MindMed & ATAI's new Programs; Usona Restarts Trials; Considering Resilience

MDMA Three Ways

In the wake of MAPS’ historic fundraising success, two MDMA related announcements came out this week.

• ATAI revealed its newest subsidiary, EmpathBio to develop an MDMA derivative for PTSD

• MindMed announced a Phase 1 trial of MDMA in combination with LSD

MAPS, of course, is conducting a Phase III trial of MDMA assisted psychotherapy for PTSD.

I think it is safe to call this model of psychedelic-assisted therapy with established molecules the first generation of Psychedelic Medicine, as both Usona and COMPASS, the presumed next in line for FDA approval, are also employing this strategy.

What might second-generation psychedelic Medicine look like?

• Novel derivatives of known molecules engineered to reduce trip duration, alter effects, improve risk profile (ie, 2b heart valve concerns, blood pressure, etc.), target different indications, and secure patent protection.

• Combination therapy: A common practice in oncology and virology, combo therapy is just what it sounds like, combining two or more drugs to improve efficacy, modify effects and risks.

• Drug + Digital Therapeutic combination (software-assisted psychedelic Medicine)

What do we know about these recent announcements?

ATAI appears to be developing an MDMA derivative in conjunction with a digital therapeutic to reduce the duration and perhaps make it an at-home therapy, while Mindmed is combining LSD with MDMA to soften the blow of looking directly into the face of God.

MDMA+LSD

“Mind Medicine… and the University Hospital Basel's Liechti Lab are now combining MDMA and LSD in a groundbreaking Phase 1 clinical trial. The Phase 1 MDMA-LSD trial is scheduled to start in Q4 of this year in Basel, Switzerland.”

MindMed is applying the scrutiny of clinical research to the well-established practice of Candyflipping.

The rationale, from the study’s description at Clinicaltrials.gov, basically says (I am paraphrasing), “LSD is intense. Sometimes people freak out, yet there are real benefits to the experience. MDMA is like a mother’s warm, cozy hug. Let’s see what happens when combining the two.”

Matthias Liechti gives the rationale more formally:

"The potential of MDMA-LSD is to create a psychological state that may have the benefits of both substances and have longer lasting effects than standalone psilocybin or LSD. Inducing an overall primarily positive acute response during psychedelic assisted therapy is critical because several studies showed that a more positive acute experience is linked to a greater therapeutic long-term effect in patients."

It will present an exciting research challenge since the pharmacokinetic profiles and peaks are different for each molecule, as noted by the duration of the trip (LSD longer than MDMA). The timing of each dosage is an interesting research question since anecdotal reports suggest different effects depending on timing.

As Michelle Janikian wrote for DoubleBlind:

“The preference around timing really depends on a few factors. Some like to avoid coming down from the MDMA while still on LSD, and so they take their molly later on in the trip (at hour four or five) to wind down from both substances around the same time. However, others swear by peaking on both substances at the same time, and so tend to take their MDMA earlier in the journey (between 45 mins and two to three hours) or even simultaneously.”

Peter Gasser, a Swiss psychiatrist who was authorized in 1988 to use MDMA and LSD in his private practice and possibly one of the most experienced people on the planet to help answer the dosing question.

Fortunately for MindMed, Gasser joined as a clinical advisor and will have much to offer to this endeavor.

MDMA+Digital Therapeutic

From Monday’s Press Release:

“ATAI Life Sciences… announced the launch of EmpathBio, a wholly-owned subsidiary developing derivatives of  3,4-methylenedioxy-methamphetamine (MDMA) for the treatment of post-traumatic stress disorder (PTSD) and other indications.”

Here are important details we can glean from pieces in Fierce Biotech and Endpoints News on Empathbio’s strategy.

• EmpathBio is seeking to create an MDMA derivative but has yet to decide on the lead candidate.

• It appears they’re hoping to reduce the duration and mitigate side effects like increases in blood pressure, heart rate, anxiety, jaw clenching.

• It is intended to be used in conjunction with a digital therapeutic possibly for at-home use

As we noted last week, pharmaceutical developers, the FDA, and clinicians are starting to accept and realize the potential of the Digital Therapeutics (DTx) trend.

The leading DTx projects are targeting mental and behavioral health conditions, not unlike the early psychedelic projects we’re seeing, and the combination will hopefully galvanize a field that has been hobbled for decades.

ATAI fully realizes the confluence of these two trends and is acting accordingly.

Usona Restarts Phase II Trials

An article from the Wisconsin State Journal notes that Usona has resumed their Phase II MDD trials after COVID forced their halt, that’s great to hear.

But two quotes in the piece caught my attention.

From Tura Patterson, Usona’s senior director of strategic partnerships:

“Part of our goal is to make this accessible and available at an affordable price to the people who need it most,” she said during a Wisconsin Technology Council webinar Tuesday. “For that to happen, I think you need to be a nonprofit.”

I understand the logic here. Without the fiduciary obligations of maximizing profits for shareholders, Usona and MAPS can lower the cost and/or reinvest to maximize patient access.

But what are the counterarguments?

In what ways might Usona and MAPS be diminishing patient benefit by going the non-profit route? What are the patient-benefit arguments for a conventional approach over a non-profit?

I imagine that the time to market is increased with a non-profit approach, thereby delaying access, but what other limitations are imposed that limit patient benefit?

***************If you have thoughts about this, please comment or reply*****************

The second is a comment from Charles Raison, director of clinical and translational research:

“Nothing is more compelling at this point than this resurgence of psychedelic medicines as potential treatments for a range of mental illnesses…People are somehow put into a state of resilience”

It is this last comment that is so compelling to me because resilience doesn’t seem to be discussed as much when talking about the mechanism of action (MOA), or the effects of psychedelics and I wish it were.

The common phrases like resetting the brain, or mystical experience, uprooting trauma, or neuroplasticity are employed to capture the MOA/effects.

But when we’re considering the transdiagnostic potential of the psychedelic experience, I think resilience is a handy framework. One way to conceptualize this was made apparent by a recent paper titled Post-Psychedelic Reductions in Experiential Avoidance Are Associated With Decreases in Depression Severity and Suicidal Ideation:

“These results suggest that psychedelics may lead to significant decreases in experiential avoidance, depression severity, and suicidal ideation. Additionally, these findings imply that reduced experiential avoidance may be a transdiagnostic mechanism mediating treatment success within psychedelic therapy.”

In other words, when one is less prone to avoiding negative, challenging, stressful, difficult emotions, situations, people, one is said to be more resilient. I hope we can see more language promoting the concept of resilience, I think it can be a subtle, but impactful metaphor.

That’s all for this week, thanks for reading!

Zach