IMPACT-2: A PHASE 2 RANDOMIZED, DOSE-RESPONSE TRIAL OF TSND-201 (METHYLONE) FOR THE TREATMENT OF PTSD

Background

TSND-201 (methylone) is currently in clinical development for the treatment of post-traumatic stress disorder (PTSD). Non-hallucinogenic compounds with rapid and sustained therapeutic benefits may be clinically useful and more accessible to patients compared to classical psychedelics. TSND-201 is a highly selective, rapid-acting neuroplastogen that releases serotonin, norepinephrine, and dopamine to increase neuroplasticity. TSND-201 is non-hallucinogenic in humans and animal models, consistent with its lack of direct activity at serotonin (5-HT)2A receptors. TSND-201 shows consistently rapid, robust, and durable benefit in animal models of PTSD, depression, and anxiety. Previously presented results from another phase 2 randomized, placebo-controlled clinical trial in participants with PTSD (IMPACT-1) demonstrated rapid, robust, and longlasting efficacy using a split dose (150 mg + 100 mg administered 90 min later) once weekly for four weeks. Based on these findings, TSND-201 was granted Breakthrough Therapy Designation by the FDA. Here, we share results that support the dose–response relationship of TSND-201 in participants with PTSD.

Methods

The IMPACT-2 study was a 12-week, multi-center, randomized clinical trial evaluating the safety, efficacy, and dose-response of 3 dose levels of TSND-201 in participants with PTSD. Eligible participants were adults with moderate-to-severe PTSD. Participants were randomized 1:1:1 to receive blinded doses of either 50 mg (N=17), 100 mg (N=15), or 150 mg (N=15) of TSND-201 given once per week for 4 weeks. Following the 4week treatment period, participants were followed for an additional 8 weeks to evaluate the durability of the therapeutic effect. PTSD symptom improvement was evaluated on the CAPS-5 and PCL-5. Safety was assessed by monitoring adverse events, vital signs, and CSSRS.

Results

On the CAPS-5, treatment with 50, 100, or 150 mg TSND-201 resulted in a mean change from baseline to Week 12 of -26.7, -26.5, and -32.9 points, respectively. Rates of response and remission demonstrated clear dose proportionality. Response (≥50% improvement on the CAPS-5) and remission (≤11 points total score on the CAPS-5) rates for the 50, 100, 150 mg doses were 64.3%, 76.9%, and 78.6%, and 42.9%, 46.2%, or 71.4%, respectively, demonstrating a clear dose response. Results from the unblinding questionnaire revealed that most participants guessed that they received the low dose, regardless of actual treatment received: 41.5%, 40.0%, and 40.0% in the 50, 100, and 150 mg groups, respectively. Only 1 participant (6.7%) in the high dose group correctly guessed they received the high dose compared with 2 patients (13.3%) in the 100 mg group and 3 patients (17.8%) in the 50 mg group. TSND-201 was well-tolerated with an adverse event profile consistent with prior studies.

Conclusion

TSND-201 demonstrated rapid, robust, and durable effects on PTSD symptoms and clear dose-proportional activity with favorable tolerability. Overall, the study supports further clinical development of TSND-201 as a treatment for PTSD.