FDA News

FDA advisory committees support ‘game-changing’ drug brexanolone for postpartum depression

By a 17-1 vote on Friday, the FDA’s Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee said the benefits of Sage Therapeutics’ brexanolone injection outweigh the risks for managing postpartum depression.

The committees also unanimously agreed that Sage Therapeutics presented “substantial evidence” to support its claim of brexanolone’s effectiveness for postpartum depression and voted 16-2 that the company sufficiently characterized loss-of-consciousness events to allow brexanolone to be used safely.

Brexanolone is a positive allosteric modulator of gamma-aminobutyric-acid type A receptors. The injection would be taken once per postpartum depression episode and be the first medication targeted exclusively for the treatment of postpartum depression, according to Sage Therapeutics.

Multiple studies have found significant and clinically meaningful reductions of postpartum depression at 60-hour and 30-day time intervals in patients who received brexanolone vs. those who received placebo, representatives from Sage Therapeutics said during the hearing.

“Brexanolone is chemically identical to the the endogenous neuroactive steroid allopregnanolone. ... [and] has the potential to provide women suffering from postpartum depression the rapid and sustained improvement they need to feel well, care for themselves and their families,” Stephen J. Kanes, MD, PhD , chief medical officer of Sage Therapeutics, said.

Other clinicians have also touted the positive impact brexanolone would have on women with postpartum depression.

“The term ‘game-changer’ gets tossed around a lot in describing medicines. Rarely does that terminology rise to the significance as it does with brexanolone. ... This medication could be as significant for treating postpartum depression as Prozac was for depression when it was first introduced in the 1990s,” Ramon Solhkhah, MD, chair of psychiatry at Hackensack Meridian Health Jersey Shore University Medical Center, previously told Healio Family Medicine.

Maria Muzik, MD, co-director of Women and Infants Mental Health Program and associate professor in the department of psychiatry at the University of Michigan also previously told Healio “results from phase 3 trials were very encouraging.”

Sad Woman with Sad Baby 
By a 17-1 vote on Friday, the FDA’s Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee said the benefits of Sage Therapeutics’ brexanolone injection outweigh the risks for managing postpartum depression.
Source:Adobe

Participants at Friday’s hearing discussed whether a patient should start with a 60 μg/kg per hour dose and titrate up to 90 μg/kg per hour as needed for patients who are not responding to therapy, or start at the higher dose and decrease it as needed for tolerability.

Helen Colquhoun, MD, Sage Therapeutics’ vice president of medical science, said the company let the data decide which dose would be best and based on the data, the company favors the latter option.

“The decision to reduce the dose was made entirely by the health care professionals and doctors at the testing site based on the clinical picture in front of them. ... There were no prespecified rules regarding dosing.”

Committee members differed on the interpretation of the data to decide the dose.

“I agree from a simplicity point of view that starting at 60 μg/kg per hour dose and working up with the hope that it is an adequate dose for most people for all the obvious reasons,” Steven B. Meisel, PharmD, system director of patient safety at Fairview Health Services in Minneapolis, said.

“That said, we only had 140 patients in all three trials put together and only 38 on the 60 μg/kg per hour dose. Thirty-eight, that’s almost nothing. We have absolutely no idea if 38 is as good as or better than [the 90 μg/kg per hour dose].

Though other committee members felt they should follow the company’s lead, the lack of consensus prompted the committees to leave the decision on dose to the FDA.

Some of the adverse events patients on brexanolone experienced in the studies were loss of consciousness, sedation, dizziness, headache and somnolence, which occurred in a small number of patients, the company said.

Bernard Fischer, MD, FDA clinical team lead, took a closer look at some of the adverse events in the studies. He said there was no relationship between a woman’s age, blood level, BMI, concurrent medications, dose taken, past medical history, time since delivery, time they were on their current dose and vital signs and whether she experienced a loss of consciousness.

“This concerns us because the loss of consciousness can be abrupt in some instances, and we don’t know yet know [who] is going to be at risk for loss of consciousness. Intervention would be required in such events and in [those cases] the infusion is going to be stopped,” Fischer said.

“We don’t know yet what would happen if the infusion wasn’t stopped. We do worry, depending on where the infusion takes place, about risks to the patient, such as falls, and risks to the infant, such as dropping the infant or if the woman is breastfeeding, smothering the infant if no one was there to act,” he added.

Comments at Friday’s meeting indicated there were no reports of babies dropped during the Sage Therapeutics studies, and that the company’s REMS includes training health care professionals on the risks and mitigations from loss of consciousness and that patients with loss of consciousness recovered quickly. If approved, the labels will reflect some of the risks more than others and would indicate it should be used in women who are pregnant, Sage Therapeutics representatives said.

Background documents to today’s hearing obtained by Healio Family Medicine indicate the FDA does not currently think the drug should be administered in a patient’s home. The FDA is still trying ascertain what data Sage Therapeutics needs to provide to change this stance, according to Leah Hart, PharmD, of the FDA’s Office of Surveillance and Epidemiology.

“The FDA’s REMS proposes limiting the administration only in certified health care settings that were consistent with those utilized in the clinical development program,” Hart said, noting patients would also be supervised for 12 hours after administration of the drug.

She added that 85% of patients in the studies received the medication in a non-hospital and clinical research environment.

Panel votes

The committees’ 17-1 vote indicating the benefits of brexanolone injection outweigh the risks for managing postpartum depression came with many caveats.

“As long as the FDA incorporates many of the suggestions on patient monitoring, I think it can be administered safely,” Laurel A. Habel, MPH, PhD, associate director of cancer research at Kaiser Permanente Northern California, said.

Other members also said they voted yes, believing the FDA and the company would address many of their concerns, such as training employees and educating patients about the drug.

Kim O. Witczak, the committees’ consumer representative, acknowledged treatments for postpartum depression are needed but added she was skeptical all promises made during the meeting would be kept.

“The idea of crossing my fingers and hoping it gets done that way for the potential of what could come down the line, and it’s not that I don’t trust you guys, but I can’t rely on trust and crossing fingers,” she said.

Regarding the unanimous vote that Sage Therapeutics presented “substantial evidence” to support its claim of brexanolone’s effectiveness for postpartum depression, many committee members alluded to the strength of the company’s data.

“I was very comfortable the drug will work based on the evidence presented,” Anne-Michelle Ruha, MD, FACMT, director of the medical toxicology fellowship program at Banner University Medical Center in Tucson, Arizona, said.

Other committee members also mentioned the patient benefit.

“The studies were methodologically strong and clearly presented. [This drug] will present a substantial benefit to patients,” Marie R. Griffin, MD, MPH, of the department of health policy at Vanderbilt University Medical Center, said.

Regarding the 16-2 vote in that the company sufficiently characterized loss-of-consciousness events to allow brexanolone to be used safely, one person who voted no said it was in part due to the question’s wording.

“The word ‘characterize’ to me means do we understand why these people lost consciousness, is it predictable ... I don’t feel its adequately understood,” one committee said, while another committee member, Jess G. Fiedorowicz, MD, PhD, an associate professor in the departments of psychiatry, epidemiology and internal medicine at the University of Iowa Carver College of Medicine, attributed his no vote to insufficient information. “I have concerns about safety that cannot be addressed with available data,” Fiedorowicz said.

At least one of those committee members who voted yes said she did so with hesitation.

“I am a little conflicted, but the sponsor did a good job in characterizing these events,” Tina Valbh, PharmD, of the clinical program development and pharmacy services division at Pharmaka Consulting in Mount Dora, Florida, said.

Next steps

According to a press release from Sage Therapeutics, brexanolone’s Prescription Drug User Fee Act date is Dec. 19. The FDA does not have to abide by committee decisions, but historically it has followed committee recommendations. It was unclear at the time of this story’s posting how quickly brexanolone would be available to the public if it is indeed approved on that date. – by Janel Miller

Reference:

FDA Briefing Document Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee Meeting. Nov. 2, 2018. Topic: New Drug Application 211371/New Drug Application, brexanolone for the Treatment of Postpartum Depression. Accessed Nov. 1, 2018.

Disclosure: Healio Family Medicine was unable to determine relevant financial disclosures prior to publication.

Editor's note: This article was updated to show the correct dosage amount of brexanolone. We regret the mistake.

By a 17-1 vote on Friday, the FDA’s Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee said the benefits of Sage Therapeutics’ brexanolone injection outweigh the risks for managing postpartum depression.

The committees also unanimously agreed that Sage Therapeutics presented “substantial evidence” to support its claim of brexanolone’s effectiveness for postpartum depression and voted 16-2 that the company sufficiently characterized loss-of-consciousness events to allow brexanolone to be used safely.

Brexanolone is a positive allosteric modulator of gamma-aminobutyric-acid type A receptors. The injection would be taken once per postpartum depression episode and be the first medication targeted exclusively for the treatment of postpartum depression, according to Sage Therapeutics.

Multiple studies have found significant and clinically meaningful reductions of postpartum depression at 60-hour and 30-day time intervals in patients who received brexanolone vs. those who received placebo, representatives from Sage Therapeutics said during the hearing.

“Brexanolone is chemically identical to the the endogenous neuroactive steroid allopregnanolone. ... [and] has the potential to provide women suffering from postpartum depression the rapid and sustained improvement they need to feel well, care for themselves and their families,” Stephen J. Kanes, MD, PhD , chief medical officer of Sage Therapeutics, said.

Other clinicians have also touted the positive impact brexanolone would have on women with postpartum depression.

“The term ‘game-changer’ gets tossed around a lot in describing medicines. Rarely does that terminology rise to the significance as it does with brexanolone. ... This medication could be as significant for treating postpartum depression as Prozac was for depression when it was first introduced in the 1990s,” Ramon Solhkhah, MD, chair of psychiatry at Hackensack Meridian Health Jersey Shore University Medical Center, previously told Healio Family Medicine.

Maria Muzik, MD, co-director of Women and Infants Mental Health Program and associate professor in the department of psychiatry at the University of Michigan also previously told Healio “results from phase 3 trials were very encouraging.”

Sad Woman with Sad Baby 
By a 17-1 vote on Friday, the FDA’s Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee said the benefits of Sage Therapeutics’ brexanolone injection outweigh the risks for managing postpartum depression.
Source:Adobe

Participants at Friday’s hearing discussed whether a patient should start with a 60 μg/kg per hour dose and titrate up to 90 μg/kg per hour as needed for patients who are not responding to therapy, or start at the higher dose and decrease it as needed for tolerability.

Helen Colquhoun, MD, Sage Therapeutics’ vice president of medical science, said the company let the data decide which dose would be best and based on the data, the company favors the latter option.

“The decision to reduce the dose was made entirely by the health care professionals and doctors at the testing site based on the clinical picture in front of them. ... There were no prespecified rules regarding dosing.”

Committee members differed on the interpretation of the data to decide the dose.

“I agree from a simplicity point of view that starting at 60 μg/kg per hour dose and working up with the hope that it is an adequate dose for most people for all the obvious reasons,” Steven B. Meisel, PharmD, system director of patient safety at Fairview Health Services in Minneapolis, said.

“That said, we only had 140 patients in all three trials put together and only 38 on the 60 μg/kg per hour dose. Thirty-eight, that’s almost nothing. We have absolutely no idea if 38 is as good as or better than [the 90 μg/kg per hour dose].

Though other committee members felt they should follow the company’s lead, the lack of consensus prompted the committees to leave the decision on dose to the FDA.

Some of the adverse events patients on brexanolone experienced in the studies were loss of consciousness, sedation, dizziness, headache and somnolence, which occurred in a small number of patients, the company said.

Bernard Fischer, MD, FDA clinical team lead, took a closer look at some of the adverse events in the studies. He said there was no relationship between a woman’s age, blood level, BMI, concurrent medications, dose taken, past medical history, time since delivery, time they were on their current dose and vital signs and whether she experienced a loss of consciousness.

“This concerns us because the loss of consciousness can be abrupt in some instances, and we don’t know yet know [who] is going to be at risk for loss of consciousness. Intervention would be required in such events and in [those cases] the infusion is going to be stopped,” Fischer said.

“We don’t know yet what would happen if the infusion wasn’t stopped. We do worry, depending on where the infusion takes place, about risks to the patient, such as falls, and risks to the infant, such as dropping the infant or if the woman is breastfeeding, smothering the infant if no one was there to act,” he added.

Comments at Friday’s meeting indicated there were no reports of babies dropped during the Sage Therapeutics studies, and that the company’s REMS includes training health care professionals on the risks and mitigations from loss of consciousness and that patients with loss of consciousness recovered quickly. If approved, the labels will reflect some of the risks more than others and would indicate it should be used in women who are pregnant, Sage Therapeutics representatives said.

PAGE BREAK

Background documents to today’s hearing obtained by Healio Family Medicine indicate the FDA does not currently think the drug should be administered in a patient’s home. The FDA is still trying ascertain what data Sage Therapeutics needs to provide to change this stance, according to Leah Hart, PharmD, of the FDA’s Office of Surveillance and Epidemiology.

“The FDA’s REMS proposes limiting the administration only in certified health care settings that were consistent with those utilized in the clinical development program,” Hart said, noting patients would also be supervised for 12 hours after administration of the drug.

She added that 85% of patients in the studies received the medication in a non-hospital and clinical research environment.

Panel votes

The committees’ 17-1 vote indicating the benefits of brexanolone injection outweigh the risks for managing postpartum depression came with many caveats.

“As long as the FDA incorporates many of the suggestions on patient monitoring, I think it can be administered safely,” Laurel A. Habel, MPH, PhD, associate director of cancer research at Kaiser Permanente Northern California, said.

Other members also said they voted yes, believing the FDA and the company would address many of their concerns, such as training employees and educating patients about the drug.

Kim O. Witczak, the committees’ consumer representative, acknowledged treatments for postpartum depression are needed but added she was skeptical all promises made during the meeting would be kept.

“The idea of crossing my fingers and hoping it gets done that way for the potential of what could come down the line, and it’s not that I don’t trust you guys, but I can’t rely on trust and crossing fingers,” she said.

Regarding the unanimous vote that Sage Therapeutics presented “substantial evidence” to support its claim of brexanolone’s effectiveness for postpartum depression, many committee members alluded to the strength of the company’s data.

“I was very comfortable the drug will work based on the evidence presented,” Anne-Michelle Ruha, MD, FACMT, director of the medical toxicology fellowship program at Banner University Medical Center in Tucson, Arizona, said.

Other committee members also mentioned the patient benefit.

“The studies were methodologically strong and clearly presented. [This drug] will present a substantial benefit to patients,” Marie R. Griffin, MD, MPH, of the department of health policy at Vanderbilt University Medical Center, said.

Regarding the 16-2 vote in that the company sufficiently characterized loss-of-consciousness events to allow brexanolone to be used safely, one person who voted no said it was in part due to the question’s wording.

“The word ‘characterize’ to me means do we understand why these people lost consciousness, is it predictable ... I don’t feel its adequately understood,” one committee said, while another committee member, Jess G. Fiedorowicz, MD, PhD, an associate professor in the departments of psychiatry, epidemiology and internal medicine at the University of Iowa Carver College of Medicine, attributed his no vote to insufficient information. “I have concerns about safety that cannot be addressed with available data,” Fiedorowicz said.

At least one of those committee members who voted yes said she did so with hesitation.

“I am a little conflicted, but the sponsor did a good job in characterizing these events,” Tina Valbh, PharmD, of the clinical program development and pharmacy services division at Pharmaka Consulting in Mount Dora, Florida, said.

Next steps

According to a press release from Sage Therapeutics, brexanolone’s Prescription Drug User Fee Act date is Dec. 19. The FDA does not have to abide by committee decisions, but historically it has followed committee recommendations. It was unclear at the time of this story’s posting how quickly brexanolone would be available to the public if it is indeed approved on that date. – by Janel Miller

Reference:

FDA Briefing Document Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee Meeting. Nov. 2, 2018. Topic: New Drug Application 211371/New Drug Application, brexanolone for the Treatment of Postpartum Depression. Accessed Nov. 1, 2018.

Disclosure: Healio Family Medicine was unable to determine relevant financial disclosures prior to publication.

Editor's note: This article was updated to show the correct dosage amount of brexanolone. We regret the mistake.