What’s next for MDMA therapy following FDA rejection?

While the news is a devastating blow to the 13 million in the U.S. living with PTSD, it comes as no surprise as the decision follows the recommendation of an independent advisory committee not to approve the therapy in June.

Rejecting the NDA, the FDA issued a complete response letter (CRL) citing concerns over blinding, expectancy bias, and insufficient data to demonstrate durability. The authority has now requested a further Phase 3 trial which will take years and cost millions to complete.

Lykos Therapeutics (Formerly MAPS PBC) has requested a meeting with the FDA to discuss its resubmission.

Since the decision, three studies from Lykos have been retracted from the academic journal Psychopharmacology due to “protocol violations amounting to unethical conduct”, the organisation has laid off 75% of its staff, and Founder and President of MAPS Rick Doblin has stepped down from the board of directors. 

Doblin responded to the FDA decision stating: “MAPS and our supporters have been advocating for the development and supporting the FDA-approved research of MDMA-assisted therapy for more than 38 years; MAPS will continue working towards safe, legal access to this therapy for the more than 350 million people living with PTSD worldwide.

“Our collective commitment to MDMA-assisted therapy remains unwavering. MAPS remains fully focused on supporting culturally appropriate research, rigorous science, and drug policy reform that empowers citizen advocacy in all areas of the world including those with high incidences of trauma and limited resources.”

While the contents of the CRL letter are not available to the public, it might be assumed that the issues laid out in the letter lay the groundwork for a successful second Phase 3 trial.

Chief Executive Officer of Lykos Therapeutics, Amy Emerson, has shared disappointment at the request for this second trial, stating that: “The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades.

“While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature.”

CRL’s are not unusual following Phase 3 trials, and Pink Sheet has highlighted how the use of CRL’s by the FDA hit an all time high in 2022, with 31% of decisions on novel agents resulting in a CRL and almost half of those needing further clinical trials. 

Pink Sheet further details that CRLs with clinical concerns generally had negative outcomes, with nine needing new trials and three programmes discontinuing following receipt of a CRL.

Dr Ingmar Gorman, co-founder and CEO of Fluence, however, believes the current circumstances are promising, highlighting that: “This perspective helps us frame the current situation not as a setback, but as a natural step in the rigorous process of bringing new treatments to those who need them.

“The extensive feedback typically offered in a CRL provides a clear roadmap for approval — something that would have been unimaginable four decades ago when MDMA was first banned. 

“This marks important progress in the field of psychedelic research and mental health treatment. We’ve come a long way, and that’s worth celebrating.”

Some of the main concerns from the FDA were expectancy bias and functional unblinding in the trials, as 90% of participants in the MDMA group guessed that they had received the medicine and not a placebo. Equally, 40% of participants had tried MDMA before participating in the trial. 

Bliding is a core issue for psychedelic research as the effectiveness of current methods is limited when using compounds that have a very noticeable effect. Research suggests the need for new methods for improving psychedelic trials in order to maintain their scientific integrity if these therapies are to make it to approval, such as utilising biomarkers or real-world data.

Additionally, combining a drug with psychotherapy as a protocol is novel, and the FDA does not regulate psychotherapy, making the approval process all the more complicated. 

However, concerning MAPS’ MDMA trials, the FDA agreed to the protocols early on, and Doblin has said the authority is “moving the goalposts” now the trials are completed.

PAREA, Drug Science and Mind Medicine Australia recently published a position statement addressing the issue of blinding and expectation, as well as the issues of combining a drug with psychotherapy, the misuse risks of MDMA, training of therapists, risks of therapist misconduct and boundary violations, uncertain long-term benefits, and the negative benefit-risk ratio.

The statement suggests potential routes forward for the therapy such as basing its advancement on a model created for cannabis by the US Department of Health and Human Services (DHHS).

The statement reads: “We have previous experience with similar challenges with new medicines. The most famous is that of the first drugs for HIV, the access to which was too slow for patients who were dying, prompting the creation of the accelerated approvals process by lobbying the FDA for faster regulatory process and the NIH for more research.  

 “If MDMA does not get marketing authorisation, a model might be based on the August 2023 decision of the US Department of Health and Human Services (DHHS) to move cannabis down from Schedule I to Schedule III alongside ketamine and buprenorphine. The decision was based on an eight-factor analysis of abuse related harms and an overview of clinical use. 

“This review was led by DHHS with input from various agencies including the FDA who agreed that cannabis met the criteria of commonly accepted medical use (CAMU) so was de-facto a medicine hence could not stay in Schedule I.  

“Schedule III was seen as commensurate with its low abuse potential. Current research data for MDMA in PTSD are almost certainly stronger than any medical cannabis product so the same decision could be reached, as was done by the TGA in Australia.”

While the decision marks a major setback for Lykos, MDMA therapy may still one day reach the millions of PTSD patients in need of innovative treatments if Lykos can address the issues raised in the CRL in the new Phase 3 trial. Additionally, it may be that emerging New Chemical Entities with improved profiles to MDMA may pip MDMA to the approval post elsewhere.

Political pressure is also on to get access to MDMA therapy for patients, with over 80 US lawmakers urging Biden to allow approval of the therapy for US veterans and advocacy organisations supporting the advancement of MDMA therapy for this patient population. 

Non-profit organisation, VETS: Veterans Exploring Treatment Solutions, commented on the development to say: “Roughly 20 veterans die by suicide every day. A recent study estimates the number could be as high as 44. This is unacceptable. 

“The potential of MDMA-assisted therapy to help veterans heal from post-traumatic stress disorder (PTSD) remains paramount. We will not allow bureaucratic processes to deter us from advocating for approval of this transformative treatment.

“While we understand and respect the FDA’s commitment to safety, we urge careful consideration of the cost of inaction. 

“The fight for safe, legal access to MDMA-assisted therapy may have hit a roadblock, but VETS stands resolute. We wholeheartedly believe that every veteran deserves access to the most effective forms of healthcare available. We are never out of the fight.”

Heroic Hearts, a non-profit organisation supporting veterans into legal psychedelic therapies, stated: “As leading federal advocates for Veterans’ access to MDMA-AT, Healing Breakthrough & Heroic Hearts are deeply concerned by the FDA’s denial of Lykos’ NDA for MDMA-AT. This is the epitome of bureaucratic red tape – and the result is people will keep dying. MDMA-AT is the most effective treatment ever developed for PTSD, a condition at the core of the Veteran suicide crisis that claims over 17 lives each day.

“The FDA’s decision is a missed opportunity to embrace groundbreaking science, save countless Veteran lives, and honor the sacrifices made by those who served our country. If this critical treatment remains inaccessible, we face losing an additional 6,000 Veterans to suicide this year alone—and every year thereafter.

“Healing Breakthrough and Heroic Hearts Project will not relent. Our commitment to advocating for this life-saving treatment is unequivocal. We will continue to push for progress, collaborate with stakeholders, and fight persistently until MDMA-AT is available to every Veteran who desperately needs and deserves it.”

Elsewhere in the world, Canada and Australia have already begun allowing access to MDMA-assisted therapy in specific circumstances for select, authorised patients, and the Dutch State Commission on MDMA recently released its report advising the Government to allow access to MDMA therapy for people living with PTSD. Equally, other companies are developing treatments with psychedelics such as psilocybin for mental health conditions including anxiety and depression, some of which are now in Phase 3 trials. 

Rivki Stern Youdkevich, Co-Founder and CEO of Shortwave Life Sciences, which is developing psychedelic treatments for anorexia nervosa, commented: “PTSD is associated with an increased risk of mortality due to comorbid conditions such as substance abuse, depression, physical health issues, as well as a higher risk of suicide.

“Risk of a new medicine or treatment versus the risk to the lives of the patient population existing without that treatment is a key consideration in the regulator’s assessment of new drugs. In the case of PTSD, the equation is very clearly positive, and even more so in the case of anorexia nervosa, which is the deadliest mental health disorder of all, with no currently approved FDA medication, and a 50% chronicity rate.

“We believe that this underlying high and positive benefit-to-risk ratio will ultimately guide the regulator to approve innovative and inherently safe psychedelic components in the treatment of life-threatening disorders. At Shortwave we are already proving the safety of our psilocybin-based combination drug and will be able to demonstrate its efficacy according to FDA regulations as we progress in our clinical trials.”

PAREA, a European advocacy organisation for access to psychedelic therapies stated: “People living with PTSD and other mental health conditions, as well as their families, had high hopes and expectations for the introduction of this new treatment option. 

“Although this decision pertains to the US and there is no current market application for this treatment in Europe, we are concerned that the regulatory expectations could set a precedent that might slow down progress in mental health innovation worldwide.”