MDMA drug developers set new priorities after Lykos was rejected for PTSD

Once confined to the party scene, midomafetamine, or MDMA (colloquially known as ecstasy), has recently gained attention for its therapeutic potential. The Schedule I drug has proven to be special promise in the treatment of post-traumatic stress disorder (PTSD), a serious mental illness with known few treatment options.

However, the field of psychedelic treatment suffered a setback when the FDA rejected Lykos Therapeutics' MDMA-assisted therapy for PTSD in August. In its full response letter, the agency said the application “could not be approved based on the data submitted to date” and asked Lykos to conduct an additional Phase III study to obtain more information about the drug's safety and effectiveness .

The Feeling It appears that the FDA's problems reflected Lykos' new drug application (NDA) rather than MDMA as a whole.

“I think the setback that Lykos has suffered is mainly reflected in Lykos.” [trial design] and not so much on MDMA,” said Matthew Baggott, co-founder and CEO of psychedelic specialist Tactogen BioSpaceand added that in addition to the 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. They are taking a wait-and-see approach to MDMA while working to make the drugs safer.

Tactogen, for example, is reviewing its strategy.

“The fact that Lykos has not received NDA approval this cycle means 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 believes will be superior to MDMA.

Psychedelic medicine colleague Atai Life Sciences is prioritizing its MDMA-based compound EMP-01 for social anxiety disorder. initiate a Phase II trial in late 2024. For PTSD, the company will “see how it works out with Lykos,” said co-CEO Srinivas Rao BioSpace.

The Lykos decision is “good overall for companies like Tactogen as we continue to have a clearer and clearer roadmap from the FDA about what they want,” Baggott said, pointing to the FDA's recent guidance, Lykos' Adcomm documents and the public statements following that meeting.

Potential for abuse?

The FDA has issued one Instructions June 2023 document for psychedelic drug trials, recognizing that these compounds present unique challenges for study design. Safety concerns cited include potential for abuse and changes in consciousness and behavior that can last for several hours.

Baggott said the biggest challenge to approving MDMA is the concept of abuse liability. Therapeutic outcomes such as feelings of self-compassion or emotional positivity are considered warning signs of possible abuse, he said. Some of these effects can be “easily mapped” using the Medical Dictionary of Regulatory Activities (MedDRA), Baggott added, but other experiences patients might have while taking MDMA are more difficult to map to standardized medical terminology. It will be “really important” to record these events in a way acceptable to the FDA.

Other experts have argued that MDMA is not commonly 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 dosage, which can lead to poor results.

The Lykos regimen requires patients to undergo three sessions under full supervision, Kornfeld noted. “People don’t get addicted from these three sessions,” he said, adding that despite fears that patients might “get a taste” of the drug and seek it out on the streets, “we really haven’t for 40 years.” “Years of real data.”

Improving the safety profile

Amid this debate, Tactogen is working to improve MDMA's safety profile through fixed-dose combinations in hopes of reducing side effects such as difficulty concentrating and mood swings observed in some participants in the days following use. The company also hopes to improve tolerability with its program that combines MDMA with citalopram, a selective serotonin reuptake inhibitor (SSRI) used to treat depression, for PTSD. Baggott expects Phase II trials of the combination to begin in 2025.

Meanwhile, with EMP-01, atai hopes to improve the safety of MDMA by focusing on one of its two enantiomers.

MDMA is an equal mixture of (S)-MDMA and (R)-MDMA. The (S)-enantiomer is very similar to a stimulant, Rao explained, with so-called entactogenic properties that produce the external, social effects of MDMA. (R)-MDMA, on the other hand, has greater exergonic activity, which is thought to contribute to the psychedelic effects, he said. Since the stimulating effect of the (S)-enantiomer is potentially cardiovascular Risks For PTSD patients, Atai used only (R)-MDMA in its candidate to potentially improve the therapeutic index of traditional MDMA.

“We found that the facility was very different than expected, and in a good way,” Rao said. In a traditional MDMA trial, a typical dose would be 150 mg, which would include 75 mg (R)-MDMA and 75 mg (S)-MDMA. Atai's molecule consists of 225 mg (R)-MDMA. In a Phase I study, it triggered psychedelic effects that went beyond hallucination, allowing for introspection and affecting patients' ability to see their lives differently, Rao said. EMP-01 was found to be well tolerated in healthy subjects.

High unmet need

Before the Lykos decision, Kornfeld sent a letter to the FDA advocating for approval of the MDMA-based therapy and said he was disappointed when it was rejected.

Kornfeld said the delay represents a “missed opportunity” to reduce the mortality rate from PTSD-related suicides in America, adding that the concern is particularly great for veterans. According to the U.S. Department of Veterans Affairs, it's seven out of 100 Veterans will have post-traumatic stress disorder. In 2021According to the Office of Mental Health and Suicide Prevention, there were over 17 veteran suicides each day.

Other countries around the world have made different decisions regarding MDMA as a therapeutic agent. In 2023, the Australian Government approved the use of MDMA for PTSD when administered as assisted therapy by an authorized prescriber.

And following the FDA's negative adcomm vote for Lykos, a Dutch panel recommended MDMA to his government to treat PTSD. “The government must act quickly to enable the therapeutic use of MDMA,” the state commission said in a statement.

One thing is certain: The unmet need in PTSD is high, Kornfeld said.

“No new medication for PTSD has been approved for more than a decade. We essentially have a PTSD epidemic. I hope MDMA is approved sooner rather than later.”