh consecutive year, the Mayo Clinic in Rochester, Minn., took the top spot in the annual honor roll of best hospitals, published July 26 by U.S. News & World Report.
The 2022 rankings, which marks the 33rd edition, showcase several methodology changes, including new ratings for ovarian, prostate, and uterine cancer surgeries that “provide patients ... with previously unavailable information to assist them in making a critical health care decision,” a news release from the publication explains.
said the release. Finally, a new metric called “home time” determines how successfully each hospital helps patients return home.
Mayo Clinic remains No. 1
For the 2022-2023 rankings and ratings, U.S. News compared more than 4,500 medical centers across the country in 15 specialties and 20 procedures and conditions. Of these, 493 were recognized as Best Regional Hospitals as a result of their overall strong performance.
The list was then narrowed to the top 20 hospitals, outlined in the honor roll below, that deliver “exceptional treatment across multiple areas of care.”
Following Mayo Clinic in the annual ranking’s top spot, Cedars-Sinai Medical Center in Los Angeles rises from No. 6 to No. 2, and New York University Langone Hospitals finish third, up from eighth in 2021.
Cleveland Clinic in Ohio holds the No. 4 spot, down two from 2021, while Johns Hopkins Hospital in Baltimore and UCLA Medical Center in Los Angeles tie for fifth place. Rounding out the top 10, in order, are: New York–Presbyterian Hospital–Columbia and Cornell, New York; Massachusetts General Hospital, Boston; Northwestern Memorial Hospital, Chicago; Stanford (Calif.) Health Care–Stanford Hospital.
The following hospitals complete the top 20 in the United States:
- 11. Barnes-Jewish Hospital, St. Louis
- 12. UCSF Medical Center, San Francisco
- 13. Hospitals of the University of Pennsylvania–Penn Presbyterian, Philadelphia
- 14. Brigham and Women’s Hospital, Boston
- 15. Houston Methodist Hospital
- 16. Mount Sinai Hospital, New York
- 17. University of Michigan Health–Michigan Medicine, Ann Arbor
- 18. Mayo Clinic–Phoenix
- 19. Vanderbilt University Medical Center, Nashville, Tenn.
- 20. Rush University Medical Center, Chicago
For the specialty rankings, the University of Texas MD Anderson Cancer Center, Houston, remains No. 1 in cancer care, the Cleveland Clinic is No. 1 in cardiology and heart surgery, and the Hospital for Special Surgery in New York is No. 1 in orthopedics.
Top five for cancer
- 1. University of Texas MD Anderson Cancer Center, Houston
- 2. Memorial Sloan Kettering Cancer Center, New York
- 3. Mayo Clinic, Rochester, Minn.
- 4. Dana-Farber/Brigham and Women’s Cancer Center, Boston
- 5. UCLA Medical Center, Los Angeles
Top five for cardiology and heart surgery
- 1. Cleveland Clinic
- 2. Mayo Clinic, Rochester, Minn.
- 3. Cedars-Sinai Medical Center, Los Angeles
- 4. New York–Presbyterian Hospital–Columbia and Cornell, New York
- 5. New York University Langone Hospitals
Top five for orthopedics
- 1. Hospital for Special Surgery, New York
- 2. Mayo Clinic, Rochester, Minn.
- 3. Cedars-Sinai Medical Center, Los Angeles
- 4. New York University Langone Hospitals
- 5. (tie) Rush University Medical Center, Chicago
- 5. (tie) UCLA Medical Center, Los Angeles
According to the news release, the procedures and conditions ratings are based entirely on objective patient care measures like survival rates, patient experience, home time, and level of nursing care. The Best Hospitals rankings consider a variety of data provided by the Centers for Medicare & Medicaid Services, American Hospital Association, professional organizations, and medical specialists.
The full report is available online.
A version of this article first appeared on Medscape.com.
For the seventh consecutive year, the Mayo Clinic in Rochester, Minn., took the top spot in the annual honor roll of best hospitals, published July 26 by U.S. News & World Report.
The 2022 rankings, which marks the 33rd edition, showcase several methodology changes, including new ratings for ovarian, prostate, and uterine cancer surgeries that “provide patients ... with previously unavailable information to assist them in making a critical health care decision,” a news release from the publication explains.
said the release. Finally, a new metric called “home time” determines how successfully each hospital helps patients return home.
Mayo Clinic remains No. 1
For the 2022-2023 rankings and ratings, U.S. News compared more than 4,500 medical centers across the country in 15 specialties and 20 procedures and conditions. Of these, 493 were recognized as Best Regional Hospitals as a result of their overall strong performance.
The list was then narrowed to the top 20 hospitals, outlined in the honor roll below, that deliver “exceptional treatment across multiple areas of care.”
Following Mayo Clinic in the annual ranking’s top spot, Cedars-Sinai Medical Center in Los Angeles rises from No. 6 to No. 2, and New York University Langone Hospitals finish third, up from eighth in 2021.
Cleveland Clinic in Ohio holds the No. 4 spot, down two from 2021, while Johns Hopkins Hospital in Baltimore and UCLA Medical Center in Los Angeles tie for fifth place. Rounding out the top 10, in order, are: New York–Presbyterian Hospital–Columbia and Cornell, New York; Massachusetts General Hospital, Boston; Northwestern Memorial Hospital, Chicago; Stanford (Calif.) Health Care–Stanford Hospital.
The following hospitals complete the top 20 in the United States:
- 11. Barnes-Jewish Hospital, St. Louis
- 12. UCSF Medical Center, San Francisco
- 13. Hospitals of the University of Pennsylvania–Penn Presbyterian, Philadelphia
- 14. Brigham and Women’s Hospital, Boston
- 15. Houston Methodist Hospital
- 16. Mount Sinai Hospital, New York
- 17. University of Michigan Health–Michigan Medicine, Ann Arbor
- 18. Mayo Clinic–Phoenix
- 19. Vanderbilt University Medical Center, Nashville, Tenn.
- 20. Rush University Medical Center, Chicago
For the specialty rankings, the University of Texas MD Anderson Cancer Center, Houston, remains No. 1 in cancer care, the Cleveland Clinic is No. 1 in cardiology and heart surgery, and the Hospital for Special Surgery in New York is No. 1 in orthopedics.
Top five for cancer
- 1. University of Texas MD Anderson Cancer Center, Houston
- 2. Memorial Sloan Kettering Cancer Center, New York
- 3. Mayo Clinic, Rochester, Minn.
- 4. Dana-Farber/Brigham and Women’s Cancer Center, Boston
- 5. UCLA Medical Center, Los Angeles
Top five for cardiology and heart surgery
- 1. Cleveland Clinic
- 2. Mayo Clinic, Rochester, Minn.
- 3. Cedars-Sinai Medical Center, Los Angeles
- 4. New York–Presbyterian Hospital–Columbia and Cornell, New York
- 5. New York University Langone Hospitals
Top five for orthopedics
- 1. Hospital for Special Surgery, New York
- 2. Mayo Clinic, Rochester, Minn.
- 3. Cedars-Sinai Medical Center, Los Angeles
- 4. New York University Langone Hospitals
- 5. (tie) Rush University Medical Center, Chicago
- 5. (tie) UCLA Medical Center, Los Angeles
According to the news release, the procedures and conditions ratings are based entirely on objective patient care measures like survival rates, patient experience, home time, and level of nursing care. The Best Hospitals rankings consider a variety of data provided by the Centers for Medicare & Medicaid Services, American Hospital Association, professional organizations, and medical specialists.
The full report is available online.
A version of this article first appeared on Medscape.com.
Are head-to-head cancer drug trials rigged?
More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.
“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.
than if the trial would have been designed with fairer rules, he explained.
This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.
Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.
‘Highly concerning’
Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.
For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.
All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.
The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.
They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.
Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.
Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”
“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
Blame industry?
Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.
“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.
“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.
Addressing this problem will likely take buy-in from multiple stakeholders.
Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.
Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.
Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.
“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.
He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.
Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”
The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.
A version of this article first appeared on Medscape.com.
More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.
“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.
than if the trial would have been designed with fairer rules, he explained.
This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.
Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.
‘Highly concerning’
Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.
For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.
All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.
The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.
They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.
Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.
Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”
“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
Blame industry?
Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.
“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.
“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.
Addressing this problem will likely take buy-in from multiple stakeholders.
Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.
Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.
Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.
“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.
He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.
Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”
The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.
A version of this article first appeared on Medscape.com.
More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.
“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.
than if the trial would have been designed with fairer rules, he explained.
This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.
Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.
‘Highly concerning’
Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.
For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.
All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.
The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.
They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.
Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.
Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”
“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
Blame industry?
Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.
“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.
“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.
Addressing this problem will likely take buy-in from multiple stakeholders.
Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.
Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.
Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.
“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.
He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.
Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”
The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.
A version of this article first appeared on Medscape.com.
Two distinct phenotypes of COVID-related myocarditis emerge
Researchers from France have identified two distinct phenotypes of fulminant COVID-19–related myocarditis in adults, with different clinical presentations, immunologic profiles, and outcomes.
Differentiation between the two bioclinical entities is important to understand for patient management and further pathophysiological studies, they said.
The first phenotype occurs early (within a few days) in acute SARS-CoV-2 infection, with active viral replication (polymerase chain reaction positive) in adults who meet criteria for multisystem inflammatory syndrome (MIS-A+).
In this early phenotype, there is “limited systemic inflammation without skin and mucosal involvement, but myocardial dysfunction is fulminant and frequently associated with large pericardial effusions. These cases more often require extracorporeal membrane oxygenation [ECMO],” Guy Gorochov, MD, PhD, Sorbonne University, Paris, said in an interview.
The second is a delayed, postinfectious, immune-driven phenotype that occurs in adults who fail to meet the criteria for MIS-A (MIS-A–).
This phenotype occurs weeks after SARS-CoV-2 infection, usually beyond detectable active viral replication (PCR–) in the context of specific immune response and severe systemic inflammation with skin and mucosal involvement. Myocardial dysfunction is more progressive and rarely associated with large pericardial effusions, Dr. Gorochov explained.
The study was published in the Journal of the American College of Cardiology.
Evolving understanding
The findings are based on a retrospective analysis of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit from March 2020 to June 2021 for suspected fulminant COVID-19 myocarditis.
Patients were confirmed to have SARS-CoV-2 infection by PCR and/or by serologic testing. As noted in other studies, the patients were predominantly young men (66%; median age, 27.5 years). Twenty-five (66%) patients were MIS-A+ and 13 (34%) were MIS-A–.
In general, the MIS-A– patients were sicker and had worse outcomes.
Specifically, compared with the MIS-A+ patients, MIS-A– patients had a shorter time between the onset of COVID-19 symptoms and the development of myocarditis, a shorter time to ICU admission, and more severe presentations assessed using lower left ventricular ejection fraction and sequential organ failure assessment scores.
MIS-A– patients also had higher lactate levels, were more likely to need venoarterial ECMO (92% vs 16%), had higher ICU mortality (31% vs. 4%), and a had lower probability of survival at 3 months (68% vs. 96%), compared with their MIS-A+ peers.
Immunologic differences
The immunologic profiles of these two distinct clinical phenotypes also differed.
In MIS-A– early-type COVID-19 myocarditis, RNA polymerase III autoantibodies are frequently positive and serum levels of antiviral interferon-alpha and granulocyte-attracting interleukin-8 are elevated.
In contrast, in MIS-A+ delayed-type COVID-19 myocarditis, RNA polymerase III autoantibodies are negative and serum levels of IL-17 and IL-22 are highly elevated.
“We suggest that IL-17 and IL-22 are novel criteria that should help to assess in adults the recently recognized MIS-A,” Dr. Gorochov told this news organization. “It should be tested whether IL-17 and IL-22 are also elevated in children with MIS-C.”
The researchers also observed “extremely” high serum IL-10 levels in both patient groups. This has been previously associated with severe myocardial injury and an increase in the risk for death in severe COVID-19 patients.
The researchers said the phenotypic clustering of patients with fulminant COVID-19–related myocarditis “seems relevant” for their management.
MIS-A– cases, owing to the high risk for evolution toward refractory cardiogenic shock, should be “urgently” referred to a center with venoarterial ECMO and closely monitored to prevent a “too-late” cannulation, especially under cardiopulmonary resuscitation, known to be associated with poor outcomes, they advised.
They noted that the five patients who died in their series had late venoarterial ECMO implantation, while undergoing multiple organ failures or resuscitation.
Conversely, the risk for evolution to refractory cardiogenic shock is lower in MIS-A+ cases. However, identifying MIS-A+ cases is “all the more important given that numerous data support the efficacy of corticosteroids and/or intravenous immunoglobulins in MIS-C,” Dr. Gorochov and colleagues wrote.
The authors of a linked editorial said the French team should be “commended on their work in furthering our understanding of fulminant myocarditis related to COVID-19 infection.”
Ajith Nair, MD, Baylor College of Medicine, and Anita Deswal, MD, MPH, University of Texas M.D. Anderson Cancer Center, both in Houston, noted that fulminant myocarditis is rare and can result from either of two mechanisms: viral tropism or an immune-mediated mechanism.
“It remains to be seen whether using antiviral therapy versus immunomodulatory therapy on the basis of clinical and cytokine profiles will yield benefits,” they wrote.
“Fulminant myocarditis invariably requires hemodynamic support and carries a high mortality risk if it is recognized late. However, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function,” they added.
“This study highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis,” Dr. Nair and Dr. Deswal concluded.
This research was supported in part by the Foundation of France, French National Research Agency, Sorbonne University, and Clinical Research Hospital. The researchers have filed a patent application based on these results. Dr. Nair and Dr. Deswal have no relevant disclosures.
A version of this article first appeared on Medscape.com.
Researchers from France have identified two distinct phenotypes of fulminant COVID-19–related myocarditis in adults, with different clinical presentations, immunologic profiles, and outcomes.
Differentiation between the two bioclinical entities is important to understand for patient management and further pathophysiological studies, they said.
The first phenotype occurs early (within a few days) in acute SARS-CoV-2 infection, with active viral replication (polymerase chain reaction positive) in adults who meet criteria for multisystem inflammatory syndrome (MIS-A+).
In this early phenotype, there is “limited systemic inflammation without skin and mucosal involvement, but myocardial dysfunction is fulminant and frequently associated with large pericardial effusions. These cases more often require extracorporeal membrane oxygenation [ECMO],” Guy Gorochov, MD, PhD, Sorbonne University, Paris, said in an interview.
The second is a delayed, postinfectious, immune-driven phenotype that occurs in adults who fail to meet the criteria for MIS-A (MIS-A–).
This phenotype occurs weeks after SARS-CoV-2 infection, usually beyond detectable active viral replication (PCR–) in the context of specific immune response and severe systemic inflammation with skin and mucosal involvement. Myocardial dysfunction is more progressive and rarely associated with large pericardial effusions, Dr. Gorochov explained.
The study was published in the Journal of the American College of Cardiology.
Evolving understanding
The findings are based on a retrospective analysis of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit from March 2020 to June 2021 for suspected fulminant COVID-19 myocarditis.
Patients were confirmed to have SARS-CoV-2 infection by PCR and/or by serologic testing. As noted in other studies, the patients were predominantly young men (66%; median age, 27.5 years). Twenty-five (66%) patients were MIS-A+ and 13 (34%) were MIS-A–.
In general, the MIS-A– patients were sicker and had worse outcomes.
Specifically, compared with the MIS-A+ patients, MIS-A– patients had a shorter time between the onset of COVID-19 symptoms and the development of myocarditis, a shorter time to ICU admission, and more severe presentations assessed using lower left ventricular ejection fraction and sequential organ failure assessment scores.
MIS-A– patients also had higher lactate levels, were more likely to need venoarterial ECMO (92% vs 16%), had higher ICU mortality (31% vs. 4%), and a had lower probability of survival at 3 months (68% vs. 96%), compared with their MIS-A+ peers.
Immunologic differences
The immunologic profiles of these two distinct clinical phenotypes also differed.
In MIS-A– early-type COVID-19 myocarditis, RNA polymerase III autoantibodies are frequently positive and serum levels of antiviral interferon-alpha and granulocyte-attracting interleukin-8 are elevated.
In contrast, in MIS-A+ delayed-type COVID-19 myocarditis, RNA polymerase III autoantibodies are negative and serum levels of IL-17 and IL-22 are highly elevated.
“We suggest that IL-17 and IL-22 are novel criteria that should help to assess in adults the recently recognized MIS-A,” Dr. Gorochov told this news organization. “It should be tested whether IL-17 and IL-22 are also elevated in children with MIS-C.”
The researchers also observed “extremely” high serum IL-10 levels in both patient groups. This has been previously associated with severe myocardial injury and an increase in the risk for death in severe COVID-19 patients.
The researchers said the phenotypic clustering of patients with fulminant COVID-19–related myocarditis “seems relevant” for their management.
MIS-A– cases, owing to the high risk for evolution toward refractory cardiogenic shock, should be “urgently” referred to a center with venoarterial ECMO and closely monitored to prevent a “too-late” cannulation, especially under cardiopulmonary resuscitation, known to be associated with poor outcomes, they advised.
They noted that the five patients who died in their series had late venoarterial ECMO implantation, while undergoing multiple organ failures or resuscitation.
Conversely, the risk for evolution to refractory cardiogenic shock is lower in MIS-A+ cases. However, identifying MIS-A+ cases is “all the more important given that numerous data support the efficacy of corticosteroids and/or intravenous immunoglobulins in MIS-C,” Dr. Gorochov and colleagues wrote.
The authors of a linked editorial said the French team should be “commended on their work in furthering our understanding of fulminant myocarditis related to COVID-19 infection.”
Ajith Nair, MD, Baylor College of Medicine, and Anita Deswal, MD, MPH, University of Texas M.D. Anderson Cancer Center, both in Houston, noted that fulminant myocarditis is rare and can result from either of two mechanisms: viral tropism or an immune-mediated mechanism.
“It remains to be seen whether using antiviral therapy versus immunomodulatory therapy on the basis of clinical and cytokine profiles will yield benefits,” they wrote.
“Fulminant myocarditis invariably requires hemodynamic support and carries a high mortality risk if it is recognized late. However, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function,” they added.
“This study highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis,” Dr. Nair and Dr. Deswal concluded.
This research was supported in part by the Foundation of France, French National Research Agency, Sorbonne University, and Clinical Research Hospital. The researchers have filed a patent application based on these results. Dr. Nair and Dr. Deswal have no relevant disclosures.
A version of this article first appeared on Medscape.com.
Researchers from France have identified two distinct phenotypes of fulminant COVID-19–related myocarditis in adults, with different clinical presentations, immunologic profiles, and outcomes.
Differentiation between the two bioclinical entities is important to understand for patient management and further pathophysiological studies, they said.
The first phenotype occurs early (within a few days) in acute SARS-CoV-2 infection, with active viral replication (polymerase chain reaction positive) in adults who meet criteria for multisystem inflammatory syndrome (MIS-A+).
In this early phenotype, there is “limited systemic inflammation without skin and mucosal involvement, but myocardial dysfunction is fulminant and frequently associated with large pericardial effusions. These cases more often require extracorporeal membrane oxygenation [ECMO],” Guy Gorochov, MD, PhD, Sorbonne University, Paris, said in an interview.
The second is a delayed, postinfectious, immune-driven phenotype that occurs in adults who fail to meet the criteria for MIS-A (MIS-A–).
This phenotype occurs weeks after SARS-CoV-2 infection, usually beyond detectable active viral replication (PCR–) in the context of specific immune response and severe systemic inflammation with skin and mucosal involvement. Myocardial dysfunction is more progressive and rarely associated with large pericardial effusions, Dr. Gorochov explained.
The study was published in the Journal of the American College of Cardiology.
Evolving understanding
The findings are based on a retrospective analysis of 38 patients without a history of COVID-19 vaccination who were admitted to the intensive care unit from March 2020 to June 2021 for suspected fulminant COVID-19 myocarditis.
Patients were confirmed to have SARS-CoV-2 infection by PCR and/or by serologic testing. As noted in other studies, the patients were predominantly young men (66%; median age, 27.5 years). Twenty-five (66%) patients were MIS-A+ and 13 (34%) were MIS-A–.
In general, the MIS-A– patients were sicker and had worse outcomes.
Specifically, compared with the MIS-A+ patients, MIS-A– patients had a shorter time between the onset of COVID-19 symptoms and the development of myocarditis, a shorter time to ICU admission, and more severe presentations assessed using lower left ventricular ejection fraction and sequential organ failure assessment scores.
MIS-A– patients also had higher lactate levels, were more likely to need venoarterial ECMO (92% vs 16%), had higher ICU mortality (31% vs. 4%), and a had lower probability of survival at 3 months (68% vs. 96%), compared with their MIS-A+ peers.
Immunologic differences
The immunologic profiles of these two distinct clinical phenotypes also differed.
In MIS-A– early-type COVID-19 myocarditis, RNA polymerase III autoantibodies are frequently positive and serum levels of antiviral interferon-alpha and granulocyte-attracting interleukin-8 are elevated.
In contrast, in MIS-A+ delayed-type COVID-19 myocarditis, RNA polymerase III autoantibodies are negative and serum levels of IL-17 and IL-22 are highly elevated.
“We suggest that IL-17 and IL-22 are novel criteria that should help to assess in adults the recently recognized MIS-A,” Dr. Gorochov told this news organization. “It should be tested whether IL-17 and IL-22 are also elevated in children with MIS-C.”
The researchers also observed “extremely” high serum IL-10 levels in both patient groups. This has been previously associated with severe myocardial injury and an increase in the risk for death in severe COVID-19 patients.
The researchers said the phenotypic clustering of patients with fulminant COVID-19–related myocarditis “seems relevant” for their management.
MIS-A– cases, owing to the high risk for evolution toward refractory cardiogenic shock, should be “urgently” referred to a center with venoarterial ECMO and closely monitored to prevent a “too-late” cannulation, especially under cardiopulmonary resuscitation, known to be associated with poor outcomes, they advised.
They noted that the five patients who died in their series had late venoarterial ECMO implantation, while undergoing multiple organ failures or resuscitation.
Conversely, the risk for evolution to refractory cardiogenic shock is lower in MIS-A+ cases. However, identifying MIS-A+ cases is “all the more important given that numerous data support the efficacy of corticosteroids and/or intravenous immunoglobulins in MIS-C,” Dr. Gorochov and colleagues wrote.
The authors of a linked editorial said the French team should be “commended on their work in furthering our understanding of fulminant myocarditis related to COVID-19 infection.”
Ajith Nair, MD, Baylor College of Medicine, and Anita Deswal, MD, MPH, University of Texas M.D. Anderson Cancer Center, both in Houston, noted that fulminant myocarditis is rare and can result from either of two mechanisms: viral tropism or an immune-mediated mechanism.
“It remains to be seen whether using antiviral therapy versus immunomodulatory therapy on the basis of clinical and cytokine profiles will yield benefits,” they wrote.
“Fulminant myocarditis invariably requires hemodynamic support and carries a high mortality risk if it is recognized late. However, the long-term prognosis in patients who survive the critical period is favorable, with recovery of myocardial function,” they added.
“This study highlights the ever-shifting understanding of the pathophysiology and therapeutic approaches to fulminant myocarditis,” Dr. Nair and Dr. Deswal concluded.
This research was supported in part by the Foundation of France, French National Research Agency, Sorbonne University, and Clinical Research Hospital. The researchers have filed a patent application based on these results. Dr. Nair and Dr. Deswal have no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Immune response may explain brain damage after COVID-19
It seems that the virus does not infect the brain directly. The scientists found evidence that antibodies – proteins produced by the immune system in response to viruses and other invaders – are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. The study was published in the journal Brain.
Brain tissue autopsy
“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” Avindra Nath, MD, stated in a National Institutes of Health news release. Dr. Nath, who specializes in neuroimmunology, is the clinical director at the National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”
In this study, Dr. Nath and his team examined brain tissue from a subset of patients from their previous study. The nine individuals, ages 24-73 years, died shortly after contracting COVID-19. They were chosen because structural brain scans showed signs of blood vessel damage in the brain. The samples were compared with those from 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry.
As in their earlier study, researchers found signs of leaky blood vessels based on the presence of blood proteins that normally do not cross the blood-brain barrier. This suggests that the tight junctions between the endothelial cells in the blood-brain barrier have been damaged.
Neurologic symptoms’ molecular basis
Dr. Nath and his colleagues discovered deposits of immune complexes on the surface of the cells. This finding is evidence that damage to endothelial cells was likely due to an immune response.
These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together.
“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time, the tight junctions between the endothelial cells get disrupted, causing them to leak,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”
Researchers found that in areas with damage to the endothelial cells, more than 300 genes showed decreased expression, whereas six genes were increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. As the NIH news release notes, this may provide clues to the molecular basis of neurologic symptoms related to COVID-19 and offer potential therapeutic targets.
Together, these findings give insight into the immune response damaging the brain after COVID-19 infection. But it remains unclear what antigen the immune response is targeting, because the virus itself was not detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the angiotensin-converting enzyme 2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.
‘Brain fog’ explained?
The study may also have implications for understanding and treating long-term neurologic symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” Had the patients in the study survived, the researchers believe they would likely have developed long COVID.
“It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury,” said Dr. Nath. “There could be a small, indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So, these findings have very important therapeutic implications.”
The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for post-COVID neurologic symptoms.
This study was supported by the NINDS Division of Intramural Research (NS003130) and K23NS109284, the Roy J. Carver Foundation, and the Iowa Neuroscience Institute.
A version of this article first appeared on Medscape.com. This article was translated from Medscape French edition.
It seems that the virus does not infect the brain directly. The scientists found evidence that antibodies – proteins produced by the immune system in response to viruses and other invaders – are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. The study was published in the journal Brain.
Brain tissue autopsy
“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” Avindra Nath, MD, stated in a National Institutes of Health news release. Dr. Nath, who specializes in neuroimmunology, is the clinical director at the National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”
In this study, Dr. Nath and his team examined brain tissue from a subset of patients from their previous study. The nine individuals, ages 24-73 years, died shortly after contracting COVID-19. They were chosen because structural brain scans showed signs of blood vessel damage in the brain. The samples were compared with those from 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry.
As in their earlier study, researchers found signs of leaky blood vessels based on the presence of blood proteins that normally do not cross the blood-brain barrier. This suggests that the tight junctions between the endothelial cells in the blood-brain barrier have been damaged.
Neurologic symptoms’ molecular basis
Dr. Nath and his colleagues discovered deposits of immune complexes on the surface of the cells. This finding is evidence that damage to endothelial cells was likely due to an immune response.
These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together.
“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time, the tight junctions between the endothelial cells get disrupted, causing them to leak,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”
Researchers found that in areas with damage to the endothelial cells, more than 300 genes showed decreased expression, whereas six genes were increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. As the NIH news release notes, this may provide clues to the molecular basis of neurologic symptoms related to COVID-19 and offer potential therapeutic targets.
Together, these findings give insight into the immune response damaging the brain after COVID-19 infection. But it remains unclear what antigen the immune response is targeting, because the virus itself was not detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the angiotensin-converting enzyme 2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.
‘Brain fog’ explained?
The study may also have implications for understanding and treating long-term neurologic symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” Had the patients in the study survived, the researchers believe they would likely have developed long COVID.
“It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury,” said Dr. Nath. “There could be a small, indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So, these findings have very important therapeutic implications.”
The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for post-COVID neurologic symptoms.
This study was supported by the NINDS Division of Intramural Research (NS003130) and K23NS109284, the Roy J. Carver Foundation, and the Iowa Neuroscience Institute.
A version of this article first appeared on Medscape.com. This article was translated from Medscape French edition.
It seems that the virus does not infect the brain directly. The scientists found evidence that antibodies – proteins produced by the immune system in response to viruses and other invaders – are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. The study was published in the journal Brain.
Brain tissue autopsy
“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” Avindra Nath, MD, stated in a National Institutes of Health news release. Dr. Nath, who specializes in neuroimmunology, is the clinical director at the National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think in this paper we’ve gained important insight into the cascade of events.”
In this study, Dr. Nath and his team examined brain tissue from a subset of patients from their previous study. The nine individuals, ages 24-73 years, died shortly after contracting COVID-19. They were chosen because structural brain scans showed signs of blood vessel damage in the brain. The samples were compared with those from 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry.
As in their earlier study, researchers found signs of leaky blood vessels based on the presence of blood proteins that normally do not cross the blood-brain barrier. This suggests that the tight junctions between the endothelial cells in the blood-brain barrier have been damaged.
Neurologic symptoms’ molecular basis
Dr. Nath and his colleagues discovered deposits of immune complexes on the surface of the cells. This finding is evidence that damage to endothelial cells was likely due to an immune response.
These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together.
“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time, the tight junctions between the endothelial cells get disrupted, causing them to leak,” Dr. Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”
Researchers found that in areas with damage to the endothelial cells, more than 300 genes showed decreased expression, whereas six genes were increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. As the NIH news release notes, this may provide clues to the molecular basis of neurologic symptoms related to COVID-19 and offer potential therapeutic targets.
Together, these findings give insight into the immune response damaging the brain after COVID-19 infection. But it remains unclear what antigen the immune response is targeting, because the virus itself was not detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the angiotensin-converting enzyme 2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.
‘Brain fog’ explained?
The study may also have implications for understanding and treating long-term neurologic symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” Had the patients in the study survived, the researchers believe they would likely have developed long COVID.
“It is quite possible that this same immune response persists in long COVID patients, resulting in neuronal injury,” said Dr. Nath. “There could be a small, indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So, these findings have very important therapeutic implications.”
The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for post-COVID neurologic symptoms.
This study was supported by the NINDS Division of Intramural Research (NS003130) and K23NS109284, the Roy J. Carver Foundation, and the Iowa Neuroscience Institute.
A version of this article first appeared on Medscape.com. This article was translated from Medscape French edition.
No more injections after one-off gene therapy in hemophilia B
Patients with hemophilia B face a lifelong need for regular factor IX injections.
“Removing the need for hemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life,” lead author Pratima Chowdary, MD, of the Royal Free Hospital, University College London Cancer Institute, commented in a press statement.
The team reported new results with the investigational gene therapy FLT180a in a study published in the New England Journal of Medicine.
“We found that normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of FLT180a,” the authors reported. “In all but one patient, gene therapy led to durable factor IX expression, eliminated the need for factor IX prophylaxis, and eliminated spontaneous bleeding leading to factor IX replacement.”
FLT180a (Freeline Therapeutics) is a liver-directed, adeno-associated virus (AAV) gene therapy designed to normalize levels of the factor IX protein that is needed for coagulation; however, it is produced in dangerously low levels in people with hemophilia B as a result of gene mutations.
Under the current standard of care, patients with hemophilia B require lifelong prophylaxis of regular intravenous injections with recombinant factor IX replacement therapy, and they commonly continue to experience potentially severe joint pain.
While factor-replacement therapies with longer half-lives have emerged, the prophylaxis is still invasive and extremely expensive, with the average price tag in the United States of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
Novel gene therapy
Hemophilia B is a rare and inherited genetic bleeding disorder caused by defects in the gene responsible for factor IX protein, which is needed for blood clotting.
AAV gene therapy delivers a functional copy of this gene directly to patient tissues to compensate for one that is not working properly. It leads to the synthesis of factor IX proteins and a one-time gene therapy infusion can achieve long-lasting effects, the team explained in a press release.
The results they reported come from the phase 1/2 multicenter B-AMAZE open-label trial. It involved 10 patients (all age 18 and older) with severe or moderately severe hemophilia B, defined as having a factor IX level of 2% or less that of normal values.
All patients received one-off gene therapy infusion, at one of four FLT180a doses.
All patients also received immunosuppression to prevent the body from rejecting the vector gene therapy. This consisted of glucocorticoids with or without tacrolimus for a period of ranging from several weeks to several months.
Following the FLT180a infusion, all patients showed dose-dependent increases in factor IX levels. After a median follow-up of 27.2 months (range, 19.1-42.4 months), nearly all the patients (9 of 10) continued to show sustained factor IX activity.
Steady production of factor IX activity started at month 12, with low bleeding frequency that allowed these nine patients to no longer require weekly injections of the protein.
Five of the patients had factor IX levels in the normal range, from 51% to 78%; three patients had lower increases of 23%-43% of the normal range, and one patient who had received the highest dose, had a level that was 260% of normal.
The exception was one patient who required a return to factor IX prophylaxis. He had experienced a failure in the immunosuppression regimen due to a delay in the recognition of an immune response at approximately 22 weeks after treatment, the authors reported.
The therapy was generally well tolerated, with no infusion reactions or discontinuations of infusions. As of the study cutoff, no inhibitors of factor IX were detected.
Of the adverse events, about 10% were determined to be related to the gene therapy. The most common event associated with the gene therapy was increases in liver aminotransferase, which is a concern with AAV gene therapies, the authors commented.
Otherwise, 24% of adverse events were determined to be related to the immunosuppression, and were consistent with the known safety profiles of glucocorticoids and tacrolimus.
Late increases in aminotransferase levels were reported among patients who had received prolonged tacrolimus beyond the tapering of glucocorticoid treatment.
The one serious adverse event that was reported involved an arteriovenous fistula thrombosis, which occurred in the patient who had received the highest dose of gene therapy and who showed the highest factor IX levels.
The current findings, along with data from another recent study involving gene therapy for patients with hemophilia A, emphasized that “immune responses can occur later than previously expected and may coincide with the withdrawal of immunosuppression,” the authors cautioned.
“Consistent best practices for monitoring aminotransferase levels and deciding when ALT increases warrant intervention remain a critical topic for the field,” they noted.
Meanwhile, the patients in this B-AMAZE trial all remain enrolled in a long-term follow-up study to assess the safety and durability of FLT180a over 15 years.
The trial was sponsored by University College London and funded by Freeline Therapeutics. Dr. Chowdary disclosed various relationships with industry.
A version of this article first appeared on Medscape.com.
Patients with hemophilia B face a lifelong need for regular factor IX injections.
“Removing the need for hemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life,” lead author Pratima Chowdary, MD, of the Royal Free Hospital, University College London Cancer Institute, commented in a press statement.
The team reported new results with the investigational gene therapy FLT180a in a study published in the New England Journal of Medicine.
“We found that normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of FLT180a,” the authors reported. “In all but one patient, gene therapy led to durable factor IX expression, eliminated the need for factor IX prophylaxis, and eliminated spontaneous bleeding leading to factor IX replacement.”
FLT180a (Freeline Therapeutics) is a liver-directed, adeno-associated virus (AAV) gene therapy designed to normalize levels of the factor IX protein that is needed for coagulation; however, it is produced in dangerously low levels in people with hemophilia B as a result of gene mutations.
Under the current standard of care, patients with hemophilia B require lifelong prophylaxis of regular intravenous injections with recombinant factor IX replacement therapy, and they commonly continue to experience potentially severe joint pain.
While factor-replacement therapies with longer half-lives have emerged, the prophylaxis is still invasive and extremely expensive, with the average price tag in the United States of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
Novel gene therapy
Hemophilia B is a rare and inherited genetic bleeding disorder caused by defects in the gene responsible for factor IX protein, which is needed for blood clotting.
AAV gene therapy delivers a functional copy of this gene directly to patient tissues to compensate for one that is not working properly. It leads to the synthesis of factor IX proteins and a one-time gene therapy infusion can achieve long-lasting effects, the team explained in a press release.
The results they reported come from the phase 1/2 multicenter B-AMAZE open-label trial. It involved 10 patients (all age 18 and older) with severe or moderately severe hemophilia B, defined as having a factor IX level of 2% or less that of normal values.
All patients received one-off gene therapy infusion, at one of four FLT180a doses.
All patients also received immunosuppression to prevent the body from rejecting the vector gene therapy. This consisted of glucocorticoids with or without tacrolimus for a period of ranging from several weeks to several months.
Following the FLT180a infusion, all patients showed dose-dependent increases in factor IX levels. After a median follow-up of 27.2 months (range, 19.1-42.4 months), nearly all the patients (9 of 10) continued to show sustained factor IX activity.
Steady production of factor IX activity started at month 12, with low bleeding frequency that allowed these nine patients to no longer require weekly injections of the protein.
Five of the patients had factor IX levels in the normal range, from 51% to 78%; three patients had lower increases of 23%-43% of the normal range, and one patient who had received the highest dose, had a level that was 260% of normal.
The exception was one patient who required a return to factor IX prophylaxis. He had experienced a failure in the immunosuppression regimen due to a delay in the recognition of an immune response at approximately 22 weeks after treatment, the authors reported.
The therapy was generally well tolerated, with no infusion reactions or discontinuations of infusions. As of the study cutoff, no inhibitors of factor IX were detected.
Of the adverse events, about 10% were determined to be related to the gene therapy. The most common event associated with the gene therapy was increases in liver aminotransferase, which is a concern with AAV gene therapies, the authors commented.
Otherwise, 24% of adverse events were determined to be related to the immunosuppression, and were consistent with the known safety profiles of glucocorticoids and tacrolimus.
Late increases in aminotransferase levels were reported among patients who had received prolonged tacrolimus beyond the tapering of glucocorticoid treatment.
The one serious adverse event that was reported involved an arteriovenous fistula thrombosis, which occurred in the patient who had received the highest dose of gene therapy and who showed the highest factor IX levels.
The current findings, along with data from another recent study involving gene therapy for patients with hemophilia A, emphasized that “immune responses can occur later than previously expected and may coincide with the withdrawal of immunosuppression,” the authors cautioned.
“Consistent best practices for monitoring aminotransferase levels and deciding when ALT increases warrant intervention remain a critical topic for the field,” they noted.
Meanwhile, the patients in this B-AMAZE trial all remain enrolled in a long-term follow-up study to assess the safety and durability of FLT180a over 15 years.
The trial was sponsored by University College London and funded by Freeline Therapeutics. Dr. Chowdary disclosed various relationships with industry.
A version of this article first appeared on Medscape.com.
Patients with hemophilia B face a lifelong need for regular factor IX injections.
“Removing the need for hemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life,” lead author Pratima Chowdary, MD, of the Royal Free Hospital, University College London Cancer Institute, commented in a press statement.
The team reported new results with the investigational gene therapy FLT180a in a study published in the New England Journal of Medicine.
“We found that normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of FLT180a,” the authors reported. “In all but one patient, gene therapy led to durable factor IX expression, eliminated the need for factor IX prophylaxis, and eliminated spontaneous bleeding leading to factor IX replacement.”
FLT180a (Freeline Therapeutics) is a liver-directed, adeno-associated virus (AAV) gene therapy designed to normalize levels of the factor IX protein that is needed for coagulation; however, it is produced in dangerously low levels in people with hemophilia B as a result of gene mutations.
Under the current standard of care, patients with hemophilia B require lifelong prophylaxis of regular intravenous injections with recombinant factor IX replacement therapy, and they commonly continue to experience potentially severe joint pain.
While factor-replacement therapies with longer half-lives have emerged, the prophylaxis is still invasive and extremely expensive, with the average price tag in the United States of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
Novel gene therapy
Hemophilia B is a rare and inherited genetic bleeding disorder caused by defects in the gene responsible for factor IX protein, which is needed for blood clotting.
AAV gene therapy delivers a functional copy of this gene directly to patient tissues to compensate for one that is not working properly. It leads to the synthesis of factor IX proteins and a one-time gene therapy infusion can achieve long-lasting effects, the team explained in a press release.
The results they reported come from the phase 1/2 multicenter B-AMAZE open-label trial. It involved 10 patients (all age 18 and older) with severe or moderately severe hemophilia B, defined as having a factor IX level of 2% or less that of normal values.
All patients received one-off gene therapy infusion, at one of four FLT180a doses.
All patients also received immunosuppression to prevent the body from rejecting the vector gene therapy. This consisted of glucocorticoids with or without tacrolimus for a period of ranging from several weeks to several months.
Following the FLT180a infusion, all patients showed dose-dependent increases in factor IX levels. After a median follow-up of 27.2 months (range, 19.1-42.4 months), nearly all the patients (9 of 10) continued to show sustained factor IX activity.
Steady production of factor IX activity started at month 12, with low bleeding frequency that allowed these nine patients to no longer require weekly injections of the protein.
Five of the patients had factor IX levels in the normal range, from 51% to 78%; three patients had lower increases of 23%-43% of the normal range, and one patient who had received the highest dose, had a level that was 260% of normal.
The exception was one patient who required a return to factor IX prophylaxis. He had experienced a failure in the immunosuppression regimen due to a delay in the recognition of an immune response at approximately 22 weeks after treatment, the authors reported.
The therapy was generally well tolerated, with no infusion reactions or discontinuations of infusions. As of the study cutoff, no inhibitors of factor IX were detected.
Of the adverse events, about 10% were determined to be related to the gene therapy. The most common event associated with the gene therapy was increases in liver aminotransferase, which is a concern with AAV gene therapies, the authors commented.
Otherwise, 24% of adverse events were determined to be related to the immunosuppression, and were consistent with the known safety profiles of glucocorticoids and tacrolimus.
Late increases in aminotransferase levels were reported among patients who had received prolonged tacrolimus beyond the tapering of glucocorticoid treatment.
The one serious adverse event that was reported involved an arteriovenous fistula thrombosis, which occurred in the patient who had received the highest dose of gene therapy and who showed the highest factor IX levels.
The current findings, along with data from another recent study involving gene therapy for patients with hemophilia A, emphasized that “immune responses can occur later than previously expected and may coincide with the withdrawal of immunosuppression,” the authors cautioned.
“Consistent best practices for monitoring aminotransferase levels and deciding when ALT increases warrant intervention remain a critical topic for the field,” they noted.
Meanwhile, the patients in this B-AMAZE trial all remain enrolled in a long-term follow-up study to assess the safety and durability of FLT180a over 15 years.
The trial was sponsored by University College London and funded by Freeline Therapeutics. Dr. Chowdary disclosed various relationships with industry.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
CAR T-cell therapy turns 10 and finally earns the word ‘cure’
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.