FDA MDMA therapy advice may be a setback, but it is not the end of the road

Four months ago the psychedelics industry was abuzz when Lykos Therapeutics (formerly MAPS Public Benefit Corporation) announced it had received FDA acceptance and priority review for a New Drug Application (NDA) concerning its MDMA-assisted therapy for PTSD.

While the final decision on the matter is not expected until 11 August 2024, the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) has delivered a major blow to the development.

The committee voted “no” on the question of whether the data shows the treatment’s effecitveness as well as on the question of whether the benefits outweigh the risks, with concerns raised over trial design, data gaps, and the potential for abuse and unethical practice.

As highlighted by Lykos, the FDA is not bound by PDAC’s guidance but it does take its advice into consideration – meaning the outcome is not looking good for the FDA’s final decision later this year.

Lykos has expressed its disappointment on the vote outcome given “the urgent unmet need in PTSD”, however, the organisation has acknowledged that the committee “faced a challenging and atypical assignment, which was to evaluate a therapeutic approach that combines drug therapy (MDMA) and psychological intervention.”

Amy Emerson, Chief Executive Officer of Lykos Therapeutics, stated: “We remain committed to working with the FDA to address outstanding questions so that we may find a path forward to ensure the responsible and careful introduction of MDMA-assisted therapy into the healthcare system, if approved.”

While the advisory vote may not bode well, industry stakeholders believe this is not the end of the road for MDMA-assisted psychotherapy.

With the advice concerning only the Lykos trial, there may be scope for concerns raised by the committee to be addressed in further trials, as well as other MDMA analogues or therapy designs to make it to approval.

Christian Angermayer, Founder of atai Life Sciences, believes that there is still a strong chance that, with a properly conducted Phase 3 trial, MDMA-assisted therapy will get approved.

“I (still) believe MDMA is a promising drug with tremendous therapeutic potential for patients with severe mental health issues,” wrote Angermayer.

“It isn’t MDMA itself that was rejected per se, but the specific, poor data set provided by Lykos; the committee particularly cited discrepancies in clinical trial design and conduct, inadequate collection of safety and other relevant data, bias in the evaluation of patients, and cases of patient abuse during the trials.”

Rivki Stern Youdkevich, Co-founder and CEO at Shortwave Life Sciences (SWLS), which is developing psychedelic medicines for the treatment of anorexia nervosa, has said the decision is not deterring their developments.

Youdkevich commented: “We were disappointed to learn of the panel’s recommendation but we are not discouraged.

“Mental ill health is growing at an alarming rate with an increasing number of conditions affecting more people in every age group worldwide. This necessitates novel approaches to medication and treatment, as existing therapies do not suffice. So our enthusiasm for development of psychedelics-based treatments and medicine remains undiminished.

“In fact, we are doubling down on it. Shortwave Life Sciences’ goal is to become a leader in the origination, development and operation of innovative solutions in the field of mental health. Like other psychedelics drug makers, we remain unwavering in our commitment to overcome the expected challenges on the way to approval and wide acceptance of this new field as safe, effective and viable.”

Youdkevich emphasised that the FDA’s advice will not affect Shortwave’s chances of approving its drug product for anorexia nervosa.

“Specifically at Shortwave we have several strengths in our clinical and development approach which would lead us, I believe and hope, to a positive reception,” explained Youdkevich.

“Our team of experienced clinical experts led by Dr. Nadya Lisovoder designed our clinical strategy to anticipate and meet the most stringent requirements from the regulator. We are undergoing a full set of pre-clinical studies to create a robust base of evidence and research which will illuminate our clinical trials design.

“Furthermore, our by-the-book clinical trial design will be further wisened by real-time data and learnings from our partners at the Sheba Medical Center Department of Eating disorders’ Phase 1 psilocybin-assisted therapy trial for anorexia patients.

“Our anorexia programme is based on a combination of psilocybin and additional APIs. We initially designed this combination to extend the mechanism of action of the drug, giving us flexibility in dosing of the scheduled component, psilocybin. Our drug delivery method allows for efficient administration and absorption which is currently being tested, thus maximising the effect even in a potentially lower dose of psilocybin.

“Anorexia nervosa is a life-threatening disease, with the highest mortality rate of mental health conditions and with no FDA-approved medication.

“Today, treatment for anorexia nervosa is psychotherapy based, with no standardised protocol. Our novel drug product and delivery method would naturally fit into this mode of care with the aim of achieving remission in a relatively short period, and reducing the need for years of therapy and treatment. So, although psychotherapy adds complexity to the process of regulatory approval, in our case, it is the incumbent standard of care.

“We applaud and look up to the pioneers in psychedelics drug development who are the avant-garde in creating this “new field of medicine”. They are facing head on the challenges and hurdles of evaluation and acceptance into mainstream medicine.

“Our strategy at SWLS has always been to follow in the regulatory path created by the first-comers and implement their learnings vis-a-vis the regulators. Such learning may include special attention to communication at all stages and on all aspects of trial methodology design and implementation with the regulators, to the degree trial participants are novice to the drug, as well as consideration of all aspects and the possibility of conducting blind studies with psychedelic compounds.”

While it remains to be seen if MDMA-assisted therapy will gain approval in the United States in August, the compound is gaining traction as a treatment for mental health conditions including PTSD elsewhere across the world.

Canada added MDMA-assisted therapy to its Special Access Programme in 2022 for the treatment of PTSD, and in 2023 Australia rescheduled the compound to allow authorised access to the therapy for select patients living with PTSD.

In fact, just days following the FDA’s advice, a Dutch advisory committee, which conducted a multidisciplinary analysis of the health risks of MDMA to advise the Dutch Cabinet, recommended the Government should allow access to MDMA-assisted therapy for people living with PTSD.

The independent State Commission was established by the Dutch Parliament to research the legal status of MDMA and provide advice on its medical use.

The report produced by the committee specifically advises on the pros and cons of the medicinal use of MDMA for the treatment of PTSD, advising that there appears to be sufficient scientific evidence for the effectiveness and safety of this form of therapy.

The committee has now recommended developing the medical use of MDMA for PTSD as quickly as possible, advising that regulatory frameworks are established.

In a statement, Minister Pia Dijkstra, Minister for Medical Care of the Netherlands, commented: “I am pleased that the report is now available, because it provides tools to further develop the therapeutic application of MDMA.

“Research into the therapeutic use of MDMA is promising. It is possible that MDMA as a therapy-supporting medication can help, especially for mental health patients who have been dealing with their problems for years and have not been helped by the current range of therapies.

“However, more scientific, clinical research needs to be done. With regard to the recreational use of MDMA, the report emphasises the principle of Dutch drug policy, which primarily emphasises health, prevention and reducing the harmful consequences of use, for example through monitoring and testing.

“It is therefore good that this report is now available and supports the need for substantiated policy and further scientific research.”