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RE104: A NOVEL SEROTONERGIC PSYCHEDELIC 4-OH-DIPT PRODRUG FOR THE TREATMENT OF POSTPARTUM DEPRESSION

Mark Pollack — Anita Clayton2, Camille Hoffman3, Peter Hendricks4, Daniel Fallon5, Lawrence Leeman6, Matthew Johnson7, Beatrix Taylor1, Jasna Hocevar-Trnka1, Nathan Bryson1, Joe Hirman1, Robert Alexander1, Stephen Ross8 1Reunion Neuroscience, 2University of Virginia School of Medicine, 3University of Colorado School of Medicine, 4University of Alabama at Birmingham, 5University of South Florida, 6University of New Mexico School of Medicine, 7Johns Hopkins University of Medicine, 8New York University School of Medicine

2026 ASCP Annual Meeting

We present new results from a Phase 2 trial of RE104, a novel psychedelic 5HT2A agonist prodrug of 4-OH-DIPT, in the first randomized controlled trial of a psychedelic agent for the treatment of postpartum depression (PPD). RE104, a unique, proprietary 4-OH-DiPT prodrug, is a novel psychedelic 5HT2A agonist investigational compound being developed for the treatment of postpartum depression (PPD) and other mental health conditions. Preclinical and clinical characterization confirmed similar pharmacology of RE104 to other well-characterized classical psychedelics such as psilocybin, while demonstrating a significantly shorter and reproducible acute psychedelic experience in the clinic. PPD is a serious disorder occurring in approximately 15% of pregnancies, and is associated with significant distress, dysfunction and disability in affected women as well as adverse effects on infants. Participants (N=84) were randomized to receive a single, subcutaneous dose of 30 mg or 1.5 mg (active control) RE104 for injection at 28 sites across the United States and were subsequently followed for 4 weeks posttreatment. While session monitors were involved in the preparation, dosing session monitoring and follow-up, the study treatment did not include formal psychotherapy. Eligible participants were women aged 18-45, ≤15 months post-partum, not breastfeeding, with moderate to severe depression based on an entry HAMD-17 score of ≥ 24 at screening and baseline. In addition, if applicable, eligible participants could remain on a pre-existing stable regimen of SSRIs or therapy during the study. The primary endpoint was change from baseline at Day 7 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Additional endpoints included changes in the MADRS over the course of the study, rates of response and remission, and changes in maternal function including care and relationship with the infant as assessed by the Barkin Index of Maternal Function (BIMF). Analysis of the primary outcome was via MMRM including treatment, visit and visit-by treatment interaction, and baseline MADRS; an unstructured covariance structure. Analysis of secondary endpoints was performed using descriptive statistics. A single 30 mg dose of RE104 resulted in a statistically and clinically significant reduction from baseline of 23.0 points in the MADRS total score on Day 7, as compared to a reduction of 17.2 points in the active control arm (difference of 5.80; one-sided p=0.0094). Clinically meaningful reductions in the MADRS were also observed for RE104 30 mg on the first day following administration and maintained through the Day 28 follow-up. 77.1% of participants treated with RE104 30 mg were responders (with at least 50% improvement from baseline MADRS) to therapy at Day 7 compared to 61.6% of participants on active control. 71.4% of participants on RE104 30 mg achieved remission (with a MADRS score of ≤10) at Day 7 compared to 41.0% on active control. Both response and remission improvements were maintained through the Day 28 follow-up period. Maternal well-being and function, including care of the infant as assessed by the BIMF, also demonstrated substantial improvement. RE104 was observed to be well-tolerated, during the trial with the majority of adverse events being mild to moderate in intensity, resolving spontaneously and consistent with the pharmacology observed with other agents in the class. Consistent with its pharmacokinetics, over 90% of participants on RE104 30mg showed no signs or symptoms posing a risk for discharge at the first measure of discharge readiness, taken 4 hours following treatment. Preliminary results from a contemporaneous lactation study suggest that the total amount of metabolites observed in the breastmilk represents < 0.1% of the 30 mg RE104 administered to the mother representing a safety margin that is an order of magnitude below levels that might be considered of potential concern relative to the infant. These results suggest that breastfeeding following RE104 treatment may be able to resume with limited interruption. In this first sizable randomized controlled trial of a psychedelic agent for the treatment of Postpartum Depression, administration of 30 mg of RE104, was safe and well-tolerated and resulted in rapid, significant and durable improvement.