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Will Tirzepatide Vials Help Patients? Endos Weigh in
Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.
As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”
For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)
“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.
The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.
And there’s the rub.
‘Only Two Different Doses’
Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.
“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.
“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”
If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”
Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”
And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”
A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”
But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”
In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”
The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
Protection From Compounders?
According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”
Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.
Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”
But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.
Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”
“For 20 months now,” he continued,
Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”
Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.
A version of this article appeared on Medscape.com.
Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.
As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”
For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)
“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.
The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.
And there’s the rub.
‘Only Two Different Doses’
Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.
“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.
“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”
If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”
Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”
And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”
A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”
But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”
In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”
The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
Protection From Compounders?
According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”
Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.
Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”
But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.
Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”
“For 20 months now,” he continued,
Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”
Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.
A version of this article appeared on Medscape.com.
Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.
As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”
For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)
“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.
The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.
And there’s the rub.
‘Only Two Different Doses’
Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.
“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.
“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”
If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”
Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”
And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”
A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”
But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”
In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”
The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
Protection From Compounders?
According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”
Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.
Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”
But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.
Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”
“For 20 months now,” he continued,
Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”
Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.
A version of this article appeared on Medscape.com.
Time-Restricted Eating Fails for Weight Loss and Glucose Homeostasis
, a small randomized controlled trial found.
The results suggested that any effects of TRE on weight observed in prior studies may be due to reductions in caloric intake and not timing, according to Nisa M. Maruthur, MD, MHS, of the Division of General Internal Medicine at the Johns Hopkins School of Medicine in Baltimore, and colleagues.
Published in Annals of Internal Medicine, the 12-week trial randomly assigned 41 adults aged 18-69 years with obesity and prediabetes or diet-controlled diabetes 1:1 as follows: To TRE, involving a 10-hour eating window with 80% of calories consumed before 1 PM, or to UEP, involving a ≤ 16-hour window, with at least 50% of calories consumed after 5 PM. The regimen in each group was based on the OmniHeart unsaturated fat diet and the SPICE study.
“The diet was similar to the DASH [Dietary Approaches to Stop Hypertension] diet for hypertension and maybe a bit higher in unsaturated fat and micronutrients,” said study co-author Scott J. Pilla, MD, MHS, an assistant professor of medicine at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. For each participant, macro- and micronutrient content remained constant throughout the study period, with total calories individually determined at baseline and ranging from 1600 to 3500 kcal/d. “That differs from some TRE studies in which calories were adjusted according to whether participants lost or gained weight,” he said. “This was a purely mechanistic study to determine the impact of time of eating alone with no change in calories.”
Although the current findings revealed no weight loss advantage, some evidence suggests that limiting the food consumption window to 4-10 hours naturally reduces energy intake by approximately 200-550 calories per day and can result in a loss of 3%-5% of baseline body weight for 2-12 months. In addition, TRE has been shown to improve metabolic risk factors, such as insulin resistance, blood pressure, and triglyceride concentrations — but not in this study.
The Cohort
The mean age was 59 years, 93% of patients were women, and 93% were Black. The mean body mass index was 36, and the mean baseline weight was 96.2 kg — 95.6 kg in the TRE group and 103.7 kg in the UEP group.
At 12 weeks, weight decreased comparably by 2.3 kg (95% CI, 1.0-3.5) in the TRE group and by 2.6 kg (95% CI, 1.5-3.7) in the UEP group. Change in glycemic measures did not differ between the two groups.
Interestingly, self-reporting questionnaires revealed a slight reduction in physical activity in the TRE group, an effect that requires further study. “We don’t know why but anecdotally, some TRE participants said they tended to go to bed earlier,” Dr. Pilla said. Earlier bedtimes may put an end sooner to the daily eating pattern.
Subanalyses of the data are ongoing and will be published later.
“In the context of several clinical trials that suggest a benefit of TRE, our findings suggest that if or when TRE interventions induce weight loss, it is likely in part due to a reduction in energy intake, and therefore, clinicians can counsel patients that TRE may help them lose weight by decreasing their caloric intake,” the authors wrote.
In an accompanying editorial, Krista A. Varady, PhD, and Vanessa M. Oddo, PhD, of the Department of Kinesiology and Nutrition at the University of Illinois–Chicago, said the study results have important clinical implications. “Many patients stop following standard-care diets (such as daily calorie restriction) because they become frustrated with having to monitor food intake vigilantly each day,” they wrote.
Although TRE is no more effective than other diet interventions for weight reduction, it offers a simplified approach to treat obesity by omitting the need for calorie counting. “TRE bypasses this requirement simply by allowing participants to ‘watch the clock’ instead of monitoring calories, while still producing weight loss,” they wrote.
The straightforward nature of this diet makes it well suited for remote delivery, which can reduce the scheduling and financial barriers associated with inpatient visits, they added. “Moreover, TRE does not require the purchase of expensive food products and allows a person to continue consuming familiar foods, making it a high accessible diet for lower-resource populations.”
Gastroenterologists and Obesity
Of late, support has grown for gastroenterologists to become actively involved in obesity treatment — even to “take ownership” of this field.
In a 2023 article in Gut, Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, made the case for the natural fit between gastrointestinal (GI) specialists and obesity management. He noted that obesity is a significant risk factor for GI, pancreatic, and liver diseases. It can even affect inflammatory bowel disease.
“Treating obesity starting when patients present in gastroenterology and hepatology clinics has potential to impact serious consequences of obesity such as cardiovascular risks,” he wrote.
Gastroenterologists already treat GI conditions with pharmacologic and surgical interventions that can also be used to treat obesity and improve glycemic control. These include pancreatic lipase inhibitors and incretin, bariatric endoscopy and surgery, and combination therapies targeting metabolic problems.
This study was supported by the American Heart Association.
Dr. Maruthur reported receiving royalties from a virtual diabetes prevention program. Dr. Pilla reported receiving travel, advisory, and speaker fees from the American Diabetes Association. Numerous authors reported receiving grants from government and nonprofit research funding organizations. Dr. Varady disclosed having no competing interests. Dr. Odda reported receiving research support and honoraria from government nonprofit funding organizations.
A version of this article first appeared on Medscape.com.
, a small randomized controlled trial found.
The results suggested that any effects of TRE on weight observed in prior studies may be due to reductions in caloric intake and not timing, according to Nisa M. Maruthur, MD, MHS, of the Division of General Internal Medicine at the Johns Hopkins School of Medicine in Baltimore, and colleagues.
Published in Annals of Internal Medicine, the 12-week trial randomly assigned 41 adults aged 18-69 years with obesity and prediabetes or diet-controlled diabetes 1:1 as follows: To TRE, involving a 10-hour eating window with 80% of calories consumed before 1 PM, or to UEP, involving a ≤ 16-hour window, with at least 50% of calories consumed after 5 PM. The regimen in each group was based on the OmniHeart unsaturated fat diet and the SPICE study.
“The diet was similar to the DASH [Dietary Approaches to Stop Hypertension] diet for hypertension and maybe a bit higher in unsaturated fat and micronutrients,” said study co-author Scott J. Pilla, MD, MHS, an assistant professor of medicine at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. For each participant, macro- and micronutrient content remained constant throughout the study period, with total calories individually determined at baseline and ranging from 1600 to 3500 kcal/d. “That differs from some TRE studies in which calories were adjusted according to whether participants lost or gained weight,” he said. “This was a purely mechanistic study to determine the impact of time of eating alone with no change in calories.”
Although the current findings revealed no weight loss advantage, some evidence suggests that limiting the food consumption window to 4-10 hours naturally reduces energy intake by approximately 200-550 calories per day and can result in a loss of 3%-5% of baseline body weight for 2-12 months. In addition, TRE has been shown to improve metabolic risk factors, such as insulin resistance, blood pressure, and triglyceride concentrations — but not in this study.
The Cohort
The mean age was 59 years, 93% of patients were women, and 93% were Black. The mean body mass index was 36, and the mean baseline weight was 96.2 kg — 95.6 kg in the TRE group and 103.7 kg in the UEP group.
At 12 weeks, weight decreased comparably by 2.3 kg (95% CI, 1.0-3.5) in the TRE group and by 2.6 kg (95% CI, 1.5-3.7) in the UEP group. Change in glycemic measures did not differ between the two groups.
Interestingly, self-reporting questionnaires revealed a slight reduction in physical activity in the TRE group, an effect that requires further study. “We don’t know why but anecdotally, some TRE participants said they tended to go to bed earlier,” Dr. Pilla said. Earlier bedtimes may put an end sooner to the daily eating pattern.
Subanalyses of the data are ongoing and will be published later.
“In the context of several clinical trials that suggest a benefit of TRE, our findings suggest that if or when TRE interventions induce weight loss, it is likely in part due to a reduction in energy intake, and therefore, clinicians can counsel patients that TRE may help them lose weight by decreasing their caloric intake,” the authors wrote.
In an accompanying editorial, Krista A. Varady, PhD, and Vanessa M. Oddo, PhD, of the Department of Kinesiology and Nutrition at the University of Illinois–Chicago, said the study results have important clinical implications. “Many patients stop following standard-care diets (such as daily calorie restriction) because they become frustrated with having to monitor food intake vigilantly each day,” they wrote.
Although TRE is no more effective than other diet interventions for weight reduction, it offers a simplified approach to treat obesity by omitting the need for calorie counting. “TRE bypasses this requirement simply by allowing participants to ‘watch the clock’ instead of monitoring calories, while still producing weight loss,” they wrote.
The straightforward nature of this diet makes it well suited for remote delivery, which can reduce the scheduling and financial barriers associated with inpatient visits, they added. “Moreover, TRE does not require the purchase of expensive food products and allows a person to continue consuming familiar foods, making it a high accessible diet for lower-resource populations.”
Gastroenterologists and Obesity
Of late, support has grown for gastroenterologists to become actively involved in obesity treatment — even to “take ownership” of this field.
In a 2023 article in Gut, Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, made the case for the natural fit between gastrointestinal (GI) specialists and obesity management. He noted that obesity is a significant risk factor for GI, pancreatic, and liver diseases. It can even affect inflammatory bowel disease.
“Treating obesity starting when patients present in gastroenterology and hepatology clinics has potential to impact serious consequences of obesity such as cardiovascular risks,” he wrote.
Gastroenterologists already treat GI conditions with pharmacologic and surgical interventions that can also be used to treat obesity and improve glycemic control. These include pancreatic lipase inhibitors and incretin, bariatric endoscopy and surgery, and combination therapies targeting metabolic problems.
This study was supported by the American Heart Association.
Dr. Maruthur reported receiving royalties from a virtual diabetes prevention program. Dr. Pilla reported receiving travel, advisory, and speaker fees from the American Diabetes Association. Numerous authors reported receiving grants from government and nonprofit research funding organizations. Dr. Varady disclosed having no competing interests. Dr. Odda reported receiving research support and honoraria from government nonprofit funding organizations.
A version of this article first appeared on Medscape.com.
, a small randomized controlled trial found.
The results suggested that any effects of TRE on weight observed in prior studies may be due to reductions in caloric intake and not timing, according to Nisa M. Maruthur, MD, MHS, of the Division of General Internal Medicine at the Johns Hopkins School of Medicine in Baltimore, and colleagues.
Published in Annals of Internal Medicine, the 12-week trial randomly assigned 41 adults aged 18-69 years with obesity and prediabetes or diet-controlled diabetes 1:1 as follows: To TRE, involving a 10-hour eating window with 80% of calories consumed before 1 PM, or to UEP, involving a ≤ 16-hour window, with at least 50% of calories consumed after 5 PM. The regimen in each group was based on the OmniHeart unsaturated fat diet and the SPICE study.
“The diet was similar to the DASH [Dietary Approaches to Stop Hypertension] diet for hypertension and maybe a bit higher in unsaturated fat and micronutrients,” said study co-author Scott J. Pilla, MD, MHS, an assistant professor of medicine at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. For each participant, macro- and micronutrient content remained constant throughout the study period, with total calories individually determined at baseline and ranging from 1600 to 3500 kcal/d. “That differs from some TRE studies in which calories were adjusted according to whether participants lost or gained weight,” he said. “This was a purely mechanistic study to determine the impact of time of eating alone with no change in calories.”
Although the current findings revealed no weight loss advantage, some evidence suggests that limiting the food consumption window to 4-10 hours naturally reduces energy intake by approximately 200-550 calories per day and can result in a loss of 3%-5% of baseline body weight for 2-12 months. In addition, TRE has been shown to improve metabolic risk factors, such as insulin resistance, blood pressure, and triglyceride concentrations — but not in this study.
The Cohort
The mean age was 59 years, 93% of patients were women, and 93% were Black. The mean body mass index was 36, and the mean baseline weight was 96.2 kg — 95.6 kg in the TRE group and 103.7 kg in the UEP group.
At 12 weeks, weight decreased comparably by 2.3 kg (95% CI, 1.0-3.5) in the TRE group and by 2.6 kg (95% CI, 1.5-3.7) in the UEP group. Change in glycemic measures did not differ between the two groups.
Interestingly, self-reporting questionnaires revealed a slight reduction in physical activity in the TRE group, an effect that requires further study. “We don’t know why but anecdotally, some TRE participants said they tended to go to bed earlier,” Dr. Pilla said. Earlier bedtimes may put an end sooner to the daily eating pattern.
Subanalyses of the data are ongoing and will be published later.
“In the context of several clinical trials that suggest a benefit of TRE, our findings suggest that if or when TRE interventions induce weight loss, it is likely in part due to a reduction in energy intake, and therefore, clinicians can counsel patients that TRE may help them lose weight by decreasing their caloric intake,” the authors wrote.
In an accompanying editorial, Krista A. Varady, PhD, and Vanessa M. Oddo, PhD, of the Department of Kinesiology and Nutrition at the University of Illinois–Chicago, said the study results have important clinical implications. “Many patients stop following standard-care diets (such as daily calorie restriction) because they become frustrated with having to monitor food intake vigilantly each day,” they wrote.
Although TRE is no more effective than other diet interventions for weight reduction, it offers a simplified approach to treat obesity by omitting the need for calorie counting. “TRE bypasses this requirement simply by allowing participants to ‘watch the clock’ instead of monitoring calories, while still producing weight loss,” they wrote.
The straightforward nature of this diet makes it well suited for remote delivery, which can reduce the scheduling and financial barriers associated with inpatient visits, they added. “Moreover, TRE does not require the purchase of expensive food products and allows a person to continue consuming familiar foods, making it a high accessible diet for lower-resource populations.”
Gastroenterologists and Obesity
Of late, support has grown for gastroenterologists to become actively involved in obesity treatment — even to “take ownership” of this field.
In a 2023 article in Gut, Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, made the case for the natural fit between gastrointestinal (GI) specialists and obesity management. He noted that obesity is a significant risk factor for GI, pancreatic, and liver diseases. It can even affect inflammatory bowel disease.
“Treating obesity starting when patients present in gastroenterology and hepatology clinics has potential to impact serious consequences of obesity such as cardiovascular risks,” he wrote.
Gastroenterologists already treat GI conditions with pharmacologic and surgical interventions that can also be used to treat obesity and improve glycemic control. These include pancreatic lipase inhibitors and incretin, bariatric endoscopy and surgery, and combination therapies targeting metabolic problems.
This study was supported by the American Heart Association.
Dr. Maruthur reported receiving royalties from a virtual diabetes prevention program. Dr. Pilla reported receiving travel, advisory, and speaker fees from the American Diabetes Association. Numerous authors reported receiving grants from government and nonprofit research funding organizations. Dr. Varady disclosed having no competing interests. Dr. Odda reported receiving research support and honoraria from government nonprofit funding organizations.
A version of this article first appeared on Medscape.com.
Managing Vitiligo: Combination Therapies, New Treatments
HUNTINGTON BEACH, CALIFORNIA — When patients with vitiligo see Jessica Shiu, MD, PhD, for the first time, some mention that prior healthcare providers have told them that vitiligo is merely a cosmetic issue — much to her dismay.
“Vitiligo is not a cosmetic disease,” Dr. Shiu, assistant professor of dermatology at the University of California, Irvine, said at the annual meeting of the Pacific Dermatologic Association. “It is associated with significant depression, stigmatization, and low self-esteem. I have patients who say that vitiligo has affected their marriage ... In certain cultures, it also affects their job prospects.”
As the most common pigmentary disorder, vitiligo is an autoimmune condition that often results in the recruitment of CD8+ T cells into the skin. These cells destroy melanocytes, depleting melanocytes in the epidermis. “Over time, this results in milky white patches of skin that we often see in our patients,” Dr. Shiu said.
“Depending on the site that is involved, the nonsegmental form can be further divided into focal, acrofacial, mucosal, generalized, and universal subtypes,” she said. The first step in your initial management is to determine if the vitiligo is active or stable, which can be challenging. Clinical signs of active disease include the presence of trichome vitiligo, confetti vitiligo, and koebnerization.
“Another sign of active disease is when patients tell you that their vitiligo is expanding rapidly,” Dr. Shiu added. “Stable vitiligo is more difficult to define. Many patients think their lesions don’t change, but we’re now appreciating that there can be some sites in those patients such as the hands and feet that are more susceptible to change in activity.” In general, she noted, vitiligo is considered stable when there is no change in activity for at least 12 months, and “lesions are usually completely depigmented with sharp borders.”
The level of vitiligo disease activity drives medical management. For patients with nonsegmental vitiligo who have clinical signs of active disease, the first goal is to stabilize the active disease and stop further spread of depigmentation. “This is key because losing pigment can occur very quickly, but gaining pigment back is a very slow process,” she said. Stabilization involves suppressing immune responses with topical steroids, topical calcineurin inhibitors, or 1.5% ruxolitinib cream, a JAK inhibitor that became the first Food and Drug Administration (FDA)–approved pharmacologic treatment for nonsegmental vitiligo, in 2022, for patients aged 12 years or older.
“The choice here depends somewhat on insurance coverage and shared decision-making with the patient,” Dr. Shiu said. Meanwhile, clinical trials evaluating the effect of the oral JAK inhibitors ritlecitinib, upadacitinib, povorcitinib, and baricitinib on vitiligo are underway.
Combining Phototherapy With Topical Treatment
A mainstay therapy for nonsegmental vitiligo is phototherapy, which can induce the migration of melanocyte stem cells from hair follicles. “There’s good data to show that combining topical treatment with phototherapy can augment the repigmentation that you see,” she said. “So if it’s possible, try to add phototherapy for your vitiligo patients, but sometimes, logistics for that are a challenge.”
Discussing treatment expectations with patients is key because it can take up to 1 year to see a significant response with topical immunosuppressants and narrowband ultraviolet B treatment. The head and neck areas are often the first sites to repigment, she said, followed by the extremities or the trunk. “The hands and feet are generally last; they are usually the most stubborn areas,” Dr. Shiu said. “Even when you do see repigmentation, it usually happens on the dorsal surfaces. The tips of the fingers and toes are difficult to repigment. Luckily, the face is one of the top responders, so that helps a lot.”
While some treatment efforts result in “complete and beautiful” repigmentation, she added, many yield uneven and incomplete results. “We don’t understand why repigmentation occurs in some areas but not in others,” she said. “We don’t have any biomarkers for treatment response. That is something we are looking into.”
For a patient with rapidly progressing active disease, consider an oral steroid mini-pulse 2 consecutive days per week for a maximum of 3-6 months. “I usually recommend that patients do this on Saturday and Sunday,” Dr. Shiu said. “Studies have shown this strategy can halt progression in 85%-91% of cases if patients are on it for at least 3 months.”
Relapse after successful repigmentation occurs in about 40% of cases following discontinuation of treatment, so she recommends biweekly application of 0.1% tacrolimus ointment as maintenance therapy. “Studies have shown this is enough to decrease the relapse rate to around 9%,” she said.
Tissue, Cellular Grafts
Surgical repigmentation strategies rely on transplanting normal skin to areas affected by vitiligo. In general, more than 50% of patients achieve more than 80% repigmentation. Options are divided into tissue grafts vs cellular grafts. “The old methods are tissue grafting such as punch grafting, tissue blister grafting, and spit thickness grafting, which can treat limited areas of skin,” Dr. Shiu said. Newer approaches include cellular grafting using the melanocyte-keratinocyte transplantation procedure, which can treat larger areas of skin.
The main drawback of this approach is that it is expensive and there is no insurance code for it, “but I hope that this becomes an option for our patients in the future because data indicate that repigmentation is maintained for up to 72 months after treatment,” she said.
In June 2023, an autologous cell harvesting device known as RECELL received FDA approval for repigmentation of stable vitiligo lesions. According to a press release from the manufacturer, AVITA Medical, a clinician “prepares and delivers autologous skin cells from pigmented skin to stable depigmented areas, offering a safe and effective treatment for vitiligo.”
Dr. Shiu disclosed that she received research support from AbbVie.
A version of this article first appeared on Medscape.com.
HUNTINGTON BEACH, CALIFORNIA — When patients with vitiligo see Jessica Shiu, MD, PhD, for the first time, some mention that prior healthcare providers have told them that vitiligo is merely a cosmetic issue — much to her dismay.
“Vitiligo is not a cosmetic disease,” Dr. Shiu, assistant professor of dermatology at the University of California, Irvine, said at the annual meeting of the Pacific Dermatologic Association. “It is associated with significant depression, stigmatization, and low self-esteem. I have patients who say that vitiligo has affected their marriage ... In certain cultures, it also affects their job prospects.”
As the most common pigmentary disorder, vitiligo is an autoimmune condition that often results in the recruitment of CD8+ T cells into the skin. These cells destroy melanocytes, depleting melanocytes in the epidermis. “Over time, this results in milky white patches of skin that we often see in our patients,” Dr. Shiu said.
“Depending on the site that is involved, the nonsegmental form can be further divided into focal, acrofacial, mucosal, generalized, and universal subtypes,” she said. The first step in your initial management is to determine if the vitiligo is active or stable, which can be challenging. Clinical signs of active disease include the presence of trichome vitiligo, confetti vitiligo, and koebnerization.
“Another sign of active disease is when patients tell you that their vitiligo is expanding rapidly,” Dr. Shiu added. “Stable vitiligo is more difficult to define. Many patients think their lesions don’t change, but we’re now appreciating that there can be some sites in those patients such as the hands and feet that are more susceptible to change in activity.” In general, she noted, vitiligo is considered stable when there is no change in activity for at least 12 months, and “lesions are usually completely depigmented with sharp borders.”
The level of vitiligo disease activity drives medical management. For patients with nonsegmental vitiligo who have clinical signs of active disease, the first goal is to stabilize the active disease and stop further spread of depigmentation. “This is key because losing pigment can occur very quickly, but gaining pigment back is a very slow process,” she said. Stabilization involves suppressing immune responses with topical steroids, topical calcineurin inhibitors, or 1.5% ruxolitinib cream, a JAK inhibitor that became the first Food and Drug Administration (FDA)–approved pharmacologic treatment for nonsegmental vitiligo, in 2022, for patients aged 12 years or older.
“The choice here depends somewhat on insurance coverage and shared decision-making with the patient,” Dr. Shiu said. Meanwhile, clinical trials evaluating the effect of the oral JAK inhibitors ritlecitinib, upadacitinib, povorcitinib, and baricitinib on vitiligo are underway.
Combining Phototherapy With Topical Treatment
A mainstay therapy for nonsegmental vitiligo is phototherapy, which can induce the migration of melanocyte stem cells from hair follicles. “There’s good data to show that combining topical treatment with phototherapy can augment the repigmentation that you see,” she said. “So if it’s possible, try to add phototherapy for your vitiligo patients, but sometimes, logistics for that are a challenge.”
Discussing treatment expectations with patients is key because it can take up to 1 year to see a significant response with topical immunosuppressants and narrowband ultraviolet B treatment. The head and neck areas are often the first sites to repigment, she said, followed by the extremities or the trunk. “The hands and feet are generally last; they are usually the most stubborn areas,” Dr. Shiu said. “Even when you do see repigmentation, it usually happens on the dorsal surfaces. The tips of the fingers and toes are difficult to repigment. Luckily, the face is one of the top responders, so that helps a lot.”
While some treatment efforts result in “complete and beautiful” repigmentation, she added, many yield uneven and incomplete results. “We don’t understand why repigmentation occurs in some areas but not in others,” she said. “We don’t have any biomarkers for treatment response. That is something we are looking into.”
For a patient with rapidly progressing active disease, consider an oral steroid mini-pulse 2 consecutive days per week for a maximum of 3-6 months. “I usually recommend that patients do this on Saturday and Sunday,” Dr. Shiu said. “Studies have shown this strategy can halt progression in 85%-91% of cases if patients are on it for at least 3 months.”
Relapse after successful repigmentation occurs in about 40% of cases following discontinuation of treatment, so she recommends biweekly application of 0.1% tacrolimus ointment as maintenance therapy. “Studies have shown this is enough to decrease the relapse rate to around 9%,” she said.
Tissue, Cellular Grafts
Surgical repigmentation strategies rely on transplanting normal skin to areas affected by vitiligo. In general, more than 50% of patients achieve more than 80% repigmentation. Options are divided into tissue grafts vs cellular grafts. “The old methods are tissue grafting such as punch grafting, tissue blister grafting, and spit thickness grafting, which can treat limited areas of skin,” Dr. Shiu said. Newer approaches include cellular grafting using the melanocyte-keratinocyte transplantation procedure, which can treat larger areas of skin.
The main drawback of this approach is that it is expensive and there is no insurance code for it, “but I hope that this becomes an option for our patients in the future because data indicate that repigmentation is maintained for up to 72 months after treatment,” she said.
In June 2023, an autologous cell harvesting device known as RECELL received FDA approval for repigmentation of stable vitiligo lesions. According to a press release from the manufacturer, AVITA Medical, a clinician “prepares and delivers autologous skin cells from pigmented skin to stable depigmented areas, offering a safe and effective treatment for vitiligo.”
Dr. Shiu disclosed that she received research support from AbbVie.
A version of this article first appeared on Medscape.com.
HUNTINGTON BEACH, CALIFORNIA — When patients with vitiligo see Jessica Shiu, MD, PhD, for the first time, some mention that prior healthcare providers have told them that vitiligo is merely a cosmetic issue — much to her dismay.
“Vitiligo is not a cosmetic disease,” Dr. Shiu, assistant professor of dermatology at the University of California, Irvine, said at the annual meeting of the Pacific Dermatologic Association. “It is associated with significant depression, stigmatization, and low self-esteem. I have patients who say that vitiligo has affected their marriage ... In certain cultures, it also affects their job prospects.”
As the most common pigmentary disorder, vitiligo is an autoimmune condition that often results in the recruitment of CD8+ T cells into the skin. These cells destroy melanocytes, depleting melanocytes in the epidermis. “Over time, this results in milky white patches of skin that we often see in our patients,” Dr. Shiu said.
“Depending on the site that is involved, the nonsegmental form can be further divided into focal, acrofacial, mucosal, generalized, and universal subtypes,” she said. The first step in your initial management is to determine if the vitiligo is active or stable, which can be challenging. Clinical signs of active disease include the presence of trichome vitiligo, confetti vitiligo, and koebnerization.
“Another sign of active disease is when patients tell you that their vitiligo is expanding rapidly,” Dr. Shiu added. “Stable vitiligo is more difficult to define. Many patients think their lesions don’t change, but we’re now appreciating that there can be some sites in those patients such as the hands and feet that are more susceptible to change in activity.” In general, she noted, vitiligo is considered stable when there is no change in activity for at least 12 months, and “lesions are usually completely depigmented with sharp borders.”
The level of vitiligo disease activity drives medical management. For patients with nonsegmental vitiligo who have clinical signs of active disease, the first goal is to stabilize the active disease and stop further spread of depigmentation. “This is key because losing pigment can occur very quickly, but gaining pigment back is a very slow process,” she said. Stabilization involves suppressing immune responses with topical steroids, topical calcineurin inhibitors, or 1.5% ruxolitinib cream, a JAK inhibitor that became the first Food and Drug Administration (FDA)–approved pharmacologic treatment for nonsegmental vitiligo, in 2022, for patients aged 12 years or older.
“The choice here depends somewhat on insurance coverage and shared decision-making with the patient,” Dr. Shiu said. Meanwhile, clinical trials evaluating the effect of the oral JAK inhibitors ritlecitinib, upadacitinib, povorcitinib, and baricitinib on vitiligo are underway.
Combining Phototherapy With Topical Treatment
A mainstay therapy for nonsegmental vitiligo is phototherapy, which can induce the migration of melanocyte stem cells from hair follicles. “There’s good data to show that combining topical treatment with phototherapy can augment the repigmentation that you see,” she said. “So if it’s possible, try to add phototherapy for your vitiligo patients, but sometimes, logistics for that are a challenge.”
Discussing treatment expectations with patients is key because it can take up to 1 year to see a significant response with topical immunosuppressants and narrowband ultraviolet B treatment. The head and neck areas are often the first sites to repigment, she said, followed by the extremities or the trunk. “The hands and feet are generally last; they are usually the most stubborn areas,” Dr. Shiu said. “Even when you do see repigmentation, it usually happens on the dorsal surfaces. The tips of the fingers and toes are difficult to repigment. Luckily, the face is one of the top responders, so that helps a lot.”
While some treatment efforts result in “complete and beautiful” repigmentation, she added, many yield uneven and incomplete results. “We don’t understand why repigmentation occurs in some areas but not in others,” she said. “We don’t have any biomarkers for treatment response. That is something we are looking into.”
For a patient with rapidly progressing active disease, consider an oral steroid mini-pulse 2 consecutive days per week for a maximum of 3-6 months. “I usually recommend that patients do this on Saturday and Sunday,” Dr. Shiu said. “Studies have shown this strategy can halt progression in 85%-91% of cases if patients are on it for at least 3 months.”
Relapse after successful repigmentation occurs in about 40% of cases following discontinuation of treatment, so she recommends biweekly application of 0.1% tacrolimus ointment as maintenance therapy. “Studies have shown this is enough to decrease the relapse rate to around 9%,” she said.
Tissue, Cellular Grafts
Surgical repigmentation strategies rely on transplanting normal skin to areas affected by vitiligo. In general, more than 50% of patients achieve more than 80% repigmentation. Options are divided into tissue grafts vs cellular grafts. “The old methods are tissue grafting such as punch grafting, tissue blister grafting, and spit thickness grafting, which can treat limited areas of skin,” Dr. Shiu said. Newer approaches include cellular grafting using the melanocyte-keratinocyte transplantation procedure, which can treat larger areas of skin.
The main drawback of this approach is that it is expensive and there is no insurance code for it, “but I hope that this becomes an option for our patients in the future because data indicate that repigmentation is maintained for up to 72 months after treatment,” she said.
In June 2023, an autologous cell harvesting device known as RECELL received FDA approval for repigmentation of stable vitiligo lesions. According to a press release from the manufacturer, AVITA Medical, a clinician “prepares and delivers autologous skin cells from pigmented skin to stable depigmented areas, offering a safe and effective treatment for vitiligo.”
Dr. Shiu disclosed that she received research support from AbbVie.
A version of this article first appeared on Medscape.com.
FROM PDA 2024
KRAS Inhibitors in Pancreatic Cancer: Hope on the Horizon?
Finding effective treatments for the disease continues to be a challenge.
No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.
Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.”
Until recently.
In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers.
A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.
“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
A Challenging Cancer
Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.
But it’s still early days on the evidence front.
The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far.
The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.
Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.
And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.
For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.
In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations.
At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.
Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks.
Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%.
Revolution Medicines is now planning a phase 3 trial.
Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.
While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said.
Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained.
In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.
Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes.
Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing.
“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.”
Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.
But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?”
Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy.
Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.
Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”
Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.
A version of this article first appeared on Medscape.com.
Finding effective treatments for the disease continues to be a challenge.
No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.
Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.”
Until recently.
In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers.
A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.
“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
A Challenging Cancer
Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.
But it’s still early days on the evidence front.
The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far.
The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.
Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.
And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.
For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.
In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations.
At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.
Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks.
Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%.
Revolution Medicines is now planning a phase 3 trial.
Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.
While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said.
Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained.
In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.
Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes.
Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing.
“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.”
Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.
But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?”
Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy.
Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.
Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”
Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.
A version of this article first appeared on Medscape.com.
Finding effective treatments for the disease continues to be a challenge.
No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.
Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.”
Until recently.
In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers.
A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.
“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
A Challenging Cancer
Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.
But it’s still early days on the evidence front.
The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far.
The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.
Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.
And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.
For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.
In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations.
At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.
Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks.
Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%.
Revolution Medicines is now planning a phase 3 trial.
Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.
While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said.
Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained.
In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.
Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes.
Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing.
“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.”
Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.
But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?”
Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy.
Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.
Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”
Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.
A version of this article first appeared on Medscape.com.
Ivonescimab: Possible New First-Line Standard in PD-L1–Positive Advanced NSCLC?
according to recent findings from the HARMONi-2 trial.
“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China,
The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC.
Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial.
Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.
Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater).
Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001).
The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55).
The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study.
Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%).
Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.
The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab.
In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).
Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said.
Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.
He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”
Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025.
HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more).
Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.
A version of this article first appeared on Medscape.com.
according to recent findings from the HARMONi-2 trial.
“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China,
The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC.
Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial.
Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.
Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater).
Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001).
The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55).
The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study.
Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%).
Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.
The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab.
In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).
Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said.
Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.
He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”
Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025.
HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more).
Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.
A version of this article first appeared on Medscape.com.
according to recent findings from the HARMONi-2 trial.
“This is the first randomized, phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in advanced NSCLC,” said study investigator Caicun Zhou, MD, PhD, with Shanghai Pulmonary Hospital in China,
The results highlight ivonescimab’s potential to become a “new standard of care” in advanced PD-L1–positive advanced NSCLC, said Dr. Zhou, who presented the analysis at the annual International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in San Diego. Dr. Zhou is president-elect of the IASLC.
Ivonescimab (AK112) is a novel, potentially first-in-class investigational bispecific antibody that targets PD-1 and vascular endothelial growth factor (VEGF) developed by Akeso Biopharma, which funded the HARMONi-2 trial.
Conducted at 55 centers in China, HARMONi-2 enrolled 398 patients with untreated locally advanced or metastatic NSCLC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, PD-L1 positive (with at least 1% of tumor cells expressing PD-L1), and no EGFR mutations or ALK rearrangements.
Patients were randomly allocated (1:1) to receive ivonescimab (20 mg/kg) or pembrolizumab (200 mg) every 3 weeks. The two groups were well balanced, and randomization was stratified by histology (squamous vs nonsquamous), clinical stage (IIIB/IIIC vs IV) and PD-L1 expression (PD-L1 of 1%-49% vs 50% or greater).
Dr. Zhou reported that patients who received ivonescimab were progression free for nearly twice as long as those on pembrolizumab — a median of 11.1 vs 5.8 months, indicating a 49% lower risk for progression or death (stratified hazard ratio [HR], 0.51; P < .0001).
The meaningful improvement in PFS with ivonescimab, compared with pembrolizumab, was “broadly consistent” in all prespecified subgroups, Dr. Zhou noted. That included patients with squamous NSCLC (HR, 0.48) and nonsquamous NSCLC (HR, 0.54), those with PD-L1 expression of 1%-49% (HR, 0.54) and 50% or higher (HR, 0.46), as well as those with liver metastases (HR, 0.47) and brain metastases (HR, 0.55).
The PFS benefit seen with ivonescimab in HARMONi-2 is “striking,” and the results “highlight the potential benefits of combined VEGF and PD-1 blockade together,” said John Heymach, MD, with the University of Texas MD Anderson Cancer Center in Houston, who served as discussant for the study.
Ivonescimab also led to a higher objective response rate (50% vs 38.5%) and disease control rate (89.9% vs 70.5%).
Grade 3 or higher treatment-related adverse events occurred in more patients receiving ivonescimab — 29.4% vs 15.6% on pembrolizumab. The difference largely stemmed from higher rates of proteinuria, hypertension, and lab abnormalities.
The rates of serious treatment-related adverse events were similar between the groups —20.8% in the ivonescimab group and 16.1% in the pembrolizumab group. Rates of grade 3 or higher immune-related adverse events were also similar, occurring in 7% of patients treated with ivonescimab and 8% of those receiving pembrolizumab.
In patients with squamous cell carcinoma, in particular, ivonescimab demonstrated a “very manageable” safety profile, Dr. Zhou noted. In this group, grade 3 or higher treatment-related adverse events occurred in 22.2% of patients (vs 18.7% receiving pembrolizumab).
Ivonescimab was associated with comparable but “numerically better” time to deterioration of global health status, based on the EORTC Core Quality of Life questionnaire, Dr. Zhou said.
Although the “really impressive and clinically meaningful” PFS benefits extended across different subgroups, “we await the overall survival results and additional studies done outside of China to confirm the benefit seen,” Dr. Heymach noted.
He also cautioned that, for patients with low to intermediate PD-L1 expression (1%-49%), pembrolizumab monotherapy “would not be the relevant comparator in the US and the rest of the world, and different study designs are going to be required for those populations.”
Based on the results of HARMONi-2, Akeso’s partner, Summit Therapeutics, plans to initiate HARMONi-7 in early 2025.
HARMONi-7 is currently planned as a multiregional, phase 3 clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (50% or more).
Dr. Zhou has received consulting fees from Qilu Pharmaceutical, Hengrui, and TopAlliance Biosciences and honoraria from Eli Lilly China, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, Luye Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart Therapeutics. Dr. Heymach is a consultant for AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Mirati Therapeutics, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, Spectrum Pharmaceuticals, and Takeda.
A version of this article first appeared on Medscape.com.
FROM WCLC 2024
FDA Rejects MDMA-AT for PTSD, but Lykos, Others, Vow to Push on
The Food and Drug Administration’s (FDA) decision not to approve midomafetamine-assisted therapy (MDMA-AT) for posttraumatic stress disorder (PTSD) puts the therapy’s near-term future in doubt, but officials say the rejection may not knock it out of contention as an eventual therapeutic tool for a variety of conditions.
In August the agency declined to approve the drug with currently available study data and requested that the company conduct an additional phase 3 trial. The agency’s action had potentially devastating consequences for MDMA-AT’s sponsor, Lykos Therapeutics, and was a huge disappointment for researchers, clinicians, and patients who were optimistic that it would be a new option for a condition that affects 13-17 million Americans.
For now, no other company is poised to imminently seek FDA approval for MDMA.
Despite the setback, research into MDMA that combines different psychotherapeutic approaches continues. Currently, there are seven US studies actively recruiting participants, and another 13 are registered with an eye toward starting recruitment, as reported on ClinicalTrials.gov.
The lack of FDA approval “actually increases the opportunity now for us to do trials,” said Michael Ostacher, MD, professor of psychiatry and behavioral sciences at Stanford Medicine in California. Researchers won’t have to be sponsored by Lykos to get access to MDMA.
“There’s a lot of energy and interest in doing these studies,” he said in an interview, adding that philanthropic organizations and Veterans Affairs (VA) are contributing funds to support such studies.
The VA provided a statement saying that it “intends to gather rigorous scientific evidence on the potential efficacy and safety of psychedelic compounds when used in conjunction with psychotherapy.” It also noted that “these studies will be conducted under stringent safety protocols and will mark the first time since the 1960’s that VA is funding research on such compounds.”
Rachel Yehuda, PhD, director of the Center for Psychedelic Therapy Research at Icahn School of Medicine at Mount Sinai in New York City, said in an interview that the FDA rejection “raises questions about how to keep the work going.”
Without the FDA’s imprimatur, MDMA remains a schedule 1 drug, which means it has no valid medical use.
“It’s a lot more complicated and expensive to work with a scheduled compound than to work with a compound that has been approved,” Dr. Yehuda said.
Also, without Lykos or another drug company sponsor, investigators have to find an acceptable MDMA source on their own, said Dr. Yehuda, who was an investigator on a study in which Lykos provided MDMA but was not involved in study design, data collection, analysis, or manuscript preparation.
Lykos in Disarray
Within a week of the FDA’s decision, Lykos announced it was cutting its staff by 75% and that Rick Doblin, PhD, the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS) that gave rise to Lykos, had resigned from the Lykos board.
A frequently controversial figure, Doblin has been attempting to legitimize MDMA as a therapy since the mid-1980s. He formed a public benefit corporation (PBC) in 2014 with an eye toward FDA approval. The PBC fully separated from MAPS in 2024 and became Lykos.
Although the FDA has left the door open to approval, Lykos has not released the agency’s complete response letter, so it’s not clear exactly what the FDA is seeking. In a statement, the company said it believes the issues “can be addressed with existing data, postapproval requirements, or through reference to the scientific literature.”
Lykos said in an email that it is working on “securing the meeting with the FDA” and that it “will work with the agency to determine what needs to be done to fulfill their requests.”
Soon after the FDA decision, Lykos was hit with another blow. The journal Psychopharmacology retracted an article that pooled six Lykos phase 2 studies, claiming the paper’s authors knew about unethical conduct before submission but did not inform the publisher.
Lykos said the issues could have been addressed through a correction and that it has filed a complaint with the Committee on Publication Ethics. It also noted that the misconduct at issue was reported to the FDA and Health Canada.
“However, we did not disclose the violations to the journal itself, an additional step we should have taken and regret not doing,” the company said. It added that the efficacy data in the paper were not part of the FDA submission.
Author Allison A. Feduccia, PhD, cofounder of Psychedelic Support, agreed with the retraction but disagreed with the wording. In a post on LinkedIn, she said she and other authors were not informed about the misconduct until years after the study’s submission.
Four authors — including Dr. Doblin — disagreed with the retraction.
Dr. Doblin said in a statement that he’d resigned from Lykos to escape the restrictions that came with being a fiduciary. “Now I can advocate and speak freely,” he said, adding that he could also return to his activist roots.
He predicted that Lykos would eventually gain FDA approval. But if Lykos can’t convince the agency, it have the necessary data already in hand; “potential FDA approval is now at least 2 years away, possibly more,” Dr. Doblin said in his statement.
Research Continues
Lykos is not the only company hoping to commercialize MDMA. Toronto-based Awakn Life Sciences has an MDMA preclinical development program for addiction. In addition, some companies are offering MDMA therapy through clinics, such as Numinus in Utah and Sunstone Therapies in Rockville, Maryland.
But Lykos was the closest to bringing a product to market. The company is still a sponsor of four MDMA-related clinical trials, three of which appear to be on hold. One study at the VA San Diego Healthcare System, San Diego, that is actively recruiting is an open-label trial to assess MDMA-AT in combination with brief Cognitive-Behavioral Conjoint Therapy for PTSD.
Those studies are among 13 US trials listed in ClinicalTrials.gov that have not yet begun recruiting and 7 that are actively recruiting.
Among them is a study of MDMA plus exposure therapy, funded by and conducted at Emory University in Atlanta. One of the Emory principal investigators, Barbara Rothbaum, MD, has also been named to a Lykos’ panel that would help ensure oversight of MDMA-AT post FDA approval.
Dr. Ostacher is an investigator in a study planned at VA Palo Alto Health Care System in California, that will compare MDMA-AT with cognitive processing therapy in veterans with severe PTSD. He said it will be open label in an effort to minimize expectation bias and issues with blinding — both problems that tripped up the Lykos application. Although placebo-controlled trials are the gold standard, it’s not ideal when “the purpose of the drug is for it to change how you see the world and yourself,” Dr. Ostacher said.
The study aims to see whether MDMA-AT is better than “a much shorter, less onerous, but quite evidence-based psychotherapy for PTSD,” he said.
The FDA’s decision is not the end of the road, said Dr. Ostacher. “Even though I think this makes for an obvious delay, I don’t think that it’s a permanent one,” he said.
Dr. Yehuda also said she is not ready to give up.
“We don’t plan on stopping — we plan on finding a way,” she said.
“In our experience, this is a very powerful approach that helps a lot of people that haven’t found help using other approaches, and when it’s in the hands of really trusted, experienced, ethical clinicians in a trusted environment, this could be a real game changer for people who have not been able to find belief by traditional methods,” she said.
Dr. Ostacher reported no relevant financial relationships. Dr. Yahuda is the principal investigator on clinical trials for the Center for Psychedelic Psychotherapy and Trauma Research that are sponsored by the Multidisciplinary Association for Psychedelic Studies and COMPASS Pathways.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration’s (FDA) decision not to approve midomafetamine-assisted therapy (MDMA-AT) for posttraumatic stress disorder (PTSD) puts the therapy’s near-term future in doubt, but officials say the rejection may not knock it out of contention as an eventual therapeutic tool for a variety of conditions.
In August the agency declined to approve the drug with currently available study data and requested that the company conduct an additional phase 3 trial. The agency’s action had potentially devastating consequences for MDMA-AT’s sponsor, Lykos Therapeutics, and was a huge disappointment for researchers, clinicians, and patients who were optimistic that it would be a new option for a condition that affects 13-17 million Americans.
For now, no other company is poised to imminently seek FDA approval for MDMA.
Despite the setback, research into MDMA that combines different psychotherapeutic approaches continues. Currently, there are seven US studies actively recruiting participants, and another 13 are registered with an eye toward starting recruitment, as reported on ClinicalTrials.gov.
The lack of FDA approval “actually increases the opportunity now for us to do trials,” said Michael Ostacher, MD, professor of psychiatry and behavioral sciences at Stanford Medicine in California. Researchers won’t have to be sponsored by Lykos to get access to MDMA.
“There’s a lot of energy and interest in doing these studies,” he said in an interview, adding that philanthropic organizations and Veterans Affairs (VA) are contributing funds to support such studies.
The VA provided a statement saying that it “intends to gather rigorous scientific evidence on the potential efficacy and safety of psychedelic compounds when used in conjunction with psychotherapy.” It also noted that “these studies will be conducted under stringent safety protocols and will mark the first time since the 1960’s that VA is funding research on such compounds.”
Rachel Yehuda, PhD, director of the Center for Psychedelic Therapy Research at Icahn School of Medicine at Mount Sinai in New York City, said in an interview that the FDA rejection “raises questions about how to keep the work going.”
Without the FDA’s imprimatur, MDMA remains a schedule 1 drug, which means it has no valid medical use.
“It’s a lot more complicated and expensive to work with a scheduled compound than to work with a compound that has been approved,” Dr. Yehuda said.
Also, without Lykos or another drug company sponsor, investigators have to find an acceptable MDMA source on their own, said Dr. Yehuda, who was an investigator on a study in which Lykos provided MDMA but was not involved in study design, data collection, analysis, or manuscript preparation.
Lykos in Disarray
Within a week of the FDA’s decision, Lykos announced it was cutting its staff by 75% and that Rick Doblin, PhD, the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS) that gave rise to Lykos, had resigned from the Lykos board.
A frequently controversial figure, Doblin has been attempting to legitimize MDMA as a therapy since the mid-1980s. He formed a public benefit corporation (PBC) in 2014 with an eye toward FDA approval. The PBC fully separated from MAPS in 2024 and became Lykos.
Although the FDA has left the door open to approval, Lykos has not released the agency’s complete response letter, so it’s not clear exactly what the FDA is seeking. In a statement, the company said it believes the issues “can be addressed with existing data, postapproval requirements, or through reference to the scientific literature.”
Lykos said in an email that it is working on “securing the meeting with the FDA” and that it “will work with the agency to determine what needs to be done to fulfill their requests.”
Soon after the FDA decision, Lykos was hit with another blow. The journal Psychopharmacology retracted an article that pooled six Lykos phase 2 studies, claiming the paper’s authors knew about unethical conduct before submission but did not inform the publisher.
Lykos said the issues could have been addressed through a correction and that it has filed a complaint with the Committee on Publication Ethics. It also noted that the misconduct at issue was reported to the FDA and Health Canada.
“However, we did not disclose the violations to the journal itself, an additional step we should have taken and regret not doing,” the company said. It added that the efficacy data in the paper were not part of the FDA submission.
Author Allison A. Feduccia, PhD, cofounder of Psychedelic Support, agreed with the retraction but disagreed with the wording. In a post on LinkedIn, she said she and other authors were not informed about the misconduct until years after the study’s submission.
Four authors — including Dr. Doblin — disagreed with the retraction.
Dr. Doblin said in a statement that he’d resigned from Lykos to escape the restrictions that came with being a fiduciary. “Now I can advocate and speak freely,” he said, adding that he could also return to his activist roots.
He predicted that Lykos would eventually gain FDA approval. But if Lykos can’t convince the agency, it have the necessary data already in hand; “potential FDA approval is now at least 2 years away, possibly more,” Dr. Doblin said in his statement.
Research Continues
Lykos is not the only company hoping to commercialize MDMA. Toronto-based Awakn Life Sciences has an MDMA preclinical development program for addiction. In addition, some companies are offering MDMA therapy through clinics, such as Numinus in Utah and Sunstone Therapies in Rockville, Maryland.
But Lykos was the closest to bringing a product to market. The company is still a sponsor of four MDMA-related clinical trials, three of which appear to be on hold. One study at the VA San Diego Healthcare System, San Diego, that is actively recruiting is an open-label trial to assess MDMA-AT in combination with brief Cognitive-Behavioral Conjoint Therapy for PTSD.
Those studies are among 13 US trials listed in ClinicalTrials.gov that have not yet begun recruiting and 7 that are actively recruiting.
Among them is a study of MDMA plus exposure therapy, funded by and conducted at Emory University in Atlanta. One of the Emory principal investigators, Barbara Rothbaum, MD, has also been named to a Lykos’ panel that would help ensure oversight of MDMA-AT post FDA approval.
Dr. Ostacher is an investigator in a study planned at VA Palo Alto Health Care System in California, that will compare MDMA-AT with cognitive processing therapy in veterans with severe PTSD. He said it will be open label in an effort to minimize expectation bias and issues with blinding — both problems that tripped up the Lykos application. Although placebo-controlled trials are the gold standard, it’s not ideal when “the purpose of the drug is for it to change how you see the world and yourself,” Dr. Ostacher said.
The study aims to see whether MDMA-AT is better than “a much shorter, less onerous, but quite evidence-based psychotherapy for PTSD,” he said.
The FDA’s decision is not the end of the road, said Dr. Ostacher. “Even though I think this makes for an obvious delay, I don’t think that it’s a permanent one,” he said.
Dr. Yehuda also said she is not ready to give up.
“We don’t plan on stopping — we plan on finding a way,” she said.
“In our experience, this is a very powerful approach that helps a lot of people that haven’t found help using other approaches, and when it’s in the hands of really trusted, experienced, ethical clinicians in a trusted environment, this could be a real game changer for people who have not been able to find belief by traditional methods,” she said.
Dr. Ostacher reported no relevant financial relationships. Dr. Yahuda is the principal investigator on clinical trials for the Center for Psychedelic Psychotherapy and Trauma Research that are sponsored by the Multidisciplinary Association for Psychedelic Studies and COMPASS Pathways.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration’s (FDA) decision not to approve midomafetamine-assisted therapy (MDMA-AT) for posttraumatic stress disorder (PTSD) puts the therapy’s near-term future in doubt, but officials say the rejection may not knock it out of contention as an eventual therapeutic tool for a variety of conditions.
In August the agency declined to approve the drug with currently available study data and requested that the company conduct an additional phase 3 trial. The agency’s action had potentially devastating consequences for MDMA-AT’s sponsor, Lykos Therapeutics, and was a huge disappointment for researchers, clinicians, and patients who were optimistic that it would be a new option for a condition that affects 13-17 million Americans.
For now, no other company is poised to imminently seek FDA approval for MDMA.
Despite the setback, research into MDMA that combines different psychotherapeutic approaches continues. Currently, there are seven US studies actively recruiting participants, and another 13 are registered with an eye toward starting recruitment, as reported on ClinicalTrials.gov.
The lack of FDA approval “actually increases the opportunity now for us to do trials,” said Michael Ostacher, MD, professor of psychiatry and behavioral sciences at Stanford Medicine in California. Researchers won’t have to be sponsored by Lykos to get access to MDMA.
“There’s a lot of energy and interest in doing these studies,” he said in an interview, adding that philanthropic organizations and Veterans Affairs (VA) are contributing funds to support such studies.
The VA provided a statement saying that it “intends to gather rigorous scientific evidence on the potential efficacy and safety of psychedelic compounds when used in conjunction with psychotherapy.” It also noted that “these studies will be conducted under stringent safety protocols and will mark the first time since the 1960’s that VA is funding research on such compounds.”
Rachel Yehuda, PhD, director of the Center for Psychedelic Therapy Research at Icahn School of Medicine at Mount Sinai in New York City, said in an interview that the FDA rejection “raises questions about how to keep the work going.”
Without the FDA’s imprimatur, MDMA remains a schedule 1 drug, which means it has no valid medical use.
“It’s a lot more complicated and expensive to work with a scheduled compound than to work with a compound that has been approved,” Dr. Yehuda said.
Also, without Lykos or another drug company sponsor, investigators have to find an acceptable MDMA source on their own, said Dr. Yehuda, who was an investigator on a study in which Lykos provided MDMA but was not involved in study design, data collection, analysis, or manuscript preparation.
Lykos in Disarray
Within a week of the FDA’s decision, Lykos announced it was cutting its staff by 75% and that Rick Doblin, PhD, the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS) that gave rise to Lykos, had resigned from the Lykos board.
A frequently controversial figure, Doblin has been attempting to legitimize MDMA as a therapy since the mid-1980s. He formed a public benefit corporation (PBC) in 2014 with an eye toward FDA approval. The PBC fully separated from MAPS in 2024 and became Lykos.
Although the FDA has left the door open to approval, Lykos has not released the agency’s complete response letter, so it’s not clear exactly what the FDA is seeking. In a statement, the company said it believes the issues “can be addressed with existing data, postapproval requirements, or through reference to the scientific literature.”
Lykos said in an email that it is working on “securing the meeting with the FDA” and that it “will work with the agency to determine what needs to be done to fulfill their requests.”
Soon after the FDA decision, Lykos was hit with another blow. The journal Psychopharmacology retracted an article that pooled six Lykos phase 2 studies, claiming the paper’s authors knew about unethical conduct before submission but did not inform the publisher.
Lykos said the issues could have been addressed through a correction and that it has filed a complaint with the Committee on Publication Ethics. It also noted that the misconduct at issue was reported to the FDA and Health Canada.
“However, we did not disclose the violations to the journal itself, an additional step we should have taken and regret not doing,” the company said. It added that the efficacy data in the paper were not part of the FDA submission.
Author Allison A. Feduccia, PhD, cofounder of Psychedelic Support, agreed with the retraction but disagreed with the wording. In a post on LinkedIn, she said she and other authors were not informed about the misconduct until years after the study’s submission.
Four authors — including Dr. Doblin — disagreed with the retraction.
Dr. Doblin said in a statement that he’d resigned from Lykos to escape the restrictions that came with being a fiduciary. “Now I can advocate and speak freely,” he said, adding that he could also return to his activist roots.
He predicted that Lykos would eventually gain FDA approval. But if Lykos can’t convince the agency, it have the necessary data already in hand; “potential FDA approval is now at least 2 years away, possibly more,” Dr. Doblin said in his statement.
Research Continues
Lykos is not the only company hoping to commercialize MDMA. Toronto-based Awakn Life Sciences has an MDMA preclinical development program for addiction. In addition, some companies are offering MDMA therapy through clinics, such as Numinus in Utah and Sunstone Therapies in Rockville, Maryland.
But Lykos was the closest to bringing a product to market. The company is still a sponsor of four MDMA-related clinical trials, three of which appear to be on hold. One study at the VA San Diego Healthcare System, San Diego, that is actively recruiting is an open-label trial to assess MDMA-AT in combination with brief Cognitive-Behavioral Conjoint Therapy for PTSD.
Those studies are among 13 US trials listed in ClinicalTrials.gov that have not yet begun recruiting and 7 that are actively recruiting.
Among them is a study of MDMA plus exposure therapy, funded by and conducted at Emory University in Atlanta. One of the Emory principal investigators, Barbara Rothbaum, MD, has also been named to a Lykos’ panel that would help ensure oversight of MDMA-AT post FDA approval.
Dr. Ostacher is an investigator in a study planned at VA Palo Alto Health Care System in California, that will compare MDMA-AT with cognitive processing therapy in veterans with severe PTSD. He said it will be open label in an effort to minimize expectation bias and issues with blinding — both problems that tripped up the Lykos application. Although placebo-controlled trials are the gold standard, it’s not ideal when “the purpose of the drug is for it to change how you see the world and yourself,” Dr. Ostacher said.
The study aims to see whether MDMA-AT is better than “a much shorter, less onerous, but quite evidence-based psychotherapy for PTSD,” he said.
The FDA’s decision is not the end of the road, said Dr. Ostacher. “Even though I think this makes for an obvious delay, I don’t think that it’s a permanent one,” he said.
Dr. Yehuda also said she is not ready to give up.
“We don’t plan on stopping — we plan on finding a way,” she said.
“In our experience, this is a very powerful approach that helps a lot of people that haven’t found help using other approaches, and when it’s in the hands of really trusted, experienced, ethical clinicians in a trusted environment, this could be a real game changer for people who have not been able to find belief by traditional methods,” she said.
Dr. Ostacher reported no relevant financial relationships. Dr. Yahuda is the principal investigator on clinical trials for the Center for Psychedelic Psychotherapy and Trauma Research that are sponsored by the Multidisciplinary Association for Psychedelic Studies and COMPASS Pathways.
A version of this article first appeared on Medscape.com.
Metformin Led to Improvements in Women with Central Centrifugal Cicatricial Alopecia
TOPLINE:
, in a retrospective case series.
METHODOLOGY:
- Researchers conducted a case series involving 12 Black women in their 30s, 40s, and 50s, with biopsy-confirmed, treatment-refractory CCCA, a chronic inflammatory hair disorder characterized by permanent hair loss, from the Johns Hopkins University alopecia clinic.
- Participants received CCCA treatment for at least 6 months and had stagnant or worsening symptoms before oral extended-release metformin (500 mg daily) was added to treatment. (Treatments included topical clobetasol, compounded minoxidil, and platelet-rich plasma injections.)
- Scalp biopsies were collected from four patients before and after metformin treatment to evaluate gene expression changes.
- Changes in clinical symptoms were assessed, including pruritus, inflammation, pain, scalp resistance, and hair regrowth, following initiation of metformin treatment.
TAKEAWAY:
- Metformin led to significant clinical improvement in eight patients, which included reductions in scalp pain, scalp resistance, pruritus, and inflammation. However, two patients experienced worsening symptoms.
- Six patients showed clinical evidence of hair regrowth after at least 6 months of metformin treatment with one experiencing hair loss again 3 months after discontinuing treatment.
- Transcriptomic analysis revealed 34 upregulated genes, which included upregulated of 23 hair keratin-associated proteins, and pathways related to keratinization, epidermis development, and the hair cycle. In addition, eight genes were downregulated, with pathways that included those associated with extracellular matrix organization, collagen fibril organization, and collagen metabolism.
- Gene set variation analysis showed reduced expression of T helper 17 cell and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and keratin-associated proteins after treatment with metformin.
IN PRACTICE:
“Metformin’s ability to concomitantly target fibrosis and inflammation provides a plausible mechanism for its therapeutic effects in CCCA and other fibrosing alopecia disorders,” the authors concluded. But, they added, “larger prospective, placebo-controlled randomized clinical trials are needed to rigorously evaluate metformin’s efficacy and optimal dosing for treatment of cicatricial alopecias.”
SOURCE:
The study was led by Aaron Bao, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, and was published online on September 4 in JAMA Dermatology.
LIMITATIONS:
A small sample size, retrospective design, lack of a placebo control group, and the single-center setting limited the generalizability of the study findings. In addition, the absence of a validated activity or severity scale for CCCA and the single posttreatment sampling limit the assessment and comparison of clinical symptoms and transcriptomic changes.
DISCLOSURES:
The study was supported by the American Academy of Dermatology. One author reported several ties with pharmaceutical companies, a pending patent, and authorship for the UpToDate section on CCCA.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
, in a retrospective case series.
METHODOLOGY:
- Researchers conducted a case series involving 12 Black women in their 30s, 40s, and 50s, with biopsy-confirmed, treatment-refractory CCCA, a chronic inflammatory hair disorder characterized by permanent hair loss, from the Johns Hopkins University alopecia clinic.
- Participants received CCCA treatment for at least 6 months and had stagnant or worsening symptoms before oral extended-release metformin (500 mg daily) was added to treatment. (Treatments included topical clobetasol, compounded minoxidil, and platelet-rich plasma injections.)
- Scalp biopsies were collected from four patients before and after metformin treatment to evaluate gene expression changes.
- Changes in clinical symptoms were assessed, including pruritus, inflammation, pain, scalp resistance, and hair regrowth, following initiation of metformin treatment.
TAKEAWAY:
- Metformin led to significant clinical improvement in eight patients, which included reductions in scalp pain, scalp resistance, pruritus, and inflammation. However, two patients experienced worsening symptoms.
- Six patients showed clinical evidence of hair regrowth after at least 6 months of metformin treatment with one experiencing hair loss again 3 months after discontinuing treatment.
- Transcriptomic analysis revealed 34 upregulated genes, which included upregulated of 23 hair keratin-associated proteins, and pathways related to keratinization, epidermis development, and the hair cycle. In addition, eight genes were downregulated, with pathways that included those associated with extracellular matrix organization, collagen fibril organization, and collagen metabolism.
- Gene set variation analysis showed reduced expression of T helper 17 cell and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and keratin-associated proteins after treatment with metformin.
IN PRACTICE:
“Metformin’s ability to concomitantly target fibrosis and inflammation provides a plausible mechanism for its therapeutic effects in CCCA and other fibrosing alopecia disorders,” the authors concluded. But, they added, “larger prospective, placebo-controlled randomized clinical trials are needed to rigorously evaluate metformin’s efficacy and optimal dosing for treatment of cicatricial alopecias.”
SOURCE:
The study was led by Aaron Bao, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, and was published online on September 4 in JAMA Dermatology.
LIMITATIONS:
A small sample size, retrospective design, lack of a placebo control group, and the single-center setting limited the generalizability of the study findings. In addition, the absence of a validated activity or severity scale for CCCA and the single posttreatment sampling limit the assessment and comparison of clinical symptoms and transcriptomic changes.
DISCLOSURES:
The study was supported by the American Academy of Dermatology. One author reported several ties with pharmaceutical companies, a pending patent, and authorship for the UpToDate section on CCCA.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
, in a retrospective case series.
METHODOLOGY:
- Researchers conducted a case series involving 12 Black women in their 30s, 40s, and 50s, with biopsy-confirmed, treatment-refractory CCCA, a chronic inflammatory hair disorder characterized by permanent hair loss, from the Johns Hopkins University alopecia clinic.
- Participants received CCCA treatment for at least 6 months and had stagnant or worsening symptoms before oral extended-release metformin (500 mg daily) was added to treatment. (Treatments included topical clobetasol, compounded minoxidil, and platelet-rich plasma injections.)
- Scalp biopsies were collected from four patients before and after metformin treatment to evaluate gene expression changes.
- Changes in clinical symptoms were assessed, including pruritus, inflammation, pain, scalp resistance, and hair regrowth, following initiation of metformin treatment.
TAKEAWAY:
- Metformin led to significant clinical improvement in eight patients, which included reductions in scalp pain, scalp resistance, pruritus, and inflammation. However, two patients experienced worsening symptoms.
- Six patients showed clinical evidence of hair regrowth after at least 6 months of metformin treatment with one experiencing hair loss again 3 months after discontinuing treatment.
- Transcriptomic analysis revealed 34 upregulated genes, which included upregulated of 23 hair keratin-associated proteins, and pathways related to keratinization, epidermis development, and the hair cycle. In addition, eight genes were downregulated, with pathways that included those associated with extracellular matrix organization, collagen fibril organization, and collagen metabolism.
- Gene set variation analysis showed reduced expression of T helper 17 cell and epithelial-mesenchymal transition pathways and elevated adenosine monophosphate kinase signaling and keratin-associated proteins after treatment with metformin.
IN PRACTICE:
“Metformin’s ability to concomitantly target fibrosis and inflammation provides a plausible mechanism for its therapeutic effects in CCCA and other fibrosing alopecia disorders,” the authors concluded. But, they added, “larger prospective, placebo-controlled randomized clinical trials are needed to rigorously evaluate metformin’s efficacy and optimal dosing for treatment of cicatricial alopecias.”
SOURCE:
The study was led by Aaron Bao, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, and was published online on September 4 in JAMA Dermatology.
LIMITATIONS:
A small sample size, retrospective design, lack of a placebo control group, and the single-center setting limited the generalizability of the study findings. In addition, the absence of a validated activity or severity scale for CCCA and the single posttreatment sampling limit the assessment and comparison of clinical symptoms and transcriptomic changes.
DISCLOSURES:
The study was supported by the American Academy of Dermatology. One author reported several ties with pharmaceutical companies, a pending patent, and authorship for the UpToDate section on CCCA.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Thyroid Resistance Ups Mortality in Euthyroid CKD Patients
TOPLINE:
An impaired central sensitivity to thyroid hormone may be associated with an increased risk for death in patients with chronic kidney disease (CKD) and normal thyroid function.
METHODOLOGY:
- Previous studies have shown that abnormal levels of thyroid-stimulating hormone (TSH) are associated with a higher mortality risk in patients with CKD, but whether the risk extends to those with normal thyroid function remains controversial.
- Researchers investigated the association between central sensitivity to thyroid hormone and the risk for all-cause mortality in 1303 euthyroid patients with CKD (mean age, 60 years; 59% women) from the National Health and Nutrition Examination Survey database (2007-2012).
- All participants had CKD stages I-IV, defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 and/or a urinary albumin to urinary creatinine ratio ≥ 30 mg/g.
- The central sensitivity to thyroid hormone was primarily evaluated using a new central thyroid hormone resistance index, the Thyroid Feedback Quantile–based Index (TFQI), using free thyroxine and TSH concentrations.
- The participants were followed for a median duration of 115 months, during which 503 died.
TAKEAWAY:
- Patients with CKD who died during the follow-up period had a significantly higher TFQI (P < .001) than those who survived.
- The rates of all-cause mortality increased from 26.61% in the lowest TFQI tertile to 40.89% in the highest tertile (P = .001).
- A per unit increase in the TFQI was associated with a 40% increased risk for all-cause mortality (hazard ratio, 1.40; 95% CI, 1.10-1.79).
- This association between TFQI level and all-cause mortality persisted in all subgroups stratified by age, gender, race, body mass index, hypertension, diabetes, cardiovascular diseases, and CKD stages.
IN PRACTICE:
“Our study demonstrates that impaired sensitivity to thyroid hormone might be associated with all-cause mortality in CKD patients with normal thyroid function, independent of other traditional risk factors and comorbidities,” the authors wrote.
SOURCE:
This study was led by Qichao Yang and Ru Dong, Department of Endocrinology, Affiliated Wujin Hospital of Jiangsu University, Changzhou, China, and was published online on August 6, 2024, in BMC Public Health.
LIMITATIONS:
Thyroid function was measured only at baseline, and the changes in thyroid function over time were not measured. The study excluded people on thyroid hormone replacement therapy but did not consider other medication use that might have affected thyroid function, such as beta-blockers, steroids, and amiodarone. Thyroid-related antibodies, metabolic syndrome, and nonalcoholic fatty liver disease were not included in the analysis as possible confounding factors. The US-based sample requires further validation.
DISCLOSURES:
The study was supported by the Changzhou Health Commission. The authors declared no competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
An impaired central sensitivity to thyroid hormone may be associated with an increased risk for death in patients with chronic kidney disease (CKD) and normal thyroid function.
METHODOLOGY:
- Previous studies have shown that abnormal levels of thyroid-stimulating hormone (TSH) are associated with a higher mortality risk in patients with CKD, but whether the risk extends to those with normal thyroid function remains controversial.
- Researchers investigated the association between central sensitivity to thyroid hormone and the risk for all-cause mortality in 1303 euthyroid patients with CKD (mean age, 60 years; 59% women) from the National Health and Nutrition Examination Survey database (2007-2012).
- All participants had CKD stages I-IV, defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 and/or a urinary albumin to urinary creatinine ratio ≥ 30 mg/g.
- The central sensitivity to thyroid hormone was primarily evaluated using a new central thyroid hormone resistance index, the Thyroid Feedback Quantile–based Index (TFQI), using free thyroxine and TSH concentrations.
- The participants were followed for a median duration of 115 months, during which 503 died.
TAKEAWAY:
- Patients with CKD who died during the follow-up period had a significantly higher TFQI (P < .001) than those who survived.
- The rates of all-cause mortality increased from 26.61% in the lowest TFQI tertile to 40.89% in the highest tertile (P = .001).
- A per unit increase in the TFQI was associated with a 40% increased risk for all-cause mortality (hazard ratio, 1.40; 95% CI, 1.10-1.79).
- This association between TFQI level and all-cause mortality persisted in all subgroups stratified by age, gender, race, body mass index, hypertension, diabetes, cardiovascular diseases, and CKD stages.
IN PRACTICE:
“Our study demonstrates that impaired sensitivity to thyroid hormone might be associated with all-cause mortality in CKD patients with normal thyroid function, independent of other traditional risk factors and comorbidities,” the authors wrote.
SOURCE:
This study was led by Qichao Yang and Ru Dong, Department of Endocrinology, Affiliated Wujin Hospital of Jiangsu University, Changzhou, China, and was published online on August 6, 2024, in BMC Public Health.
LIMITATIONS:
Thyroid function was measured only at baseline, and the changes in thyroid function over time were not measured. The study excluded people on thyroid hormone replacement therapy but did not consider other medication use that might have affected thyroid function, such as beta-blockers, steroids, and amiodarone. Thyroid-related antibodies, metabolic syndrome, and nonalcoholic fatty liver disease were not included in the analysis as possible confounding factors. The US-based sample requires further validation.
DISCLOSURES:
The study was supported by the Changzhou Health Commission. The authors declared no competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
An impaired central sensitivity to thyroid hormone may be associated with an increased risk for death in patients with chronic kidney disease (CKD) and normal thyroid function.
METHODOLOGY:
- Previous studies have shown that abnormal levels of thyroid-stimulating hormone (TSH) are associated with a higher mortality risk in patients with CKD, but whether the risk extends to those with normal thyroid function remains controversial.
- Researchers investigated the association between central sensitivity to thyroid hormone and the risk for all-cause mortality in 1303 euthyroid patients with CKD (mean age, 60 years; 59% women) from the National Health and Nutrition Examination Survey database (2007-2012).
- All participants had CKD stages I-IV, defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 and/or a urinary albumin to urinary creatinine ratio ≥ 30 mg/g.
- The central sensitivity to thyroid hormone was primarily evaluated using a new central thyroid hormone resistance index, the Thyroid Feedback Quantile–based Index (TFQI), using free thyroxine and TSH concentrations.
- The participants were followed for a median duration of 115 months, during which 503 died.
TAKEAWAY:
- Patients with CKD who died during the follow-up period had a significantly higher TFQI (P < .001) than those who survived.
- The rates of all-cause mortality increased from 26.61% in the lowest TFQI tertile to 40.89% in the highest tertile (P = .001).
- A per unit increase in the TFQI was associated with a 40% increased risk for all-cause mortality (hazard ratio, 1.40; 95% CI, 1.10-1.79).
- This association between TFQI level and all-cause mortality persisted in all subgroups stratified by age, gender, race, body mass index, hypertension, diabetes, cardiovascular diseases, and CKD stages.
IN PRACTICE:
“Our study demonstrates that impaired sensitivity to thyroid hormone might be associated with all-cause mortality in CKD patients with normal thyroid function, independent of other traditional risk factors and comorbidities,” the authors wrote.
SOURCE:
This study was led by Qichao Yang and Ru Dong, Department of Endocrinology, Affiliated Wujin Hospital of Jiangsu University, Changzhou, China, and was published online on August 6, 2024, in BMC Public Health.
LIMITATIONS:
Thyroid function was measured only at baseline, and the changes in thyroid function over time were not measured. The study excluded people on thyroid hormone replacement therapy but did not consider other medication use that might have affected thyroid function, such as beta-blockers, steroids, and amiodarone. Thyroid-related antibodies, metabolic syndrome, and nonalcoholic fatty liver disease were not included in the analysis as possible confounding factors. The US-based sample requires further validation.
DISCLOSURES:
The study was supported by the Changzhou Health Commission. The authors declared no competing interests.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Metabolism Biomarkers on Newborn Screen May Help Predict SIDS
new data suggest.
Findings of the study by Scott P. Oltman, MS, of the Department of Epidemiology & Biostatistics, University of California, San Francisco, and colleagues were published in JAMA Pediatrics.
The case-controlled study showed a link between aberrant metabolic analytes at birth and SIDS. Researchers used data from the California Office of Statewide Health Planning and Development and the California Department of Public Health and included 2.3 million infants born between 2005 and 2011 in the dataset.
Of the 2.3 million infants, 354 had SIDS. The researchers found that 14 newborn screening metabolites were significantly associated with SIDS. After the screens, the babies who had elevated metabolite markers, compared with the control babies had 14.4 times higher odds of having SIDS, the researchers reported.
“It’s really promising research,” Joanna J. Parga-Belinkie, MD, an attending neonatologist who was not involved in the study, said in an interview. She practices in the Division of Neonatology at Children’s Hospital of Philadelphia in Pennsylvania. “It doesn’t really give us the answer to what causes SIDS, but I think in the long term it’s going to inform a lot of research that will help us understand whether there are biomarkers that can predict SIDS.”
Other studies have looked at different metabolic markers to see if they can help predict SIDS, she said, but the innovation in this study is that it uses newborn screens, which are collected on all babies born in a hospital. Dr. Parga-Belinkie added that another strength of the study is its large sample size and matched controls to compare the SIDS cases with healthy babies.
“That said, newborn screens are a screening test, they are not diagnostic,” Dr. Parga-Belinkie said. “We definitely need further testing to see if (the metabolic biomarkers) really make that link to SIDS.”
It will be important to test this in a prospective study over time and in real time, she said, which is something the authors acknowledge. They list the retrospective design of the study as a major limitation.
These study results won’t change the counseling for families on decreasing risk, Dr. Parga-Belinkie said, “because there’s not a clear biomarker that has emerged and we don’t have a clear link yet.” Safe sleep hygiene will continue to be the primary focus of counseling parents, such as placing the baby on its back on a firm, flat surface with no loose bedding or stuffed animals.
The study authors said several things will need to be clarified with future research, noting that a majority of the infants in the California database were of Hispanic ethnicity. Testing other populations will help determine generalizability.
Also, there has been ambiguity in the definition of SIDS, which has led to inconsistencies in classifying a death as SIDS or death from an unknown cause of suffocation or asphyxiation.
They added: “It may also be the case that these markers are predictive and reliable but not causal in nature and distinguishing between the two is a crucial topic for future investigation.”
This work was supported in part by the California Preterm Birth Initiative within the University of California, San Francisco, and by the National Institutes of Health. Mr. Oltman reported having a patent pending for a newborn metabolic vulnerability model for identifying preterm infants at risk of adverse outcomes and uses thereof. One coauthor reported having a patent pending and a patent issued; another reported having a patent pending for a newborn metabolic vulnerability model for identifying preterm infants at risk of adverse outcomes and uses thereof. Dr. Parga-Belinkie declared no relevant financial disclosures.
new data suggest.
Findings of the study by Scott P. Oltman, MS, of the Department of Epidemiology & Biostatistics, University of California, San Francisco, and colleagues were published in JAMA Pediatrics.
The case-controlled study showed a link between aberrant metabolic analytes at birth and SIDS. Researchers used data from the California Office of Statewide Health Planning and Development and the California Department of Public Health and included 2.3 million infants born between 2005 and 2011 in the dataset.
Of the 2.3 million infants, 354 had SIDS. The researchers found that 14 newborn screening metabolites were significantly associated with SIDS. After the screens, the babies who had elevated metabolite markers, compared with the control babies had 14.4 times higher odds of having SIDS, the researchers reported.
“It’s really promising research,” Joanna J. Parga-Belinkie, MD, an attending neonatologist who was not involved in the study, said in an interview. She practices in the Division of Neonatology at Children’s Hospital of Philadelphia in Pennsylvania. “It doesn’t really give us the answer to what causes SIDS, but I think in the long term it’s going to inform a lot of research that will help us understand whether there are biomarkers that can predict SIDS.”
Other studies have looked at different metabolic markers to see if they can help predict SIDS, she said, but the innovation in this study is that it uses newborn screens, which are collected on all babies born in a hospital. Dr. Parga-Belinkie added that another strength of the study is its large sample size and matched controls to compare the SIDS cases with healthy babies.
“That said, newborn screens are a screening test, they are not diagnostic,” Dr. Parga-Belinkie said. “We definitely need further testing to see if (the metabolic biomarkers) really make that link to SIDS.”
It will be important to test this in a prospective study over time and in real time, she said, which is something the authors acknowledge. They list the retrospective design of the study as a major limitation.
These study results won’t change the counseling for families on decreasing risk, Dr. Parga-Belinkie said, “because there’s not a clear biomarker that has emerged and we don’t have a clear link yet.” Safe sleep hygiene will continue to be the primary focus of counseling parents, such as placing the baby on its back on a firm, flat surface with no loose bedding or stuffed animals.
The study authors said several things will need to be clarified with future research, noting that a majority of the infants in the California database were of Hispanic ethnicity. Testing other populations will help determine generalizability.
Also, there has been ambiguity in the definition of SIDS, which has led to inconsistencies in classifying a death as SIDS or death from an unknown cause of suffocation or asphyxiation.
They added: “It may also be the case that these markers are predictive and reliable but not causal in nature and distinguishing between the two is a crucial topic for future investigation.”
This work was supported in part by the California Preterm Birth Initiative within the University of California, San Francisco, and by the National Institutes of Health. Mr. Oltman reported having a patent pending for a newborn metabolic vulnerability model for identifying preterm infants at risk of adverse outcomes and uses thereof. One coauthor reported having a patent pending and a patent issued; another reported having a patent pending for a newborn metabolic vulnerability model for identifying preterm infants at risk of adverse outcomes and uses thereof. Dr. Parga-Belinkie declared no relevant financial disclosures.
new data suggest.
Findings of the study by Scott P. Oltman, MS, of the Department of Epidemiology & Biostatistics, University of California, San Francisco, and colleagues were published in JAMA Pediatrics.
The case-controlled study showed a link between aberrant metabolic analytes at birth and SIDS. Researchers used data from the California Office of Statewide Health Planning and Development and the California Department of Public Health and included 2.3 million infants born between 2005 and 2011 in the dataset.
Of the 2.3 million infants, 354 had SIDS. The researchers found that 14 newborn screening metabolites were significantly associated with SIDS. After the screens, the babies who had elevated metabolite markers, compared with the control babies had 14.4 times higher odds of having SIDS, the researchers reported.
“It’s really promising research,” Joanna J. Parga-Belinkie, MD, an attending neonatologist who was not involved in the study, said in an interview. She practices in the Division of Neonatology at Children’s Hospital of Philadelphia in Pennsylvania. “It doesn’t really give us the answer to what causes SIDS, but I think in the long term it’s going to inform a lot of research that will help us understand whether there are biomarkers that can predict SIDS.”
Other studies have looked at different metabolic markers to see if they can help predict SIDS, she said, but the innovation in this study is that it uses newborn screens, which are collected on all babies born in a hospital. Dr. Parga-Belinkie added that another strength of the study is its large sample size and matched controls to compare the SIDS cases with healthy babies.
“That said, newborn screens are a screening test, they are not diagnostic,” Dr. Parga-Belinkie said. “We definitely need further testing to see if (the metabolic biomarkers) really make that link to SIDS.”
It will be important to test this in a prospective study over time and in real time, she said, which is something the authors acknowledge. They list the retrospective design of the study as a major limitation.
These study results won’t change the counseling for families on decreasing risk, Dr. Parga-Belinkie said, “because there’s not a clear biomarker that has emerged and we don’t have a clear link yet.” Safe sleep hygiene will continue to be the primary focus of counseling parents, such as placing the baby on its back on a firm, flat surface with no loose bedding or stuffed animals.
The study authors said several things will need to be clarified with future research, noting that a majority of the infants in the California database were of Hispanic ethnicity. Testing other populations will help determine generalizability.
Also, there has been ambiguity in the definition of SIDS, which has led to inconsistencies in classifying a death as SIDS or death from an unknown cause of suffocation or asphyxiation.
They added: “It may also be the case that these markers are predictive and reliable but not causal in nature and distinguishing between the two is a crucial topic for future investigation.”
This work was supported in part by the California Preterm Birth Initiative within the University of California, San Francisco, and by the National Institutes of Health. Mr. Oltman reported having a patent pending for a newborn metabolic vulnerability model for identifying preterm infants at risk of adverse outcomes and uses thereof. One coauthor reported having a patent pending and a patent issued; another reported having a patent pending for a newborn metabolic vulnerability model for identifying preterm infants at risk of adverse outcomes and uses thereof. Dr. Parga-Belinkie declared no relevant financial disclosures.
FROM JAMA PEDIATRICS