RE104 Reduces Postpartum Depression Symptoms by Day 7 in Phase 2 RECONNECT

Reunion Neuroscience announced on August 19, 2025, that the phase 2 RECONNECT trial met its primary endpoint, with RE104 providing a significant reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 7 in patients with postpartum depression (PPD).1

“Despite its prevalence and severity, current treatment options for PPD remain limited and are often slow-acting and burdensome, leaving many new mothers without timely, effective care,” said lead investigator Anita H. Clayton, MD, Wilford W. Spradlin Professor and Chair of Psychiatry and Neurobehavioral Sciences at the University of Virginia School of Medicine, in a statement.

Two years ago, on August 4, 2023, the US Food & Drug Administration approved zuranolone, a GABA-positive allosteric modulator, for PPD.2 Clinical trials had shown that zuranolone could reduce depression symptoms on day 3, with continued improvement over 45 days. However, barriers could be in the way of new mothers obtaining zuranolone, such as insurance plans or the lack of breastfeeding data, emphasizing the importance of other effective treatments for PPD.3

“Findings from the RECONNECT trial are promising and underscore RE104’s potential as a single subcutaneous injection therapy that addresses limitations of current treatments by delivering symptom relief quickly and safely following a single dose of therapy, with minimal disruption to caregiving responsibilities and a lack of sedation,” Clayton continued.1

RE104, a patented prodrug of 4-OH-DiPT, is administered via a single subcutaneous injection and designed to deliver a short, acute psychoactive experience similar to longer psychoactive experiences with psilocybin or LSD. Investigators evaluated the safety and efficacy of RE104 (30 mg; subcutaneous) in RECONNECT, a randomized, double-blind, parallel-group, active dose-controlled clinical trial across 38 US clinical research sites.1

RECONNECT included 84 adult females (mean age, 32 years; range, 21 – 45) with moderate-to-severe PPD, defined as a Hamilton Depression Rating Scale (HAMD-17) ≥ 24. On average, participants were PPD for 7.3 months (range, 1.5 – 17.5). Eight patients (9.5%) had a previous psychedelic experience more than 12 months before screening.1

In the trial, RE104 30 mg provided a significant reduction from baseline of 23.0 points in the MADRS total score on Day 7, compared with a reduction of 17.2 points in patients treated in the active control arm with a 1.5 mg dose of RE104 (difference, 4.80; P = .0094). Investigators also observed clinically meaningful reductions in MADRS for RE104 30 mg on the first day after administration and maintained through the follow-up on day 28.1

In total, 77.1% of patients treated with RE104 30 mg demonstrated a response to therapy at day 7, with ≥ 50% improvement from baseline in MADRS total score, compared to 61.6% of patients who received Active Control. Additionally, 71.4% of patients treated with RE104 30 mg achieved remission by day 7 (total MADRS score of ≤ 10), compared to 41% of patients who received active control. Participants maintained response and remission rates through day 28.1

RE104 also improved scores in the Barkin Index of Maternal Functioning scale, providing insight into the patients’ well-being and ability to manage life with a new baby.1

RE105 had a well-tolerated safety profile, consistent with phase 1 data and other psychedelic agents. The most common treatment-emergent adverse event was nausea (43.9%) and headache (34.1%), both mild to moderate and resolved spontaneously.1

No serious treatment-emergent adverse events occurred, nor evidence of treatment-emergent suicidal ideation, seizures, or serotonin toxicity. Most patients (92.7%) receiving RE104 30 mg had no symptoms or signs that would pose a risk for discharge at the first measure of discharge readiness, 4 hours following treatment.1

Reunion also announced preliminary results, which found that the total amount of metabolites in breastmilk represents < 0.1% of the 30 mg RE104, which is below the level that might potentially cause risk to the infant. Although the FDA still needs to review data, Reunion believes this finding suggests that mothers can safely return to breastfeeding following RE104 treatment.1

The Company plans to initiate a phase 3 trial for RE104 in 2026.1

“I look forward to the continued evaluation of RE104 in a Phase 3 trial and believe it could represent a significant shift in the treatment of maternal mental health disorders,” Clayton said.1

References

1. Reunion Neuroscience Announces Positive Topline Results from RECONNECT Phase 2 Clinical Trial of RE104 for the Treatment of Postpartum Depression (PPD). Reunion Neuroscience. August 18, 2025. https://reunionneuro.com/2025/08/18/reunion-neuroscience-announces-positive-topline-results-from-reconnect-phase-2-clinical-trial-of-re104-for-the-treatment-of-postpartum-depression-ppd/. Accessed August 19, 2025.

2. Derman, C. Zuranolone Offers New Hope for Treating Postpartum Depression in New Mothers. HCPLive. August 4, 2024. https://www.hcplive.com/view/zuranolone-offers-new-hope-for-treating-postpartum-depression-in-new-mothers. Accessed August 19, 2025.

3. Your Patient Has Postpartum Depression: Do You Use Zuranolone or a Traditional Antidepressant?. Massachusetts General Hospital Center for Women’s Mental Health. September 4, 2024. https://womensmentalhealth.org/posts/zuranolone-or-traditional-antidepressant-for-postpartum-depression/. Accessed August 19, 2025.