FDA Psychopharmacologic Advisory Committee Votes Against Supporting Effectiveness of MDMA for PTSD

The US Food and Drug Administration (FDA) Psychopharmacologic Advisory Committee (PDAC) voted 2-9 against supporting the effectiveness of MDMA in the treatment of adult patients with PTSD, relative to clinical trial data from the MAPP1 and MAPP 2 trials sponsored by Lykos Therapeutics.

The decision is anticipated to influence the final FDA decision on the company's New Drug Application (NDA) for MDMA-assisted psychotherapy for the treatment of adults with PTSD, which is scheduled for final decision by mid-August this year.

The committee additionally voted 1-10 to reject that the benefits of MDMA in combination with the FDA’s proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD.

Below is a live report of the FDA PDAC meeting as covered by HCPLive.

5:20 PM ET Update

Following the public hearing session, the PDAC reviewed the discussion questions itemized for the conclusion of the meeting. Here are summaries of their perspectives.

Question 1: Discuss the evidence of effectiveness for MDMA for the treatment of PTSD.

Panel members including Walter S. Dunn, MD, PhD, assistant clinical professor at University of California Los Angeles, largely highlighted concerns with the functional unblinding of the the pivotal MAPP1 and MAPP2 trials and participating therapists, in which MDMA-assisted therapy was compared to placebo in the treatment of PTSD.

Jess G. Fiedorowicz, MD, PhD, head and chief of the department of mental health at The Ottawa Hospital, highlighted the high level of patient engagement, endorsement, and limited dropout surrounding the clinical trials; however, these factors again may have been influenced by the functional unblinding, Fiedorowicz said. He echoed other colleagues in expressing concerns over public hearing comments regarding trial research misconduct as it related to treatment outcomes.

Paul E. Holtzheimer, MD, MS, deputy director for research at the National Center for PTSD, noted a particular issue with the available data is that lone psychedelic therapy is not evidenced beyond the support of successive psychotherapy; it remains an investigative therapy in the scope of the research.

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

Sentiments from the committee reflected concerns around the available safety data beyond the acute treatment stage, particularly in continued MDMA-assisted psychotherapy sessions beyond the tested 3-session regimen. Experts believed the cardiovascular and blood pressure-related outcomes observed in the phase 3 trial could be potentially mitigated by the FDA's proposed REMS.

Additionally, unreported adverse events potentially tied to the psychotherapeutic effects of MDMA were frequently raised as an issue by committee members.

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

Dunn mentioned the risk of patients being coerced and/or manipulated in the acute and sub-acute stages of care, with regard to the "openness" effect associated with MDMA—warranting a review and monitoring of that outcome going forward. Additionally, he posited whether patients would be recommended to safely titrate other psychiatric therapies if eligible for MDMA-assisted therapy, and whether such a recommendation would be associated with any adverse event risks from coming off current medication.

He and other colleagues also expressed interest in more formally setting precedent for which licensed, qualified care providers are involved in the acute care and monitoring settings.

Elizabeth Rebo, PharmD, executive director of pharmacy quality and medication safety at Kaiser Permanente, questioned the ability to enforce consistent guidance on protocol to discharge a patient from outpatient care and allow them to eventually operate a vehicle after MDMA administration. Other colleagues expressed concern over fall risks and other physical incapabilities post-treatment.

Question 4: 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 MDMA if approved for PTSD.

Melissa D. Barone, PsyD, adjunct assistant professor of psychiatry at University of Maryland School of Medicine, expressed the want for care provider education—both from psychedelic therapy experts who are uninvolved with the drug sponsor, and with regard to potential non-psychiatric health risks including how to manage a patient with raised blood pressure post-MDMA dose as observed in some patients in the MAPP1 and MAPP2 trials.

Other comments noted the difficult to adequately comment on the proposed topic without more substantial evidence surrounding the duration and characteristics of MDMA psychoactive effect on treated patients. Experts also expressed interest in more opportunities for third-party reporting centric for patient-reported outcomes and their issues with acute care.

The subject of frequent video monitoring of psychotherapy sessions, raised also during public hearing sessions, were an expressed interest from the committee.

3:45 PM ET Update

Brett Waters, an attorney and cofounder and executive director of non-profit advocacy group Reason for Hope, shared his familial history with suicide, including his mother and grandfather, the latter being a World War II veteran. Waters described the potential aversion patients with psychiatric illness may have with SSRIs that are the currently lone FDA-approved therapies for PTSD.

“I appreciate the thoughtful questions the committee has asked in evaluating this very challenging and novel application, however I urge that you not lose the forest through the trees,” Waters said. “MDMA-assisted therapy offers a seemingly obvious and logical approach to PTSD treatment, as the drug’s ability to rapidly establish therapeutic rapport and reduce fear response makes it easier to commit to and engage in a psychotherapeutic process that involves confronting often highly traumatic memories.”

Brian Pace, PhD, a lecturer in psychedelic studies in the department of plant pathology at The Ohio State University and coauthor of a citizens petition raising concerns with Lykos’ NDA, echoed comments criticizing the conduct of the clinical trials and “dubious, grandiose” claims of the ultimate benefit of applied psychedelic therapy.

Rev. Joe Welker, a pastor at East Craftsbury Presbyterian Church and self-described whistleblower on the psychedelic industry in his prior work with Johns Hopkins University raised issues with the “spiritual and religious conflicts of interests” pertinent to the background of the research’s development.

A self-described patient who said they underwent a single round of MDMA-assisted therapy to treat their PTSD in a clinical trial earlier this year, said the experience has “completely derailed” their life, including symptoms of exhaustion, cognitive impairment, brain fog, headaches, and more.

Deran Young, a licensed therapist and founder of Black Therapists Rock, positively described her experience with MDMA-assisted psychotherapy specifically for the treatment of racially-based trauma.

Naomi Mathis, assistant national legislative director at Disabled American Veterans (DAV), emphasized “the need for innovation” in PTSD care for impacted veterans; she called the MDMA-assisted therapy data for such patients “promising.”

“While DAV does not take a stance on the state of the science, we are heartened to see such research take place,” Mathis said.

All available public hearing comments are available to watch here.

3:15 PM ET Update

The afternoon portion of the committee meeting agenda opened with public comments.

Brian Dempsey, government affairs director at the Wounded Warrior Project, spoke positively on the adoption of MDMA-assisted psychotherapy for the treatment of veterans with PTSD. A significant majority of veterans experiencing trauma primarily seek care through the Veterans Affairs (VA) program, Dempsey said, though they can experience longer wait times, provider churn and emphases on prescription medication through the VA.

“All of these points underscore how increasing demand, unique interaction with the healthcare system, and willingness to try new approaches when others aren’t working are extremely present factors for veterans suffering from invisible wounds of service,” Dempsey said. He quoted a veteran who received MDMA-assisted care through their network, who advocated for its effectiveness in helping them to regulate and process their emotions.

“We believe there are still important considerations about patient education, treatment scalability, and impact on employment that need to be addressed, but we are wholly committed to finding new options for care for veterans who want and need care that they deserve,” Dempsey said.

Robert M. Grant, MD, MPH, professor of medicine at University of California-San Francisco, previously sponsored by Lykos 2 years ago, discussed his experiences as a trained MDMA-assisted therapy care provider and the importance of managing PTSD particularly as it relates to mitigate its effect on the prevalence and exacerbation of chronic, severe conditions. He noted the frequency of underlying PTSD in patients in emergency care settings is higher than most would imagine: a patient with liver failure due to an alcohol use disorder spurred by trauma, or a patient with cardiac failure due to excessive tobacco use driven by PTSD, among others. These don’t also speak for patients being treated for suicide attempts due to their PTSD.

“PTSD is an underlying driver for much of our disease burden broadly, and existing therapies for PTSD are relatively ineffective and poorly tolerated, with less than 5% of the affected population being willing to start and complete the current standard of care,” Grant said. “I find the (Lykos MDMA-assisted therapy data) evidence to be convincing and compelling—especially when combined with the substantial phase 2 program…not being discussed in this meeting.”

Russell Hausfeld, a journalist with Psymposia, raised concerns regarding potential exploitation and mistreatment of veteran patients involved in clinical trials with the company.

Next, a self-described veteran of the Iraq War with PTSD described how the condition impacted his mental, emotional, social and professional wellbeing. The veteran described undergoing a number of therapies, practices and resources to alleviate his symptoms to no significant benefit; he described suicidal ideation at a point when he believed his PTSD couldn’t be effectively treated.

“I cannot put into words how much this drug-assisted therapy helped me when I got into (the trial),” the veteran said. “The parts of me that I thought were permanently damaged—the way I saw the world and my response to stimuli had changed. The innocuous sounds and actions that you guys would not notice, that used to fill me with rage, anger, fear, anxiety and shame, they now go by so unnoticed that I feel normal.”

Nese Devenot, PhD, senior lecturer at Johns Hopkins University and coauthor of a citizens petition to extend the open public hearing, said she believes Lykos “obscured its actual intervention” in the FDA submission, calling for an independent review of all relevant clinical trial video recordings observing the dosed patient-clinician interaction.

Michael Abrams, MPH, PhD, senior health researcher from the Public Citizen’s Health Research Group, further discussed the “functionally unblinded” nature of the MAPP1 and MAPP2 trials and its possible influence toward favorable drug effects.

“Patients and therapists likely knew who received the drug, and anecdotes suggest some therapists abused that knowledge to manipulate patient beliefs,” Abrams said.

Jonathan Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences at Albert Einstein College of Medicine and chair on the council on research at the American Psychiatric Association, stressed the unmet therapeutic needs of the approximate 13 million US adults with PTSD; however, he also expressed caution behind the prospect of treating with MDMA.

“MDMA represents a promising treatment for a devastating illness—however, there are significant limitations to the current evidence base on MDMA for PTSD,” Alpert said.

Albert cited the clinical trial data’s functional unblinding, the high rate of lifetime MDMA use among study participants, the nature of the time-intensive novel psychotherapy session, and the currently limited long-term data regarding safety outcomes and PTSD relapse rates beyond 2 months post-treatment.

“The APA supports research and therapeutic discovery into psychedelic agents that’s pursued with the same scientific integrity, rigor and regulatory standards applied to other promising therapies in medicine,” Alpert said.

Ifetayo Harvey, executive director of the People of Color Psychedelic Collective, criticized the inadequate inclusion of non-White trial participants.

Kayla Greenstein, a PhD candidate from the University of Sydney, expressed concern with the theoretical underpinnings and the “use of touch” in psychedelic therapy sessions. Greenstein additionally called Lykos’ statement that MDMA facilitates memory recollection a “highly controversial idea.”

12:40 PM ET Update

Victoria Sammarco, PharmD, MBA, a risk management analyst for the Center for Drug Evaluation and Research (CDER) at the FDA, provided a detailed overview of the FDA’s proposed risk evaluation and mitigation strategy (REMS) for the application of MDMA-assisted therapy to treat patients with PTSD. A full description of the FDA’s REMS proposal can be found below today’s updates.

The components of an FDA REMS plan can include medication guides or patient package inserts; communication plans for healthcare providers; packaging and safe disposal technologies; elements to assure safe use (ETASU); implementation systems; and timetables for the submission of relevant assessments.

Among the risks associated with MDMA for which the FDA is considering a REMS are the effects linked to illicit MDMA (ecstasy) use, including:

• Reduced inhibition
• Openness to suggestion
• A range of intense emotions
• Altered sensory perception
• Impaired ability to perceive and predict motion

Such effects could put patients at risk of hospitalization, death, or other events of significant consequence.

“The agency’s rationale for our proposed REMS is rooted in the patient impairment expected from MDMA administration, and the need to ensure patients are safe from serious harm from impairment,” Sammarco said. “The agency’s proposed REMS is informed by the strict controls that were in place during clinical development."

Such controls included the following:

• Monitoring patients in a controlled setting for an extended period, including overnight stays after most medication settings.
• Two therapists required to be present during medication sessions.
• Patients were instructed not to drive until the following day after receiving MDMA.

The proposed REMS goal, Sammarco said, is to mitigate “serious harm resulting from patient impairment from MDMA administration by ensuring that during and after MDMA administration, patients are managed in a medically supervised healthcare setting.”

12:30 PM ET Update

David Millis, MD, clinical reviewer in the division of psychiatry at the FDA, provided a presentation on the agency’s assessment of MDMA capsules relevant to Lykos Therapeutics’ proposed NDA.

In first reviewing the characteristics of PTSD, Millis described it as a “disabling condition” frequented with intrusive memories, nightmares, hyperarousal and avoidant behavior following exposure to serious trauma including actual or threatened death, serious injury or violence including sexual assault. It is highly comorbid with mood, anxiety and substance use disorders, and may lead to significantly increased risk of suicidality.

Regarding MDMA, Millis described the drug’s chemical structure to ampehtamines, while its pharmacological mechanism acts as a serotonin, norepinephrine and dopamine reuptake inhibitor and releasing agent. The proposed dosage would be an oral option taken 3 times at least 3 weeks apart in a supervised treatment session over the course of 4 months. The add-on psychotherapy course would occur in between medication administrations.

Only SSRIs paroxetine and sertraline are currently approved by the FDA to treat PTSD, Millis highlighted—though both agents are limited by approximate 60% response rates, boxed warnings for suicidal ideation and behavior risks with SSRIs, and an incapability to treat the root cause of PTSD, only the symptoms.

The proposed dosing regimen is as follows, with medication sessions occurring ≥21 days between one another:

• Session 1: 68 mg initial administration, followed by a second dose of 34 mg 1.5 – 2 hours later (total, 102 mg)
• Session 2: 100 mg initial administration, followed by a second dose of 50 mg (total, 150 mg)
• Session 3: 100 mg initial administration, followed by a second dose of 50 mg (total, 150 mg)

“The applicant is proposing a novel treatment paradigm,” Millis said. “Rather than a chronic daily administration, the proposed MDMA regimen is more circumscribed. This time-limited treatment is intended to provide lasting relief from PTSD symptoms.”

Regarding regulatory history and the key issues with the proposed drug, Millis addressed the winding and complex background of the therapeutic development of MDMA.

First, he acknowledged the FDA’s concern about potential functional unblinding, as stated by Tiffany R. Farchione, MD, in her opening remarks. Millis noted that at the end of Lykos’ phase 2 trial, the FDA suggested active comparators be used to limit the effect of functional unblinding (i.e., patients being aware they have received the psychoactive drug instead of placebo). They recommended comparators including niacin or lower-dose MDMA.

Millis said the company and the FDA did not reach an agreement on the adequacy of the blinding process during this 2016 meeting, with Lykos stating niacin may worsen PTSD symptoms, while lower-dose MDMA could exacerbate anxiety in some trial participants.

“We rely on data from adequate and well-controlled trials to provide the basis for a substantial evidence of effectiveness,” Millis said. “Among other characteristics, to be considered adequate and well-controlled, a study must incorporate a design that permits valid comparison with a control condition, and measures must be taken to minimize bias.”

In the specific case of comparing MDMA to placebo for the treatment of PTSD, Millis explained, a patients’ awareness that they are receiving the psychoactive drug may positively influence their treatment—while the disappointment a patient feels in realizing they are in the placebo arm may harm their treatment process.

Next, Millis reviewed prior discussions with the company’s submission for a special protocol assessment (SPA) for the phase 3 MAPP1 trial in 2017. SPAs are a process in which individual new drug (IND) applicants try to reach an agreement with the FDA on the design of a study intended to support an eventual marketing approval.

By March 2017, an SPA No Agreement letter was issued, Millis said, with disagreements between the agency and company on the proposed statistical analyses and choice of secondary endpoint in MAPP1 (see below). There was agreement, however, on the company’s plan to minimize bias via blinded centralized independent rater pools to administer the primary outcome measure via video interviews, as well as the use of MDMA-assisted therapy as the MAPP1 treatment arm, versus identical psychotherapy with inactive placebo serving as the control.

The FDA and company additionally agreed on the established definitions for treatment response, loss of PTSD diagnosis, and remission per in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) (see DSM diagnostic criteria for PTSD below).

Additionally, the No Agreement letter from the FDA stated that all phase 1 – 3 clinical trials must document adverse events associated with potential abuse or overdose in MDMA-treated patients. It additionally stated that all clinical safety and efficacy trials should be evaluated for central nervous system (CNS)-related adverse events “that may suggest the test drug produces effects that will be sought out for abuse purposes.”

Similar to Farchione, Millis highlighted the agency’s request for data regarding the presence of “euphoria-like response” to help interpret the potential for abuse of a clinically tested drug.

“However, in reviewing the clinical study reports submitted with the application, we noticed a striking lack of abuse-related adverse events,” Millis said. “When we followed up the applicant about their abuse potential assessment methodology, they clarified that they did not systematically collect abuse-related adverse events in the guidance. Rather, they only documented events identified as unfavorable.”

Millis said it is a “major concern” that this evidence in missing in the regulatory application for MDMA, saying it would serve as key data to help characterize the CNS effects of the drug. “As a result of not having this data, our ability to properly describe the expected severity and frequency of these events in product labeling is affected,” he said.

The FDA is also without adequate data that would help to inform the duration of MDMA effect that would help clinicians safely discharge their patients, as well as to help the agency appropriately describe the effects of the drug in potential labeling.

Among the other events of note in the regulatory history of Lykos’ NDA application, Millis highlighted the granted Breakthrough Therapy Designation for MDMA as a PTSD treatment—based on phase 1 and 2 data—in August 2017; the company’s agreement to the FDA’s recommended Participant Blinding Survey for MAPP2 in October 2020; and Lykos’ agreement to submit said survey results in accompaniment with the NDA submission in May 2023.

The FDA stated the unblinding survey results from MAPP2 showed that most trial participants could adequately guess which treatment arm they were randomized to.

Millis additionally reviewed the proposed psychotherapy intervention component of the indication, as per the MAPS Manual for MDMA-Assisted Psychotherapy in the Treatment of Posttraumatic Stress Disorder. He noted the guide provides general principles on therapeutic approach among treated patients, giving the therapist flexibility to choose therapeutic modalities with which the therapist is familiar.

“The content or the approach of these integrated sessions was not standardized in the treatment manuals, and was left up to the individual therapist…and could vary considerably from therapist to therapist,” Millis said.

In reviewing the phase 3 findings from MAPP1, MAPP2 and the observational follow-up MPLONG trial, Millis noted that the FDA agreed to Lykos’ proposed threshold of ≥10-point change on CAPS-5 score denoting PTSD response. Descriptions of the MAPP1 and MAPP2 trial findings are posted below.

Regarding safety outcomes from the pivotal trials, Millis noted the risk of rapid elevation in both heart rate and blood pressure was highest among patients with preexisting cardiovascular disease; however, only 6.1% of patients receiving MDMA in the trials reported a systolic blood pressure of >180 mmHg following their dose. Millis did note, however, that MDMA may include potential for proarrhythmic outcomes based on trial data.

Suicidal ideation and behavior was not evidently increased in the immediate 24 – 72 hours following MDMA dosing sessions, despite the known heightened risk of such conditions in patients with PTSD, Millis said. He also noted that some of the adverse events related to the stimulant or serotonergic properties associated with MDMA may include insomnia, sleep disorders, anxiety, restlessness and nervousness.

Millis provided further details on the abuse potential of MDMA, highlighting a review from the FDA Controlled Substance Staff that which suggests MDMA has abuse potential that parallels Schedule II stimulants including morphine, oxycodone and methyphenidate. The agency did not require Lykos to perform a dedicated human abuse potential study due to sufficient published literature on the subject already.

“Overall, the safety profile for MDMA observed in the development program is consistent with its known effects,” Millis said. “However, certain risks cannot be fully characterized based on the safety data from this program.”

The “relatively small safety database” from the MAPP trial program may be acceptable if FDA can agree that the proposed 3-dose time-limited treatment regimen of MDMA-assisted therapy is indeed effective and durable for the treatment of PTSD, Millis said.

11 AM ET Update

Kelley O’Donnell, MD, PhD, research assistant professor of psychiatry at NYU Grossman School of Medicine and director of clinical training at the NYU Langone Center for Psychedelic Medicine, provided a clinician’s perspective on the available clinical efficacy and safety data supporting Lykos’ FDA application.

O’Donnell said her interest in the mounting evidence supporting the proposed indication piqued with data showing the drug may catalyze the effects of psychotherapy—a far cry from the lessons she learned only about MDMA’s harmful effects in medical school. She echoed Lykos representatives’ sentiments regarding unmet needs for the PTSD patient population (below update), highlighting the combined issue of limited efficacy with psychotherapy and SSRIs plus increased patient risk of severe outcomes including suicidality.

“We generally don’t think of psychotherapy as a rapid-acting treatment for PTSD,” O’Donnell said. “One challenge in trauma treatment is the therapeutic processing of traumatic memories can only happen when a patient feels safe. But many patients with PTSD move through the world feeling fundamentally unsafe—in their own bodies and in their relationships with others.”

This, O’Donnell explained, is why the relatively rapid results of MDMA-assisted therapy in clinical trials has been such a “rewarding” outcome for her and her peers. O’Donnell described the benefits of MDMA on psychotherapy as four-fold.

• It may increase a patient’s sense of empathy and connectedness.
• It may foster a patient’s sense of safety and trust.
• It may increase recall of affectively charge memories.
• Its serotonergic effects often translate to transiently reduced anxiety.

O’Donnell additionally noted that patients with meaningful reduction of PTSD symptoms from MDMA-assisted psychotherapy also experienced functional improvements: they had greater capability to pursue personal goals and maintain meaningful relationships. Even patients with residual symptoms of PTSD after treatment generally were able to process trauma at the end of the regimen, reporting greater senses of safety, trust and self-efficacy.

“In this combination treatment, the acute effectiveness of MDMA facilitates the psychotherapy—strengthening the therapeutic alliance, facilitating the patient’s development of insights and tools, and continue to cultivate long after the acute effects are worn off,” O’Donnell said. “I look forward to being better able to support my patients and those who care for them with this valuable and urgently needed care option for PTSD.”

10:30 AM ET Update

It has been 20 years since the FDA has approved a drug for the treatment of PTSD. As Lykos Therapeutics representatives explained in the PDAC meeting, there’s an even longer history of clinical utility of MDMA that which be underreported.

While introducing her team’s presentation of clinical data supporting Lykos’ NDA for MDMA-assisted therapy to treat patients with PTSD, Amy Laverdiere, MBA, Program Lead at Lykos detailed the clinical history of MDMA in psychiatric care—a history that is subjected to stigmatization by most laypeople.

“MDMA is not a new drug, and while it can be misunderstood due to its illicit counterpart, it actually has a well-documented history in the psychiatric field,” Laverdiere said.

Laverdiere detailed the use of the drug in the 1970s and 1980s in combination with talk therapy—somewhat similar to Lykos’ proposed use in combination with psychotherapy for patients with PTSD—as well preliminary research from before that time showing the psychoactive drug can be beneficial for patients with psychiatric disease, particularly in helping patients to more adequately process, regulate and convey difficult emotions.

Lykos’ research involving 427 participants in 17 clinical treated with MDMA is preceded by earlier work assessing the drug in approximately 4000 patients.

“We know psychotherapy can be effective, but only if patients are able to tolerate the treatment,” Laverdiere said. “The available data and mechanism of action suggest that MDMA catalyzes the effectiveness of psychotherapy by facilitating memory recollection and extending the patient’s window of tolerance for revisiting distressing thoughts or experiences. Studies of MDMA show improved self-awareness and pro-social effects that enhance the therapeutic alliance between the patient and their therapist.”

Indeed, this mechanism of action would particularly benefit the unmet needs of patients with PTSD, who generally present with difficulties processing and deliberating on emotions in a way that may curb the benefit of standard-care psychotherapy.

Jerry Rosenbaum, MD, director of the Center for the Neuroscience of Psychedelics at Massachusetts General Hospital Research Institute, and Stanley Cobb Professor of Psychiatry at Harvard Medical School, followed Laverdiere’s presentation with a lengthier review of the unmet needs of patients with PTSD—a psychiatric condition estimated to affect approximately 13 million US adults.

PTSD symptoms can last for, on average, 6 years; up to 3 in every 5 patients remain symptomatic despite their treatment, and half (48%) remain untreated altogether, Rosenbaum explained. Compared to those without PTSD, patients face a 47% greater risk of mortality, due to comorbidities including increased suicidality.

“Although PTSD is associated with exposure to deployment and combat, consequent to a number of potential experiences, civilian trauma is actually more common,” Rosenbaum said. “Individuals exposed to sexual violence, for example, or an unexpected death in the family or a life-threatening traumatic event may also develop PTSD.”

Rosenbaum reviewed the DSM-5 criteria for PTSD, which includes the following:

• Exposure to actual or threatened death, serious injury or sexual violence
• Clinically significant distress/impairment
• Effects non-attributable to substances or other medical diagnoses
• ≥1 month of disturbance
• Presence of ≥1 intrusion symptom
• ≥1 symptom of persistent avoidance
• ≥2 symptoms of negative alterations to cognition and mood
• ≥2 symptoms of altered arousal and reactivity

More simply, Rosembaum explained, the condition may be characterized into 4 symptom clusters: avoidance of triggers; intrusion; negative thoughts and feelings; and arousal and reactivity.

With current treatment options psychotherapy and selective serotonin reuptake inhibitors (SSRIs), there are apparent benefits and shortcomings with each. Rosenbaum highlighted the clinically meaningful reduction of PTSD symptoms through psychotherapy, though also noted high rates of dropout due to exacerbated distress experienced by patients, as well as the limited access of the practice. With SSRIs, patient have been shown to experience greater improvement in clinician-assessed scales for PTSD symptoms versus placebo— but response rates struggle to exceed 60%, and the drug class is only capable to target symptomology.

"Several pharmacologic agents are used off-label and concurrently, despite lacking evidence of efficacy and not being approved for the PTSD indication—which speaks to the demand from prescribers for novel-indicated therapeutics to provide our patients new tools to alleviate symptoms,” Rosenbaum said.

Lykos representatives further provided clinical efficacy and safety data supporting MDMA-assisted therapy from the phase 3 MAPP trial program; you can find a summary of the trial’s findings below.

9:45 AM ET Update

Tiffany R. Farchione, MD, director of the division of psychiatry in the office of neuroscience at the FDA, provided the agency’s opening remarks earlier this morning.

“This application is both consequential and complex,” Farchione said.

In reviewing the clinical program supporting the Lykos Therapeutics New Drug Application (NDA) for MDMA-assisted therapy in the treatment of PTSD, Farchione did acknowledge the MAPP1 and MAPP2 trials showed positive, clinically-meaningful improvement of patients over short-term periods—findings that which were bolstered by long-term, open-label follow-up suggesting a durable effect of MDMA in treated patients. However, she noted as well that several factors impact the interpretability of these trial results.

For one, the trial data are impacted by “functional unblinding,” meaning it is nearly impossible to blind studies due to the acute psychoactive effects of MDMA. Though the trials are designed and conducted in double-blind design, participants are confident to guess their treatment assignment, which may influence expectation bias.

Potentially as a result, the follow-up assessments featured a 25% participant dropout since the parent trial, and a trend of intercurrent, non-study drug use among participants.

Additionally, Farchione noted the poor characterization of psychotherapy in the clinical trials; the practice conducted concurrent with MDMA administration was not compared in efficacy to any other method of therapy, and its clinical value in care for patients with PTSD was not observed with the addition of a lone MDMA arm in the clinical trials.

Regarding the safety outcomes, Farchione said MDMA’s associated adverse events were consistent with the known effects of the drug; however, adverse events related to the potential for drug abuse were not adequately collected nor reported.

“It is the lack of data collection on the subjective effects of MDMA that may the greatest impact on our regulatory decision-making,” Farchione said. “Although the agency had advised the applicant to collect adverse events that are associated with abuse—effects that were deemed positive, favorable or neutral—things like euphoria or elated mood were not captured, despite the fact that these effects are part of the evaluation of abuse potential, as we outline in our guidance on this issue.”

Farchione further explained subjective effects of MDMA can persist for several hours, leaving patients impaired and in a vulnerable state. “If this product were to be approved, we believe the REMS will be necessary to ensure safe use and to mitigate the risk of serious harm that can result from patient impairment.”

“Although this application presents a number of complex review issues, it does include 2 positive studies in which patients in the (MDMA) arm experienced statistically significant and clinically meaningful improvement in their PTSD symptoms, and that improvement appears to be sustainable for at least several months after the end of the acute treatment period, despite no additional doses of (MDMA),” Farchione continued.

Farchione concluded by providing the 2 key discussion topics and voting questions each that will be addressed by the PDAC.

Discussion 1: The evidence of effectiveness for MDMA for the treatment of PTSD, with consideration toward the potential impact of functional unblinding on interpretability of efficacy results, the durability fo effect, and the role of psychological intervention in the treatment paradigm.

Discussion 2: Whether the available data are adequate to characterize the safety of MDMA for the treatment of PTSD, with consideration to limited data collected on events deemed positive, favorable or neutral that would inform the potential for abuse as well as lacking data from some clinical laboratory tests, as well as any other data-related safety concerns characterizing MDMA.

Voting Question 1: Do the available data show that the drug is effective in patients with posttraumatic stress disorder?

Voting Question 2: 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?

8:00 AM ET Update

The US Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) meets today, June 4, to review the effectiveness of midomafetamine (MDMA) for the treatment of patients with post-traumatic stress disorder (PTSD).¹

The meeting, scheduled from 8:30 AM – 5:30 PM ET, will review the clinical efficacy, safety and known benefit-risk profile of MDMA as an add-on therapeutic to psychotherapy in patients with PTSD—specifically as evidenced in research conducted and supported by Lykos Therapeutics (formerly MAPS Public Benefit Corporation) as part of their New Drug Application (NDA) submitted to the FDA for MDMA-assisted therapy to treat patients with PTSD.

Additionally, the PDAC meeting will review a risk evaluation and mitigation strategy (REMS) proposed by the FDA to address the potential acute and long-term safety concerns, as well as ethical risks, associated with providing the psychedelic therapy to patients with psychiatric condition.

At the conclusion of the meeting, a vote will be called for the committee to vote on the following questions, as phrased in the agenda meeting draft made available prior to June 4:

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

About MDMA

MDMA is an oral, synthetic psychoactive compound that includes stimulant and psychedelic properties. Previously studied and used in psychiatric practice about 5 decades ago,² MDMA was designated a schedule I drug by the FDA in the 1980s, similarly to marijuana (cannabis) and lysergic acid diethylamide (LSD), among other drugs previously known for recreational misuse.³

However, the FDA granted MDMA breakthrough therapy designation in August 2017, on the basis of MAPS’ phase 2 trial data showing that 61% of patients with treatment-resistant PTSD no longer qualified for their diagnosis after 3 sessions of MDMA-assisted psychotherapy.⁴

The clinical benefit of MDMA in conjunction with psychotherapy appears to be the drug’s ability to “enhance the effects” of therapy itself in patients with PTSD.⁵ Animal models have shown that MDMA increases brain-derive neurotrophic factor expression in the amygdala, which correlates with the eradication of fear memories. Human neuroimaging studies additionally show MDMA is linked to amygdalar BOLD activity reduction when presented with negative emotional stimuli.

Explained more succinctly by prolific investigator Bessel van der Kolk, MD, to HCPLive last week: “MDMA really helped people to get in touch more with much more complex issues than the trauma.”⁶

“You have a much more complex set of mental problems besides the particular memory of the trauma,” van der Kolk explained about PTSD. “And those set of mental functions really prevents people from getting better, because if you cannot control your emotions, you become extremely fearful when you start recalling the traumatic incidents. And you may actually freak out, shut down become very agitated—you cannot go there.”

In clinical trials, MDMA doses has shown a capability to help patients with PTSD “go there” in concurrent psychotherapy sessions, leading to more beneficial outcomes.

About MAPP1 and MAPP2

Lykos’ NDA is supported by findings from the follow-up phase 3 program: a pair of phase 3 trials named MAPP1 and MAPP2, wherein participants with PTSD underwent 3 treatment cycles of MDMA-assisted therapy for 3 weeks each.⁵ Investigators sought a primary endpoint in change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) from baseline, as well as secondary endpoints regarding improvement in PTSD-associated functional impairment from baseline, versus a placebo arm.

Investigators led by Jennifer M. Mitchell, PhD, professor of neurology at UCSF Weill Institute for Neurosciences, used a study drug manufactured by Onyx Scientific and compounded by Sharp Clinical Services, in accordance with Current Good Manufacturing Practice (CGMP) standards.

The team found that MDMA-assisted therapy was associated with significant attenuation of PTSD symptoms per CAPS-5—a mean change of -11.9 (95% CI, -6.3 to -17.4) in scores from baseline to 18 weeks among participants who completed the 3-course regimen versus the placebo arm (P <.0001). Measures of clinician-rated functional impairment per Sheehan Disability Scale (SDS) were also significantly improved in the MDMA-assisted therapy arm versus placebo (-3.1 vs -2.0) during the same time period.

Additionally, investigators reported that 28 (67%) participants who completed the MDMA regimen no longer met diagnostic criteria for PTSD at 18 weeks, versus 12 (32%) of the placebo arm after 3 psychotherpay sessions. Another 14 (33%) of MDMA-treated participants met the criteria for PTSD remission after 3 sessions, versus 2 (5%) from the placebo arm.

Regarding safety, mild to moderate treatment-emergent adverse events (TEAEs) that were more prevalent in the MDMA arm than placebo included muscle tightness, decreased appetite, nausea, hyperhidrosis, and a sensation of cold temperature. Investigators observed no increased AEs relevant to suicidality, per Columbia Suicide Severity Rating Scale (C-SSRS), in the MDMA arm. Treated patients additionally reported a transient increase in systolic and diastolic blood pressure, as well as heart rate.

Interestingly, more than 90% of all trial participants reported suicidal ideation in their lifetime, and 17 (37%) patients in the MDMA arm and 14 (32%) patients in the placebo arm reported suicidal ideation at baseline.

Mitchell and colleagues noted in their assessment of the findings that the effect size of 0.91 observed with MDMA-assisted therapy versus placebo was greater than that for any other pharmacotherapy assessed for PTSD

“These data illustrate the potential benefit of MDMA-assisted therapy for PTSD over the FDA-approved first-line pharmacotherapies sertraline and paroxetine, which have both exhibited smaller effect sizes in pivotal studies,” they wrote. “Previous comparison of change in CAPS score between sertraline and placebo showed effect sizes of 0.31 and 0.37. Similarly, comparison of change in CAPS score between paroxetine and placebo showed effect sizes of 0.56, 0.45 and 0.09.”

About the FDA’s REMS proposal for MDMA

The FDA shared a draft of its REMS proposal for MDMA with the PDAC meeting agenda, detailing recommended requirements, policies and resources that will work to “ensure the benefits outweigh the risks of serious harm resulting from patient impairment from (MDMA) administration).”⁷ As they note, patient impairment is indeed an expected effect from the investigative therapy that requires safeguards promoting safety.

In their REMS proposal, the FDA detailed that MDMA may only be dispensed in certain health care settings, to patients with evidence or other documentation of safe-use conditions, with each patient subject to monitoring and enrollment in a data registry.

“The enrollment will inform patients about the risk of impairment and the serious harm that may result, the need to report adverse events, and the patient agrees to be discharged to an accompanying adult and not drive or operate heavy machinery in the immediate period after the medication session,” the statement read.

Additionally, healthcare settings would be required to develop and put in place policies and practices that ensure each of the following:

1. A prescriber is available during MDMA administration and the monitoring period to determine if the second dose is held for safety or tolerability concerns.
2. ≥2 healthcare providers are onsite to monitor the patients’ medical and psychological status for ≥8 hours and until patient is stable for discharge; 1 provider must be licensed.
3. Emergency action plans are in place to escalate care if needed.
4. Plans are set to address when a patient may require longer monitoring.
5. The patient is stable when discharged from the healthcare setting.
6. The patient is released to an accompanying adult after each session involving medication.
7. Patients are followed up with after discharge from each such session.

Regarding the proposed patient registry, the FDA stated their proposed REMS would ensure patient data collection will help to inform the agency of signs and symptoms from either mental or physical distress experienced by patients treated with MDMA. It would also help to inform the FDA on the onset and duration of short-term effects of the drug, as well as whether care required escalation based on outcomes.

“In addition, information regarding patient safety between treatments will be collected including events that result in increased risk due to impaired judgement, or worsening of psychological disorders that cause disability, hospitalization, or death,” the FDA stated. “Registry data will also be used to determine whether changes to monitoring and other safe use behaviors in the REMS are needed.”

References

1. ^{US Food & Drug Administration. UPDATED MEETING TIME AND PUBLIC PARTICIPATION INFORMATION: June 4, 2024: Meeting of the Psychopharmacologic Drugs Advisory Committee Meeting Announcement. Web page. Last updated May 31, 2024. Accessed June 3, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/updated-meeting-time-and-public-participation-information-june-4-2024-meeting-psychopharmacologic#event-information}
2. ^{Weleff J, Akiki TJ, Barnett BS. Bibliometric Analysis of Academic Journal Articles Reporting Results of Psychedelic Clinical Studies. J Psychoactive Drugs. 2023;55(4):434-444. doi:10.1080/02791072.2022.2133757}
3. ^{DEA. Drug Scheduling. Web page. Accessed June 4, 2024. https://www.dea.gov/drug-information/drug-scheduling}
4. ^{Hoffman M. FDA Grants MDMA Breakthrough Therapy Designation for PTSD. HCPLive. Published August 31, 2017. https://www.hcplive.com/view/fda-grants-mdma-breakthrough-therapy-designation-for-ptsd}
5. ^{Mitchell JM, Ot'alora G M, van der Kolk B, et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med. 2023;29(10):2473-2480. doi:10.1038/s41591-023-02565-4}
6. ^{Kunzmann K. Bessel van der Kolk, MD: What MDMA-Assisted Therapy Taught us About PTSD. HCPLive. Published May 31, 2024. https://www.hcplive.com/view/bessel-van-der-kolk-mdma-assisted-therapy-taught-ptsd}
7. ^{US Food & Drug Administration. FDA Briefing Document. Psychopharmacologic Drugs Advisory Committee Meeting. June 4, 2024. Division of Psychiatry/Office of Neuroscience. Accessed June 3, 2024. https://www.fda.gov/media/178984/download}