HOUSTON – Selected patients who need operations, such as paraesophageal hernia repair and Heller myotomy, for benign hiatal diseases can have laparoscopic outpatient procedures with outcomes comparable with those of inpatients, a Canadian retrospective cohort study found.

“When comparing planned day-case patients with those who had planned admissions, we found that postoperative complication was the only statistically significant different outcome. Our data show same-day discharge resulted in no postoperative mortality, and no difference in postoperative morbidity, emergency room visits, and readmissions compared to traditional inpatient care,” said Juan Carlos Molina, MD, of McGill University Health Centre in Montreal, reporting the study results at the annual meeting of the American Society of Gastrointestinal and Endoscopic Surgeons.

HOUSTON – Selected patients who need operations, such as paraesophageal hernia repair and Heller myotomy, for benign hiatal diseases can have laparoscopic outpatient procedures with outcomes comparable with those of inpatients, a Canadian retrospective cohort study found.

“When comparing planned day-case patients with those who had planned admissions, we found that postoperative complication was the only statistically significant different outcome. Our data show same-day discharge resulted in no postoperative mortality, and no difference in postoperative morbidity, emergency room visits, and readmissions compared to traditional inpatient care,” said Juan Carlos Molina, MD, of McGill University Health Centre in Montreal, reporting the study results at the annual meeting of the American Society of Gastrointestinal and Endoscopic Surgeons.

HOUSTON – Selected patients who need operations, such as paraesophageal hernia repair and Heller myotomy, for benign hiatal diseases can have laparoscopic outpatient procedures with outcomes comparable with those of inpatients, a Canadian retrospective cohort study found.

“When comparing planned day-case patients with those who had planned admissions, we found that postoperative complication was the only statistically significant different outcome. Our data show same-day discharge resulted in no postoperative mortality, and no difference in postoperative morbidity, emergency room visits, and readmissions compared to traditional inpatient care,” said Juan Carlos Molina, MD, of McGill University Health Centre in Montreal, reporting the study results at the annual meeting of the American Society of Gastrointestinal and Endoscopic Surgeons.

BOSTON – A lot has changed in GI technology since V. Raman Muthusamy, MD, the incoming chair of the AGA Center for GI Innovation and Technology(CGIT), completed his GI fellowship training 15 years ago.

“I would say that between half and two-thirds of what I do today for actual patient care delivery is from technologies that have been completed since my fellowship or [from] applications of those technologies that are new,” he said in a video interview conducted during the 2017 AGA Technology Summit, which is sponsored by the center. So if you think you’re not impacted by innovation, think again.

“I think like many practicing physicians we have great technology, but we can think of ways to do things better,” continued Dr. Muthusamy, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles.

One of the goals of the center is to streamline the process of taking a good idea and making it into a product and a company. Dr. Muthusamy said such streamlining is important because the current “daunting” development process has led to many good ideas “dying on the vine” before they could be implemented. He says the CGIT, by bringing together key stakeholders from the medical, business, and regulatory arenas, can help bring forth the latest technologies to directly benefit GI patients.

[email protected]

BOSTON – A lot has changed in GI technology since V. Raman Muthusamy, MD, the incoming chair of the AGA Center for GI Innovation and Technology(CGIT), completed his GI fellowship training 15 years ago.

“I would say that between half and two-thirds of what I do today for actual patient care delivery is from technologies that have been completed since my fellowship or [from] applications of those technologies that are new,” he said in a video interview conducted during the 2017 AGA Technology Summit, which is sponsored by the center. So if you think you’re not impacted by innovation, think again.

“I think like many practicing physicians we have great technology, but we can think of ways to do things better,” continued Dr. Muthusamy, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles.

One of the goals of the center is to streamline the process of taking a good idea and making it into a product and a company. Dr. Muthusamy said such streamlining is important because the current “daunting” development process has led to many good ideas “dying on the vine” before they could be implemented. He says the CGIT, by bringing together key stakeholders from the medical, business, and regulatory arenas, can help bring forth the latest technologies to directly benefit GI patients.

[email protected]

BOSTON – A lot has changed in GI technology since V. Raman Muthusamy, MD, the incoming chair of the AGA Center for GI Innovation and Technology(CGIT), completed his GI fellowship training 15 years ago.

“I would say that between half and two-thirds of what I do today for actual patient care delivery is from technologies that have been completed since my fellowship or [from] applications of those technologies that are new,” he said in a video interview conducted during the 2017 AGA Technology Summit, which is sponsored by the center. So if you think you’re not impacted by innovation, think again.

“I think like many practicing physicians we have great technology, but we can think of ways to do things better,” continued Dr. Muthusamy, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles.

One of the goals of the center is to streamline the process of taking a good idea and making it into a product and a company. Dr. Muthusamy said such streamlining is important because the current “daunting” development process has led to many good ideas “dying on the vine” before they could be implemented. He says the CGIT, by bringing together key stakeholders from the medical, business, and regulatory arenas, can help bring forth the latest technologies to directly benefit GI patients.

[email protected]

Photo by Rod Waddington

The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.

For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.

And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.

“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.

“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”

Dr Jemal and his colleagues described this study in the journal Cancer.

The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.

They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.

ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.

In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.

In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.

The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).

For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).

Leukemia was not included in this analysis because it was not among the top 5 cancers.

Photo by Rod Waddington

The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.

For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.

And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.

“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.

“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”

Dr Jemal and his colleagues described this study in the journal Cancer.

The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.

They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.

ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.

In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.

In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.

The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).

For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).

Leukemia was not included in this analysis because it was not among the top 5 cancers.

Photo by Rod Waddington

The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.

For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.

And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.

“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.

“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”

Dr Jemal and his colleagues described this study in the journal Cancer.

The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.

They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.

ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.

In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.

In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.

The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).

For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).

Leukemia was not included in this analysis because it was not among the top 5 cancers.

Image by Spencer Phillips

SCOTTSDALE, ARIZONA—The investigational therapy SPK-9001 delivers “consistent and sustained” increases in factor IX (FIX) activity in patients with hemophilia B, according to researchers.

All 10 subjects who received SPK-9001 in a phase 1/2 trial have consistently achieved the targeted therapeutic range of FIX activity.

There have been no confirmed bleeds, and 9 of the subjects have not received any infusions of FIX therapy since receiving SPK-9001.

SPK-9001 reduced the patients’ annualized bleeding rate by 96% and the annualized infusion rate by 99%.

Adam Cuker, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and his colleagues presented these results at the Hemostasis and Thrombosis Research Society 2017 Scientific Symposium.

The trial is sponsored by Spark Therapeutics and Pfizer, the companies developing SPK-9001.

SPK-9001 is a bio-engineered adeno-associated virus capsid expressing a codon-optimized, high-activity human FIX variant enabling endogenous production of FIX.

In the phase 1/2 trial, 10 hemophilia B patients received a single administration of SPK-9001 (5 x 10¹¹ vector genomes/kg body weight).

As of the data cutoff (March 24, 2017), 9 of the 10 patients have not taken FIX concentrates to prevent or control bleeding events since they received SPK-9001.

One patient with severe joint disease has self-administered infusions. The patient self-infused FIX therapy for a suspected ankle bleed on day 2 after receiving SPK-9001 and self-administered precautionary infusions another 9 times between December 2, 2016, and January 2, 2017, for persistent knee pain. The patient has not used additional FIX therapy since January 2.

For all 10 patients, the mean steady-state FIX activity level 12 weeks after SPK-9001 administration was a sustained 33% (range as of the data cutoff: 14% to 81%).

Based on individual patient history prior to the study, the annualized bleeding rate was reduced by 96% to a mean of 0.39 annual bleeds, compared with 9.2 bleeds before SPK-9001 administration.

The annualized infusion rate was reduced 99% to a mean of 0.98 annual infusions, compared with 68.5 infusions before SPK-9001 administration.

To date, no serious adverse events have been reported, including no FIX inhibitors and no thrombotic events.

Two of the 10 patients experienced an asymptomatic, transient elevation in liver enzymes, or decline in FIX activity, potentially indicative of an immune response to the Spark100 vector capsid, that occurred several weeks post-infusion.

Both patients received a tapering dose of oral corticosteroids, after which their alanine aminotransferase levels returned to baseline.

The FIX activity level of one of these patients has stabilized at approximately 15% for more than 9 weeks post-corticosteroid use. The other patient had a FIX activity level between 70% and 80% upon completion of steroid use. 

Image by Spencer Phillips

SCOTTSDALE, ARIZONA—The investigational therapy SPK-9001 delivers “consistent and sustained” increases in factor IX (FIX) activity in patients with hemophilia B, according to researchers.

All 10 subjects who received SPK-9001 in a phase 1/2 trial have consistently achieved the targeted therapeutic range of FIX activity.

There have been no confirmed bleeds, and 9 of the subjects have not received any infusions of FIX therapy since receiving SPK-9001.

SPK-9001 reduced the patients’ annualized bleeding rate by 96% and the annualized infusion rate by 99%.

Adam Cuker, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and his colleagues presented these results at the Hemostasis and Thrombosis Research Society 2017 Scientific Symposium.

The trial is sponsored by Spark Therapeutics and Pfizer, the companies developing SPK-9001.

SPK-9001 is a bio-engineered adeno-associated virus capsid expressing a codon-optimized, high-activity human FIX variant enabling endogenous production of FIX.

In the phase 1/2 trial, 10 hemophilia B patients received a single administration of SPK-9001 (5 x 10¹¹ vector genomes/kg body weight).

As of the data cutoff (March 24, 2017), 9 of the 10 patients have not taken FIX concentrates to prevent or control bleeding events since they received SPK-9001.

One patient with severe joint disease has self-administered infusions. The patient self-infused FIX therapy for a suspected ankle bleed on day 2 after receiving SPK-9001 and self-administered precautionary infusions another 9 times between December 2, 2016, and January 2, 2017, for persistent knee pain. The patient has not used additional FIX therapy since January 2.

For all 10 patients, the mean steady-state FIX activity level 12 weeks after SPK-9001 administration was a sustained 33% (range as of the data cutoff: 14% to 81%).

Based on individual patient history prior to the study, the annualized bleeding rate was reduced by 96% to a mean of 0.39 annual bleeds, compared with 9.2 bleeds before SPK-9001 administration.

The annualized infusion rate was reduced 99% to a mean of 0.98 annual infusions, compared with 68.5 infusions before SPK-9001 administration.

To date, no serious adverse events have been reported, including no FIX inhibitors and no thrombotic events.

Two of the 10 patients experienced an asymptomatic, transient elevation in liver enzymes, or decline in FIX activity, potentially indicative of an immune response to the Spark100 vector capsid, that occurred several weeks post-infusion.

Both patients received a tapering dose of oral corticosteroids, after which their alanine aminotransferase levels returned to baseline.

The FIX activity level of one of these patients has stabilized at approximately 15% for more than 9 weeks post-corticosteroid use. The other patient had a FIX activity level between 70% and 80% upon completion of steroid use. 

Image by Spencer Phillips

SCOTTSDALE, ARIZONA—The investigational therapy SPK-9001 delivers “consistent and sustained” increases in factor IX (FIX) activity in patients with hemophilia B, according to researchers.

All 10 subjects who received SPK-9001 in a phase 1/2 trial have consistently achieved the targeted therapeutic range of FIX activity.

There have been no confirmed bleeds, and 9 of the subjects have not received any infusions of FIX therapy since receiving SPK-9001.

SPK-9001 reduced the patients’ annualized bleeding rate by 96% and the annualized infusion rate by 99%.

Adam Cuker, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and his colleagues presented these results at the Hemostasis and Thrombosis Research Society 2017 Scientific Symposium.

The trial is sponsored by Spark Therapeutics and Pfizer, the companies developing SPK-9001.

SPK-9001 is a bio-engineered adeno-associated virus capsid expressing a codon-optimized, high-activity human FIX variant enabling endogenous production of FIX.

In the phase 1/2 trial, 10 hemophilia B patients received a single administration of SPK-9001 (5 x 10¹¹ vector genomes/kg body weight).

As of the data cutoff (March 24, 2017), 9 of the 10 patients have not taken FIX concentrates to prevent or control bleeding events since they received SPK-9001.

One patient with severe joint disease has self-administered infusions. The patient self-infused FIX therapy for a suspected ankle bleed on day 2 after receiving SPK-9001 and self-administered precautionary infusions another 9 times between December 2, 2016, and January 2, 2017, for persistent knee pain. The patient has not used additional FIX therapy since January 2.

For all 10 patients, the mean steady-state FIX activity level 12 weeks after SPK-9001 administration was a sustained 33% (range as of the data cutoff: 14% to 81%).

Based on individual patient history prior to the study, the annualized bleeding rate was reduced by 96% to a mean of 0.39 annual bleeds, compared with 9.2 bleeds before SPK-9001 administration.

The annualized infusion rate was reduced 99% to a mean of 0.98 annual infusions, compared with 68.5 infusions before SPK-9001 administration.

To date, no serious adverse events have been reported, including no FIX inhibitors and no thrombotic events.

Two of the 10 patients experienced an asymptomatic, transient elevation in liver enzymes, or decline in FIX activity, potentially indicative of an immune response to the Spark100 vector capsid, that occurred several weeks post-infusion.

Both patients received a tapering dose of oral corticosteroids, after which their alanine aminotransferase levels returned to baseline.

The FIX activity level of one of these patients has stabilized at approximately 15% for more than 9 weeks post-corticosteroid use. The other patient had a FIX activity level between 70% and 80% upon completion of steroid use. 

Photo by Aaron Logan

WASHINGTON, DC—A chimeric antigen receptor (CAR) T-cell therapy is active against multiple myeloma (MM), according to preclinical research.

The therapy, known as P-BCMA-101, demonstrated persistent anti-tumor activity in a mouse model of MM.

Treatment with P-BCMA-101 eliminated tumors after relapse and prolonged survival in the mice, when compared to other CAR-T cell therapies.

These results were presented in a poster at the AACR Annual Meeting 2017 (abstract 3759).

The research was conducted by employees of Poseida Therapeutics Inc., the company developing P-BCMA-101, as well as others.

About P-BCMA-101

The researchers explained that P-BCMA-101 employs a B-cell maturation antigen (BCMA)-specific Centyrin™ rather than a single-chain variable fragment (scFv) for antigen detection.

Centyrins™ are fully human and have similar binding affinities as scFvs. However, Centyrins are smaller, more thermostable, and predicted to be less immunogenic.

P-BCMA-101 is engineered using the PiggyBac™ DNA modification system. PiggyBac eliminates the need to use lentivirus or gamma-retrovirus as a gene delivery mechanism, resulting in improved manufacturing and cost savings.

In addition, the increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be “flipped” to enable depletion in case adverse events occur. And the selectable gene allows for enrichment of CARTyrin+ cells using a non-genotoxic drug.

Findings

The researchers found that more than 70% of P-BCMA-101 cells possessed a stem cell memory phenotype, creating a significant population of self-renewing, multipotent progenitors capable of reconstituting the entire spectrum of memory and effector T-cell subsets required to prevent cancer relapse. Similar competitor products typically report 0% to 20% stem cell memory phenotype.

In addition, P-BCMA-101 was enriched with more than 95% of T cells successfully modified, which compares favorably to the roughly 30% to 50% commonly expected with clinical manufacture using lentivirus.

P-BCMA-101 did not exhibit effects of CAR-mediated tonic signaling, a common cause of T-cell exhaustion that leads to poor durability. Tonic signaling is caused by oligomerization of unstable binding domains commonly seen with traditional scFv CARs.

The researchers tested P-BCMA-101 in NSG mice bearing luciferase+ MM.1S cells. The mice received a single administration of either 4 x 10⁶ or 12 x 10⁶ P-BCMA-101 cells.

P-BCMA-101 treatment reduced tumor burden to the limit of detection within 7 days. Conversely, all untreated control mice succumbed to MM within 4 weeks.

P-BCMA-101 expanded and persisted in the treated mice, eliminated tumors following relapse, and prolonged survival.

Most treated mice survived 110 days, and none of them died from tumor burden during the study. This compares favorably to lentivirus-based products that have shown roughly 50-day survival in the same model.

Based on these results, Poseida plans to initiate a phase 1 trial of P-BCMA-101 in patients with relapsed or refractory MM.

Photo by Aaron Logan

WASHINGTON, DC—A chimeric antigen receptor (CAR) T-cell therapy is active against multiple myeloma (MM), according to preclinical research.

The therapy, known as P-BCMA-101, demonstrated persistent anti-tumor activity in a mouse model of MM.

Treatment with P-BCMA-101 eliminated tumors after relapse and prolonged survival in the mice, when compared to other CAR-T cell therapies.

These results were presented in a poster at the AACR Annual Meeting 2017 (abstract 3759).

The research was conducted by employees of Poseida Therapeutics Inc., the company developing P-BCMA-101, as well as others.

About P-BCMA-101

The researchers explained that P-BCMA-101 employs a B-cell maturation antigen (BCMA)-specific Centyrin™ rather than a single-chain variable fragment (scFv) for antigen detection.

Centyrins™ are fully human and have similar binding affinities as scFvs. However, Centyrins are smaller, more thermostable, and predicted to be less immunogenic.

P-BCMA-101 is engineered using the PiggyBac™ DNA modification system. PiggyBac eliminates the need to use lentivirus or gamma-retrovirus as a gene delivery mechanism, resulting in improved manufacturing and cost savings.

In addition, the increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be “flipped” to enable depletion in case adverse events occur. And the selectable gene allows for enrichment of CARTyrin+ cells using a non-genotoxic drug.

Findings

The researchers found that more than 70% of P-BCMA-101 cells possessed a stem cell memory phenotype, creating a significant population of self-renewing, multipotent progenitors capable of reconstituting the entire spectrum of memory and effector T-cell subsets required to prevent cancer relapse. Similar competitor products typically report 0% to 20% stem cell memory phenotype.

In addition, P-BCMA-101 was enriched with more than 95% of T cells successfully modified, which compares favorably to the roughly 30% to 50% commonly expected with clinical manufacture using lentivirus.

P-BCMA-101 did not exhibit effects of CAR-mediated tonic signaling, a common cause of T-cell exhaustion that leads to poor durability. Tonic signaling is caused by oligomerization of unstable binding domains commonly seen with traditional scFv CARs.

The researchers tested P-BCMA-101 in NSG mice bearing luciferase+ MM.1S cells. The mice received a single administration of either 4 x 10⁶ or 12 x 10⁶ P-BCMA-101 cells.

P-BCMA-101 treatment reduced tumor burden to the limit of detection within 7 days. Conversely, all untreated control mice succumbed to MM within 4 weeks.

P-BCMA-101 expanded and persisted in the treated mice, eliminated tumors following relapse, and prolonged survival.

Most treated mice survived 110 days, and none of them died from tumor burden during the study. This compares favorably to lentivirus-based products that have shown roughly 50-day survival in the same model.

Based on these results, Poseida plans to initiate a phase 1 trial of P-BCMA-101 in patients with relapsed or refractory MM.

Photo by Aaron Logan

WASHINGTON, DC—A chimeric antigen receptor (CAR) T-cell therapy is active against multiple myeloma (MM), according to preclinical research.

The therapy, known as P-BCMA-101, demonstrated persistent anti-tumor activity in a mouse model of MM.

Treatment with P-BCMA-101 eliminated tumors after relapse and prolonged survival in the mice, when compared to other CAR-T cell therapies.

These results were presented in a poster at the AACR Annual Meeting 2017 (abstract 3759).

The research was conducted by employees of Poseida Therapeutics Inc., the company developing P-BCMA-101, as well as others.

About P-BCMA-101

The researchers explained that P-BCMA-101 employs a B-cell maturation antigen (BCMA)-specific Centyrin™ rather than a single-chain variable fragment (scFv) for antigen detection.

Centyrins™ are fully human and have similar binding affinities as scFvs. However, Centyrins are smaller, more thermostable, and predicted to be less immunogenic.

P-BCMA-101 is engineered using the PiggyBac™ DNA modification system. PiggyBac eliminates the need to use lentivirus or gamma-retrovirus as a gene delivery mechanism, resulting in improved manufacturing and cost savings.

In addition, the increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be “flipped” to enable depletion in case adverse events occur. And the selectable gene allows for enrichment of CARTyrin+ cells using a non-genotoxic drug.

Findings

The researchers found that more than 70% of P-BCMA-101 cells possessed a stem cell memory phenotype, creating a significant population of self-renewing, multipotent progenitors capable of reconstituting the entire spectrum of memory and effector T-cell subsets required to prevent cancer relapse. Similar competitor products typically report 0% to 20% stem cell memory phenotype.

In addition, P-BCMA-101 was enriched with more than 95% of T cells successfully modified, which compares favorably to the roughly 30% to 50% commonly expected with clinical manufacture using lentivirus.

P-BCMA-101 did not exhibit effects of CAR-mediated tonic signaling, a common cause of T-cell exhaustion that leads to poor durability. Tonic signaling is caused by oligomerization of unstable binding domains commonly seen with traditional scFv CARs.

The researchers tested P-BCMA-101 in NSG mice bearing luciferase+ MM.1S cells. The mice received a single administration of either 4 x 10⁶ or 12 x 10⁶ P-BCMA-101 cells.

P-BCMA-101 treatment reduced tumor burden to the limit of detection within 7 days. Conversely, all untreated control mice succumbed to MM within 4 weeks.

P-BCMA-101 expanded and persisted in the treated mice, eliminated tumors following relapse, and prolonged survival.

Most treated mice survived 110 days, and none of them died from tumor burden during the study. This compares favorably to lentivirus-based products that have shown roughly 50-day survival in the same model.

Based on these results, Poseida plans to initiate a phase 1 trial of P-BCMA-101 in patients with relapsed or refractory MM.

Red blood cells

The US Food and Drug Administration (FDA) has determined that the risk evaluation and mitigation strategy (REMS) for erythropoiesis-stimulating agents (ESAs) is no longer necessary.

The REMS was limited to the use of epoetin alfa (marketed as Epogen and Procrit) and darbepoetin alfa (marketed as Aranesp) to treat patients with anemia due to myelosuppressive chemotherapy.

The FDA said the REMS is no longer necessary to ensure that the benefits of Epogen/Procrit and Aranesp outweigh the risks these drugs pose, which include shortened overall survival and an increased risk of tumor progression or recurrence in patients with cancer.

The FDA has released the REMS requirements for these ESAs and said the risks the drugs pose can be communicated by the current product prescribing information.

The FDA decided the REMS is no longer needed based on its own analyses and an evaluation of the REMS assessment submitted by Amgen, Inc., the company that markets Epogen/Procrit and Aranesp.

Details on the analyses and evaluation are available from the following page on the FDA website: Information on Erythropoiesis-Stimulating Agents (ESA) Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp).

Red blood cells

The US Food and Drug Administration (FDA) has determined that the risk evaluation and mitigation strategy (REMS) for erythropoiesis-stimulating agents (ESAs) is no longer necessary.

The REMS was limited to the use of epoetin alfa (marketed as Epogen and Procrit) and darbepoetin alfa (marketed as Aranesp) to treat patients with anemia due to myelosuppressive chemotherapy.

The FDA said the REMS is no longer necessary to ensure that the benefits of Epogen/Procrit and Aranesp outweigh the risks these drugs pose, which include shortened overall survival and an increased risk of tumor progression or recurrence in patients with cancer.

The FDA has released the REMS requirements for these ESAs and said the risks the drugs pose can be communicated by the current product prescribing information.

The FDA decided the REMS is no longer needed based on its own analyses and an evaluation of the REMS assessment submitted by Amgen, Inc., the company that markets Epogen/Procrit and Aranesp.

Details on the analyses and evaluation are available from the following page on the FDA website: Information on Erythropoiesis-Stimulating Agents (ESA) Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp).

Red blood cells

The US Food and Drug Administration (FDA) has determined that the risk evaluation and mitigation strategy (REMS) for erythropoiesis-stimulating agents (ESAs) is no longer necessary.

The REMS was limited to the use of epoetin alfa (marketed as Epogen and Procrit) and darbepoetin alfa (marketed as Aranesp) to treat patients with anemia due to myelosuppressive chemotherapy.

The FDA said the REMS is no longer necessary to ensure that the benefits of Epogen/Procrit and Aranesp outweigh the risks these drugs pose, which include shortened overall survival and an increased risk of tumor progression or recurrence in patients with cancer.

The FDA has released the REMS requirements for these ESAs and said the risks the drugs pose can be communicated by the current product prescribing information.

The FDA decided the REMS is no longer needed based on its own analyses and an evaluation of the REMS assessment submitted by Amgen, Inc., the company that markets Epogen/Procrit and Aranesp.

Details on the analyses and evaluation are available from the following page on the FDA website: Information on Erythropoiesis-Stimulating Agents (ESA) Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp).

WASHINGTON – It’s been a “relatively positive” year for heart failure research and advances in patient care, Christopher M. O’Connor, MD, said at the annual meeting of the American College of Cardiology.

“Having been in this field for 30 years looking at clinical trials, generally for every 10 important trials done in a year, 1 has been positive and 9 have been negative; if we look at the past year, it’s more like 5 and 6. So, not a bad year for cardiomyopathy,” declared Dr. O’Connor, CEO and executive director of the Inova Heart and Vascular Institute in Falls Church, Va., and president-elect of the Heart Failure Society of America.

Bruce Jancin/Frontline Medical News

The good news

• Empagliflozin (Jardiance) earns FDA approval for reduction in risk of cardiovascular death in type 2 diabetes patients. “This is one of the most amazing stories in heart failure,” said Dr. O’Connor, who is also professor of medicine at Duke University in Durham, N.C.

The pivotal EMPA-REG OUTCOME study showed a highly significant 35% reduction in the secondary endpoint of risk of hospitalization for heart failure, as well the decrease in cardiovascular mortality which was the primary endpoint and proved persuasive to the FDA (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

“It was a remarkable development. Because of this trial, there are now a number of ongoing phase III clinical trials looking at this class of drugs in heart failure patients with and without diabetes, which makes this a very important research movement. We are now looking deeper at phenotypes and trying to get more specific with these drug therapies,” he said.

• A new and improved LVAD. This fully magnetically levitated centrifugal-flow pump type of left ventricular assist device for advanced heart failure showed superior event-free survival, compared with a commercially available axial continuous-flow pump LVAD in the randomized MOMENTUM-3 trial (N Engl J Med. 2017 Feb 2;376[5]:440-50).

The novel pump was designed to overcome a significant problem with axial continuous-flow LVADs: a proclivity for pump thrombosis. The magnetically levitated centrifugal-flow pump proved a smashing success in this regard, with zero cases of pump thrombosis occurring during the 6-month study.

“This may be the first time in the history of heart failure research that the engineers have beaten the biologists in important clinical outcomes,” the cardiologist quipped.

• Omecamtiv mecarbil successfully addresses impaired contractility in heart failure with reduced ejection fraction (HFrEF). This drug, a selective cardiac myosin activator, resulted in increased duration of systole and improved stroke volume accompanied by reductions in heart rate, left ventricular end-diastolic and -systolic dimensions, and NT-proBNP in the 87-site, 13-country, phase II COSMIC-HF study (Lancet. 2016 Dec 10;388[10062]:2895-903).

“This is probably the most novel new drug mechanism out there in clinical trials,” according to Dr. O’Connor.

On the basis of the highly encouraging results for the surrogate endpoints assessed in COSMIC-HF, a large phase III clinical trial known as GALACTIC is underway.

• Palliative care gets a welcome boost. Dr. O’Connor was a coinvestigator in PAL-HF, a single-center study presented at the 2016 annual meeting of the Heart Failure Society of America.

“This is a very important trial of palliative care in advanced heart failure. We probably don’t have as much evidence in this space as we should,” he observed. “This was a multidisciplinary intervention in which we gave the patients a medical tool kit to alleviate pain, dyspnea, and discomfort. The tool kit included benzodiazepines, sleep medications, sublingual nitroglycerin, and morphinelike products, all very carefully monitored by staff coordinators.”

The primary outcome was change in two validated heart failure quality of life measures. Both instruments documented significant improvement compared with usual care.

“There was no decrease in mortality, which wasn’t a goal in this advanced heart failure population, and no reduction in heart failure hospitalizations, but there were significant reductions in depression and anxiety,” Dr. O’Connor said.

• Vericiguat. This oral soluble cyclic guanylate cyclase stimulator missed its primary endpoint in the phase II dose-escalation SOCRATES-REDUCED trial in patients with HFrEF (JAMA. 2015 Dec 1;314[21]:2251-62), but showed an impressive improvement in quality of life. It is now the subject of the ongoing, randomized, phase III VICTORIA trial involving a planned 4,000 patients with HFrEF with the composite primary endpoint of cardiovascular death or heart failure hospitalization.

The phase II SOCRATES-PRESERVED trial also missed its primary endpoint but showed a clinically meaningful improvement in quality of life in patients with heart failure with preserved ejection fraction (HFpEF) (Eur Heart J. 2017 Mar 22. doi: 10.1093/eurheartj/ehw593). Discussions are ongoing as to whether the next step should be a confirmatory phase II study or a move straight to phase III.

The bad news

• NSAIDs linked to increased risk of heart failure. European investigators analyzed five population-based databases totaling more than 8.3 million individuals and determined that current use of any of more than two dozen NSAIDs was associated with significantly increased risk of hospital admission for heart failure. The risk appeared to be dose dependent and varied between individual agents, ranging from a 16% increased risk with naproxen to an 83% increase with ketorolac (Toradol) (BMJ. 2016 Sep 28. doi: 10.1136/bmj.4857).

• Therapeutic natriuretic peptides hit bottom. The negative results for the investigational agent ularitide in patients with acute decompensated heart failure in the large phase III TRUE-AHF trial presented at the 2016 meeting of the American Heart Association, following upon an earlier negative study of the related drug nesiritide (Natrecor) in more than 7,100 acute heart failure patients (N Engl J Med. 2011 Jul 7; 365:32-43), probably spells the end of the line for this strategy of boosting outcomes in acute heart failure, according to Dr. O’Connor.

Moreover, Novartis has announced that the phase III RELAX-AHF-2 trial of serelaxin in 6,600 patients with acute heart failure failed to meet its primary endpoints of reduced cardiovascular deaths or reduced worsening of heart failure. The trial will be formally presented later this year.

“Ularitide seemed to show an early improvement in heart failure events that was not sustained in-hospital, and there was absolutely no difference in mortality. The drug probably acts like a pharmacologic tourniquet, in my view. So I think this field of therapeutic natriuretic peptides is probably closed,” he said.

• ICDs don’t reduce mortality in patients with nonischemic heart failure. This was the conclusion reached in the DANISH trial, in which more than 1,100 patients with symptomatic systolic heart failure were randomized to an ICD or usual care (N Engl J Med. 2016 Sep 29;375[13]:1221-30).

“This study really shook up the field, raising the question, ‘Are we using defibrillators too frequently in this population?’ It has stimulated a lot of discussion, including within the guidelines committee,” according to Dr. O’Connor.

• Tolvaptan nixed for acute decompensated heart failure. The TACTICS-HF trial studied the use of tolvaptan (Samsca), an oral vasopressin-2 receptor antagonist, to reduce dyspnea in patients hospitalized with acute decompensated heart failure. Dr. O’Connor was a coinvestigator in the study, which showed that tolvaptan was no better than placebo at 8 and 24 hours (J Am Coll Cardiol. 2017 Mar 21;69[11]:1399-406).

“For now, the routine use of vasopressin antagonists in acute heart failure is not to be encouraged, although there may still be subsets where it’s worth trying – certainly in severe hyponatremia,” the cardiologist said.

• GUIDE-IT gets lost. This was a roughly 1,000-patient randomized trial of a treatment strategy aimed at improving clinical outcomes by aggressively titrating evidence-based heart failure therapies in order to suppress natriuretic peptide biomarkers. GUIDE-IT was stopped early by the data safety monitoring board due to a lack of discernible difference in outcomes, compared with usual care. Dr. O’Connor, a coinvestigator, termed the soon-to-be-published study “a disappointment.”

Sleep apnea studies show silver lining

Sleep apnea is common in patients with heart failure and is associated with worse clinical heart failure outcomes. But in the large, randomized SERVE-HF trial, investigators showed that treatment of central sleep apnea with adaptive servo-ventilation in patients with HFrEF unexpectedly increased mortality, compared with optimal medical therapy (N Engl J Med. 2015 Sep 17;373:1095-105). In a more recent secondary analysis, however, the SERVE-HF investigators found that the increased risk for cardiovascular death associated with adaptive servo-ventilation was actually restricted to patients with a very poor left ventricular ejection fraction of 30% or less, and there was a signal of possible benefit in patients in the top tier of LVEF, at 36%-45% (Lancet Respir Med. 2016 Nov; 4[11]:873-81).

This observation dovetails nicely with the findings of the CAT-HF trial presented by Dr. O’Connor at the 2016 World Congress on Heart Failure. In this phase II study, 215 patients with acute decompensated heart failure and either obstructive or central sleep apnea were randomized to optimal medical therapy alone or in combination with adaptive servo-ventilation. There was no overall difference in outcome between the two groups; however, in the subgroup of patients with HFpEF, the risk of the primary composite endpoint was reduced by 62% with adaptive servo-ventilation.

As a result of these intriguing findings from SERVE-HF and CAT-HF, a registry and/or randomized clinical trial of adaptive servo-ventilation in patients with HFpEF is now being considered under NIH sponsorship, according to Dr. O’Connor.

He reported having no financial conflicts.

[email protected]
 

WASHINGTON – It’s been a “relatively positive” year for heart failure research and advances in patient care, Christopher M. O’Connor, MD, said at the annual meeting of the American College of Cardiology.

“Having been in this field for 30 years looking at clinical trials, generally for every 10 important trials done in a year, 1 has been positive and 9 have been negative; if we look at the past year, it’s more like 5 and 6. So, not a bad year for cardiomyopathy,” declared Dr. O’Connor, CEO and executive director of the Inova Heart and Vascular Institute in Falls Church, Va., and president-elect of the Heart Failure Society of America.

Bruce Jancin/Frontline Medical News

The good news

• Empagliflozin (Jardiance) earns FDA approval for reduction in risk of cardiovascular death in type 2 diabetes patients. “This is one of the most amazing stories in heart failure,” said Dr. O’Connor, who is also professor of medicine at Duke University in Durham, N.C.

The pivotal EMPA-REG OUTCOME study showed a highly significant 35% reduction in the secondary endpoint of risk of hospitalization for heart failure, as well the decrease in cardiovascular mortality which was the primary endpoint and proved persuasive to the FDA (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

“It was a remarkable development. Because of this trial, there are now a number of ongoing phase III clinical trials looking at this class of drugs in heart failure patients with and without diabetes, which makes this a very important research movement. We are now looking deeper at phenotypes and trying to get more specific with these drug therapies,” he said.

• A new and improved LVAD. This fully magnetically levitated centrifugal-flow pump type of left ventricular assist device for advanced heart failure showed superior event-free survival, compared with a commercially available axial continuous-flow pump LVAD in the randomized MOMENTUM-3 trial (N Engl J Med. 2017 Feb 2;376[5]:440-50).

The novel pump was designed to overcome a significant problem with axial continuous-flow LVADs: a proclivity for pump thrombosis. The magnetically levitated centrifugal-flow pump proved a smashing success in this regard, with zero cases of pump thrombosis occurring during the 6-month study.

“This may be the first time in the history of heart failure research that the engineers have beaten the biologists in important clinical outcomes,” the cardiologist quipped.

• Omecamtiv mecarbil successfully addresses impaired contractility in heart failure with reduced ejection fraction (HFrEF). This drug, a selective cardiac myosin activator, resulted in increased duration of systole and improved stroke volume accompanied by reductions in heart rate, left ventricular end-diastolic and -systolic dimensions, and NT-proBNP in the 87-site, 13-country, phase II COSMIC-HF study (Lancet. 2016 Dec 10;388[10062]:2895-903).

“This is probably the most novel new drug mechanism out there in clinical trials,” according to Dr. O’Connor.

On the basis of the highly encouraging results for the surrogate endpoints assessed in COSMIC-HF, a large phase III clinical trial known as GALACTIC is underway.

• Palliative care gets a welcome boost. Dr. O’Connor was a coinvestigator in PAL-HF, a single-center study presented at the 2016 annual meeting of the Heart Failure Society of America.

“This is a very important trial of palliative care in advanced heart failure. We probably don’t have as much evidence in this space as we should,” he observed. “This was a multidisciplinary intervention in which we gave the patients a medical tool kit to alleviate pain, dyspnea, and discomfort. The tool kit included benzodiazepines, sleep medications, sublingual nitroglycerin, and morphinelike products, all very carefully monitored by staff coordinators.”

The primary outcome was change in two validated heart failure quality of life measures. Both instruments documented significant improvement compared with usual care.

“There was no decrease in mortality, which wasn’t a goal in this advanced heart failure population, and no reduction in heart failure hospitalizations, but there were significant reductions in depression and anxiety,” Dr. O’Connor said.

• Vericiguat. This oral soluble cyclic guanylate cyclase stimulator missed its primary endpoint in the phase II dose-escalation SOCRATES-REDUCED trial in patients with HFrEF (JAMA. 2015 Dec 1;314[21]:2251-62), but showed an impressive improvement in quality of life. It is now the subject of the ongoing, randomized, phase III VICTORIA trial involving a planned 4,000 patients with HFrEF with the composite primary endpoint of cardiovascular death or heart failure hospitalization.

The phase II SOCRATES-PRESERVED trial also missed its primary endpoint but showed a clinically meaningful improvement in quality of life in patients with heart failure with preserved ejection fraction (HFpEF) (Eur Heart J. 2017 Mar 22. doi: 10.1093/eurheartj/ehw593). Discussions are ongoing as to whether the next step should be a confirmatory phase II study or a move straight to phase III.

The bad news

• NSAIDs linked to increased risk of heart failure. European investigators analyzed five population-based databases totaling more than 8.3 million individuals and determined that current use of any of more than two dozen NSAIDs was associated with significantly increased risk of hospital admission for heart failure. The risk appeared to be dose dependent and varied between individual agents, ranging from a 16% increased risk with naproxen to an 83% increase with ketorolac (Toradol) (BMJ. 2016 Sep 28. doi: 10.1136/bmj.4857).

• Therapeutic natriuretic peptides hit bottom. The negative results for the investigational agent ularitide in patients with acute decompensated heart failure in the large phase III TRUE-AHF trial presented at the 2016 meeting of the American Heart Association, following upon an earlier negative study of the related drug nesiritide (Natrecor) in more than 7,100 acute heart failure patients (N Engl J Med. 2011 Jul 7; 365:32-43), probably spells the end of the line for this strategy of boosting outcomes in acute heart failure, according to Dr. O’Connor.

Moreover, Novartis has announced that the phase III RELAX-AHF-2 trial of serelaxin in 6,600 patients with acute heart failure failed to meet its primary endpoints of reduced cardiovascular deaths or reduced worsening of heart failure. The trial will be formally presented later this year.

“Ularitide seemed to show an early improvement in heart failure events that was not sustained in-hospital, and there was absolutely no difference in mortality. The drug probably acts like a pharmacologic tourniquet, in my view. So I think this field of therapeutic natriuretic peptides is probably closed,” he said.

• ICDs don’t reduce mortality in patients with nonischemic heart failure. This was the conclusion reached in the DANISH trial, in which more than 1,100 patients with symptomatic systolic heart failure were randomized to an ICD or usual care (N Engl J Med. 2016 Sep 29;375[13]:1221-30).

“This study really shook up the field, raising the question, ‘Are we using defibrillators too frequently in this population?’ It has stimulated a lot of discussion, including within the guidelines committee,” according to Dr. O’Connor.

• Tolvaptan nixed for acute decompensated heart failure. The TACTICS-HF trial studied the use of tolvaptan (Samsca), an oral vasopressin-2 receptor antagonist, to reduce dyspnea in patients hospitalized with acute decompensated heart failure. Dr. O’Connor was a coinvestigator in the study, which showed that tolvaptan was no better than placebo at 8 and 24 hours (J Am Coll Cardiol. 2017 Mar 21;69[11]:1399-406).

“For now, the routine use of vasopressin antagonists in acute heart failure is not to be encouraged, although there may still be subsets where it’s worth trying – certainly in severe hyponatremia,” the cardiologist said.

• GUIDE-IT gets lost. This was a roughly 1,000-patient randomized trial of a treatment strategy aimed at improving clinical outcomes by aggressively titrating evidence-based heart failure therapies in order to suppress natriuretic peptide biomarkers. GUIDE-IT was stopped early by the data safety monitoring board due to a lack of discernible difference in outcomes, compared with usual care. Dr. O’Connor, a coinvestigator, termed the soon-to-be-published study “a disappointment.”

Sleep apnea studies show silver lining

Sleep apnea is common in patients with heart failure and is associated with worse clinical heart failure outcomes. But in the large, randomized SERVE-HF trial, investigators showed that treatment of central sleep apnea with adaptive servo-ventilation in patients with HFrEF unexpectedly increased mortality, compared with optimal medical therapy (N Engl J Med. 2015 Sep 17;373:1095-105). In a more recent secondary analysis, however, the SERVE-HF investigators found that the increased risk for cardiovascular death associated with adaptive servo-ventilation was actually restricted to patients with a very poor left ventricular ejection fraction of 30% or less, and there was a signal of possible benefit in patients in the top tier of LVEF, at 36%-45% (Lancet Respir Med. 2016 Nov; 4[11]:873-81).

This observation dovetails nicely with the findings of the CAT-HF trial presented by Dr. O’Connor at the 2016 World Congress on Heart Failure. In this phase II study, 215 patients with acute decompensated heart failure and either obstructive or central sleep apnea were randomized to optimal medical therapy alone or in combination with adaptive servo-ventilation. There was no overall difference in outcome between the two groups; however, in the subgroup of patients with HFpEF, the risk of the primary composite endpoint was reduced by 62% with adaptive servo-ventilation.

As a result of these intriguing findings from SERVE-HF and CAT-HF, a registry and/or randomized clinical trial of adaptive servo-ventilation in patients with HFpEF is now being considered under NIH sponsorship, according to Dr. O’Connor.

He reported having no financial conflicts.

[email protected]
 

WASHINGTON – It’s been a “relatively positive” year for heart failure research and advances in patient care, Christopher M. O’Connor, MD, said at the annual meeting of the American College of Cardiology.

“Having been in this field for 30 years looking at clinical trials, generally for every 10 important trials done in a year, 1 has been positive and 9 have been negative; if we look at the past year, it’s more like 5 and 6. So, not a bad year for cardiomyopathy,” declared Dr. O’Connor, CEO and executive director of the Inova Heart and Vascular Institute in Falls Church, Va., and president-elect of the Heart Failure Society of America.

Bruce Jancin/Frontline Medical News

The good news

• Empagliflozin (Jardiance) earns FDA approval for reduction in risk of cardiovascular death in type 2 diabetes patients. “This is one of the most amazing stories in heart failure,” said Dr. O’Connor, who is also professor of medicine at Duke University in Durham, N.C.

The pivotal EMPA-REG OUTCOME study showed a highly significant 35% reduction in the secondary endpoint of risk of hospitalization for heart failure, as well the decrease in cardiovascular mortality which was the primary endpoint and proved persuasive to the FDA (N Engl J Med. 2015 Nov 26;373[22]:2117-28).

“It was a remarkable development. Because of this trial, there are now a number of ongoing phase III clinical trials looking at this class of drugs in heart failure patients with and without diabetes, which makes this a very important research movement. We are now looking deeper at phenotypes and trying to get more specific with these drug therapies,” he said.

• A new and improved LVAD. This fully magnetically levitated centrifugal-flow pump type of left ventricular assist device for advanced heart failure showed superior event-free survival, compared with a commercially available axial continuous-flow pump LVAD in the randomized MOMENTUM-3 trial (N Engl J Med. 2017 Feb 2;376[5]:440-50).

The novel pump was designed to overcome a significant problem with axial continuous-flow LVADs: a proclivity for pump thrombosis. The magnetically levitated centrifugal-flow pump proved a smashing success in this regard, with zero cases of pump thrombosis occurring during the 6-month study.

“This may be the first time in the history of heart failure research that the engineers have beaten the biologists in important clinical outcomes,” the cardiologist quipped.

• Omecamtiv mecarbil successfully addresses impaired contractility in heart failure with reduced ejection fraction (HFrEF). This drug, a selective cardiac myosin activator, resulted in increased duration of systole and improved stroke volume accompanied by reductions in heart rate, left ventricular end-diastolic and -systolic dimensions, and NT-proBNP in the 87-site, 13-country, phase II COSMIC-HF study (Lancet. 2016 Dec 10;388[10062]:2895-903).

“This is probably the most novel new drug mechanism out there in clinical trials,” according to Dr. O’Connor.

On the basis of the highly encouraging results for the surrogate endpoints assessed in COSMIC-HF, a large phase III clinical trial known as GALACTIC is underway.

• Palliative care gets a welcome boost. Dr. O’Connor was a coinvestigator in PAL-HF, a single-center study presented at the 2016 annual meeting of the Heart Failure Society of America.

“This is a very important trial of palliative care in advanced heart failure. We probably don’t have as much evidence in this space as we should,” he observed. “This was a multidisciplinary intervention in which we gave the patients a medical tool kit to alleviate pain, dyspnea, and discomfort. The tool kit included benzodiazepines, sleep medications, sublingual nitroglycerin, and morphinelike products, all very carefully monitored by staff coordinators.”

The primary outcome was change in two validated heart failure quality of life measures. Both instruments documented significant improvement compared with usual care.

“There was no decrease in mortality, which wasn’t a goal in this advanced heart failure population, and no reduction in heart failure hospitalizations, but there were significant reductions in depression and anxiety,” Dr. O’Connor said.

• Vericiguat. This oral soluble cyclic guanylate cyclase stimulator missed its primary endpoint in the phase II dose-escalation SOCRATES-REDUCED trial in patients with HFrEF (JAMA. 2015 Dec 1;314[21]:2251-62), but showed an impressive improvement in quality of life. It is now the subject of the ongoing, randomized, phase III VICTORIA trial involving a planned 4,000 patients with HFrEF with the composite primary endpoint of cardiovascular death or heart failure hospitalization.

The phase II SOCRATES-PRESERVED trial also missed its primary endpoint but showed a clinically meaningful improvement in quality of life in patients with heart failure with preserved ejection fraction (HFpEF) (Eur Heart J. 2017 Mar 22. doi: 10.1093/eurheartj/ehw593). Discussions are ongoing as to whether the next step should be a confirmatory phase II study or a move straight to phase III.

The bad news

• NSAIDs linked to increased risk of heart failure. European investigators analyzed five population-based databases totaling more than 8.3 million individuals and determined that current use of any of more than two dozen NSAIDs was associated with significantly increased risk of hospital admission for heart failure. The risk appeared to be dose dependent and varied between individual agents, ranging from a 16% increased risk with naproxen to an 83% increase with ketorolac (Toradol) (BMJ. 2016 Sep 28. doi: 10.1136/bmj.4857).

• Therapeutic natriuretic peptides hit bottom. The negative results for the investigational agent ularitide in patients with acute decompensated heart failure in the large phase III TRUE-AHF trial presented at the 2016 meeting of the American Heart Association, following upon an earlier negative study of the related drug nesiritide (Natrecor) in more than 7,100 acute heart failure patients (N Engl J Med. 2011 Jul 7; 365:32-43), probably spells the end of the line for this strategy of boosting outcomes in acute heart failure, according to Dr. O’Connor.

Moreover, Novartis has announced that the phase III RELAX-AHF-2 trial of serelaxin in 6,600 patients with acute heart failure failed to meet its primary endpoints of reduced cardiovascular deaths or reduced worsening of heart failure. The trial will be formally presented later this year.

“Ularitide seemed to show an early improvement in heart failure events that was not sustained in-hospital, and there was absolutely no difference in mortality. The drug probably acts like a pharmacologic tourniquet, in my view. So I think this field of therapeutic natriuretic peptides is probably closed,” he said.

• ICDs don’t reduce mortality in patients with nonischemic heart failure. This was the conclusion reached in the DANISH trial, in which more than 1,100 patients with symptomatic systolic heart failure were randomized to an ICD or usual care (N Engl J Med. 2016 Sep 29;375[13]:1221-30).

“This study really shook up the field, raising the question, ‘Are we using defibrillators too frequently in this population?’ It has stimulated a lot of discussion, including within the guidelines committee,” according to Dr. O’Connor.

• Tolvaptan nixed for acute decompensated heart failure. The TACTICS-HF trial studied the use of tolvaptan (Samsca), an oral vasopressin-2 receptor antagonist, to reduce dyspnea in patients hospitalized with acute decompensated heart failure. Dr. O’Connor was a coinvestigator in the study, which showed that tolvaptan was no better than placebo at 8 and 24 hours (J Am Coll Cardiol. 2017 Mar 21;69[11]:1399-406).

“For now, the routine use of vasopressin antagonists in acute heart failure is not to be encouraged, although there may still be subsets where it’s worth trying – certainly in severe hyponatremia,” the cardiologist said.

• GUIDE-IT gets lost. This was a roughly 1,000-patient randomized trial of a treatment strategy aimed at improving clinical outcomes by aggressively titrating evidence-based heart failure therapies in order to suppress natriuretic peptide biomarkers. GUIDE-IT was stopped early by the data safety monitoring board due to a lack of discernible difference in outcomes, compared with usual care. Dr. O’Connor, a coinvestigator, termed the soon-to-be-published study “a disappointment.”

Sleep apnea studies show silver lining

Sleep apnea is common in patients with heart failure and is associated with worse clinical heart failure outcomes. But in the large, randomized SERVE-HF trial, investigators showed that treatment of central sleep apnea with adaptive servo-ventilation in patients with HFrEF unexpectedly increased mortality, compared with optimal medical therapy (N Engl J Med. 2015 Sep 17;373:1095-105). In a more recent secondary analysis, however, the SERVE-HF investigators found that the increased risk for cardiovascular death associated with adaptive servo-ventilation was actually restricted to patients with a very poor left ventricular ejection fraction of 30% or less, and there was a signal of possible benefit in patients in the top tier of LVEF, at 36%-45% (Lancet Respir Med. 2016 Nov; 4[11]:873-81).

This observation dovetails nicely with the findings of the CAT-HF trial presented by Dr. O’Connor at the 2016 World Congress on Heart Failure. In this phase II study, 215 patients with acute decompensated heart failure and either obstructive or central sleep apnea were randomized to optimal medical therapy alone or in combination with adaptive servo-ventilation. There was no overall difference in outcome between the two groups; however, in the subgroup of patients with HFpEF, the risk of the primary composite endpoint was reduced by 62% with adaptive servo-ventilation.

As a result of these intriguing findings from SERVE-HF and CAT-HF, a registry and/or randomized clinical trial of adaptive servo-ventilation in patients with HFpEF is now being considered under NIH sponsorship, according to Dr. O’Connor.

He reported having no financial conflicts.

[email protected]
 

Postoperative oxygen therapy in patients with previously undetected obstructive sleep apnea (OSA) led to a reduction in apnea-hypopnea index (AHI) events per hour with no increase in apnea-hypopnea event duration.

The results suggest that postoperative oxygen could be useful in patients with OSA who refuse continuous positive airway pressure (CPAP) therapy, those with newly diagnosed OSA, and those with suspected OSA.

The researchers set out to determine if postoperative oxygen therapy could improve oxygenation in patients with previously undiagnosed OSA, reasoning that the intervention could reduce adverse events.

The study, published in CHEST (2017 March;151[3]:597-611), provided generally good news, but with a caveat: “Essentially we are saying, yes, if you give supplemental oxygen, you improve oxygenation of the patient. But overall we have to be careful because a significant number of patients have significant carbon dioxide retention when receiving supplemental oxygen. So we have to monitor patients – not just oxygen, but we may have to monitor carbon dioxide levels, too,” said lead study author Frances Chung, MBBS, professor of anesthesiology at the University of Toronto and Toronto Western Hospital.

The researchers randomized 123 patients with an AHI of at least five events per hour to postoperative oxygen (3 L/min for 3 nights via nasal prongs) or no postoperative oxygen.

On the third night, the oxygen group had a higher average oxygen saturation than controls (95.2% plus or minus 3.2% vs. 91.4% plus or minus 3.5%; P less than .0001) and a lower oxygen desaturation index (median, 2.3 events per hour vs. median, 18.5; P less than .0001).

A lower number of AHI events per hour occurred in the oxygen group (median, 8.0) than in the control group (median, 15.6; P = .016).

On average, the longest apnea-hypopnea event (median, 33.8 seconds) was shorter for a patient on oxygen, compared with a patient who did not receive oxygen (median, 49.6 seconds; P = .002).

But one finding surprised the researchers and led to some concern: Across both groups, 11.4% of patients experienced substantial CO₂ retention. Specifically, for at least 10% of 1 of the nights, these patients had a partial pressure of CO₂ of at least 55 mm Hg, according to measurements taken with a transcutaneous CO₂ monitor. Of the 14 patients who experienced this event, 13 were receiving oxygen.

Dr. Chung said the results argue strongly for postsurgical oxygen in patients with OSA, who are known to be at increased risk for complications. “We are not doing something about it, and we should be doing something. Because one death from a complication is too many,” she said.

The study was funded by the University Health Network Foundation, Toronto, and the University of Toronto. Dr. Chung reported receiving research grant support from Ontario Ministry of Health Innovation Grant, University Health Network Foundation, ResMed Foundation, Acacia, and Medtronic.

Postoperative oxygen therapy in patients with previously undetected obstructive sleep apnea (OSA) led to a reduction in apnea-hypopnea index (AHI) events per hour with no increase in apnea-hypopnea event duration.

The results suggest that postoperative oxygen could be useful in patients with OSA who refuse continuous positive airway pressure (CPAP) therapy, those with newly diagnosed OSA, and those with suspected OSA.

The researchers set out to determine if postoperative oxygen therapy could improve oxygenation in patients with previously undiagnosed OSA, reasoning that the intervention could reduce adverse events.

The study, published in CHEST (2017 March;151[3]:597-611), provided generally good news, but with a caveat: “Essentially we are saying, yes, if you give supplemental oxygen, you improve oxygenation of the patient. But overall we have to be careful because a significant number of patients have significant carbon dioxide retention when receiving supplemental oxygen. So we have to monitor patients – not just oxygen, but we may have to monitor carbon dioxide levels, too,” said lead study author Frances Chung, MBBS, professor of anesthesiology at the University of Toronto and Toronto Western Hospital.

The researchers randomized 123 patients with an AHI of at least five events per hour to postoperative oxygen (3 L/min for 3 nights via nasal prongs) or no postoperative oxygen.

On the third night, the oxygen group had a higher average oxygen saturation than controls (95.2% plus or minus 3.2% vs. 91.4% plus or minus 3.5%; P less than .0001) and a lower oxygen desaturation index (median, 2.3 events per hour vs. median, 18.5; P less than .0001).

A lower number of AHI events per hour occurred in the oxygen group (median, 8.0) than in the control group (median, 15.6; P = .016).

On average, the longest apnea-hypopnea event (median, 33.8 seconds) was shorter for a patient on oxygen, compared with a patient who did not receive oxygen (median, 49.6 seconds; P = .002).

But one finding surprised the researchers and led to some concern: Across both groups, 11.4% of patients experienced substantial CO₂ retention. Specifically, for at least 10% of 1 of the nights, these patients had a partial pressure of CO₂ of at least 55 mm Hg, according to measurements taken with a transcutaneous CO₂ monitor. Of the 14 patients who experienced this event, 13 were receiving oxygen.

Dr. Chung said the results argue strongly for postsurgical oxygen in patients with OSA, who are known to be at increased risk for complications. “We are not doing something about it, and we should be doing something. Because one death from a complication is too many,” she said.

The study was funded by the University Health Network Foundation, Toronto, and the University of Toronto. Dr. Chung reported receiving research grant support from Ontario Ministry of Health Innovation Grant, University Health Network Foundation, ResMed Foundation, Acacia, and Medtronic.

Postoperative oxygen therapy in patients with previously undetected obstructive sleep apnea (OSA) led to a reduction in apnea-hypopnea index (AHI) events per hour with no increase in apnea-hypopnea event duration.

The results suggest that postoperative oxygen could be useful in patients with OSA who refuse continuous positive airway pressure (CPAP) therapy, those with newly diagnosed OSA, and those with suspected OSA.

The researchers set out to determine if postoperative oxygen therapy could improve oxygenation in patients with previously undiagnosed OSA, reasoning that the intervention could reduce adverse events.

The study, published in CHEST (2017 March;151[3]:597-611), provided generally good news, but with a caveat: “Essentially we are saying, yes, if you give supplemental oxygen, you improve oxygenation of the patient. But overall we have to be careful because a significant number of patients have significant carbon dioxide retention when receiving supplemental oxygen. So we have to monitor patients – not just oxygen, but we may have to monitor carbon dioxide levels, too,” said lead study author Frances Chung, MBBS, professor of anesthesiology at the University of Toronto and Toronto Western Hospital.

The researchers randomized 123 patients with an AHI of at least five events per hour to postoperative oxygen (3 L/min for 3 nights via nasal prongs) or no postoperative oxygen.

On the third night, the oxygen group had a higher average oxygen saturation than controls (95.2% plus or minus 3.2% vs. 91.4% plus or minus 3.5%; P less than .0001) and a lower oxygen desaturation index (median, 2.3 events per hour vs. median, 18.5; P less than .0001).

A lower number of AHI events per hour occurred in the oxygen group (median, 8.0) than in the control group (median, 15.6; P = .016).

On average, the longest apnea-hypopnea event (median, 33.8 seconds) was shorter for a patient on oxygen, compared with a patient who did not receive oxygen (median, 49.6 seconds; P = .002).

But one finding surprised the researchers and led to some concern: Across both groups, 11.4% of patients experienced substantial CO₂ retention. Specifically, for at least 10% of 1 of the nights, these patients had a partial pressure of CO₂ of at least 55 mm Hg, according to measurements taken with a transcutaneous CO₂ monitor. Of the 14 patients who experienced this event, 13 were receiving oxygen.

Dr. Chung said the results argue strongly for postsurgical oxygen in patients with OSA, who are known to be at increased risk for complications. “We are not doing something about it, and we should be doing something. Because one death from a complication is too many,” she said.

The study was funded by the University Health Network Foundation, Toronto, and the University of Toronto. Dr. Chung reported receiving research grant support from Ontario Ministry of Health Innovation Grant, University Health Network Foundation, ResMed Foundation, Acacia, and Medtronic.

WAILEA, HAWAII – The search is on for new topical therapies for actinic keratoses (AKs) that patients will find more appealing than what’s now available, according to Neal Bhatia, MD.

Compliance with current topical field agents for actinic keratoses is not great. Many patients balk at the intense local skin reactions these agents elicit. There is a misplaced sense, especially among patients who don’t grasp the relationship between AKs and squamous cell carcinoma, that the treatment is worse than the disease, Dr. Bhatia said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Research Foundation.

Bruce Jancin/Frontline Medical News

[email protected]

WAILEA, HAWAII – The search is on for new topical therapies for actinic keratoses (AKs) that patients will find more appealing than what’s now available, according to Neal Bhatia, MD.

Compliance with current topical field agents for actinic keratoses is not great. Many patients balk at the intense local skin reactions these agents elicit. There is a misplaced sense, especially among patients who don’t grasp the relationship between AKs and squamous cell carcinoma, that the treatment is worse than the disease, Dr. Bhatia said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Research Foundation.

Bruce Jancin/Frontline Medical News

[email protected]

WAILEA, HAWAII – The search is on for new topical therapies for actinic keratoses (AKs) that patients will find more appealing than what’s now available, according to Neal Bhatia, MD.

Compliance with current topical field agents for actinic keratoses is not great. Many patients balk at the intense local skin reactions these agents elicit. There is a misplaced sense, especially among patients who don’t grasp the relationship between AKs and squamous cell carcinoma, that the treatment is worse than the disease, Dr. Bhatia said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Research Foundation.

Bruce Jancin/Frontline Medical News

[email protected]

SAN DIEGO – In the first year since Delaware Valley Nephrology joined an end–stage renal disease seamless care organization, patient hospitalizations have declined by 40% and rehospitalizations by 20%, according to Edward R. Jones, MD.

At the annual meeting of the American College of Physicians, Dr. Jones, a nephrologist at a Philadelphia-based practice, described his experience with the alternative payment model, which focuses on managing costs while providing better health outcomes.

[email protected]

SAN DIEGO – In the first year since Delaware Valley Nephrology joined an end–stage renal disease seamless care organization, patient hospitalizations have declined by 40% and rehospitalizations by 20%, according to Edward R. Jones, MD.

At the annual meeting of the American College of Physicians, Dr. Jones, a nephrologist at a Philadelphia-based practice, described his experience with the alternative payment model, which focuses on managing costs while providing better health outcomes.

[email protected]

SAN DIEGO – In the first year since Delaware Valley Nephrology joined an end–stage renal disease seamless care organization, patient hospitalizations have declined by 40% and rehospitalizations by 20%, according to Edward R. Jones, MD.

At the annual meeting of the American College of Physicians, Dr. Jones, a nephrologist at a Philadelphia-based practice, described his experience with the alternative payment model, which focuses on managing costs while providing better health outcomes.

[email protected]