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Live Coverage: FDA Advisory Committee Reviews MDMA-Assisted Therapy for PTSD

Today, the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) convenes to discuss Lykos Therapeutics’ MDMA-assisted therapy for PTSD New Drug Application (NDA).

The meeting, which is scheduled to run from 8:30AM – 5:30PM ET, will feature presentations from both FDA and Lykos, as well as public comments. At the end of the meeting, PDAC members will vote on two questions. While their votes are not binding, they might inform how the agency appraises the new drug application ahead of an August 11th decision date.

The meeting can be viewed live via YouTube.

Here, our Founder & Editor, Josh Hardman, will share periodic updates throughout the day.

Live Coverage Finished

Our live coverage has come to a close.

17:38 EST

Benefits Do Not Outweigh Risks, AdComm Finds in 10-1 Vote

PDAC has found that, when administered within the context of FDA’s proposed risk evaluation and mitigation strategy (REMS), MDMA-assisted therapy’s benefits do not outweigh its risks for the treatment of PTSD.

The verbatim question was:

Do the benefits of midomafetamine with FDA’s proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD?

The results: 1 voted yes, 10 voted no.

Only Dunn voted yes.

17:28 EST

In 9-2 Vote, AdComm Finds Available Data Insufficient to Show MDMA-AT Effective in PTSD

The committee has resolved that the available data do not show the intervention is effective in patients with PTSD.

The verbatim question was:

Do the available data show that the drug is effective in patients with posttraumatic stress disorder?

The results: 2 voted yes, 9 voted no.

Dunn and Hertig voted yes, while the other committee members voted no. Hertig shared that he “believes the therapy holds clinical promise.”

15:07 EST

Committee Discusses Potential for Patient Impairment

We’re now moving to the next discussion question, the last one before the two voting questions:

DISCUSSION: Discuss whether the proposed risk mitigation is sufficient to mitigate serious harm resulting from patient impairment. Include any additional safety monitoring conditions needed for the safe administration and monitoring of midomafetamine if approved for PTSD.

Dunn reiterated concerns about therapist dyads where there is a fiduciary or personal relationship, as well as his preference that both therapists be licensed.

Rebo said that, because we don’t have the monitoring and safety requirements ‘fully baked’, she would have to say ‘no’.

Barone echoed Dunn’s comments about having two licensed providers, noting that trainees “should not be used as staff”. Any trainee would be “the third person in the room”, she added, “they’re in a learning role”.

Joniak-Grant reiterated her concerns about a lack of clarity around what ‘on-site’ means, as well as concerns around having the sponsor being the only purveyor of training. “One thing I do wanna point out”, she said, “is there’s been some talk about doing surveillance”, such as through recording sessions and so on. But, “surveillance rarely ever gets looked at”, she continued, adding that “there needs to be very explicit directions in terms of what we are going to do with that surveilled information”.

Witczak said there needs to be a ‘clear pathway’ for reporting adverse events and harms, as well as follow-up.

16:54 EST

Committee Discusses Potential for Patient Impairment

The AdComm is now discussing the third question:

3. DISCUSSION: Discuss the potential for patient impairment to occur with midomafetamine and the potential for serious harm that may result due to the impairment. 

The discussion and voting should be based on what was contained in the briefing documents and open public hearing, an FDA representative said, noting that the matters it is investigating are ‘unconfirmed’.

Dunn kicks the discussion off yet again. Among other things, he expressed concern around patients weaning off any background medications in the post-approval setting. “I think it’s fair game that anything untoward that occurs during that [weaning-off] period be associated with the treatment package”, he added.

Rebo said that she would want to see “very strict guardrails” around discharge criteria, and wondered whether we might need to have patients stay overnight to be sure.

Amirshahi said that she has seen many intoxicated patients during her time in emergency medicine, and added that one of her concerns is the need for ancillary staff to assist with potential incidents like falls or elopement.

16:37 EST

"There are significant holes in the data"

The committee is now turning to the second discussion question:

2. DISCUSSION: Discuss whether the available data are adequate to characterize the safety of midomafetamine for the treatment of PTSD. 

  • Consider the limited data collected on events deemed positive, favorable, or neutral that would inform abuse potential for this program and the lack of data from some clinical laboratory tests.
  • Comment on whether you have concerns about other safety issues and what additional data would be useful to characterize the safety of midomafetamine.

Dunn kicks off the discussion once again. He expresses concerns about the lack of data from clinical laboratory tests, especially should patients need ‘much longer treatment courses’ in clinical practice. 

“I think there’s some clearly missing safety data”, Holtzheimer said, but feels “pretty confident this could be done with postmarketing studies”. But issues of patient vulnerability and boundary violations are concerning, he added, and wondered how this would be monitored and controlled. (Dunn made similar comments immediately prior.)

Amirshahi, a toxicologist, said that she feels “there are significant holes in the data”, such as with hepatotoxicity, hyponatremia, drug-drug interactions, and so on. She also encouraged the committee to focus on the sponsor’s apparent ignoring of the agency’s request for data relevant to abuse potential.

Hertig echoed his colleagues’ comments and expressed particular concern around limited data related to abuse potential, such as ‘positive’ adverse events.

Joniak-Grant said that the fact that 40% of participants had used MDMA prior to the trial might make the safety profile reported in the studies look more positive than in actuality. She went on to share further concerns on the safety front, and added that the sponsor had not come back to them on questions raised earlier in the day.

The committee chair, Narendran, said that there’s not enough data to characterise the safety; “there’s a lot of holes in this dataset”.

“If you’d have done discharge EKGs you’d have had – left and right – all kinds of things”, he said, noting that he has seen this in his own amphetamine research. He doesn’t think a REMS can manage these risks, and added that illicit use “is gonna soar” if the present product is approved.

16:00 EST

AdComm Begins Discussion; Airs Concerns About Study Design, Conduct

The advisory committee has begun discussing the questions put before it, starting with:

1. DISCUSSION: Discuss the evidence of effectiveness for midomafetamine for the treatment of post-traumatic stress disorder (PTSD). Consider the following:

  • The potential impact of functional unblinding on interpretability of efficacy results
  • The durability of effect
  • The role of psychological intervention in the treatment paradigm

Dunn said that his major issue is the combination of misconduct and methodological issues like the unknown role of expectation bias. In the former, he trusts the agency is investigating, but in the latter he worries that there is not sufficient data to evaluate its contribution.

He also said there are “serious questions” about whether the sponsor can oversee the training of therapists in a responsible way. “Unfortunately, there has potentially been some misconduct”, he said, “that has corrupted our ability to interpret the data.”

Holtzheimer said he shares concerns about study conduct, so would limit his comments to other matters. He believes expectation bias could potentially account for a lot of the acute difference between the two arms in the study. He’s also not convinced on durability, given issues he sees with MPLONG.

Barone echoed these concerns, and that “it seems like there are so many problems with the data”, adding that “each one alone might be okay, but when you pile them on top of each other…I think there’s just a lot of questions still”.

In terms of the psychotherapy side, “the way that it is presented in the application makes it impossible to disentangle the two”, Barone added. She also cited a lack of standardisation, noting that this makes it difficult to determine how safe and effective it is.

Joniak-Grant said that, based on the data, she believes MDMA is likely effective. But, “in terms of this study, this trial, I’m concerned about the unblinding of therapists”, she said, adding that she is “really concerned about this lack of inclusion of BIPOC participants”.

“I have real concerns with the validity of the data and the allegations of misconduct”, she added, “especially as a patient representative.” “I can’t in good conscience support something where these many harms are being reported”, she continued.

She further critiqued the fact that around 40% of participants had used MDMA before, arguing that this “stacks the deck”.

Fiedorowicz noted that the treatment effects in the studies were large, and that ordinarily these types of effect sizes would reassure him regarding bias. But, he believes the ‘movement’ around psychedelic medicines warrants consideration in this regard. He went on to list other concerns about the studies, and said the allegations of misconduct are very concerning.

Witczak, the consumer representative, said that she is pleased to see this treatment being something that’s ‘being looked at’, “but at the same time…I’m pretty concerned with the misconduct allegations”. Usually, she said, these things happen after a drug comes to market, but in this situation, we have the chance to investigate before it reaches that point.

Kaiser Permanente’s Rebo echoed others’ concerns and added that she was surprised Lykos did not deliver the abuse potential related data that the agency had asked for.

Hertig also echoed his peers’ comments. He commended the agency and sponsor “for looking at these novel therapies”, and said he is excited and hopeful. “That said, I liken this a little to ‘we’re building the airplane while we’re flying it'”, he continued, noting that the safety concerns were particularly concerning to him in this regard.

Canuso shared others’ sentiments regarding ‘the promise and the caveats’. She also highlighted that more patients had exposure to MDMA prior to enrolling in the studies than SSRIs.

Iyengar is up next. He says that, given that psychotherapy is so apparently integral to the intervention, even a two-by-two design might not make sense. He asked, rhetorically, whether getting such a therapy through the FDA is out of the question, whether it can make a special case out of it, and so on.

Amirshahi wondered whether there is a way that we can better study the relative contribution of the psychotherapy.

Narendran said that he’s “not convinced at all that this drug is effective, based on the data I saw”.

“Going forward, for psychedelics to be approved,” he continued, ‘there need to be more complex models.’

15:58 EST

Lykos’ Lilienstein returns briefly to address earlier questions from the FDA. “In many ways we’re creating a new field of medicine”, she added, “and we don’t take that lightly; it’s a really significant responsibility.”

“We take all concerns around harms and clinical trial conduct and research conduct very seriously as well”, she added, noting that we owe it to patients who are suffering to sort through the complexities.

15:48 EST

A Mixed Bag of Public Comments

We heard, by my count:

  • 20 comments broadly in support of MDMA-assisted therapy’s approval;
  • 10 comments against;
  • 2 neutral comments.

14:00 EST

Public Weighs In During Extended Session

We’re back from lunch break (or, dinner for this correspondent) and the Open Public Hearing session has commenced.

Over the next 1:45 hours we will hear from members of the public who requested to provide oral comments. (To read our summary of written comments, see our coverage: Patients, Practitioners, Researchers and Public Submit Comments Ahead of FDA Advisory Committee on MDMA, May 29.)

Speakers have three minutes each. We won’t recount each and every one here.

Robert Grant, a UCSF professor who worked on a MAPS-sponsored study some years ago, expressed support for the approval of MDMA-assisted therapy within the context of a REMS.

Russell Hausfeld, an investigative journalist who writes at Psymposia, among other places, drew on reporting he did for Truthdig that profiled certain veterans who felt mistreated by MAPS, the nonprofit that used to wholly own MAPS PBC (which became Lykos Therapeutics).

During the session, we are also hearing from individual veterans as well as veteran advocacy organisations themselves. Those who spoke generally supported the approval of MDMA-assisted therapy, or at least further research. Individuals included Lykos trial participant Jonathan Lubecky and organisations like the Wounded Warrior Project, Veterans of Foreign Wars and Disabled American Veterans.

Neşe Devenot said that “this committee has been misled by Lykos to believe that this intervention was non-directive”, arguing that MAPS founder Rick Doblin based the therapeutic approach used by Lykos on the teachings of Stanislav Grof. Devenot also says that the company ‘would like the committee to believe that instances of abuse were limited to a single event in a Phase 2 study’, but argued that issues were more prevalent and quoted a purported Phase 3 participant. “Given the stakes, all the video tapes throughout MAPS/Lykos’ clinical trials must be independently reviewed”, her closing slide read.

Michael Abrams, a Senior Health Researcher at Public Citizen’s Health Research Group, expressed concerns about the lack of clarity around the contribution of psychotherapy to outcomes, which FDA itself recognised throughout the morning’s proceedings. He highlighted other concerns, before concluding that “the benefits are insufficient to outweigh the many risks”, urging the committee to vote no.

Jonathan Alpert, Chair of the American Psychiatric Association’s Council on Research, highlighted a major need for effective, affordable PTSD treatments. “MDMA represents a promising treatment for a devastating illness”, he noted, but said there are “significant” issues with the available evidence, recounting many of the issues identified by FDA before the lunch break. He concluded with the following remarks:

Ifetayo Harvey, Executive Director of the People of Color Psychedelic Collective, said that, “in spite of my treatment as a [former] employee”, she is grateful to MAPS for leading research into MDMA. She went on to critique the lack of non-white study participants, ‘crossed boundaries’, and ‘various discrepancies’. Harvey believes there must be more research on MDMA before it’s brought to the public via the FDA. “I hope that, after this hearing, the field starts to hold itself to a higher standard”, she said in closing.

Kayla Greenstien said that she is “deeply concerned about the Lykos model of MDMA-assisted therapy”, noting specifically the ‘inner healing intelligence’ mechanism of action that’s implicit in the protocol, as well as the use of therapeutic touch. She described Stanislav Grof’s work as “homophobic and misogynistic”. “I wish I could support this application, however I feel that approving this version of MDMA-assisted therapy would result in substantial harms”, she said in closing.

Brett Waters of Reason for Hope “urged that [the committee] not lose the forest for the trees”, adding that “a truly novel treatment of this source is desperately needed”.

Brian Pace, lecturer at Ohio State University and co-author of the citizen petition that sought to establish today’s extended public hearing. “I submit that Lykos is a therapy cult”, he said in opening his comments, arguing that “this lens explains the mounting criticism against them”. He argued that the organisation is pursuing “global spiritual conversion”, and shared a Bloomberg article where Rick Doblin reportedly guided a veteran through an MDMA session at Burning Man.

Joe Welker, “speaking as a former member of the psychedelic industry”, spoke of Rick Doblin’s forwarding of a “religious and spiritual agenda”. “It would be harder to find a bigger promoter of MDMA use in American history than Dr. Doblin”, he further claimed.

Beau Witka shared their lasting difficulties following a guided MDMA session that took place outside of clinical trials. The individual who guided him had trained at the California Institute of Integral Studies, he noted, but the experience “completely derailed my life”, he said. He reported symptoms of “extreme exhaustion, brain fog, severe cognitive impairment,” and others. He said that he would like to see the drug legalised for medical use, but that he cannot support approval until there is more focus on training and how to support those who have extended difficulties.

Deran Young, founder of Black Therapists Rock, said that MDMA-assisted therapy “offers a beacon of hope”.

A trial participant, who initially received placebo but eventually received MDMA via a follow-up study, said that after the intervention she “gets to fully live her life.” “The placebo sessions didn’t quite stick like the MDMA sessions did”, she said, adding that she “connected to my mind, body and soul in a way that restored my faith again.” “The patient is doing the work”, she added, noting that “I and every participant in these trials ‘put in the work'”.

Manish Agrawal, co-founder and CEO of Sunstone Therapies, shared the testimony of a trial participant who received MDMA-assisted therapy and saw substantial improvement. “This is just one positive story of many”, he said, before endorsing the approval of the intervention.

Sasha Sisko raised various concerns about Rick Doblin’s conduct, going so far as to accuse him of violating the Nuremberg Code with regard to his apparent interest in bringing MDMA-assisted therapy to conflict zones.

A statement was read on behalf of Meaghan Buisson, which detailed non-consensual touch and sexual assault during Lykos’ Phase 2 program. Buisson feels that their experience was not adequately reflected in the study publication, nor was it appropriately responded to by the organisation. “The sponsor lied to the committee about adverse events and safety monitoring”, the statement further alleges, before “urging the panel to reconsider the veracity of Lykos’ claims.”

Several other MDMA-assisted therapy trial participants, such as Lori Tipton, shared positive experiences from the studies.

Debbie Plotnick, Executive Vice President for State and Federal Advocacy at Mental Health America, advocated for the approval of novel mental health therapies like MDMA-assisted therapy.

12:24 EST

AdComm Asks Questions of FDA

Walter Dunn begins by asking two questions of the agency. The first draws on the ICER review to ask about claims that investigators discouraged people from encouraging in MPLONG, that therapists discouraged reports of adverse events, and so on. “Is the agency investigating this?”, he asked.

Farchione said that “there isn’t a lot I can say with regard specific details” in terms of what she is looking into. “We certainly take those allegations very seriously and are quite concerned”, she said, adding that “we do have inspections ongoing at this point, but can’t really speak to the details as those are ongoing.”

Satish Iyengar, Professor of Statistics at the University of Pittsburgh, asked whether an analysis is possible that accounts for inter-therapist (dyad) variability in outcomes. Inter-site variability had been reviewed, the agency said, but not inter-therapist.

Holtzheimer asked how therapist unblinding might lead to differences in how the psychotherapy is delivered between the two arms. Lykos told him that there was assessment of fidelity to the protocol in both arms, but Holtzheimer asked FDA if it had reviewed such data.

“I would just say that based on the description of the therapy in the manual, and the sort of flexibility inherent in the manualised psychotherapy, we assumed that there would be variability among the different therapeutic approaches,” Farchione said. Whether that differed based on therapists’ guesses of treatment assignment, ‘we don’t have any insight into that’.

Joniak-Grant said that, as a patient, the flexibility in Lykos’ therapy manual makes her uneasy. She asked how the FDA might manage this.

“The difficult thing…is that we don’t regulate psychotherapy, and also we don’t really have any say in the design or the implementation of the particular therapy that is going to be used”, Farchione said.

“Even when it comes to the parameters of the REMS”, she said, it comes down to safety and monitoring, not the psychotherapy component.

She also asked that, if inspections into allegations of misconduct are ongoing, could the product come to market before those are completed?

Farchione said that the agency “would complete the inspections before taking action.”

Hertig asked the agency to comment on accessibility: “I’m trying to get a sense for, after we do all of these things, how many patients are gonna get access?”

“We don’t have an answer to that”, Farchione said. “In terms of trying to design a REMS that can appropriately mitigate the risks we have identified,” the agency had tried to consider accessibility, too.

“But at the same time, we do have a lot of unknowns, and we do have some clear risks with this product”, she added.

“We do periodic REMS assessments as well”, she added, suggesting that new information could justify modifying a REMS.

Witczak, the consumer representative, asked if there would be a way (in the postmarketing world) to separate out drug-related vs. psychotherapy-related incidents or adverse events.

Farchione suggested that state medical boards and other licensing bodies, as well as the potential for criminal charges, would need to play a role in regulating the delivery of MDMA-assisted therapy, if approved. ‘The FDA can’t regulate everything’, she implied.

Amirshahi brought up hyponatremia, noting that it hadn’t been discussed in great detail thus far. “Do we have a plan for that?”, she asked.

Farchione said that “we are considering what kind of postmarketing requirements” the agency might mandate, both for clinical laboratory assessments and additional data from cardiovascular studies.

Barone said that the fact that the therapy guide had such flexibility is inconsistent with clinical practice guidelines for PTSD, and asked how the FDA views it.

Farchione said that “there is not a great answer to that question”, reiterating that the psychotherapy does not fall within its remit.

Dunn asked another question, asking how the agency views the incident in a Phase 2 study that “happened long after the last dose was administered”. Given the drug’s pro-social effects, would the agency be monitoring for these types of longer-term events?

Farchione said that this is an area in which it would be useful to hear from the committee, such as how to incorporate this type of monitoring into its REMS structure. She noted that ‘the further out you get from the administration session, the harder it is to attribute that to the drug’, though.

Dunn also wondered whether, if Lykos’ model of psychological intervention was demonstrated as essential to the safety of the drug product, FDA could mandate it.

FDA’s Cynthia LaCivita said that would be something the agency would have to look into, as this is something novel for them.

Dunn then asked what the rationale was with regard to only requiring one licensed therapist in the room. “Why not have both be licensed?”, he asked.

Farchione explained that this mirrored the trials, adding that it “primarily has to do with the concerns of balancing access, as well”.

Dunn reminded the audience that the transgression in the Phase 2 study happened with an unlicensed therapist. Dunn also said he was “thinking about for-profit operations which may misrepresent the training status of people who are unlicensed, claiming they are in training when they’re not”, adding that his personal feeling is that both therapists should hold licenses.

Joniak-Grant also commented on the licensure element, reminding the agency that power imbalances in the relationship between therapists might reduce the likelihood of the lesser-credentialed therapist reporting the other in the case of misconduct.

She also sought clarification for what ‘on-site’ means, saying that the “idea that someone is just going to be ‘around'” might not be enough for patients.

Canuso asked how there was no requirement for laboratory assessment at the time of submission.

“It was missed”, Farchione admitted. “Every program we have ever reviewed has labs…perhaps the primary reviewer, because it’s always there, just didn’t notice it wasn’t”, she continued, adding that “both the applicant and we have to take responsibility for [that].” “It is a hole in the program”, she acknowledged.

Dunn asked whether the agency has data regarding how many additional hours of therapy those in the MDMA arm might have received versus those in the placebo arm, as some had additional integration sessions. ‘That’s probably a question for the sponsor’, Farchione said.

Dunn then asked whether the agency would consider a warning label for the therapist, pointing to things like transference, and citing a Stanford animal study where mice ‘acted differently’ when in the presence of mice that had ingested MDMA.

Even though the prescribing information is generally directed toward the prescriber, an FDA staffer said, one might expect the therapists to be familiar.

Witczak asked if the total number of study participants is adequate, in the FDA’s mind.

Farchione said that if this were something that needed to be dosed more frequently, the agency would expect more data, “primarily to have more safety data”. But, given the proposed protocol, it’s a different matter.

Narendran said he was “struggling with” a lot of missing data, and asked FDA whether the agency could restrict patient populations to maintain safety, such as for cardiovascular risk.

“It’s certainly something that we could consider”, Farchione said, which was echoed by Director of the Division of Risk Management, LaCivita. They both encouraged the committee to make suggestions to the agency after lunch.

11:11 EST

FDA Presentations

We’re back after a short break in proceedings. FDA will now deliver several presentations, starting with Clinical Reviewer David Millis’ remarks.

After reviewing high-level details related to PTSD and the product under review, Millis shared some of the regulatory history.

Firstly, he shared an overview of discussions between the agency and Lykos on the topic of unblinding concerns. During a 2016 end-of-phase 2 meeting, the agency expressed concern about possible functional unblinding (see page 12 onwards of the FDA’s briefing document for more). Millis explained that functional unblinding “contributes to expectation bias” among both participants and investigators.

He then discussed the Special Protocol Assessment (SPA) that Lykos initially requested in January 2017. FDA disagreed with the proposed statistical analyses and secondary endpoint choice, in that first instance, but ultimately agreed to a revised SPA in July 2017 (for a blow-by-blow account, see the briefing document).

Such an agreement, however, “does not guarantee that the trial results will be deemed adequate to support approval”, Millis highlighted.

He then turned to “a striking lack” of abuse-related adverse event documentation in the MAPP1 study report, which might limit the agency’s ability to explain the MDMA experience in prescribing information, or to determine abuse liability. The agency also does not know when the effects of MDMA might begin to be felt, or when they might subside, he said. This would have been helpful when delineating monitoring requirements or expectations.

The final ‘review issue’ he highlighted is the role of psychological intervention in the development program, given the agency’s limited ability to describe psychotherapy or to regulate it.

He also said the type of intervention differed throughout the protocol. “The content or approach of integrative sessions”, for example, was not specified in the manual, Millis said. He added that this could vary from therapist to therapist.

Under a REMS, FDA can ensure a patient is monitored for safety, but cannot dictate that a patient is offered or engages in psychotherapy.

Olivia Morgan, Statistical Reviewer, takes to the podium to present the agency’s efficacy analysis.

Morgan’s presentation shared various statistical analyses, one of which appears to show that participants who chose not to enrol in MPLONG had higher CAPS-5 total scores at the end of the Phase 3 studies:

Other analyses suggested that interim use of other psychotropic substances might have impacted the interpretability of MPLONG.

Millis returned to emphasise key uncertainties about efficacy:

  • functional unblinding;
  • durability of effect;
  • role of psychological support.

He then reviewed safety, where he explained some of the common adverse events before focusing on cardiovascular risks, which should be appropriately labelled if the product is approved.

‘Overall, the available data is insufficient to fully assess the cardiovascular effects of [MDMA]’, Millis said. A study could be performed in the postmarketing setting to attempt to ascertain this, he said.

Millis did not raise major concerns regarding suicidality, based on the data, and noted high baseline levels of suicidality in the patient population and trial participant set.

On the topic of hepatotoxicity, Millis explained that there were no post-baseline liver function laboratory assessments in the Phase 3 studies. “Risk may be low if used as intended”, his slides read, but more data is needed to properly characterise that risk.

In terms of abuse potential, the agency’s review concluded that MDMA “has abuse potential that parallels that of the Schedule II stimulants”.

In summary, Millis said that the safety profile is consistent with the known effects of MDMA, but some safety concerns were not adequately assessed, particularly cardiovascular, hepatotoxicity, abuse-related effects and discharge criteria for medication sessions.

The available safety data may be adequate to assess risks based on the proposed time-limited dosing regiment, Millis said, but more data may be needed to support chronic-intermittent use of the drug.

Victoria Sammarco, Risk Management Analyst at the agency, explained the agency’s proposed REMS.

“The agency believes a REMS will be necessary”, she said, before discussing what it might look like.

The agency proposes the following:

9:56 EST

AdComm Asks Questions of Lykos

Now that Lykos’ presentations have concluded, PDAC asks questions of the sponsor.

Walter Dunn, Assistant Clinical Professor in the Department of Psychiatry at UCLA, and Director of the Interventional Psychiatry Service at the West Los Angeles VA Medical Center, asked about the role of psychotherapy in driving safety.

Yazar-Klosinski said that the company views the psychotherapy as contributing to safety. Kelley O’Donnell said that the kind of psychological support provided in the sessions was informed by the ‘first wave’ of MDMA therapy, alluding to 20th-century uses of the drug.

“That being said, I think over the next several years we’re going to find that other psychotherapies can take advantage of these effects”, she added.

He then asked about the ICER review, which noted misconduct in the trials. He asked when Lykos was first made aware of these allegations, and the steps they took to investigate and rule out these issues.

Lykos’ Lilienstein said that the company was initially made aware of the event in late 2018, and conducted an internal investigation.

Dunn further questioned the company about allegations, found in the ICER review, that patients were excluded or discouraged from participating MPLONG.

Lilienstein said that this issue was investigated, and that some participants chose not to participate. “There was at least one participant that I was aware of that, because they felt they were doing so poorly, participation in the study would negatively impact them”.

Paul Holtzheimer, Deputy Director for Research and Director of the VA PTSD Brain Bank, asked how the company measured the integrity and quality of psychotherapy provided between the two arms of the studies.

Yazar-Klosinski pointed to processes such as adherence rating.

Kim Witczak, the committee’s consumer representative, asked whether the manualised therapy would be ‘proprietary’ and/or ‘required’. She also asked about how hype and expectancy might have influenced efficacy, as well as things like suggestibility. Witczak noted that she is ‘happy to see’ the development of psychedelics.

“The therapy method is not proprietary to us”, Yazar-Klosinski said.  “That’s one of the reasons that we chose ‘psychological intervention'” as a term, she said, as it could allow for broader uses. In the first instance, however, Lykos will train therapists in accordance with its Phase 3 study protocol.

Kelley O’Donnell explained that, in therapist training, they emphasise how power dynamics can play out in MDMA-assisted therapy, as in other psychotherapies. She also said that they consider how they might be priming patients to expect certain results.

“It’s so important that the training goes beyond the manual”, she added. “I think, most crucially, is the supervision that happens afterwards”, she noted, saying that “it’s in that period that we really learn what these things mean; what vulnerability looks like”, and so on.

Elizabeth Joniak-Grant, patient representative and sociologist and qualitative research consultant at the Injury Prevention Research at University of North Carolina, Chapel Hill, said “let’s try not to gloss over this misconduct; it was sexual misconduct”. She added that patients with PTSD are often likely to have trauma stemming from sexual violence, so it is important not to skip over this fact.

Joniak-Grant asked Lykos what percentage of participants in the studies had previously used MDMA, and how many times; “there could be a self-selection bias at play”, she said.

She also highlighted that participants had to agree to certain lifestyle modifications, and sought clarification on this. She also sought to clarify how patients were recruited.

Yazar-Klosinski explained that 40% of those in the MDMA arm of the Phase 3 studies had a history of illicit MDMA use and 39% of those in the placebo group. She then shared a subgroup analysis that appears to show past MDMA use has no significant impact on outcomes.

In terms of lifestyle modifications, she noted that participants had to agree to fast prior to medication sessions, regular follow-ups with the study team, and so on.

On the topic of recruitment, the CSO said the company used ‘standard methods’, such as a recruitment website.

Joniak-Grant pushed back, saying there’s “really not” a standardised approach to recruitment, asking for further information.

Lykos’ Lilienstein sought to clarify, stating that a lot of recruitment came from referrals. The website, meanwhile, “was distributed through the sponsor’s network and investigators network as well”.

“Why did participants choose to discontinue treatment?”, Joniak-Grant asked as a final question. Lykos shared a slide and said that one MDMA arm participant dropped out due to depression.

Joniak-Grant pushed further, still, asking why the patient represented in the slide above chose to withdraw consent. Lykos did not have an answer, and said they would get back to the committee later.

John Hertig, Associate Professor in the Department of Pharmacy Practice at Butler University College of Pharmacy and Health Sciences, asked for more information on the limited roll-out and other items related to avoiding diversion.

How the drug is dispensed is the subject of ongoing negotiation with FDA and DEA, Yazar-Klosinski explained, but it would be done on-site.

On the limited roll-out: “We would start with a smaller number of commercial sites that could meet” its requirements, in order to “sort of pilot what its risk mitigation procedures are able to detect”. The metrics for how it would expand patient access, however, are still under development. “We’re envisaging this as a staged roll-out”, she said.

Maryann Amirshahi, Professor of Emergency Medicine at Georgetown, and Co-Medical Director of the National Capital Poison Center, asked whether Lykos evaluated whether participants went on to use illicit MDMA after being exposed to MDMA in the studies. “We’re managing more and more severe cases of MDMA overdose”, Amirshahi said, referring to her professional work.

Her second question revolved around access, given the length of therapy sessions, for example. She asked what Lykos’ plans were regarding cost-effectiveness analysis and reimbursement.

Lilienstein said that there were ‘no adverse events in our Phase 3 trials…of anyone using illicit MDMA’, and that in MPLONG they assessed whether participants had used MDMA in the interim time period. ‘Some’ had, she said, providing data showing that 7 patients who had received MDMA through the included studies went on to use illicit MDMA.

On the topic of access, Yazar-Klosinski pointed to an insurance code that it had achieved through collaboration with another company (Compass Pathways), as well as economic modelling efforts.

Elizabeth Rebo, Executive Director, Pharmacy Quality and Medication Safety, National Pharmacy Services at Kaiser Permanente, asked about liver function tests.

“We recognise that we still need to do more”, Lilienstein replied, adding that a postmarketing study to evaluate impact on liver and liver function is under discussion with the agency.

Jess Fiedorowicz, Head of the Department of Mental Health at The Ottawa Hospital, and Professor in Adult Psychiatry at University of Ottawa asked if there were any sex or gender-based differences in safety and efficacy.

Yazar-Klosinski shared a slide showing that both males and females had results that favoured MMDA.

Fiedorowicz then asked if there was any evaluation of expectancy of benefit in the phase 3 studies.

A statistical consultant to Lykos sought to answer the question via the following slide:

But Fiedorowicz clarified that he was interested in expectancy, not blind integrity. Lykos did not have data on prospective expectancy, it said.

Non-voting industry representative Carla Canuso, VP Head of Neuropsychiatry Clinical Development at Janssen (who was among the team that led the development of Spravato) asked about intercurrent interventions received between Phase 3 study participation and MPLONG.

Yazar-Klosinski shared a slide showing various types of psychotherapy that participants had received in the interim, such as eye movement desensitization processing, group psychotherapy, and so on.

In terms of pharmacological treatments, 27% of MDMA arm participants had taken antidepressants in the interim vs. 13% in the placebo arm. “Any off-label treatments?” Canuso asked, but Yazar-Klosinski said that they did not collect such data.

Dunn returned to ask (among other things) whether data suggest the intensity of the acute subjective experience correlates to outcomes.

Given that the company did not collect subjective effects during the administration sessions, Yazar-Klosinski said, it’s not something they could analyse.

Dunn then asked about the credentials of the two monitors. One will be licensed, and the other can be on the path to licensure, a Lykos representative responded.

With reference to the ‘misconduct and probably criminal violations’ that happened in a Phase 2 study of MDMA, Dunn further questioned whether the relationship between therapists should be looked at: e.g., if two therapists are in a personal (referring to Donna Dryer and Richard Yensen) or fiduciary relationship, might it compromise their ability or willingness to intervene?

Yazar-Klosinski agreed that it is something that’s worth considering ‘putting guardrails’ around.

The meeting’s chair, Rajesh Narendran, attending psychiatrist at Resolve Crisis Services and Professor in Radiology and Psychiatry at the University of Pittsburgh School of Medicine, asked whether the company intends to exclude people with borderline personality disorder, substance use, and so on.

Lilienstein noted that these populations have not been studied, which would be reflected in the label and it would be down to a benefit-risk conversation between a patient and their provider.

Narendran then asked about tachycardia, asking whether there were clear cut-offs around monitoring, e.g. ‘don’t discharge them until certain vitals are met’.

Lykos invited a cardiologist and electrophysiologist to answer the question. He acknowledged that the patients in the trials were highly selected and thus deemed at low risk for cardiac events. He said it is unlikely for a patient to have a significant arrhythmia without having symptoms, which is important – he said – because attempting to monitor cardiac vitals during the administration session would be difficult.

9:55 EST

Lykos CSO Yazar-Klosinski returns to the podium to summarise the benefit-risk of MDMA-assisted therapy, as the company views it.

“Staged and controlled” is how she described the potential roll-out of MDMA-assisted therapy, if approved.

9:48 EST

Kelley O’Donnell, Research Assistant Professor of Psychiatry at NYU School of Medicine and Director of Training at the  NYU Langone Center for Psychedelic Medicine, provides the clinician perspective.

“The acute drug effects of MDMA really do assist the psychotherapeutic process”, she said, pointing out a number of different ways in which this might happen, for example by fostering a patient’s sense of safety and trust, or where the serotonergic effects of the drug may lead to transiently reduced anxiety.

“The complexity of this treatment…should not preclude approval”, she said.

9:32 EST

Now, Alia Lilienstein, Lykos’ Sr. Medical Director and Head of Clinical Science, presents on Safety.

The safety database includes 477 participants exposed to MDMA, 50 of which were in studies carried out by NIDA.

While almost all participants (in both arms) experienced at least one adverse event, just one MDMA-treated participant dropped out of the study due to adverse events, according to Lilienstein.

She acknowledged Lykos’ deficiency in that it didn’t collect information on ‘positive’ adverse events, and noted that the company would be prepared to collect this information in a post-approval context, if necessary.

Suicidal symptom frequency was comparable between the placebo and MDMA groups, she highlighted.

On the topic of the proposed REMS, Lilienstein set out several elements:

She further explained that the company plans to work with a “limited number of sites” initially (we had speculated on this in earlier coverage), and that it will provide training for therapists in the treatment approach used in Phase 3 studies.

Lilienstein also acknowledged the role that post-marketing studies, such as clinical laboratory studies, and surveillance can play.

9:08 EST

Lykos CSO Presents on Efficacy

Berra Yazar-Klosinski, Chief Scientific Officer at Lykos, will now present on efficacy.

(We won’t recount much of this presentation here, as most readers will be familiar with the study design and outcomes of Lykos’ trials. Interested readers can review the sponsor’s briefing document for more.)

Yazar-Klosinski highlighted the fact that MDMA “does not require daily dosing or steady state plasma level to be effective in PTSD”, setting it apart from current pharmacologic treatments which are often dosed daily.

She later provided a look at the company’s MPLONG observational long-term follow-up study:

9:00 EST

Next up is Jerry Rosenbaum, Director of the Center for the Neuroscience of Psychedelics at Mass. General Hospital Research Institute and Professor of Psychiatry at Harvard Medical School. He is invited by Lykos to discuss the unmet need among PTSD patients.

He presents a number of statistics: 48% of PTSD patients remain untreated, for example. The most common type of trauma among PTSD sufferers is sexual violence, followed closely by those who experienced a traumatic event in their social or family network.

Common comorbidities include anxiety disorders, depression, substance use disorders and suicidal ideation, he added, before explaining how current therapies for PTSD “can be difficult to tolerate and can be ineffective for some patients”.

8:54 EST

Lykos' Presentations Begin

The next 90-minutes or so will see various members of Lykos’ team present.

Amy Laverdiere, Program Lead at Lykos, kicks things off. She explained that there has been ‘cumulative experience’ with MDMA, which informed the company’s development program.

That includes around 4,000 people documented to have taken MDMA “in earlier clinical practice”, such as in the 1970s and ’80s, she said.

The specific mechanisms of MDMA “are not completely understood”, Laverdiere said, it appear to facilitate memory recollection and “extends tolerance for revisiting distressing thoughts or experiences”, as well as increasing self-awareness “leading to introspection and personal reflection”.

When combined with ‘psychological intervention’, an “acute treatment to reduce symptoms associated with PTSD” is achieved, she claimed.

The post-approval plan, she noted, includes REMS, controlled distribution, and so on.

8:38 EST

“This application is both consequential and complex”, says FDA's Tiffany Farchione

Tiffany Farchione, Director in the agency’s Division of Psychiatry, gets things underway in earnest with opening remarks.

“This application is both consequential and complex”, she said in opening, before giving an overview of PTSD, current treatment options, and a quick overview of present interest in psychedelic drug development.

Farchione then recapped Lykos’ proposed treatment paradigm: 3 sessions of MDMA administration alongside psychological intervention, across a 4-month course.

MDMA’s investigational new drug application was submitted in 2001, she reminded the audience, pointing out how much has changed. “We have been learning as we go along”, she added.

Two short-term studies, both positive with clinically-meaningful improvements in PTSD seen, are present; but complicated by several factors, notably functional unblinding (“Acute effects of [MDMA] make it nearly impossible to blind studies”), which can lead to expectation bias.

Lykos attempted to mitigate and assess impact of bias, Farchione noted, but said that the impact of widespread unblinding in the trials cannot be understood.

A durable effect, she noted, might be more likely to be attributable to the drug vs. placebo response, as we may predict that expectancy effects would wane over time. Long-term follow-up, then, might be the key.

But, MPLONG – the company’s long-term follow-up study – had its own issues, such as attrition (25% dropout between parent study and follow-up), intercurrent use of non-study drugs, variable follow-up intervals, and the unblinding of participants in MAPP1 (the company’s first Phase 3 study).

“FDA does not regulate the practice of psychotherapy”, Farchione said, turning now to the role of psychotherapy in the intervention.

The “contribution of psychotherapy has not been characterized”, her slides read, and “there have been no rigorous studies comparing this particular manualised therapy to other psychotherapeutic approaches”.

“If this product were to be approved, we can’t label it for use on its own,” she said, adding that the agency also does not have evidence that the psychotherapy is necessary to achieve the desired effect.

In terms of safety, Farchione highlighted that the cardiac safety profile of MDMA is not well characterised, and the QT assessment is incomplete. Further, there is limited clinical laboratory data available for review, she noted. This would “likely necessitate additional postmarketing studies, if we were to approve this product.”

Lykos did not capture effects that were deemed positive, such as euphoria, which limits the agency’s ability to understand abuse potential, Farchione also noted.

As predicted, FDA believes that a Risk Evaluation and Mitigation Strategy (REMS) will be necessary to “ensure safe use and mitigate the risk of severe harms that can result from patient impairment”.

Despite the complex review issues raised by the data package, it does contain two positive Phase 3 studies and some evidence of durability, she said.

Farchione also shared the discussion and voting questions for the day ahead:

8:30 EST

AdComm Kicks Off

And we’re off! Thanks for joining us bright and early for today’s significant meeting, which sets many ‘firsts’. Perhaps most notably, it’s the first time an FDA Advisory Committee has met to discuss a psychedelic-based new drug application (NDA), definitional disputes aside.

The first 10 minutes of the meeting will be taken up largely by formalities, with our Chair, Rajesh Narendran, and Designated Federal Officer, Joyce Frimpong, taking the lead. Thereafter, we will hear from Tiffany Farchione, Director in the Division of Psychiatry at the agency for brief opening remarks.

I won’t be recounting every twist and turn of today’s meeting here. Instead, I will aim to cover things that I deem pertinent, as far as possible.

MEETING COMMENCES AT 8:30 EST

Our AdComm Coverage Will Commence Shortly

Hi all, it’s Josh Hardman here; I’ll be kicking off our live coverage shortly.

In the meantime, you can get yourself oriented and prepared with the following materials:

  • Patients, Practitioners, Researchers and Public Submit Comments Ahead of FDA Advisory Committee on MDMA (Psychedelic Alpha, May 29th);
  • What to Expect: FDA Advisory Committee Set to Review MDMA-Assisted Therapy for PTSD (Psychedelic Alpha, May 27th);
  • Download briefing documents, the agenda, meeting roster and more via FDA.
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Josh Hardman

Josh has been writing, talking and working on the business, science and policy of psychedelics since he launched Psychedelic Alpha in early 2020. You can connect with him on LinkedIn or via email.