FDA News

FDA committees do not support buprenorphine/samidorphan for major depression

In a combined meeting, the FDA’s Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted unfavorably for buprenorphine/samidorphan intended for the adjunctive treatment of major depression.

The joint committee evaluated the new drug application for a fixed-dose combination product containing buprenorphine and samidorphan that targets the opioid system, known as ALKS 5461 (Alkermes), intended as an adjunctive treatment for MDD.

At the meeting, the Committee voted on three core questions:

  • Has substantial evidence been presented to support the effectiveness of buprenorphine/samidorphan for the adjunctive treatment of MDD? Against 20-3
  • Has Alkermes adequately characterized the safety profile of buprenorphine/samidorphan for adjunctive treatment of MDD? For 13-10
  • Do the data show a favorable benefit-risk profile of buprenorphine/samidorphan to support approval? Against 21-2

The committee also discussed the potential risks associated with the use, misuse and abuse of buprenorphine/samidorphan in post-market settings. One of the main points was that although Alkermes presented supportive short-term data, there is not enough information on the long-term efficacy and safety of the drug.

The drug has been studied in four placebo-controlled trials (three phase 3 and one phase 2) —two of which met their primary endpoint.

Data from a 1-year, open-label extension study presented early this year at the 2018 American Society of Clinical Psychopharmacology annual meeting revealed that ALKS 5461 showed antidepressant effects for up to 52 weeks of treatment in patients with major depressive disorder. Additionally, recently-published evidence from two phase three clinical trials, known as FORWARD-4 and FORWARD-5, of ALKS 5461 supports its safety and effectiveness in decreasing symptoms of major depression when added to standard antidepressant treatment.

The product, formulated as a tablet for sublingual administration, would be available in buprenorphine/samidorphan 2 mg/2 mg, 1 mg/1 mg and 0.5 mg/0.5 mg strengths; but, the target dosage for most patients would be 2 mg/2 mg per day, according to the FDA briefing document.

Committee concerns

“It’s important to note that FDA and the applicant do not agree on whether this drug has met the standard for substantial evidence for effectiveness,” Mitchell Mathis, MD, division director of psychiatry products at FDA, said in the opening remarks.

Three of these studies used a novel study design: a 2-stage, sequential parallel comparison design meant to reduce the higher placebo response often seen in studies of antidepressants. However, this design has not yet been determined to be statistically acceptable to the FDA.

During the meeting, the FDA expressed concern about the sequential parallel comparison design used in the studies. This is the first time studies with a sequential parallel comparison design have been submitted to the FDA’s Division of Psychiatry Products to provide evidence of efficacy for a new drug.

Usually studies for antidepressant treatments examine an efficacy endpoint at a specific time point following several weeks of therapy, according to the FDA. These trials achieved primary endpoint because researchers averaged patients’ depression symptoms over multiple weeks, which is not standard for antidepressant trials. Although averaging scores from multiple weeks can reduce the symptom changes that often vary over time throughout treatment, scores at the final time point carry less weight.

Although one of the phase 3 studies met its primary endpoint, the committees expressed worry because the trial investigators used an abridged 6-item version of the Montgomery Åsberg Depression Rating Scale-10 for the primary endpoint of this principal study. The FDA’s Clinical Outcomes Assessment staff believe MADRS-6 cannot replace the MADRS-10 because it excludes concepts important in major depression, like reduced sleep, reduced appetite, concentration difficulties and suicidal thoughts, according to the review.

FDA made it clear to Alkermes that any studies using the MADRS-6 would be “considered exploratory,” according to Tiffany Farchione, MD, deputy director of the division of psychiatry products at the FDA.

Researchers also performed MADRS-10 to determine efficacy in this phase 3 study, but they averaged the scores. Semhar Ogbagaber, PhD, from the division of biometrics at FDA, pointed out that the efficacy of the buprenorphine/samidorphan 2 mg/2 mg dose used in the study was unclear because it was supported based on MADRS-10 averaged scores. However, Alkermes disagreed.

“We can use MADRS-10 to look at the data across all four studies based on the difference between two group of multiple time points,” Jerald Schindler, DrPH, vice president of biostatistics at Alkermes, said. “What this does is reduces the impact of the week-to-week variability of the data and better reflects the patients’ experience over time.”

Doing this showed that the buprenorphine/samidorphan 2 mg/2 mg dose was better than placebo in three of the four studies, according to Schindler. Taken together, “the data showed that this dose is effective for the adjunctive treatment of major depression.”

The committee also expressed concerns about using an investigational opioid system modulator. Samidorphan acts as an opioid antagonist, Edward Hawkins, PhD, pharmacologist on the controlled substance staff at FDA, explained. Although samidorphan largely negates the -opioid properties of buprenorphine, conclusive evidence is lacking and there is some evidence of a mild opiate effect from the trials.

Celeste Mallama, PhD, MPH , from the division of epidemiology, reviewed epidemiologic and surveillance data regarding buprenorphine. The FDA uses an approach to assess the risk-benefit balance of opioid-containing products that considers efficacy and safety in patients when used as directed and potential risks related to opioid misuse and abuse.

Given the rapidly growing opioid epidemic and the FDA’s commitment to combat the crisis in the U.S., there remain concerns about use, misuse and abuse of buprenorphine, she explained.

“However, comparing buprenorphine abuse patterns with those of other opioids and using these patterns to try to predict what might happen in patients being treated for depression is challenging due to the high-risk nature of the populations being treated for medication-assisted treatment,” she said. “The buprenorphine/samidorphan product under review has a new, orally-bioavailable antagonist and is indicated for a new population, therefore it is not known whether similar misuse and abuse patterns will be seen.”

Alkermes efficacy, safety data

“There is a need for therapies for patients with major depressive disorder that work through new mechanisms of action,” Lisa von Moltke, MD, senior vice president of clinical development at Alkermes, said.

Schindler talked about the four pivotal trials. Although one of the phase 3 studies did not meet its primary endpoint, which was change in MADRS-10 scores at week 5, patients did see improvement in depression symptoms, he said.

Gary Bloomgren, MD, vice president of drug safety and pharmacovigilance at Alkermes, talked about clinical safety and risk mitigation strategies. Alkermes added samidorphan to mitigate the abuse potential of buprenorphine.

Generally, the treatment showed safety compared with placebo. The common adverse events — mainly gastrointestinal — were mild to moderate in severity and were mainly associated with treatment initiation, he said.

He explained there was low potential for abuse with buprenorphine/samidorphan based on findings from the Human Abuse Potential Study conducted to mitigate the abuse potential of using buprenorphine. Additionally, there was little evidence of withdrawal and no evidence of dependence in the development program, according to Bloomgren.

“Buprenorphine/samidorphan contains buprenorphine and during an opioid crisis we want to ensure, and we are committed to make every effort that buprenorphine/samidorphan is used in an informed and appropriate manner,” he said. “We’re also very much committed to educating health care providers and patients to the appropriate use of this product in the marketplace and implementing additional post-marketing safety initiatives, which included [Risk Evaluation and Mitigation Strategies].”

Their Risk Evaluation and Mitigation Strategies focuses on mitigating misuse and accidental exposure, Bloomgren explained, and includes a medication guide for patients as well as communication materials, a website and call center for professionals.

Sanjay Mathew, MD, from Baylor College of Medicine, shared his clinical perspective and gave his opinion on the benefit-risk profile of the combination.

“In my view, this drug has a positive benefit-risk profile. Its efficacy is comparable to what is available in terms of adjunctive therapy; it offers a new, distinct mechanism of action; and it has a favorable safety profile. In my opinion, [some patients] need these options and as clinicians, we need to have additional options for our patients.” – by Savannah Demko

References:

Fava M, et al. Mol Psychiatry. 2018;doi:10.1038/s41380-018-0284-1.

FDA. New Drug Application 210417 Buprenorphine and Samidorphan for the Adjunctive Treatment of Major Depressive Disorder. https://www.fda.gov/downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM624537.pdf. Accessed on Nov. 1, 2018.

Thase ME, et al. Abstract W34. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29-June 1, 2018; Miami Beach, Fla.

Disclosures: Healio Psychiatry was unable to confirm relevant financial disclosures at the time of publication.

In a combined meeting, the FDA’s Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted unfavorably for buprenorphine/samidorphan intended for the adjunctive treatment of major depression.

The joint committee evaluated the new drug application for a fixed-dose combination product containing buprenorphine and samidorphan that targets the opioid system, known as ALKS 5461 (Alkermes), intended as an adjunctive treatment for MDD.

At the meeting, the Committee voted on three core questions:

  • Has substantial evidence been presented to support the effectiveness of buprenorphine/samidorphan for the adjunctive treatment of MDD? Against 20-3
  • Has Alkermes adequately characterized the safety profile of buprenorphine/samidorphan for adjunctive treatment of MDD? For 13-10
  • Do the data show a favorable benefit-risk profile of buprenorphine/samidorphan to support approval? Against 21-2

The committee also discussed the potential risks associated with the use, misuse and abuse of buprenorphine/samidorphan in post-market settings. One of the main points was that although Alkermes presented supportive short-term data, there is not enough information on the long-term efficacy and safety of the drug.

The drug has been studied in four placebo-controlled trials (three phase 3 and one phase 2) —two of which met their primary endpoint.

Data from a 1-year, open-label extension study presented early this year at the 2018 American Society of Clinical Psychopharmacology annual meeting revealed that ALKS 5461 showed antidepressant effects for up to 52 weeks of treatment in patients with major depressive disorder. Additionally, recently-published evidence from two phase three clinical trials, known as FORWARD-4 and FORWARD-5, of ALKS 5461 supports its safety and effectiveness in decreasing symptoms of major depression when added to standard antidepressant treatment.

The product, formulated as a tablet for sublingual administration, would be available in buprenorphine/samidorphan 2 mg/2 mg, 1 mg/1 mg and 0.5 mg/0.5 mg strengths; but, the target dosage for most patients would be 2 mg/2 mg per day, according to the FDA briefing document.

Committee concerns

“It’s important to note that FDA and the applicant do not agree on whether this drug has met the standard for substantial evidence for effectiveness,” Mitchell Mathis, MD, division director of psychiatry products at FDA, said in the opening remarks.

Three of these studies used a novel study design: a 2-stage, sequential parallel comparison design meant to reduce the higher placebo response often seen in studies of antidepressants. However, this design has not yet been determined to be statistically acceptable to the FDA.

PAGE BREAK

During the meeting, the FDA expressed concern about the sequential parallel comparison design used in the studies. This is the first time studies with a sequential parallel comparison design have been submitted to the FDA’s Division of Psychiatry Products to provide evidence of efficacy for a new drug.

Usually studies for antidepressant treatments examine an efficacy endpoint at a specific time point following several weeks of therapy, according to the FDA. These trials achieved primary endpoint because researchers averaged patients’ depression symptoms over multiple weeks, which is not standard for antidepressant trials. Although averaging scores from multiple weeks can reduce the symptom changes that often vary over time throughout treatment, scores at the final time point carry less weight.

Although one of the phase 3 studies met its primary endpoint, the committees expressed worry because the trial investigators used an abridged 6-item version of the Montgomery Åsberg Depression Rating Scale-10 for the primary endpoint of this principal study. The FDA’s Clinical Outcomes Assessment staff believe MADRS-6 cannot replace the MADRS-10 because it excludes concepts important in major depression, like reduced sleep, reduced appetite, concentration difficulties and suicidal thoughts, according to the review.

FDA made it clear to Alkermes that any studies using the MADRS-6 would be “considered exploratory,” according to Tiffany Farchione, MD, deputy director of the division of psychiatry products at the FDA.

Researchers also performed MADRS-10 to determine efficacy in this phase 3 study, but they averaged the scores. Semhar Ogbagaber, PhD, from the division of biometrics at FDA, pointed out that the efficacy of the buprenorphine/samidorphan 2 mg/2 mg dose used in the study was unclear because it was supported based on MADRS-10 averaged scores. However, Alkermes disagreed.

“We can use MADRS-10 to look at the data across all four studies based on the difference between two group of multiple time points,” Jerald Schindler, DrPH, vice president of biostatistics at Alkermes, said. “What this does is reduces the impact of the week-to-week variability of the data and better reflects the patients’ experience over time.”

Doing this showed that the buprenorphine/samidorphan 2 mg/2 mg dose was better than placebo in three of the four studies, according to Schindler. Taken together, “the data showed that this dose is effective for the adjunctive treatment of major depression.”

The committee also expressed concerns about using an investigational opioid system modulator. Samidorphan acts as an opioid antagonist, Edward Hawkins, PhD, pharmacologist on the controlled substance staff at FDA, explained. Although samidorphan largely negates the -opioid properties of buprenorphine, conclusive evidence is lacking and there is some evidence of a mild opiate effect from the trials.

PAGE BREAK

Celeste Mallama, PhD, MPH , from the division of epidemiology, reviewed epidemiologic and surveillance data regarding buprenorphine. The FDA uses an approach to assess the risk-benefit balance of opioid-containing products that considers efficacy and safety in patients when used as directed and potential risks related to opioid misuse and abuse.

Given the rapidly growing opioid epidemic and the FDA’s commitment to combat the crisis in the U.S., there remain concerns about use, misuse and abuse of buprenorphine, she explained.

“However, comparing buprenorphine abuse patterns with those of other opioids and using these patterns to try to predict what might happen in patients being treated for depression is challenging due to the high-risk nature of the populations being treated for medication-assisted treatment,” she said. “The buprenorphine/samidorphan product under review has a new, orally-bioavailable antagonist and is indicated for a new population, therefore it is not known whether similar misuse and abuse patterns will be seen.”

Alkermes efficacy, safety data

“There is a need for therapies for patients with major depressive disorder that work through new mechanisms of action,” Lisa von Moltke, MD, senior vice president of clinical development at Alkermes, said.

Schindler talked about the four pivotal trials. Although one of the phase 3 studies did not meet its primary endpoint, which was change in MADRS-10 scores at week 5, patients did see improvement in depression symptoms, he said.

Gary Bloomgren, MD, vice president of drug safety and pharmacovigilance at Alkermes, talked about clinical safety and risk mitigation strategies. Alkermes added samidorphan to mitigate the abuse potential of buprenorphine.

Generally, the treatment showed safety compared with placebo. The common adverse events — mainly gastrointestinal — were mild to moderate in severity and were mainly associated with treatment initiation, he said.

He explained there was low potential for abuse with buprenorphine/samidorphan based on findings from the Human Abuse Potential Study conducted to mitigate the abuse potential of using buprenorphine. Additionally, there was little evidence of withdrawal and no evidence of dependence in the development program, according to Bloomgren.

“Buprenorphine/samidorphan contains buprenorphine and during an opioid crisis we want to ensure, and we are committed to make every effort that buprenorphine/samidorphan is used in an informed and appropriate manner,” he said. “We’re also very much committed to educating health care providers and patients to the appropriate use of this product in the marketplace and implementing additional post-marketing safety initiatives, which included [Risk Evaluation and Mitigation Strategies].”

PAGE BREAK

Their Risk Evaluation and Mitigation Strategies focuses on mitigating misuse and accidental exposure, Bloomgren explained, and includes a medication guide for patients as well as communication materials, a website and call center for professionals.

Sanjay Mathew, MD, from Baylor College of Medicine, shared his clinical perspective and gave his opinion on the benefit-risk profile of the combination.

“In my view, this drug has a positive benefit-risk profile. Its efficacy is comparable to what is available in terms of adjunctive therapy; it offers a new, distinct mechanism of action; and it has a favorable safety profile. In my opinion, [some patients] need these options and as clinicians, we need to have additional options for our patients.” – by Savannah Demko

References:

Fava M, et al. Mol Psychiatry. 2018;doi:10.1038/s41380-018-0284-1.

FDA. New Drug Application 210417 Buprenorphine and Samidorphan for the Adjunctive Treatment of Major Depressive Disorder. https://www.fda.gov/downloads/AdvisoryCommittees /CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM624537.pdf. Accessed on Nov. 1, 2018.

Thase ME, et al. Abstract W34. Presented at: American Society of Clinical Psychopharmacology Annual Meeting; May 29-June 1, 2018; Miami Beach, Fla.

Disclosures: Healio Psychiatry was unable to confirm relevant financial disclosures at the time of publication.