With a target PDUFA date of August 11th, FDA is expected to make a decision on Lykos Therapeutics’ MDMA-assisted therapy for PTSD New Drug Application (NDA) at some point this week.
As we brace for a deluge of mainstream media coverage and insider reactions, I’m taking the opportunity to provide a brief assortment of notes and thoughts. I begin by providing a quick sketch of the potential decisions we might see FDA arrive at, before a brief look at where we stand at the moment, including some updates.
This is not an overview article, nor is it rehashing the debates and happenings of the past few months. On those topics, I often wonder what more can be said.
What Might FDA Decide this Week?
As the FDA prepares to post its decision on Lykos’ New Drug Application (NDA), we might expect to see one of three outcomes this week:
- FDA approves MDMA-assisted therapy for PTSD
- FDA issues a Complete Response Letter
- FDA delays its decision
Let’s look at these outcomes, very briefly, in turn.
Approval
Of course, this is what the company along with many advocates and patients will be hoping for. In spite of very poor showings at committees and meetings like ICER’s and the FDA AdComm on the topic, there is still a reasonable chance that MDMA-assisted therapy could squeak through. If so, it would be the first PTSD drug to be approved by the agency for more than two decades.
While any approval will be a watershed moment for the field, the strings that the agency decides to attach to such an approval will temper the reach of the therapy.
We know the agency would mandate a strict Risk Evaluation and Mitigation Strategy (REMS) to manage the ways in which MDMA-assisted therapy is delivered, but there is little clarity over other requirements the FDA might include in any approval, such as the scope and resource-intensity of postmarketing studies that the agency could require. Well, that’s if the agency deems this additional data could be collected in a postmarketing environment… if not, it might reject the package for the time being.
Other outstanding questions include the final labelling language, specifics of the REMS like Elements to Assure Safe Use (ETASU), DEA rescheduling dynamics (at both the federal and state level), and so on.
Complete Response Letter
If FDA is not satisfied with Lykos’ NDA, it will likely issue what’s known as a Complete Response Letter (CRL). Quite simply, this informs the sponsor that the agency will not be approving the NDA as is. The CRL also tends to discuss why the submission is not approvable and how the sponsor can work to address these issues.
In this sense, a CRL is not an outright rejection. If the agency identifies only minor deficiencies, the sponsor can resubmit the package via a Class I resubmission. In these cases, the FDA is supposed to respond within two months. If more substantial modifications to the program are required, a sponsor can resubmit via a Class II resubmission. Here, the agency generally has six months to respond.
These letters are typically kept confidential, so we shouldn’t expect to review a copy any time soon. Lykos might hint at the reasons discussed in the letter in its own public communications, such as whether the problems identified are related to clinical or quality issues, though this is at its discretion.
Data suggest that around a third of NDAs received CRLs (though that figure has bounced around quite substantially from year to year), and that CRLs which mention clinical concerns are generally harder to turn around into an approval.
As such, the obvious and key question in the event of Lykos being issued a CRL is how rectifiable the issues are. If they’re clinical, it might warrant an additional clinical program (i.e., one or more trials), which could really test the company’s ability to find fresh funding.
Delay
As we have mentioned a few times in our recent reporting, it’s not unheard of for the agency to delay its decision. In late March, for example, the agency extended the review period of Applied Therapeutics’ govorestat for the treatment of classic galactosemia by three months1.
Reasons could range from general backlog in the agency/division through to NDA-specific factors such as the agency’s inspections.
If the agency does choose to delay its decision target date, it may or may not choose to publicly announce a new target date.
Vibe Check
In her 2023 book, I Feel Love, journalist Rachel Nuwer charts the history of how MDMA ‘emerged from the shadows to the forefront of a medical revolution’. Of course, MAPS and Lykos have played a leadership role in this (re-)emergence. But I’m doubtful that either organisation is feeling a lot of love right now.
It doesn’t need rehashing here, as the regular reader will be aware of various thorns in the company’s side, perhaps most notably the damning appraisals from both ICER (see ICER Panel Rejects MDMA-Assisted Therapy, Highlights Evidence Gaps and Study Flaws in 14-1 Vote) and one of FDA’s own advisory committees (see Analysis: FDA Advisory Committee Snubs MDMA-Assisted Therapy for PTSD in Overwhelming “No” Vote).
The most pertinent question now, then, might be whether one side of the deliberative scales (two positive phase 3 studies, decades of MDMA use in the community and a relatively well characterised safety profile, the level of unmet need among PTSD patients and public awareness of this tragic fact, the agency’s interest in encouraging drug development in mental health, and other assorted factors that might contribute to political will for approval) might outweigh the other (gaps in Lykos’ NDA, publicised instances of misconduct and complaints of more, questions around the validity of the company’s study design and conduct and that of psychedelic research more generally).
While an increasingly factionalised psychedelics field has made landing on either side of these scales seem like an obvious choice or moral imperative—to the extent that those that come down on the other side of the scales are labelled as having blood on their hands, or are otherwise guilty for innumerable future suffering—in the eyes of the FDA, it really isn’t that straightforward.
With public trust in the FDA wavering and scandals like the opioid crisis well within the present zeitgeist, it’s looking at the scales with great pressure.
For the FDA, on one of the scales’ plates is well-publicised pressure to approve MDMA from a politically delicate group, veterans, as well as prominent figures like Elon Musk and Dan Crenshaw; expectation and desperation from healthcare providers and patients; intention to encourage continued development of innovative neuropsychiatric treatments; and so on.
On the other plate sits a whole other world of potential hurt for the agency. Approving MDMA could open up the agency to allegations of caving to lobbying and political pressure, being wooed by what some portray to be shoddy science, and ignoring the expertise of its own advisory committee. Now, this is not so much of a worry if MDMA-assisted therapy is ultimately rolled out in a safe and effective manner. But FDA will be imagining the worst-case scenarios, with things like the opioid and Aduhelm scandals top of mind.
All this to say, I certainly wouldn’t relish a seat on that FDA review team.
But FDA, which is privy to far more information and data than your humble correspondent, has a much clearer image of the NDA and associated program and launch plans than we do. After all, the agency has the power to request pretty much anything from the sponsor, with regards to the studies represented in the NDA, as part of specific inspections or in the general course of its reviewing the dossier.
Given that all of this takes place in private, however, it’s hard to imagine just how closely the agency is reviewing the program, or even which elements are under inspection.
According to reporting by Olivia Goldhill in STAT, for example, FDA hadn’t reached out to certain participants or their representatives in the course of those inspections, at least at the time of her writing. Goldhill said that this “raises questions about how the agency is pursuing the accusations, and whether a decision on the treatment could be delayed.”
Indeed, there are many questions.
How Many Problems Were There in Lykos’ Pivotal Studies?
One of the key questions that many have been aiming to get a handle on is just how many discrete cases of misconduct or serious harms there were in the Phase 3 program. Getting at this answer isn’t easy, especially given the fact that many of the reports about such incidents are anonymised. While it’s of course important to respect the requests of sources and informants, it does make this whole endeavour trickier.
This public information void has whipped up skepticism around Lykos’ published data, which is no small accusation. (In a recent episode of the Psychiatry Tomorrow podcast, Owen Muir pointed out that withholding information around things like serious adverse events from the FDA would be a serious and indictable offence.)
In a Letter to the Editor published in these pages in July2, a prominent critic of Lykos’, Neşe Devenot, said that her group was “in touch with 8 contacts with evidence of systemic problems and overlapping abuses across Phase 3 trial sites.”
But it’s not exactly clear who those eight contacts are, or how many discrete (vs. overlapping) cases of abuses or ethical violations they represent. We do know that they’re not all trial participants, as Devenot herself went on to add that the octette “includes Phase 2 and 3 participants, former employees, and clients of Phase 3 therapists and MAPS-trained guides.”
I asked Devenot whether she could confirm how many of those eight contacts were Phase 2 or 3 trial participants where the harms or issues raised relate directly to the trials. Devenot told me that her group is “withholding all identifying information of trial participants in order to protect them from Lykos’ ongoing intimidation campaign”3. Lykos could “cross-reference details with information that employees should not have access to”, she said, pointing to Business Insider’s reporting on the matter.
But this is all beside the point. Psychedelic Alpha does not, and has never, sought identifying information on such participants (in fact, I have made it clear that we would prefer not to receive such information). We simply wanted an answer on the number of participants or cases directly relating to the Phase 2 or 3 trials. Unfortunately, that answer has not been provided.
It’s clear, then, that getting a read on just how many trial participants this claim represents is not going to be possible for now.
Lykos has had no luck here, either: the company reached out to Devenot to request a discussion, but she did not engage under the advice of her legal counsel, she tells me. “I would be more than happy to speak with FDA investigators”, Devenot told me, but they haven’t reached out despite her groups’ outreach.
So, we’re at a stalemate.
What might the path forward entail? Perhaps FDA doesn’t believe that the information provided to them by these informants is worthy of inspection, or within the remit of said inspections, and so it will not be following up. Or, perhaps FDA is working its way through its inspections and is yet to get to these cases, in which case we might be headed for a delay on the decision. Or, might we expect Devenot et al. to provide further details or evidence in the coming days or weeks, as the decision date nears or lapses?
One can only speculate, for now.
Lykos Launches 'New Initiatives'
Lykos, which is paying penance for its former strategy of minimal engagement, is at last seeking to get ahead of things. Last Thursday, the company announced ‘new initiatives and measures for additional oversight’ of MDMA-assisted therapy, if it secures approval.
Those measures include an independent advisory board which the company says will inform it on “key elements of a potential commercial launch, including therapy training, ethics and healthcare integration”.
The independent advisory board “comprised of external experts” includes Barbara Rothbaum, a Professor of Psychiatry at Emory University School of Medicine; Loree Sutton, psychiatrist and retired military officer who was the U.S. Army’s highest-ranking psychiatrist; and, Robert Chesnut, who was General Counsel and then Chief Ethics Officer at Airbnb, among other roles.
But the board has already come under fire from those questioning the independence of its members. Rothbaum, for example, has been involved in and excited about MDMA research for some time, and Emory University hopes to be among the first providers of the therapy if approved. Sutton, meanwhile, told CNN that she called Rick Doblin himself “to encourage his work” while she was still working in the U.S. Army.
Is there anything wrong with an independent advisory board including individuals that are excited about new treatments for PTSD4, and/or that have experience in MDMA research, though? It’s a tricky balance.
On the one hand, if such advisors and researchers are deemed to be embedded within the psychedelics ‘field’, they’re seen by some as conflicted or assumed to be ‘true believers’ with an almost religious fervour5. But, if they don’t have any substantive experience with psychedelic research or practise, they’re accused of lacking the requisite knowledge of its specificities and quirks, as seen in the charges levied at ICER, its CEPAC committee, and FDA’s AdComm. Can Lykos win, here?
Aside from its advisory board, Lykos also announced it’s working with “top behavioral health facilities to help ensure these sites are prepared to implement the measures utilized in Lykos’ clinical trials”. Those include Sheppard Pratt, Hackensack Meridian Health, and Sunstone Therapies. It also emphasised that both DEA requirements and a REMS program will serve as additional layers of oversight.
Lastly, the company explained that it aims to collaborate on therapist training, in order to gain “external perspective of institutions and health systems” as opposed to going it alone. This is a thorny subject, as FDA AdComm members expressed concern about Lykos being the only purveyor of training, given instances and allegations of misconduct.
Of course, these latter two efforts are dependent, really, on Lykos obtaining approval from the FDA. If that’s not achieved in the near future, all bets are off.
In that case, the future for Lykos more generally looks incredibly challenging and uncertain. So too does Amy Emerson’s role at the helm, on which she cast doubt herself in a recent Endpoints News interview.
Closing Thoughts
Regardless of the FDA’s decision, which we will be sure to cover when it happens, it’s worth stepping back and appreciating just how far the field—warts and all—has come in the past twenty years or so.
In 2002, President Joe Biden introduced the Reducing Americans’ Vulnerability to Ecstasy Act in an attempt to crack down on the use of ecstasy at live music events and raves by placing significant responsibilities, liabilities and punishments on business owners, promoters and even volunteers of such events. This week, twenty-two years later, just over sixty House members, led by Republican Jack Bergman, have written to Biden urging for the approval of MDMA-assisted therapy. No specific value judgement is required to recognise that this is an enormous shift in perceptions of MDMA.
As we head into this period of intense public interest and scrutiny, I also wanted to add that I appreciate how challenging these last few months have been for many of you reading this. I mean, it’s been difficult for me… and my only real job is to write about these happenings and attempt to give the varying views and camps a fair shake. So, I really can’t imagine how tough it’s been for those with far more skin in the game than I.
Related Coverage
- Pα+ Psychedelic Bulletin #167: Lykos Insiders, Affiliates Respond to Critics… (Jul 12, 2024)
- Pα+ Psychedelic Bulletin #166: Crenshaw and Musk Weigh In on MDMA; Drug Devs Clarify Trial Design In Wake of AdComm… (Jul 5, 2024)
- Pα+ Analysis: FDA Advisory Committee Snubs MDMA-Assisted Therapy for PTSD in Overwhelming “No” Vote (Jun 11, 2024)
- Live Coverage: FDA Advisory Committee Reviews MDMA-Assisted Therapy for PTSD (Jun 4, 2024)
- Pα+ ICER Panel Rejects MDMA-Assisted Therapy, Highlights Evidence Gaps and Study Flaws in 14-1 Vote (May 31, 2024)
- Pα+ Patients, Practitioners, Researchers and Public Submit Comments Ahead of FDA Advisory Committee on MDMA (May 29, 2024)
- Exclusive: Therapists and Trialists from Lykos’ Phase 3 MDMA-Assisted Therapy Studies Push Back on ICER’s Critical Draft Report (Apr 29, 2024)
- Pα+ Library: Bifurcated Scheduling
- Pα+ Library: Psychedelic REMS
- However, the original PDUFA date was set for late August, so FDA gave the sponsor around five months notice of its decision to extend the review period in this case.
- Which served as Devenot’s right of reply to an assortment of anonymised and paraphrased critiques of her and her colleagues that appeared in the previous week’s Issue.
- Devenot told me that “Lykos and its investors have recruited Elon Musk, Rep. Dan Crenshaw, and Robert F. Kennedy Jr. to promote disinformation and silence whistleblowers.” Lykos sources tell me, however, that the company was dismayed by at least some of these figures’ comments, and emphasised that the company itself had no role in it.
- Recent reporting in The Wall Street Journal noted: “Lykos said any scientists conducting clinical trials have hope and optimism that their treatment will work, and its scientists had good reason to think the drug would help patients, given its use in therapy in the 1970s before it was made illegal.”
- A charge which has really pissed off some of the researchers and clinicians I have spoken with over the past year or so.
