After the FDA declined to approve Lykos Therapeutics’ MDMA-assisted therapy for post-traumatic stress disorder, companies are pivoting away from or delaying similar therapeutics targeting the psychiatric disease.
Once confined to the party scene, midomafetamine, or MDMA (colloquially known as ecstasy), has garnered recent attention for its therapeutic potential. The Schedule I drug has shown particular promise in treating post-traumatic stress disorder (PTSD), a serious mental illness with notoriously few treatment options.
The psychedelic treatment space was struck a blow, however, when the FDA rejected Lykos Therapeutics’ MDMA-assisted therapy for PTSD in August. In its Complete Response Letter, the agency said the application “could not be approved based on data submitted to date” and requested that Lykos conduct an additional Phase III trial to glean more information on the drug’s safety and efficacy.
The sentiment appears to be that the FDA’s issues were more reflective of Lykos’ new drug application (NDA) than MDMA on the whole.
“I think the setback Lykos had mostly reflects on Lykos’ [trial design] and not so much on MDMA,” Matthew Baggott, co-founder and CEO of psychedelics-focused Tactogen, told BioSpace, adding that in addition to data deficiencies, there may have been “extra-scientific” factors, including political pressure.
Still, some psychedelic drug developers are reassessing their pipelines and prioritizing other assets, taking a wait-and-see approach to MDMA while working to make the drugs safer.
Tactogen, for one, is reexamining its strategy.
“The fact that Lykos didn’t get their NDA approved on this cycle means that we are seriously considering prioritizing our novel compounds and waiting to move forward with our MDMA product,” Baggott said. Tactogen’s pipeline includes a number of preclinical molecules that Baggott said he believes will be superior to MDMA.
Fellow psychedelic drug developer atai Life Sciences is prioritizing its MDMA-based asset, EMP-01, in social anxiety disorder, initiating a Phase II trial in late 2024. For PTSD, the company will “see how things work out with Lykos,” co-CEO Srinivas Rao told BioSpace.
The Lykos decision is “overall good for companies like Tactogen in that we’ve continued to get a clearer and cleaner roadmap from the FDA as to what they want,” Baggott said, noting recent FDA guidance, the documents from the Lykos adcomm and the public statements that followed that meeting.
Potential for Abuse?
The FDA issued a guidance document in June 2023 for psychedelic drug trials, acknowledging that these compounds carry unique challenges for study design. Among the safety-related concerns noted are abuse potential and alterations to consciousness and behavior that can last for several hours.
Baggott said the biggest perceived challenge to MDMA’s approval is the concept of abuse liability. Therapeutic outcomes such as feelings of self-compassion or emotional positivity are considered warning signs for possible abuse, he said. Some of these effects are “easily mapped” using the medical dictionary for regulatory activities (MedDRA), Baggott added, but other experiences patients may have while on MDMA are more difficult to assign standardized medical terminology. Capturing these events in a way that is acceptable to the FDA will be “really important.”
Other experts have argued that MDMA is not frequently abused in recreational settings. Howard Kornfeld, a medical director at Recovery Without Walls who worked with patients treated with MDMA in the 1980s before it was a scheduled drug, said it is rarely abused. He clarified that in “unusual situations,” MDMA can be taken in the wrong dose, leading to bad outcomes.
Lykos’ regimen requires patients to undergo three sessions, completely supervised, Kornfeld noted. “People aren’t going to get addicted from these three sessions,” he said, adding that despite concerns over patients “getting a taste” of the drug and seeking it out on the streets, “we really haven’t seen that in 40 years of real-world data.”
Improving the Safety Profile
Amidst this debate, Tactogen is working to improve the safety profile of MDMA through fixed dose combinations in hopes of decreasing side effects like difficulty concentrating and mood instability seen in some participants in the days after use. The company also hopes to improve tolerability with its program combining MDMA with citalopram, a selective serotonin reuptake inhibitor (SSRI) used to treat depression, for PTSD. Baggott anticipates beginning Phase II trials with the combo in 2025.
Meanwhile, with EMP-01, atai is hoping to improve the safety of MDMA by focusing on one of its two enantiomers.
MDMA is an equal mixture of both (S)-MDMA and (R)-MDMA. The (S) enantiomer is very much like a stimulant, Rao explained, with so-called entactogenic properties that induce the external, social effects of MDMA. (R)-MDMA, on the other hand, has more exergonic activity thought to contribute to the psychedelic effects, he said. With the stimulant effects of the (S) enantiomer posing potential cardiovascular risks for PTSD patients, atai used only (R)-MDMA in its candidate to potentially improve the therapeutic index of traditional MDMA.
“What we found is that the compound was very different than anticipated, and in a good way,” Rao said. In a traditional MDMA trial, a common dose would be 150 mg, which would include 75 mg of (R)-MDMA and 75 mg of (S)-MDMA. Atai’s molecule comprises 225 mg of (R)-MDMA. In a Phase I trial, it elicited psychedelic effects beyond hallucination, enabling introspection and affecting patients’ ability to see their lives differently, Rao said. EMP-01 was found to be well-tolerated in healthy volunteers.
High Unmet Need
Prior to the Lykos decision, Kornfeld sent a letter to the FDA advocating for the MDMA-based therapy to be approved, and said he was disappointed when it was rejected.
Kornfeld said the delay is a “loss of opportunity” to lower the death rate from PTSD-related suicides in America, adding that concern is especially high for veterans. According to the U.S. Department of Veterans Affairs, seven out of every 100 veterans will have PTSD. In 2021, there were over 17 veteran suicides per day, per the Office of Mental Health and Suicide Prevention.
Around the world, other countries have made a different decision regarding MDMA as a therapeutic. In 2023, Australia’s government approved the use of MDMA for PTSD, as long as it is administered as an assisted therapy by an authorized prescriber.
And on the heels of the negative Lykos FDA adcomm vote, a Dutch panel recommended MDMA to its government for the treatment of PTSD. “The government must act expeditiously to enable the therapeutic use of MDMA,” a statement from the state commission said.
One thing is certain: unmet need in PTSD is high, Kornfeld said.
“There has not been a new drug approved for PTSD for more than a decade. We basically have an epidemic of PTSD. I’m hoping that MDMA can get approval sooner rather than later.”
