Last week the Food and Drug Administration approved a first-of-its-kind drug specifically indicated for postpartum depression. The drug developed by Sage Therapeutics and marketed as Zulpresso (aka brexanolone) is administered as a continuous 60-hour IV drip, is fast acting, and its antidepressant effects can last for a month. Will it be a game changer for new mothers or just another marketing travesty?
Brexanolone received FDA “Breakthrough Therapy Designation” in 2016, allowing the company to speed up the development and approval process to address “significant unmet need” for postpartum depression treatment. The drug originally was studied as a treatment for seizure patients. However, it failed to meet the clinical study primary endpoints and the seizure studies were halted in 2017, though not before its antidepressant properties were discovered.
According to the FDA briefing documents, brexanolone is “a new molecular entity not currently marketed anywhere in the world for any indication.” Although the mechanism by which brexanolone actually treats postpartum depression is not entirely known, it is chemically identical to allopgrenanolone, a “positive allosteric modulator of GABAA receptors.” According to Wikipedia, GABAA receptor PAMs used as drugs have mainly sedative and anxiolytic effects. Examples of GABAAPAMs include benzodiazepines (e.g. Valium and Xanax) and sleep aid drugs (e.g. Ambien).
Postpartum depression (PDD) is characterized by a feeling of hopelessness lasting more than two weeks after giving birth. It affects approximately one in nine women who have given birth in the U.S., about 400,000 women annually. Severe PPD can be serious yet far less common than the “baby blues” (sadness that lasts three to five days after childbirth and affects up to 80% of new mothers). Symptoms of PPD may include sadness, anxiety, irritability, withdrawing from friends or family, experiencing difficulty bonding with the newborn, and thinking about harming herself or, more rarely, her baby.
Although this drug is already being touted by the media and medical and patient advocacy communities as a “game changer,” the reality is that this drug was studied in relatively few women, and the pharmaceutical manufacturer oversaw the overall study design and interpretation of the results. The FDA approval was based primarily on three studies comprising a total of 247 women — 140 received the drug and 107 received a placebo. As a side note, almost all the patients were caucasian so there is no way to know the safety or effectiveness for other racial or ethnic groups, since drug efficacy often varies by ethnicity. Such a limited and homogeneous pool of women hardly constitutes this as a robust and valid study before rolling this drug out to the general public.
The two efficacy studies, based on the Hamilton Depression Scale (HAM-D), found modest but significant approval by the end of the continuous 60-hour infusion for brexnolone compared to the placebo. However, the drug exhibited inconsistent results at day 30 — one study showed a benefit while the other did not. Sage’s CEO defended the drug on a call with investors, stating: “The placebo response was more volatile, which accounted for the inability to show a durable benefit in the moderate study.” In other words, there could be a placebo effect which is not uncommon for antidepressant trials. This lack of a clearly demonstrable benefit of the drug versus no drug is troublesome, and cries out for further study before it is blessed with a seal of approval and marketed to doctors and new mothers.
More importantly, the potential for harm was more common in brexanolone compared to the placebo. The most commonly experienced side effects of the drug ranged from headaches, dizziness, nausea, infusion site pain, somnolence, and fatigue, to more severe effects such as increased risk of sedation, and total loss of consciousness. Also, we still don’t know about the drug’s effect on breastfeeding babies as women were not allowed to breastfeed during this study.
ONE IS THE LONELIEST NUMBER
Although the FDA ultimately approved the drug, it first convened a joint FDA Advisory Committee of Psychopharmacologic and Risk Safety Management members in November 2018 to evaluate and provide external advice on brexanolone. Ultimately, after reviewing the clinical studies, this FDA Advisory Committee recommended approval of brexanolone by a 17-1 member vote.
As is frequently the case, I was the only NO vote. I voted NO because as the sole Consumer Representative on the committee I didn’t believe the company had demonstrated that the potential benefits outweighed the potential for harm. There are real-world implications once these drugs are approved, touted in the news and placed on the market, advertised with an FDA stamp of approval on them and counted on without question by the doctors prescribing them to potentially hundreds of thousands of new mothers and their families who are looking for hope and relief.
I had, and have, serious reservations about the long-term safety data of this 60-hour continuous IV drug. I was and am concerned because the loss of consciousness can be abrupt in some instances, and we don’t yet know who is going to be at risk for loss of consciousness. Immediate intervention would be required in such events and in those cases the infusion would need to be stopped. But we don’t know what would happen if the infusion wasn’t stopped. I worry, depending on where the infusion takes place, about the risks to the mother — and the risks to their babies, such as dropping them, or even accidentally smothering the baby if there is no one there to quickly respond. Or the effect of the drug on babies that are breastfed.
Like the recent nasal spray for depression that was recently recommended, this drug will come with a Risk Evaluation Mitigation Strategy program. According to the Zulpresso REMS program, “Patients must be continuously monitored for the duration of the infusion and 12 hours after, by a health care provider who can intervene if the patient experiences excessive sedation or loss of consciousness.” Again, many committee members assume the REMS program will address and solve for any safety concerns. I only wish the media had read the post-meeting transcripts and not simply reported on the numerical vote. They would have quickly realized that there was a lot of discussion around safety, and the transcripts help color the true discussion around these controversial drug approvals. There is often a long debate following the question of whether a drug’s benefits outweigh the risks and therefore should be approved. Many committee members vote yes, yet still have considerable safety concerns that don’t get accurately reported.
For example, one member stated, “I have concerns about safety that cannot be fully answered by the limited data… I’m concerned about loss of consciousness and sedation.” There was also some disagreement on the panel as to what specific type of professional and/or facility would qualify, with some stating that only a hospital setting with a trained nurse would be sufficient, whereas others felt that alternative professionals could be trained and settings configured to perform the type of monitoring that was done in the trials. Panel members also debated the type of interaction the mother should be allowed with her newborn while she receives the infusion. All of this information is necessary for the public to get a true sense of the issues surrounding a new drug approval. And the answers to these concerns should be clear and unambiguous before approval and rollout.
While I acknowledge that treatments for postpartum depression are needed, I am skeptical that all promises made during the FDA meeting will be kept and followed through with. I cannot in good conscience cross my fingers and hope that the drug with its REMS program gets administered properly for the potential benefit. It wasn’t a risk that I was willing to take. REMS programs are neither enforceable nor a guarantee of safety. As a member of the FDA Advisory Committee, I believe it’s our moral obligation to make sure that all drugs with this risk potential are scrutinized and held to a higher standard in the approval process. More research is needed before we can be sure that this is not just the latest in a long line of drugs offered to women as a quick fix with minimal efficacy and the potential for unintended side effects. I fail to see why scientifically proper studies cannot be completed prior to rollout of this new drug treatment, to ensure efficacy and safety. A rushed study process reinforces my concerns, especially when the company performing the studies is the manufacturer and there are no true checks and balances in the system.
FOLLOW THE MONEY
Given the costly nature of Zulpresso ($34,000/treatment) and having to spend 2 1/2 days in a healthcare setting, one has to wonder if there will one day be a pill version available. In January, Sage announced that the next drug in its pipeline is a more convenient, once-daily pill for women suffering from PPD. The FDA is permitting Sage to conduct fewer and shorter clinical trials for its second drug, currently known as SAGE-217. Some Wall Street analysts predict that the Zulpresso IV drug may amass peak annual revenue approximating $300 million. However, SAGE-217 could generate billions of dollars in sales as an entirely new way to treat postpartum depression and major depressive disorders. That’s because the drug works much the same way as Zulpresso, but as a pill taken once per day it wouldn’t have the practical limitations of a 60-hour infusion.
Since postpartum depression affects as many as one in nine new mothers, it definitely appears that a pill format is destined to be a blockbuster. Yet there’s a difference between a drug that works and a drug that merely sells. In my opinion, many mental health conditions are ripe for “diagnostic creep,” perhaps better described as “selling sickness,” which blurs lines between normal situational human experiences and those which truly merit pharmaceutical intervention. The “selling sickness” systemic bias can lead to greatly expanding the pool of potential patients for drug treatment within the postpartum depression “market.” For example, years before Zulpresso was approved, Sage Therapeutics launched a postpartum depression “disease awareness” campaign with the slogan “Silence Sucks,” which showed women sucking on pacifiers and encouraged mothers to talk about their postpartum depression. They were creating demand before the drug even came to market. The unbranded company-funded “Silence Sucks” website has since been removed. This whole approach reeks of preying on fear.
At the end of the day, is this drug approval really about advancing the treatment for women truly suffering from postpartum depression or is it about marketing hope to make a profit?
FAITH AND HOPE
I will never forget one of the stories told during the FDA open public hearing. This young man came on his own time and dime to tell his wife’s tragic story of postpartum depression. While they were waiting for the antidepressant Zoloft to “kick in” after their son was born, she took her own life. He was desperately pleading in the forum, and was convinced that if the fast-acting infusion drug had been available for her that she would still be around. Instead he is wifeless and his son is now motherless. I felt his pain and it took everything in me not to cry as several years ago I experienced a similar tragic loss.
To this man, wherever he is: believe it or not, I am fighting for you, your wife and for the many women who suffer from postpartum depression. We will never know if this particular drug could have saved her life. But I do know this… we, the public, want to believe and hope that “new discovery” drugs will help more than they will harm. But we all deserve to have more assurance about both their efficacy and their safety BEFORE they are given a stamp of approval and brought to market. Our pharmaceutical approval processes should not be based on “hope,” but rather should have appropriately conducted trials and studies to support broad rollout. That should not be too much to ask of and by all constituents in this process.
