RE104 · program
Luvesilocin (RE104) for Postpartum depression
- FDA Breakthrough Therapy (Postpartum Depression; Granted 2026-02-23)
Indications for RE104: Postpartum depression · Phase 2 Generalized anxiety disorder · Phase 2
Luvesilocin (RE104), a subcutaneous prodrug of the short-acting psychedelic 4-OH-DiPT, for moderate-to-severe postpartum depression — the company's lead indication and the first sizable randomized controlled trial of a psychedelic agent in PPD. RECONNECT (NCT06342310, RE104-201-PPD) randomized 84 women across 38 US sites to a single subcutaneous dose of 30 mg RE104 or 1.5 mg as an active control, with session monitors but no formal psychotherapy, and 28 days of follow-up. It met its primary endpoint: a 23.0-point reduction in MADRS total score at Day 7 versus 17.2 points on active control (difference 5.80; one-sided p=0.0094), from a baseline MADRS of 33.4. Day 7 response was 77.1% vs 61.6% and remission 71.4% vs 41.0%, both maintained through Day 28, with supporting gains on the Barkin Index of Maternal Function, HAM-A and CGI-I. There were no serious adverse events; nausea (43.9%) and headache (34.1%) were the most common TEAEs, and 92.7% of patients were discharge-ready at 4 hours. A companion Phase 1 lactation study (NCT06659263) found breast-milk transfer below 0.1% of the maternal dose, supporting resumption of breastfeeding with minimal interruption. Reunion completed its End-of-Phase-2 meeting in December 2025 and reported FDA feedback that a single successful Phase 3 trial would complete the pivotal package for registration; FDA granted Breakthrough Therapy designation on 2026-02-23. The company has guided to initiating that pivotal Phase 3 — with FDA-supported enrollment of breastfeeding women — during 2026, but as of 2026-07-24 no Phase 3 study is registered on ClinicalTrials.gov under this sponsor and no initiation has been announced, so the program is recorded at Phase 2.
Development timeline
- Program returns to active, pre-Phase-3, after the positive Phase 2: FDA granted Breakthrough Therapy designation for luvesilocin in PPD, following a December 2025 End-of-Phase-2 meeting at which FDA indicated that a single additional successful Phase 3 trial would complete the pivotal package required for registration. Reunion guides to initiating that Phase 3 in 2026. NOT recorded as phase_3 — no Phase 3 study is registered under this sponsor and no initiation has been announced as of 2026-07-24.↗
- metFull RECONNECT Phase 2 dataset presented at the ACNP Annual Meeting: MADRS separation from Day 1 sustained through Day 28, plus response, remission, HAM-A, CGI-I and Barkin Index of Maternal Function improvements, from a baseline MADRS of 33.4.↗
- metRECONNECT Phase 2 topline in postpartum depression: a single 30 mg subcutaneous dose of RE104 met the primary endpoint with a 23.0-point MADRS reduction at Day 7 vs 17.2 points on 1.5 mg active control (difference 5.80; one-sided p=0.0094), with 77.1% response and 71.4% remission at Day 7 and no serious adverse events.↗
- RECONNECT actual primary completion per ClinicalTrials.gov (actual study completion 2025-06-16); Reunion announced last patient dosed on 2025-05-19, on schedule, with topline guided to 3Q 2025. Enrollment closed at 84 patients across 38 US sites.
- RECONNECT (NCT06342310, RE104-201-PPD) actual study start per ClinicalTrials.gov — a multicenter, randomized, triple-masked, parallel-group dose-controlled Phase 2 of a single subcutaneous dose of RE104 30 mg vs 1.5 mg active control in moderate-to-severe PPD, primary endpoint change from baseline in MADRS total score at Day 7. Reunion separately announced first patient dosed on 2024-07-23; the registry's actual start date is used here and the roughly five-week gap is unexplained by either source.
Readouts
- 2026-01-20ReportedFull resultsmetNCT06342310
Full RECONNECT Phase 2 dataset presented at the ACNP Annual Meeting: MADRS separation from Day 1 sustained through Day 28, plus response, remission, HAM-A, CGI-I and Barkin Index of Maternal Function improvements, from a baseline MADRS of 33.4. ↗
- 2025-08-18ReportedTopline datametNCT06342310
RECONNECT Phase 2 topline in postpartum depression: a single 30 mg subcutaneous dose of RE104 met the primary endpoint with a 23.0-point MADRS reduction at Day 7 vs 17.2 points on 1.5 mg active control (difference 5.80; one-sided p=0.0094), with 77.1% response and 71.4% remission at Day 7 and no serious adverse events. ↗
Clinical trials in Postpartum depression
NCT06659263RE104-102-NHLVPhase 1Completedn=14
A Phase 1, Open-label, Single Dose Study to Evaluate the Concentration of RE104 and Its Major Metabolites in Breast Milk and Plasma of Healthy Lactating Women
metsecondaryRelative infant dose / total transfer of RE104 and 4-OH-DiPT into breast milk after a single 30 mg subcutaneous dose — Total metabolite transfer <0.1% of the maternal 30 mg dose
Preliminary results reported alongside the RECONNECT data: total drug and metabolite appearing in breast milk represented less than 0.1% of the 30 mg dose administered to the mother — described by the investigators as an order of magnitude below levels of potential concern for the infant, suggesting breastfeeding may resume with limited interruption. This is a strategically important result because RECONNECT itself excluded breastfeeding women; FDA has since supported enrolling breastfeeding women in the planned Phase 3.
NCT06342310RE104-201-PPDPhase 2Completedn=84
A Multicenter, Randomized, Double-Blind, Parallel-Group Dose-Controlled Study Evaluating the Safety and Efficacy of RE104 for Injection in the Treatment of Patients With Postpartum Depression (PPD) — RECONNECT
metsecondaryMADRS remission rate (total score <=10) at Day 7 — 71.4% (RE104 30 mg) vs 41.0% (1.5 mg active control)
The widest separation of any endpoint: a 30.4-percentage-point remission gap at Day 7, maintained through Day 28. No p-value was disclosed.
metsafetySafety, tolerability and discharge readiness — Nausea 43.9%, headache 34.1%; 92.7% discharge-ready at 4 hours post-dose
No serious adverse events. The majority of TEAEs were mild to moderate, self-resolving and consistent with the pharmacology of the class. 92.7% of patients on 30 mg showed no signs or symptoms posing a discharge risk at the first assessment, 4 hours after treatment — the operational claim underpinning the short-session thesis.
metprimaryMADRS total score, change from baseline at Day 7 (RE104 30 mg vs RE104 1.5 mg active control) — LS mean difference 5.80 points (-23.0 with 30 mg vs -17.2 with 1.5 mg active control; baseline MADRS 33.4 in the 30 mg arm) (0.0094 (one-sided))
Primary endpoint met. A single subcutaneous 30 mg dose produced a statistically and clinically significant MADRS reduction at Day 7 versus a 1.5 mg active control. Note the comparator is a low active dose, not placebo, so the 17.2-point control response is large and the between-arm difference correspondingly modest.
metsecondaryMADRS response rate (>=50% reduction from baseline) at Day 7 — 77.1% (RE104 30 mg) vs 61.6% (1.5 mg active control)
Response favored 30 mg and was maintained through the Day 28 follow-up. No p-value was disclosed for this endpoint.
metsecondaryBarkin Index of Maternal Function (BIMF), HAM-A and CGI-I
Maternal well-being and function, including care of and relationship with the infant as measured by the BIMF, showed substantial improvement, with supporting gains on the Hamilton Anxiety Rating Scale and CGI-I. Reported qualitatively at ACNP and in the ASCP abstract; no point estimates were disclosed, so effect size is left null.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| RE104 for Injection (subcutaneous, single 30 mg dose)cleavable glutarate ester prodrug Single subcutaneous injection. Phase 2 RECLAIM (GAD): 30 mg vs placebo — the only RE104 trial to date using a true placebo comparator rather than a 1.5 mg active control. Phase 2 RECONNECT (PPD) and Phase 2 REKINDLE (adjustment disorder): 30 mg vs 1.5 mg active control. Phase 1 single ascending dose: 5, 10, 20, 30, 35 and 40 mg SC across six cohorts (36 active, 12 placebo). No GAD-specific dose-ranging was run; the 30 mg dose was carried over from the successful PPD study. No repeat-dose regimen has been studied. | Subcutaneous | Single dose | t½ 3.4 h · Tmax 1 h · F 88.6% |
Mechanism of action
RE104 is an inactive-by-design ester prodrug: it is cleaved to 4-OH-DiPT in under 30 minutes in mouse, rat and human plasma at 37 degrees C, and is undetectable in plasma within 5 minutes of subcutaneous administration in vivo. The prodrug itself binds 5-HT2A only weakly (Ki 4,300 nM) and is functionally inactive (inositol-phosphate EC50 >30,000 nM); the pharmacology belongs entirely to the liberated 4-OH-DiPT, which binds 5-HT2A with Ki 120 nM and behaves as a near-full agonist at 5-HT2A in G-protein dissociation assays, with agonist activity also at 5-HT2B and 5-HT2C. 4-OH-DiPT is a positional/alkyl analogue of psilocin and is reported to be more selective across the 5-HT receptor family than psilocin. It produces the head-twitch response in mice, and HTR intensity tracks plasma 4-OH-DiPT concentration (r-squared 0.7019), consistent with classical 5-HT2A psychedelic pharmacology. The anxiolytic rationale specific to this indication is preclinical: in mice, 4-OH-DiPT enhanced fear extinction by activating basolateral-amygdala interneurons via 5-HT2A to increase GABAergic inhibition of principal neurons — a plausible mechanism for suppressing learned fear, and the closest published mechanistic support for a generalized-anxiety indication. The defining property remains kinetic rather than receptor-level: subcutaneous delivery of a rapidly cleaved ester gives a Tmax of ~1 h and a terminal half-life of 2.72-4.12 h for 4-OH-DiPT, roughly halving the acute psychedelic window relative to psilocybin.
| Target | Action | Affinity |
|---|---|---|
| 5-HT2AprimaryHTR2A | Agonist | Ki 120 nMⓘ |
| 5-HT2BHTR2B | Agonist | —ⓘ |
← Full RE104 compound page (identity, identifiers, all indications)
Sources
- NCT06342310 (RE104-201-PPD, RECONNECT) — A Multicenter, Randomized, Double-Blind, Parallel-Group Dose-Controlled Study Evaluating the Safety and Efficacy of RE104 for Injection in the Treatment of Patients With Postpartum Depression — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT06659263 (RE104-102-NHLV) — A Phase 1, Open-label, Single Dose Study to Evaluate the Concentration of RE104 and Its Major Metabolites in Breast Milk and Plasma of Healthy Lactating Women — ClinicalTrials.gov (U.S. National Library of Medicine)
- RE104: A novel serotonergic psychedelic 4-OH-DIPT prodrug for the treatment of postpartum depression (Pollack et al., 2026 ASCP Annual Meeting, session W100) — American Society of Clinical Psychopharmacology (via CNS Pulse)
- RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine. ACS Chem Neurosci. 2024 Jun 19 — ACS Chemical Neuroscience (American Chemical Society) via PubMed Central
- Reunion Neuroscience Announces Positive Topline Results from RECONNECT Phase 2 Clinical Trial of RE104 for the Treatment of Postpartum Depression (PPD) (2025-08-18) — Reunion Neuroscience Inc.
- Reunion Neuroscience Presents Full Data from RECONNECT Phase 2 Clinical Trial of RE104 for the Treatment of Postpartum Depression (PPD) at ACNP Annual Meeting (2026-01-20) — Reunion Neuroscience Inc.
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RE104: A Double-Blind, Randomized, Single Ascending Dose Placebo-Controlled Study. J Clin Psychopharmacol. 2025 Sep-Oct — Journal of Clinical Psychopharmacology (Wolters Kluwer) via PubMed Central
- U.S. FDA Grants Reunion Neuroscience's Luvesilocin (RE104) Breakthrough Therapy Designation Status (2026-02-23) — designation is for PPD only; RECLAIM GAD still described as planned — Reunion Neuroscience Inc.