Pharmacology

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.

“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.

The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.

“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.

However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”

Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.

“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.

However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”

Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.

Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.

And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.

In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
 

‘Pressing need’ to address obesity; semaglutide filed for obesity

There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.

Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.

In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”

Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.

Topline results from STEP 1 were presented June 4, 2020.

And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.

The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
 

Most patients had 5% weight loss with semaglutide

The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m² or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.

Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).

On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.

Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.

Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).

Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).

At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).

Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).

About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.

Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.

In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
 

GI disorders and ‘important limitations’

More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).

More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.

Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.

Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.

The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.

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

The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.

“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.

The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.

“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.

However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”

Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.

“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.

However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”

Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.

Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.

And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.

In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
 

‘Pressing need’ to address obesity; semaglutide filed for obesity

There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.

Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.

In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”

Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.

Topline results from STEP 1 were presented June 4, 2020.

And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.

The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
 

Most patients had 5% weight loss with semaglutide

The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m² or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.

Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).

On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.

Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.

Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).

Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).

At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).

Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).

About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.

Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.

In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
 

GI disorders and ‘important limitations’

More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).

More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.

Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.

Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.

The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.

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

The phase 3a STEP 1 trial that investigated the use of semaglutide (Novo Nordisk), a glucagonlike peptide–1 (GLP-1) agonist, for weight loss is aptly named, some say.

“In sum, we have a long way to go to control the obesity epidemic ... but on the face of it, the STEP 1 trial (like its name) is a good beginning,” wrote coeditorialists Julie R. Ingelfinger, MD, from Harvard Medical School, Boston, and a deputy editor of the New England Journal of Medicine, and Clifford J. Rosen, MD, from Tufts University School of Medicine, also in Boston.

The trial findings by John P.H. Wilding, DM, University of Liverpool (England), and colleagues and an accompanying editorial were published online Feb. 10, 2021, in the New England Journal of Medicine.

“The results are encouraging, with significantly more patients in the semaglutide group having clinically important weight loss,” Dr. Ingelfinger and Dr. Rosen stressed.

However, they also cautioned that “despite the positive results of this trial, the present study has some important limitations” and “there are concerns, including adverse events (mostly gastrointestinal – nausea, sometimes vomiting, and diarrhea) related primarily to the class of the agent.”

Two U.K. experts drew similar takeaways, speaking to the U.K. Science Media Centre.

“This was a well-designed study with unequivocal findings,” which showed that semaglutide “is indeed likely to be a game-changer in the fight against obesity,” according to Baptiste Leurent, PhD, London School of Hygiene and Tropical Medicine.

However, if the drug is approved at this dose for this use, patients would need close monitoring for gastrointestinal disorders, and “we also need to better understand what is happening once the treatment is stopped, and whether it could be taken for a shorter period of time.”

Sir Stephen O’Rahilly, MD, MRC Metabolic Diseases Unit, University of Cambridge (England), pointed out that “GLP-1 is made by cells in the intestine and levels increase in the blood after a meal, providing some of the signal to the brain that tells us we are ‘full,’ ” so GLP-1 agonists have been studied as appetite suppressants, in addition to their approved use to treat type 2 diabetes.

Only about 4.5% of participants in STEP 1 stopped taking semaglutide because of gastrointestinal issues, he noted, although more participants in that group reported problems with gallstones, which can follow rapid weight loss.

And “unlike some previous appetite suppressant drugs which caused significant psychological and psychiatric side effects, there is no evidence that semaglutide has any adverse effects of that nature,” Dr. O’Rahilly noted.

In sum, he said, “this is the start of a new era for obesity drug development with the future direction being to achieve levels of weight loss comparable to semaglutide, while having fewer side effects.”
 

‘Pressing need’ to address obesity; semaglutide filed for obesity

There is a “pressing need” to address the worldwide increase in obesity and weight-related coexisting conditions, Dr. Ingelfinger and Dr. Rosen noted.

Sustained long-term weight loss with diet and exercise is challenging; behavioral weight-loss strategies “fail more often than not,” bariatric surgery is invasive and often followed by eventual weight regain, they wrote.

In addition, said Dr. Wilding and colleagues, the “use of available [weight-loss] medications remains limited by modest efficacy, safety concerns, and cost.”

Subcutaneous semaglutide, approved for treating type 2 diabetes (as Ozempic) in adults at doses of up to 1 mg/week, induced weight loss at higher doses. The current study is part of the global Semaglutide Treatment Effect in People With Obesity program of four trials (STEP 1, 2, 3, and 4) that aimed to test the safety and efficacy of subcutaneous semaglutide 2.4 mg/week for weight loss.

Topline results from STEP 1 were presented June 4, 2020.

And as reported earlier, results from STEP 3 – a 68-week trial of semaglutide versus placebo in 611 participants who all received very intensive diet and exercise counseling – were presented at the virtual ObesityWeek 2020 meeting.

The four trials of semaglutide for weight loss have been completed and the data were submitted to the Food and Drug Administration on Dec. 4, 2020 (with a decision expected within 6 months) and to the European Medicines Agency on Dec. 18, 2020.
 

Most patients had 5% weight loss with semaglutide

The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m² or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.

Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).

On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.

Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.

Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).

Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).

At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).

Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).

About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.

Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.

In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
 

GI disorders and ‘important limitations’

More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).

More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.

Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.

Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.

The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.

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

Pooled data from four phase 2 trials reveal that patients with recent SSRI exposure were significantly more likely to continue to meet PTSD diagnostic criteria after methylenedioxymethamphetamine (MDMA)-assisted psychotherapy than their peers who had not recently taken SSRIs.

Although preliminary, the findings have implications for clinical practice if MDMA-assisted psychotherapy is approved by the Food and Drug Administration, Allison Feduccia, PhD, study coauthor and founder of the education platform Psychedelic.Support, said in an interview.

“As psychedelic medicines become available, it’s going to be important that we try to understand what factors impact the response rate and if there are ways that we can improve the treatment outcomes. Allowing for a longer period for tapering completely off SSRIs before initiating MDMA sessions might increase the effectiveness of MDMA,” Dr. Feduccia said.

The study was published online Nov. 20, 2020, in Psychopharmacology (doi: 10.1007/s00213-020-05710-w).
 

Reduced response

The primary mechanism of action of MDMA involves the same reuptake transporters that are targeted by antidepressant medications commonly prescribed for PTSD. These medications include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), NRIs, and norepinephrine-dopamine reuptake inhibitors (NDRIs).

Prior research shows that, when MDMA is coadministered with a reuptake inhibitor, subjective and psychological effects of the therapy are attenuated.

The researchers sought to determine whether or not recent tapering off of an antidepressant that targets the same primary binding sites as MDMA would affect treatment response. They analyzed data on 50 adults who underwent two sessions of MDMA-assisted psychotherapy in phase 2 clinical trials.

For 16 of these patients, SSRI therapy was tapered off prior to the MDMA sessions. For 34 patients, SSRI therapy was not tapered off, because the patients had not been taking the medication at the time of initial study screening (nontaper group).

The taper protocols specified that medications be tapered gradually over a period of weeks to minimize withdrawal symptoms and for them to be discontinued at least five half-lives of each drug prior to MDMA administration. Most participants were tapered off one drug, but some were tapered off multiple drugs.

Demographics, baseline PTSD, and depression severity were similar between the taper and the nontaper groups. Participants in the studies had chronic PTSD (symptoms lasting >6 months). Severity scores on the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) were at least 50.

After MDMA-assisted psychotherapy, the nontaper group had significantly lower (better) CAPS-IV total scores, compared with the taper group (mean, 45.7 vs. 70.3; P = .009).

About two-thirds (63.6%) of the nontaper group no longer met PTSD criteria after MDMA-assisted therapy, compared with only 25% of those in the taper group.

The nontaper group also had lower depression symptom severity scores on the Beck Depression Inventory–II, compared with the taper group (mean, 12.7 vs. 22.6; P = .010).

“Another really interesting” observation, said Dr. Feduccia, is that the expected increases in systolic and diastolic blood pressure following MDMA administration were reduced in the taper group, compared with the nontaper group.

“This suggests that MDMA didn’t have the same physiological response in individuals who tapered SSRIs. This should be followed up,” she said.

The investigators offerred several potential mechanisms for the negative effect of recent SSRI use on MDMA-assisted psychotherapy for PTSD.

These include the down-regulation of binding sites (serotonin, dopamine, and/or norepinephrine) related to SSRI use, reduced MDMA treatment-relevant increases in blood pressure in patients with recent SSRI use, and the possibility that withdrawal symptoms from SSRIs may reduce the effectiveness of MDMA psychotherapy.
 

Important clinical implications

In a comment, Steven R. Thorp, PhD, professor at Alliant International University, San Diego, said the findings are “very interesting” and likely “not well known.”

“There has been great interest in MDMA-assisted psychotherapy in recent years, and if this finding is replicated, it will have important implications for that research,” Dr. Thorp said.

“Although psychotherapy is often preferred by clients with PTSD, compared to medications, and typically shows efficacy that is as strong or stronger (and longer lasting) than medications, many individuals with PTSD are provided with medication only,” Dr. Thorp noted.

“This study suggests that, in addition to the other potential disadvantages of medications (e.g., cost, side effects, potential for addiction), those who take SSRIs, SNRIs, NRIs, and NDRIs for PTSD may also benefit less from MDMA-assisted psychotherapy,” Dr. Thorp added.

The four phase 2 studies used in the analysis were sponsored by the Multidisciplinary Association for Psychedelic Studies, a nonprofit organization. Dr. Feduccia received salary support for full-time employment with MAPS Public Benefit Corporation. Dr. Thorp disclosed no relevant financial relationships.

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

Pooled data from four phase 2 trials reveal that patients with recent SSRI exposure were significantly more likely to continue to meet PTSD diagnostic criteria after methylenedioxymethamphetamine (MDMA)-assisted psychotherapy than their peers who had not recently taken SSRIs.

Although preliminary, the findings have implications for clinical practice if MDMA-assisted psychotherapy is approved by the Food and Drug Administration, Allison Feduccia, PhD, study coauthor and founder of the education platform Psychedelic.Support, said in an interview.

“As psychedelic medicines become available, it’s going to be important that we try to understand what factors impact the response rate and if there are ways that we can improve the treatment outcomes. Allowing for a longer period for tapering completely off SSRIs before initiating MDMA sessions might increase the effectiveness of MDMA,” Dr. Feduccia said.

The study was published online Nov. 20, 2020, in Psychopharmacology (doi: 10.1007/s00213-020-05710-w).
 

Reduced response

The primary mechanism of action of MDMA involves the same reuptake transporters that are targeted by antidepressant medications commonly prescribed for PTSD. These medications include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), NRIs, and norepinephrine-dopamine reuptake inhibitors (NDRIs).

Prior research shows that, when MDMA is coadministered with a reuptake inhibitor, subjective and psychological effects of the therapy are attenuated.

The researchers sought to determine whether or not recent tapering off of an antidepressant that targets the same primary binding sites as MDMA would affect treatment response. They analyzed data on 50 adults who underwent two sessions of MDMA-assisted psychotherapy in phase 2 clinical trials.

For 16 of these patients, SSRI therapy was tapered off prior to the MDMA sessions. For 34 patients, SSRI therapy was not tapered off, because the patients had not been taking the medication at the time of initial study screening (nontaper group).

The taper protocols specified that medications be tapered gradually over a period of weeks to minimize withdrawal symptoms and for them to be discontinued at least five half-lives of each drug prior to MDMA administration. Most participants were tapered off one drug, but some were tapered off multiple drugs.

Demographics, baseline PTSD, and depression severity were similar between the taper and the nontaper groups. Participants in the studies had chronic PTSD (symptoms lasting >6 months). Severity scores on the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) were at least 50.

After MDMA-assisted psychotherapy, the nontaper group had significantly lower (better) CAPS-IV total scores, compared with the taper group (mean, 45.7 vs. 70.3; P = .009).

About two-thirds (63.6%) of the nontaper group no longer met PTSD criteria after MDMA-assisted therapy, compared with only 25% of those in the taper group.

The nontaper group also had lower depression symptom severity scores on the Beck Depression Inventory–II, compared with the taper group (mean, 12.7 vs. 22.6; P = .010).

“Another really interesting” observation, said Dr. Feduccia, is that the expected increases in systolic and diastolic blood pressure following MDMA administration were reduced in the taper group, compared with the nontaper group.

“This suggests that MDMA didn’t have the same physiological response in individuals who tapered SSRIs. This should be followed up,” she said.

The investigators offerred several potential mechanisms for the negative effect of recent SSRI use on MDMA-assisted psychotherapy for PTSD.

These include the down-regulation of binding sites (serotonin, dopamine, and/or norepinephrine) related to SSRI use, reduced MDMA treatment-relevant increases in blood pressure in patients with recent SSRI use, and the possibility that withdrawal symptoms from SSRIs may reduce the effectiveness of MDMA psychotherapy.
 

Important clinical implications

In a comment, Steven R. Thorp, PhD, professor at Alliant International University, San Diego, said the findings are “very interesting” and likely “not well known.”

“There has been great interest in MDMA-assisted psychotherapy in recent years, and if this finding is replicated, it will have important implications for that research,” Dr. Thorp said.

“Although psychotherapy is often preferred by clients with PTSD, compared to medications, and typically shows efficacy that is as strong or stronger (and longer lasting) than medications, many individuals with PTSD are provided with medication only,” Dr. Thorp noted.

“This study suggests that, in addition to the other potential disadvantages of medications (e.g., cost, side effects, potential for addiction), those who take SSRIs, SNRIs, NRIs, and NDRIs for PTSD may also benefit less from MDMA-assisted psychotherapy,” Dr. Thorp added.

The four phase 2 studies used in the analysis were sponsored by the Multidisciplinary Association for Psychedelic Studies, a nonprofit organization. Dr. Feduccia received salary support for full-time employment with MAPS Public Benefit Corporation. Dr. Thorp disclosed no relevant financial relationships.

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

Pooled data from four phase 2 trials reveal that patients with recent SSRI exposure were significantly more likely to continue to meet PTSD diagnostic criteria after methylenedioxymethamphetamine (MDMA)-assisted psychotherapy than their peers who had not recently taken SSRIs.

Although preliminary, the findings have implications for clinical practice if MDMA-assisted psychotherapy is approved by the Food and Drug Administration, Allison Feduccia, PhD, study coauthor and founder of the education platform Psychedelic.Support, said in an interview.

“As psychedelic medicines become available, it’s going to be important that we try to understand what factors impact the response rate and if there are ways that we can improve the treatment outcomes. Allowing for a longer period for tapering completely off SSRIs before initiating MDMA sessions might increase the effectiveness of MDMA,” Dr. Feduccia said.

The study was published online Nov. 20, 2020, in Psychopharmacology (doi: 10.1007/s00213-020-05710-w).
 

Reduced response

The primary mechanism of action of MDMA involves the same reuptake transporters that are targeted by antidepressant medications commonly prescribed for PTSD. These medications include SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), NRIs, and norepinephrine-dopamine reuptake inhibitors (NDRIs).

Prior research shows that, when MDMA is coadministered with a reuptake inhibitor, subjective and psychological effects of the therapy are attenuated.

The researchers sought to determine whether or not recent tapering off of an antidepressant that targets the same primary binding sites as MDMA would affect treatment response. They analyzed data on 50 adults who underwent two sessions of MDMA-assisted psychotherapy in phase 2 clinical trials.

For 16 of these patients, SSRI therapy was tapered off prior to the MDMA sessions. For 34 patients, SSRI therapy was not tapered off, because the patients had not been taking the medication at the time of initial study screening (nontaper group).

The taper protocols specified that medications be tapered gradually over a period of weeks to minimize withdrawal symptoms and for them to be discontinued at least five half-lives of each drug prior to MDMA administration. Most participants were tapered off one drug, but some were tapered off multiple drugs.

Demographics, baseline PTSD, and depression severity were similar between the taper and the nontaper groups. Participants in the studies had chronic PTSD (symptoms lasting >6 months). Severity scores on the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) were at least 50.

After MDMA-assisted psychotherapy, the nontaper group had significantly lower (better) CAPS-IV total scores, compared with the taper group (mean, 45.7 vs. 70.3; P = .009).

About two-thirds (63.6%) of the nontaper group no longer met PTSD criteria after MDMA-assisted therapy, compared with only 25% of those in the taper group.

The nontaper group also had lower depression symptom severity scores on the Beck Depression Inventory–II, compared with the taper group (mean, 12.7 vs. 22.6; P = .010).

“Another really interesting” observation, said Dr. Feduccia, is that the expected increases in systolic and diastolic blood pressure following MDMA administration were reduced in the taper group, compared with the nontaper group.

“This suggests that MDMA didn’t have the same physiological response in individuals who tapered SSRIs. This should be followed up,” she said.

The investigators offerred several potential mechanisms for the negative effect of recent SSRI use on MDMA-assisted psychotherapy for PTSD.

These include the down-regulation of binding sites (serotonin, dopamine, and/or norepinephrine) related to SSRI use, reduced MDMA treatment-relevant increases in blood pressure in patients with recent SSRI use, and the possibility that withdrawal symptoms from SSRIs may reduce the effectiveness of MDMA psychotherapy.
 

Important clinical implications

In a comment, Steven R. Thorp, PhD, professor at Alliant International University, San Diego, said the findings are “very interesting” and likely “not well known.”

“There has been great interest in MDMA-assisted psychotherapy in recent years, and if this finding is replicated, it will have important implications for that research,” Dr. Thorp said.

“Although psychotherapy is often preferred by clients with PTSD, compared to medications, and typically shows efficacy that is as strong or stronger (and longer lasting) than medications, many individuals with PTSD are provided with medication only,” Dr. Thorp noted.

“This study suggests that, in addition to the other potential disadvantages of medications (e.g., cost, side effects, potential for addiction), those who take SSRIs, SNRIs, NRIs, and NDRIs for PTSD may also benefit less from MDMA-assisted psychotherapy,” Dr. Thorp added.

The four phase 2 studies used in the analysis were sponsored by the Multidisciplinary Association for Psychedelic Studies, a nonprofit organization. Dr. Feduccia received salary support for full-time employment with MAPS Public Benefit Corporation. Dr. Thorp disclosed no relevant financial relationships.

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

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

A large analysis of Medicare data from all 50 states suggests that vedolizumab may be just as effective as anti–tumor necrosis factor (anti-TNF) agents in controlling inflammatory bowel disease (IBD) in patients aged over 65 years, with fewer infectious disease hospitalizations.

The study was prompted by the fact that older adults are greatly underrepresented in clinical trials of approved IBD medications. There is a second peak in IBD diagnosis among people in their 50s and 60s, and IBD patients are living longer with more effective medications. So although a significant number of IBD patients are aged 65 years or older, that group encompasses less than 1% of adults in clinical trials, Bharati Kochar, MD, reported at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“Therefore, we don’t know how well these medications work and how safe they are specifically in older adults,” said Dr. Kochar, a gastroenterologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.

The data largely support what had been known mechanistically about vedolizumab. “It suggests that both drugs work well enough to prevent [IBD-related] hospitalizations, but clearly there was a benefit toward the safer medication, Entyvio [vedolizumab], in the infection-related hospitalizations. That’s not the only readout in infections, but it is an important readout because infections that get hospitalized are the ones that predict mortality and disability,” said Matthew Ciorba, MD, who attended the session. Dr. Ciorba is director of the IBD Center at Washington University in St. Louis and was not involved in the study.

“I think this study is reassuring to clinicians. It provides important clinical data that support what we know about the mechanisms of vedolizumab. The safety data we predicted is borne out in this large and well-done study,” said Dr. Ciorba.

A large analysis of Medicare data from all 50 states suggests that vedolizumab may be just as effective as anti–tumor necrosis factor (anti-TNF) agents in controlling inflammatory bowel disease (IBD) in patients aged over 65 years, with fewer infectious disease hospitalizations.

The study was prompted by the fact that older adults are greatly underrepresented in clinical trials of approved IBD medications. There is a second peak in IBD diagnosis among people in their 50s and 60s, and IBD patients are living longer with more effective medications. So although a significant number of IBD patients are aged 65 years or older, that group encompasses less than 1% of adults in clinical trials, Bharati Kochar, MD, reported at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“Therefore, we don’t know how well these medications work and how safe they are specifically in older adults,” said Dr. Kochar, a gastroenterologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.

The data largely support what had been known mechanistically about vedolizumab. “It suggests that both drugs work well enough to prevent [IBD-related] hospitalizations, but clearly there was a benefit toward the safer medication, Entyvio [vedolizumab], in the infection-related hospitalizations. That’s not the only readout in infections, but it is an important readout because infections that get hospitalized are the ones that predict mortality and disability,” said Matthew Ciorba, MD, who attended the session. Dr. Ciorba is director of the IBD Center at Washington University in St. Louis and was not involved in the study.

“I think this study is reassuring to clinicians. It provides important clinical data that support what we know about the mechanisms of vedolizumab. The safety data we predicted is borne out in this large and well-done study,” said Dr. Ciorba.

A large analysis of Medicare data from all 50 states suggests that vedolizumab may be just as effective as anti–tumor necrosis factor (anti-TNF) agents in controlling inflammatory bowel disease (IBD) in patients aged over 65 years, with fewer infectious disease hospitalizations.

The study was prompted by the fact that older adults are greatly underrepresented in clinical trials of approved IBD medications. There is a second peak in IBD diagnosis among people in their 50s and 60s, and IBD patients are living longer with more effective medications. So although a significant number of IBD patients are aged 65 years or older, that group encompasses less than 1% of adults in clinical trials, Bharati Kochar, MD, reported at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

“Therefore, we don’t know how well these medications work and how safe they are specifically in older adults,” said Dr. Kochar, a gastroenterologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston.

The data largely support what had been known mechanistically about vedolizumab. “It suggests that both drugs work well enough to prevent [IBD-related] hospitalizations, but clearly there was a benefit toward the safer medication, Entyvio [vedolizumab], in the infection-related hospitalizations. That’s not the only readout in infections, but it is an important readout because infections that get hospitalized are the ones that predict mortality and disability,” said Matthew Ciorba, MD, who attended the session. Dr. Ciorba is director of the IBD Center at Washington University in St. Louis and was not involved in the study.

“I think this study is reassuring to clinicians. It provides important clinical data that support what we know about the mechanisms of vedolizumab. The safety data we predicted is borne out in this large and well-done study,” said Dr. Ciorba.

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

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

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

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

Certain drugs currently used to treat benign prostatic hyperplasia (BPH) may provide neuroprotection and delay or prevent the onset of Parkinson’s disease, new research suggests. Treatment of BPH with terazosin (Hytrin), doxazosin (Cardura), or alfuzosin (Uroxatral), all of which enhance glycolysis, was associated with a lower risk of developing Parkinson’s disease than patients taking a drug used for the same indication, tamsulosin (Flomax), which does not affect glycolysis.

“If giving someone terazosin or similar medications truly reduces their risk of disease, these results could have significant clinical implications for neurologists,” said lead author Jacob E. Simmering, PhD, assistant professor of internal medicine at the University of Iowa, Iowa City.

There are few reliable neuroprotective treatments for Parkinson’s disease, he said. “We can manage some of the symptoms, but we can’t stop it from progressing. If a randomized trial finds the same result, this will provide a new option to slow progression of Parkinson’s disease.”

The pathogenesis of Parkinson’s disease is heterogeneous, however, and not all patients may benefit from glycolysis-enhancing drugs, the investigators noted. Future research will be needed to identify potential candidates for this treatment, and clarify the effects of these drugs, they wrote.

The findings were published online Feb. 1, 2021, in JAMA Neurology.
 

Time-dependent effects

The major risk factor for Parkinson’s disease is age, which is associated with impaired energy metabolism. Glycolysis is decreased among patients with Parkinson’s disease, yet impaired energy metabolism has not been investigated widely as a pathogenic factor in the disease, the authors wrote.

Studies have indicated that terazosin increases the activity of an enzyme important in glycolysis. Doxazosin and alfuzosin have a similar mechanism of action and enhance energy metabolism. Tamsulosin, a structurally unrelated drug, has the same mechanism of action as the other three drugs, but does not enhance energy metabolism.

In this report, the researchers investigated the hypothesis that patients who received therapy with terazosin, doxazosin, or alfuzosin would have a lower risk of developing Parkinson’s disease than patients receiving tamsulosin. To do that, they used health care utilization data from Denmark and the United States, including the Danish National Prescription Registry, the Danish National Patient Registry, the Danish Civil Registration System, and the Truven Health Analytics MarketScan database.

The investigators searched the records for patients who filled prescriptions for any of the four drugs of interest. They excluded any patients who developed Parkinson’s disease within 1 year of starting medication. Because use of these drugs is rare among women, they included only men in their analysis.

They looked at patient outcomes beginning at 1 year after the initiation of treatment. They also required patients to fill at least two prescriptions before the beginning of follow-up. Patients who switched from tamsulosin to any of the other drugs, or vice versa, were excluded from analysis.

The investigators used propensity-score matching to ensure that patients in the tamsulosin and terazosin/doxazosin/alfuzosin groups were similar in terms of their other potential risk factors. The primary outcome was the development of Parkinson’s disease.

They identified 52,365 propensity score–matched pairs in the Danish registries and 94,883 pairs in the Truven database. The mean age was 67.9 years in the Danish registries and 63.8 years in the Truven database, and follow-up was approximately 5 years and 3 years respectively. Baseline covariates were well balanced between cohorts.

Among Danish patients, those who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease versus those who took tamsulosin (hazard ratio, 0.88). Similarly, patients in the Truven database who took terazosin, doxazosin, or alfuzosin had a lower risk of developing Parkinson’s disease than those who took tamsulosin (HR, 0.63).

In both cohorts, the risk for Parkinson’s disease among patients receiving terazosin, doxazosin, or alfuzosin, compared with those receiving tamsulosin, decreased with increasing numbers of prescriptions filled. Long-term treatment with any of the three glycolysis-enhancing drugs was associated with greater risk reduction in the Danish (HR, 0.79) and Truven (HR, 0.46) cohorts versus tamsulosin.

Differences in case definitions, which may reflect how Parkinson’s disease was managed, complicate comparisons between the Danish and Truven cohorts, said Dr. Simmering. Another challenge is the source of the data. “The Truven data set was derived from insurance claims from people with private insurance or Medicare supplemental plans,” he said. “This group is quite large but may not be representative of everyone in the United States. We would also only be able to follow people while they were on one insurance plan. If they switched coverage to a company that doesn’t contribute data, we would lose them.”

The Danish database, however, includes all residents of Denmark. Only people who left the country were lost to follow-up.

The results support the hypothesis that increasing energy in cells slows disease progression, Dr. Simmering added. “There are a few conditions, mostly REM sleep disorders, that are associated with future diagnosis of Parkinson’s disease. Right now, we don’t have anything to offer people at elevated risk of Parkinson’s disease that might prevent the disease. If a controlled trial finds that terazosin slows or prevents Parkinson’s disease, we would have something truly protective to offer these patients.”
 

Biomarker needed

Commenting on the results, Alberto J. Espay, MD, MSc, professor of neurology at the University of Cincinnati Academic Health Center, was cautious. “These findings are of unclear applicability to any particular patient without a biomarker for a deficit of glycolysis that these drugs are presumed to affect,” Dr. Espay said. “Hence, there is no feasible or warranted change in practice as a result of this study.”

Pathogenic mechanisms are heterogeneous among patients with Parkinson’s disease, Dr. Espay added. “We will need to understand who among the large biological universe of Parkinson’s patients may have impaired energy metabolism as a pathogenic mechanism to be selected for a future clinical trial evaluating terazosin, doxazosin, or alfuzosin as a potential disease-modifying intervention.”

Parkinson’s disease is not one disease, but a group of disorders with unique biological abnormalities, said Dr. Espay. “We know so much about ‘Parkinson’s disease’ and next to nothing about the biology of individuals with Parkinson’s disease.”

This situation has enabled the development of symptomatic treatments, such as dopaminergic therapies, but failed to yield disease-modifying treatments, he said.

The University of Iowa contributed funds for this study. Dr. Simmering has received pilot funding from the University of Iowa Institute for Clinical and Translational Science. He had no conflicts of interest to disclose. Dr. Espay disclosed no relevant financial relationships.  

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

Science by press release and preprint has cooled clinician enthusiasm for the use of colchicine in nonhospitalized patients with COVID-19, despite a pressing need for early treatments.

Photo by Jimmy Hamelin

As previously reported by this news organization, a Jan. 22 press release announced that the massive ColCORONA study missed its primary endpoint of hospitalization or death among 4,488 newly diagnosed patients at increased risk for hospitalization.

But it also touted that use of the anti-inflammatory drug significantly reduced the primary endpoint in 4,159 of those patients with polymerase chain reaction–confirmed COVID and led to reductions of 25%, 50%, and 44%, respectively, for hospitalizations, ventilations, and death.

Lead investigator Jean-Claude Tardif, MD, director of the Montreal Heart Institute Research Centre, deemed the findings a “medical breakthrough.”

When the preprint released a few days later, however, newly revealed confidence intervals showed colchicine did not meaningfully reduce the need for mechanical ventilation (odds ratio, 0.50; 95% confidence interval, 0.23-1.07) or death alone (OR, 0.56; 95% CI, 0.19-1.66).

Further, the significant benefit on the primary outcome came at the cost of a fivefold increase in pulmonary embolism (11 vs. 2; P = .01), which was not mentioned in the press release.

“Whether this represents a real phenomenon or simply the play of chance is not known,” Dr. Tardif and colleagues noted later in the preprint.

“I read the preprint on colchicine and I have so many questions,” Aaron E. Glatt, MD, spokesperson for the Infectious Diseases Society of America and chief of infectious diseases, Mount Sinai South Nassau, Hewlett, N.Y., said in an interview. “I’ve been burned too many times with COVID and prefer to see better data.

“People sometimes say if you wait for perfect data, people are going to die,” he said. “Yeah, but we have no idea if people are going to die from getting this drug more than not getting it. That’s what concerns me. How many pulmonary emboli are going to be fatal versus the slight benefit that the study showed?”

The pushback to the non–peer-reviewed data on social media and via emails was so strong that Dr. Tardif posted a nearly 2,000-word letter responding to the many questions at play.

Chief among them was why the trial, originally planned for 6,000 patients, was stopped early by the investigators without consultation with the data safety monitoring board (DSMB).

The explanation in the letter that logistical issues like running the study call center, budget constraints, and a perceived need to quickly communicate the results left some calling foul that the study wasn’t allowed to finish and come to a more definitive conclusion.

“I can be a little bit sympathetic to their cause but at the same time the DSMB should have said no,” said David Boulware, MD, MPH, who led a recent hydroxychloroquine trial in COVID-19. “The problem is we’re sort of left in limbo, where some people kind of believe it and some say it’s not really a thing. So it’s not really moving the needle, as far as guidelines go.”

Indeed, a Twitter poll by cardiologist James Januzzi Jr., MD, captured the uncertainty, with 28% of respondents saying the trial was “neutral,” 58% saying “maybe but meh,” and 14% saying “colchicine for all.”

Another poll cheekily asked whether ColCORONA was the Gamestop/Reddit equivalent of COVID.

“The press release really didn’t help things because it very much oversold the effect. That, I think, poisoned the well,” said Dr. Boulware, professor of medicine in infectious diseases at the University of Minnesota, Minneapolis.

“The question I’m left with is not whether colchicine works, but who does it work in,” he said. “That’s really the fundamental question because it does seem that there are probably high-risk groups in their trial and others where they benefit, whereas other groups don’t benefit. In the subgroup analysis, there was absolutely no beneficial effect in women.”

According to the authors, the number needed to treat to prevent one death or hospitalization was 71 overall, but 29 for patients with diabetes, 31 for those aged 70 years and older, 53 for patients with respiratory disease, and 25 for those with coronary disease or heart failure.

Men are at higher risk overall for poor outcomes. But “the authors didn’t present a multivariable analysis, so it is unclear if another factor, such as a differential prevalence of smoking or cardiovascular risk factors, contributed to the differential benefit,” Rachel Bender Ignacio, MD, MPH, infectious disease specialist, University of Washington, Seattle, said in an interview.

Importantly, in this pragmatic study, duration and severity of symptoms were not reported, observed Dr. Bender Ignacio, who is also a STOP-COVID-2 investigator. “We don’t yet have data as to whether colchicine shortens duration or severity of symptoms or prevents long COVID, so we need more data on that.”

The overall risk for serious adverse events was lower in the colchicine group, but the difference in pulmonary embolism (PE) was striking, she said. This could be caused by a real biologic effect, or it’s possible that persons with shortness of breath and hypoxia, without evident viral pneumonia on chest x-ray after a positive COVID-19 test, were more likely to receive a CT-PE study.

The press release also failed to include information, later noted in the preprint, that the MHI has submitted two patents related to colchicine: “Methods of treating a coronavirus infection using colchicine” and “Early administration of low-dose colchicine after myocardial infarction.”

Reached for clarification, MHI communications adviser Camille Turbide said in an interview that the first patent “simply refers to the novel concept of preventing complications of COVID-19, such as admission to the hospital, with colchicine as tested in the ColCORONA study.”

The second patent, she said, refers to the “novel concept that administering colchicine early after a major adverse cardiovascular event is better than waiting several days,” as supported by the COLCOT study, which Dr. Tardif also led.

The patents are being reviewed by authorities and “Dr. Tardif has waived his rights in these patents and does not stand to benefit financially at all if colchicine becomes used as a treatment for COVID-19,” Ms. Turbide said.

Dr. Tardif did not respond to interview requests for this story. Dr. Glatt said conflicts of interest must be assessed and are “something that is of great concern in any scientific study.”

Cardiologist Steve Nissen, MD, of the Cleveland Clinic said in an interview that, “despite the negative results, the study does suggest that colchicine might have a benefit and should be studied in future trials. These findings are not sufficient evidence to suggest use of the drug in patients infected with COVID-19.”

He noted that adverse effects like diarrhea were expected but that the excess PE was unexpected and needs greater clarification.

“Stopping the trial for administrative reasons is puzzling and undermined the ability of the trial to give a reliable answer,” Dr. Nissen said. “This is a reasonable pilot study that should be viewed as hypothesis generating but inconclusive.”

Several sources said a new trial is unlikely, particularly given the cost and 28 trials already evaluating colchicine. Among these are RECOVERY and COLCOVID, testing whether colchicine can reduce the duration of hospitalization or death in hospitalized patients with COVID-19.

Because there are so many trials ongoing right now, including for antivirals and other immunomodulators, it’s important that, if colchicine comes to routine clinical use, it provides access to treatment for those not able or willing to access clinical trials, rather than impeding clinical trial enrollment, Dr. Bender Ignacio suggested.

“We have already learned the lesson in the pandemic that early adoption of potentially promising therapies can negatively impact our ability to study and develop other promising treatments,” she said.

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the National Heart, Lung, and Blood Institute of the National Institutes of Health; Montreal philanthropist Sophie Desmarais, and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators. Dr. Glatt reported no conflicts of interest. Dr. Boulware reported receiving $18 in food and beverages from Gilead Sciences in 2018.
 

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

Science by press release and preprint has cooled clinician enthusiasm for the use of colchicine in nonhospitalized patients with COVID-19, despite a pressing need for early treatments.

Photo by Jimmy Hamelin

As previously reported by this news organization, a Jan. 22 press release announced that the massive ColCORONA study missed its primary endpoint of hospitalization or death among 4,488 newly diagnosed patients at increased risk for hospitalization.

But it also touted that use of the anti-inflammatory drug significantly reduced the primary endpoint in 4,159 of those patients with polymerase chain reaction–confirmed COVID and led to reductions of 25%, 50%, and 44%, respectively, for hospitalizations, ventilations, and death.

Lead investigator Jean-Claude Tardif, MD, director of the Montreal Heart Institute Research Centre, deemed the findings a “medical breakthrough.”

When the preprint released a few days later, however, newly revealed confidence intervals showed colchicine did not meaningfully reduce the need for mechanical ventilation (odds ratio, 0.50; 95% confidence interval, 0.23-1.07) or death alone (OR, 0.56; 95% CI, 0.19-1.66).

Further, the significant benefit on the primary outcome came at the cost of a fivefold increase in pulmonary embolism (11 vs. 2; P = .01), which was not mentioned in the press release.

“Whether this represents a real phenomenon or simply the play of chance is not known,” Dr. Tardif and colleagues noted later in the preprint.

“I read the preprint on colchicine and I have so many questions,” Aaron E. Glatt, MD, spokesperson for the Infectious Diseases Society of America and chief of infectious diseases, Mount Sinai South Nassau, Hewlett, N.Y., said in an interview. “I’ve been burned too many times with COVID and prefer to see better data.

“People sometimes say if you wait for perfect data, people are going to die,” he said. “Yeah, but we have no idea if people are going to die from getting this drug more than not getting it. That’s what concerns me. How many pulmonary emboli are going to be fatal versus the slight benefit that the study showed?”

The pushback to the non–peer-reviewed data on social media and via emails was so strong that Dr. Tardif posted a nearly 2,000-word letter responding to the many questions at play.

Chief among them was why the trial, originally planned for 6,000 patients, was stopped early by the investigators without consultation with the data safety monitoring board (DSMB).

The explanation in the letter that logistical issues like running the study call center, budget constraints, and a perceived need to quickly communicate the results left some calling foul that the study wasn’t allowed to finish and come to a more definitive conclusion.

“I can be a little bit sympathetic to their cause but at the same time the DSMB should have said no,” said David Boulware, MD, MPH, who led a recent hydroxychloroquine trial in COVID-19. “The problem is we’re sort of left in limbo, where some people kind of believe it and some say it’s not really a thing. So it’s not really moving the needle, as far as guidelines go.”

Indeed, a Twitter poll by cardiologist James Januzzi Jr., MD, captured the uncertainty, with 28% of respondents saying the trial was “neutral,” 58% saying “maybe but meh,” and 14% saying “colchicine for all.”

Another poll cheekily asked whether ColCORONA was the Gamestop/Reddit equivalent of COVID.

“The press release really didn’t help things because it very much oversold the effect. That, I think, poisoned the well,” said Dr. Boulware, professor of medicine in infectious diseases at the University of Minnesota, Minneapolis.

“The question I’m left with is not whether colchicine works, but who does it work in,” he said. “That’s really the fundamental question because it does seem that there are probably high-risk groups in their trial and others where they benefit, whereas other groups don’t benefit. In the subgroup analysis, there was absolutely no beneficial effect in women.”

According to the authors, the number needed to treat to prevent one death or hospitalization was 71 overall, but 29 for patients with diabetes, 31 for those aged 70 years and older, 53 for patients with respiratory disease, and 25 for those with coronary disease or heart failure.

Men are at higher risk overall for poor outcomes. But “the authors didn’t present a multivariable analysis, so it is unclear if another factor, such as a differential prevalence of smoking or cardiovascular risk factors, contributed to the differential benefit,” Rachel Bender Ignacio, MD, MPH, infectious disease specialist, University of Washington, Seattle, said in an interview.

Importantly, in this pragmatic study, duration and severity of symptoms were not reported, observed Dr. Bender Ignacio, who is also a STOP-COVID-2 investigator. “We don’t yet have data as to whether colchicine shortens duration or severity of symptoms or prevents long COVID, so we need more data on that.”

The overall risk for serious adverse events was lower in the colchicine group, but the difference in pulmonary embolism (PE) was striking, she said. This could be caused by a real biologic effect, or it’s possible that persons with shortness of breath and hypoxia, without evident viral pneumonia on chest x-ray after a positive COVID-19 test, were more likely to receive a CT-PE study.

The press release also failed to include information, later noted in the preprint, that the MHI has submitted two patents related to colchicine: “Methods of treating a coronavirus infection using colchicine” and “Early administration of low-dose colchicine after myocardial infarction.”

Reached for clarification, MHI communications adviser Camille Turbide said in an interview that the first patent “simply refers to the novel concept of preventing complications of COVID-19, such as admission to the hospital, with colchicine as tested in the ColCORONA study.”

The second patent, she said, refers to the “novel concept that administering colchicine early after a major adverse cardiovascular event is better than waiting several days,” as supported by the COLCOT study, which Dr. Tardif also led.

The patents are being reviewed by authorities and “Dr. Tardif has waived his rights in these patents and does not stand to benefit financially at all if colchicine becomes used as a treatment for COVID-19,” Ms. Turbide said.

Dr. Tardif did not respond to interview requests for this story. Dr. Glatt said conflicts of interest must be assessed and are “something that is of great concern in any scientific study.”

Cardiologist Steve Nissen, MD, of the Cleveland Clinic said in an interview that, “despite the negative results, the study does suggest that colchicine might have a benefit and should be studied in future trials. These findings are not sufficient evidence to suggest use of the drug in patients infected with COVID-19.”

He noted that adverse effects like diarrhea were expected but that the excess PE was unexpected and needs greater clarification.

“Stopping the trial for administrative reasons is puzzling and undermined the ability of the trial to give a reliable answer,” Dr. Nissen said. “This is a reasonable pilot study that should be viewed as hypothesis generating but inconclusive.”

Several sources said a new trial is unlikely, particularly given the cost and 28 trials already evaluating colchicine. Among these are RECOVERY and COLCOVID, testing whether colchicine can reduce the duration of hospitalization or death in hospitalized patients with COVID-19.

Because there are so many trials ongoing right now, including for antivirals and other immunomodulators, it’s important that, if colchicine comes to routine clinical use, it provides access to treatment for those not able or willing to access clinical trials, rather than impeding clinical trial enrollment, Dr. Bender Ignacio suggested.

“We have already learned the lesson in the pandemic that early adoption of potentially promising therapies can negatively impact our ability to study and develop other promising treatments,” she said.

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the National Heart, Lung, and Blood Institute of the National Institutes of Health; Montreal philanthropist Sophie Desmarais, and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators. Dr. Glatt reported no conflicts of interest. Dr. Boulware reported receiving $18 in food and beverages from Gilead Sciences in 2018.
 

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

Science by press release and preprint has cooled clinician enthusiasm for the use of colchicine in nonhospitalized patients with COVID-19, despite a pressing need for early treatments.

Photo by Jimmy Hamelin

As previously reported by this news organization, a Jan. 22 press release announced that the massive ColCORONA study missed its primary endpoint of hospitalization or death among 4,488 newly diagnosed patients at increased risk for hospitalization.

But it also touted that use of the anti-inflammatory drug significantly reduced the primary endpoint in 4,159 of those patients with polymerase chain reaction–confirmed COVID and led to reductions of 25%, 50%, and 44%, respectively, for hospitalizations, ventilations, and death.

Lead investigator Jean-Claude Tardif, MD, director of the Montreal Heart Institute Research Centre, deemed the findings a “medical breakthrough.”

When the preprint released a few days later, however, newly revealed confidence intervals showed colchicine did not meaningfully reduce the need for mechanical ventilation (odds ratio, 0.50; 95% confidence interval, 0.23-1.07) or death alone (OR, 0.56; 95% CI, 0.19-1.66).

Further, the significant benefit on the primary outcome came at the cost of a fivefold increase in pulmonary embolism (11 vs. 2; P = .01), which was not mentioned in the press release.

“Whether this represents a real phenomenon or simply the play of chance is not known,” Dr. Tardif and colleagues noted later in the preprint.

“I read the preprint on colchicine and I have so many questions,” Aaron E. Glatt, MD, spokesperson for the Infectious Diseases Society of America and chief of infectious diseases, Mount Sinai South Nassau, Hewlett, N.Y., said in an interview. “I’ve been burned too many times with COVID and prefer to see better data.

“People sometimes say if you wait for perfect data, people are going to die,” he said. “Yeah, but we have no idea if people are going to die from getting this drug more than not getting it. That’s what concerns me. How many pulmonary emboli are going to be fatal versus the slight benefit that the study showed?”

The pushback to the non–peer-reviewed data on social media and via emails was so strong that Dr. Tardif posted a nearly 2,000-word letter responding to the many questions at play.

Chief among them was why the trial, originally planned for 6,000 patients, was stopped early by the investigators without consultation with the data safety monitoring board (DSMB).

The explanation in the letter that logistical issues like running the study call center, budget constraints, and a perceived need to quickly communicate the results left some calling foul that the study wasn’t allowed to finish and come to a more definitive conclusion.

“I can be a little bit sympathetic to their cause but at the same time the DSMB should have said no,” said David Boulware, MD, MPH, who led a recent hydroxychloroquine trial in COVID-19. “The problem is we’re sort of left in limbo, where some people kind of believe it and some say it’s not really a thing. So it’s not really moving the needle, as far as guidelines go.”

Indeed, a Twitter poll by cardiologist James Januzzi Jr., MD, captured the uncertainty, with 28% of respondents saying the trial was “neutral,” 58% saying “maybe but meh,” and 14% saying “colchicine for all.”

Another poll cheekily asked whether ColCORONA was the Gamestop/Reddit equivalent of COVID.

“The press release really didn’t help things because it very much oversold the effect. That, I think, poisoned the well,” said Dr. Boulware, professor of medicine in infectious diseases at the University of Minnesota, Minneapolis.

“The question I’m left with is not whether colchicine works, but who does it work in,” he said. “That’s really the fundamental question because it does seem that there are probably high-risk groups in their trial and others where they benefit, whereas other groups don’t benefit. In the subgroup analysis, there was absolutely no beneficial effect in women.”

According to the authors, the number needed to treat to prevent one death or hospitalization was 71 overall, but 29 for patients with diabetes, 31 for those aged 70 years and older, 53 for patients with respiratory disease, and 25 for those with coronary disease or heart failure.

Men are at higher risk overall for poor outcomes. But “the authors didn’t present a multivariable analysis, so it is unclear if another factor, such as a differential prevalence of smoking or cardiovascular risk factors, contributed to the differential benefit,” Rachel Bender Ignacio, MD, MPH, infectious disease specialist, University of Washington, Seattle, said in an interview.

Importantly, in this pragmatic study, duration and severity of symptoms were not reported, observed Dr. Bender Ignacio, who is also a STOP-COVID-2 investigator. “We don’t yet have data as to whether colchicine shortens duration or severity of symptoms or prevents long COVID, so we need more data on that.”

The overall risk for serious adverse events was lower in the colchicine group, but the difference in pulmonary embolism (PE) was striking, she said. This could be caused by a real biologic effect, or it’s possible that persons with shortness of breath and hypoxia, without evident viral pneumonia on chest x-ray after a positive COVID-19 test, were more likely to receive a CT-PE study.

The press release also failed to include information, later noted in the preprint, that the MHI has submitted two patents related to colchicine: “Methods of treating a coronavirus infection using colchicine” and “Early administration of low-dose colchicine after myocardial infarction.”

Reached for clarification, MHI communications adviser Camille Turbide said in an interview that the first patent “simply refers to the novel concept of preventing complications of COVID-19, such as admission to the hospital, with colchicine as tested in the ColCORONA study.”

The second patent, she said, refers to the “novel concept that administering colchicine early after a major adverse cardiovascular event is better than waiting several days,” as supported by the COLCOT study, which Dr. Tardif also led.

The patents are being reviewed by authorities and “Dr. Tardif has waived his rights in these patents and does not stand to benefit financially at all if colchicine becomes used as a treatment for COVID-19,” Ms. Turbide said.

Dr. Tardif did not respond to interview requests for this story. Dr. Glatt said conflicts of interest must be assessed and are “something that is of great concern in any scientific study.”

Cardiologist Steve Nissen, MD, of the Cleveland Clinic said in an interview that, “despite the negative results, the study does suggest that colchicine might have a benefit and should be studied in future trials. These findings are not sufficient evidence to suggest use of the drug in patients infected with COVID-19.”

He noted that adverse effects like diarrhea were expected but that the excess PE was unexpected and needs greater clarification.

“Stopping the trial for administrative reasons is puzzling and undermined the ability of the trial to give a reliable answer,” Dr. Nissen said. “This is a reasonable pilot study that should be viewed as hypothesis generating but inconclusive.”

Several sources said a new trial is unlikely, particularly given the cost and 28 trials already evaluating colchicine. Among these are RECOVERY and COLCOVID, testing whether colchicine can reduce the duration of hospitalization or death in hospitalized patients with COVID-19.

Because there are so many trials ongoing right now, including for antivirals and other immunomodulators, it’s important that, if colchicine comes to routine clinical use, it provides access to treatment for those not able or willing to access clinical trials, rather than impeding clinical trial enrollment, Dr. Bender Ignacio suggested.

“We have already learned the lesson in the pandemic that early adoption of potentially promising therapies can negatively impact our ability to study and develop other promising treatments,” she said.

The trial was coordinated by the Montreal Heart Institute and funded by the government of Quebec; the National Heart, Lung, and Blood Institute of the National Institutes of Health; Montreal philanthropist Sophie Desmarais, and the COVID-19 Therapeutics Accelerator launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard. CGI, Dacima, and Pharmascience of Montreal were also collaborators. Dr. Glatt reported no conflicts of interest. Dr. Boulware reported receiving $18 in food and beverages from Gilead Sciences in 2018.
 

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

New experimental vaccines could stop the worst effects of synthetic fentanyl and carfentanil, two drugs that have been major drivers of the opioid epidemic in the United States, according to a new study published in ACS Chemical Biology on Feb. 3, 2021.

During several experiments in mice, the vaccines prevented respiratory depression, which is the main cause of overdose deaths. The vaccines also reduced the amount of drug that was distributed to the brain. Once in the brain, synthetic opioids prompt the body to slow down breathing, and when too much of the drug is consumed, breathing can stop.

“Synthetic opioids are not only extremely deadly but also addictive and easy to manufacture, making them a formidable public health threat, especially when the coronavirus crisis is negatively impacting mental health,” Kim Janda, PhD, a chemist at Scripps Research Institute in La Jolla, Calif., who developed the vaccines, said in a statement.

Fentanyl is up to 100 times stronger than morphine, and carfentanil, which is often used by veterinarians to sedate large animals such as elephants, is up to 10,000 times stronger than morphine. Carfentanil isn’t as well-known as a street drug, but it’s being used more often as an additive in heroin and cocaine.

“We’ve shown it is possible to prevent these unnecessary deaths by eliciting antibodies that stop the drug from reaching the brain,” he said.

The vaccines could be used in emergency situations to treat overdoses and as a therapy for those with substance abuse disorders, Dr. Janda said. In addition, the vaccines could protect military officers who are exposed to opioids as chemical weapons, and they may also help opioid-sniffing police dogs to train for the job.

The vaccines are still in the early stages of testing, but looking at the latest data “brings us hope that this approach will work to treat a number of opioid-related maladies,” Dr. Janda said.

In December, the CDC reported that more than 81,000 drug overdose deaths happened in the United States between May 2019 and May 2020, which was the highest number ever recorded in a 12-month period. Synthetic opioids, particularly illegally created fentanyl, were to blame.

“Unfortunately, the rise in carfentanil and fentanyl overdose incidents is placing further strain on already overwhelmed public health systems currently battling a pandemic,” Dr. Janda said. “We look forward to continuing our vaccine research and translating it to the clinic, where we can begin to make an impact on the opioid crisis.”

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

New experimental vaccines could stop the worst effects of synthetic fentanyl and carfentanil, two drugs that have been major drivers of the opioid epidemic in the United States, according to a new study published in ACS Chemical Biology on Feb. 3, 2021.

During several experiments in mice, the vaccines prevented respiratory depression, which is the main cause of overdose deaths. The vaccines also reduced the amount of drug that was distributed to the brain. Once in the brain, synthetic opioids prompt the body to slow down breathing, and when too much of the drug is consumed, breathing can stop.

“Synthetic opioids are not only extremely deadly but also addictive and easy to manufacture, making them a formidable public health threat, especially when the coronavirus crisis is negatively impacting mental health,” Kim Janda, PhD, a chemist at Scripps Research Institute in La Jolla, Calif., who developed the vaccines, said in a statement.

Fentanyl is up to 100 times stronger than morphine, and carfentanil, which is often used by veterinarians to sedate large animals such as elephants, is up to 10,000 times stronger than morphine. Carfentanil isn’t as well-known as a street drug, but it’s being used more often as an additive in heroin and cocaine.

“We’ve shown it is possible to prevent these unnecessary deaths by eliciting antibodies that stop the drug from reaching the brain,” he said.

The vaccines could be used in emergency situations to treat overdoses and as a therapy for those with substance abuse disorders, Dr. Janda said. In addition, the vaccines could protect military officers who are exposed to opioids as chemical weapons, and they may also help opioid-sniffing police dogs to train for the job.

The vaccines are still in the early stages of testing, but looking at the latest data “brings us hope that this approach will work to treat a number of opioid-related maladies,” Dr. Janda said.

In December, the CDC reported that more than 81,000 drug overdose deaths happened in the United States between May 2019 and May 2020, which was the highest number ever recorded in a 12-month period. Synthetic opioids, particularly illegally created fentanyl, were to blame.

“Unfortunately, the rise in carfentanil and fentanyl overdose incidents is placing further strain on already overwhelmed public health systems currently battling a pandemic,” Dr. Janda said. “We look forward to continuing our vaccine research and translating it to the clinic, where we can begin to make an impact on the opioid crisis.”

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

New experimental vaccines could stop the worst effects of synthetic fentanyl and carfentanil, two drugs that have been major drivers of the opioid epidemic in the United States, according to a new study published in ACS Chemical Biology on Feb. 3, 2021.

During several experiments in mice, the vaccines prevented respiratory depression, which is the main cause of overdose deaths. The vaccines also reduced the amount of drug that was distributed to the brain. Once in the brain, synthetic opioids prompt the body to slow down breathing, and when too much of the drug is consumed, breathing can stop.

“Synthetic opioids are not only extremely deadly but also addictive and easy to manufacture, making them a formidable public health threat, especially when the coronavirus crisis is negatively impacting mental health,” Kim Janda, PhD, a chemist at Scripps Research Institute in La Jolla, Calif., who developed the vaccines, said in a statement.

Fentanyl is up to 100 times stronger than morphine, and carfentanil, which is often used by veterinarians to sedate large animals such as elephants, is up to 10,000 times stronger than morphine. Carfentanil isn’t as well-known as a street drug, but it’s being used more often as an additive in heroin and cocaine.

“We’ve shown it is possible to prevent these unnecessary deaths by eliciting antibodies that stop the drug from reaching the brain,” he said.

The vaccines could be used in emergency situations to treat overdoses and as a therapy for those with substance abuse disorders, Dr. Janda said. In addition, the vaccines could protect military officers who are exposed to opioids as chemical weapons, and they may also help opioid-sniffing police dogs to train for the job.

The vaccines are still in the early stages of testing, but looking at the latest data “brings us hope that this approach will work to treat a number of opioid-related maladies,” Dr. Janda said.

In December, the CDC reported that more than 81,000 drug overdose deaths happened in the United States between May 2019 and May 2020, which was the highest number ever recorded in a 12-month period. Synthetic opioids, particularly illegally created fentanyl, were to blame.

“Unfortunately, the rise in carfentanil and fentanyl overdose incidents is placing further strain on already overwhelmed public health systems currently battling a pandemic,” Dr. Janda said. “We look forward to continuing our vaccine research and translating it to the clinic, where we can begin to make an impact on the opioid crisis.”

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

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

The next dramatic advance in the treatment of melanoma may arise from highly promising clinical trials in which immune checkpoint inhibitors and anti-BRAF/MEK agents are being pushed forward in the treatment paradigm and utilized as neoadjuvant therapy in patients with stage III resectable disease, John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.

These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.

“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”

Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.

Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.

CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.

In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.

“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.

Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.

There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.

Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.

Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.

“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.

Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.

Global Academy for Medical Education and this news organization are owned by the same company.

[email protected]

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.

In outpatients with COVID-19, peginterferon lambda has the potential to prevent clinical deterioration and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).

Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
 

Fewer side effects

To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.

Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.

The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
 

Greater benefit with higher baseline load

A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
 

More patients SARS-CoV-2 RNA negative

By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
 

Respiratory symptoms improved faster

Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).

Laboratory adverse events, similar for both groups, were mild.

“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.

“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.

Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.

“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.

The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.