CYB003 · program
CYB003 (deupsilocin) for Major depressive disorder
- Breakthrough Therapy
Phase 3 PARADIGM pivotal program evaluating CYB003 as an adjunctive (add-on) treatment for moderate-to-severe MDD in patients inadequately responding to a stable antidepressant. PARADIGM comprises two 12-week randomized, double-blind, placebo-controlled studies (APPROACH, NCT06564818, ~220 patients; EMBRACE, NCT06793397, ~330 patients) plus a long-term extension (EXTEND, NCT06605105). Patients receive two active doses (8 mg or 16 mg) ~3 weeks apart vs placebo; primary endpoint is change in MADRS at 6 weeks after the first dose. FDA granted Breakthrough Therapy Designation on 13 Mar 2024. APPROACH topline data is expected in Q4 2026. Originated by Cybin Inc., now doing business as Helus Pharma (which refers to the compound as HLP003).
Development timeline
- Helus Pharma reaffirmed that Phase 3 APPROACH data for HLP003 (CYB003) in MDD is expected in Q4 2026 (disclosed in a US$50M financing announcement). APPROACH topline not yet reported as of 2026-06-25.↗
- Corporate rebrand: Cybin Inc. began doing business as Helus Pharma and commenced trading on Nasdaq (ticker HELP; formerly CYBN on NYSE American); CYB003 referred to as HLP003. No change to development status: HLP003 remains in Phase 3 for MDD with Breakthrough Therapy Designation.↗
- metPhase 2 12-month durability: 100% response, 71% remission, ~23-pt MADRS reduction after two 16 mg doses.↗
- Cybin initiated the Phase 3 PARADIGM pivotal program (APPROACH initiated; EMBRACE and EXTEND to follow); APPROACH to enroll 220 patients at 36 sites across the U.S. and Europe, topline expected in 2026.↗
- FDA granted Breakthrough Therapy Designation for CYB003 in MDD (first known BTD for an adjunctive psychedelic-based therapy for MDD); Cybin also reported positive four-month durability data (75% remission after two 16 mg doses; mean 22-point MADRS reduction).↗
- metPhase 2 met primary: -14 MADRS vs placebo at 3 wk (single 12 mg dose; p<0.0005); 79% remission at 6 wk after two 12 mg doses.↗
- Phase 1/2a study (NCT05385783, n=57, healthy participants and MDD) primary completion. The MDD efficacy cohort met the primary endpoint: mean -14 point MADRS difference vs placebo at 3 weeks after a single 12 mg dose (p<0.0005, Cohen's d 2.151); 79% remission at 6 weeks after two 12 mg doses.
Readouts
- Q4 2026AnticipatedTopline datapendingNCT06564818
Phase 3 APPROACH topline data expected in Q4 2026. ↗
- 2024-11-18ReportedFull resultsmetNCT05385783
Phase 2 12-month durability: 100% response, 71% remission, ~23-pt MADRS reduction after two 16 mg doses. ↗
- 2023-11-30ReportedTopline datametNCT05385783
Phase 2 met primary: -14 MADRS vs placebo at 3 wk (single 12 mg dose; p<0.0005); 79% remission at 6 wk after two 12 mg doses. ↗
Clinical trials in Major depressive disorder
NCT06793397CYB003-003 (EMBRACE)Phase 3Recruitingn=330
EMBRACE: An Efficacy and Safety, Phase III, Multi-center, Double-Blind, Randomized Controlled Study Comparing 2 Active Doses of CYB003 and Placebo in Eligible Participants With Major Depressive Disorder
NCT06605105CYB003-004 (EXTEND)Phase 3Recruitingn=468
EXTEND: A Phase III Long-Term Extension Trial With Optional Additional Doses of CYB003 to Assess the Safety and Long-term Efficacy in Participants With Major Depressive Disorder
NCT06564818CYB003-002 (APPROACH)Phase 3Recruitingn=220
APPROACH: A Phase III, Placebo-Controlled, Randomized, Double-Blind Trial of Oral Doses of CYB003 to Assess Combined Safety and Efficacy in Humans With Major Depressive Disorder
NCT05385783CYB003-001Phase 1/2Completedn=57
A Phase I/IIa, Randomized, Double-Blind, Placebo-Controlled Study With an Open-Label Relative Bioavailability and Food Effect Cohort to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Oral Doses of CYB003 in Healthy Participants With and Without Major Depressive Disorder (MDD)
metsecondaryRemission rate at 6 weeks after two 12 mg doses — 79% of patients in remission
At 6 weeks, incremental MADRS reductions were seen with 79% of patients in remission after two 12 mg doses; favorable safety/tolerability with no treatment-related serious adverse events at 12 mg and 16 mg.
metprimaryMADRS change from baseline at 3 weeks after a single 12 mg dose (vs placebo) — mean -14 point MADRS difference vs placebo (per company: -14.08; Cohen's d 2.151) (<0.0005)
Primary efficacy endpoint achieved: rapid, statistically significant reduction in depression symptoms after a single 12 mg dose of CYB003 vs placebo at 3 weeks, with a clear incremental benefit of a second dose.
metsecondaryDurability of response at 4 months after two 16 mg doses — 75% remission; mean 22-point MADRS reduction from baseline
Robust, sustained improvement at four months with 75% of participants in remission after two 16 mg doses and a mean 22-point MADRS reduction; reported alongside FDA Breakthrough Therapy Designation.
metsecondaryDurability of response at 12 months after two 16 mg doses — 100% response, 71% remission; mean ~23-point MADRS reduction from baseline (n=7)
Unprecedented 12-month durability: 100% of participants responsive and 71% in remission after two 16 mg doses, with a ~23-point MADRS reduction vs baseline; no new adverse events and no reports of suicidality during follow-up.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| CYB003 oral capsule 16 mg oral capsule; two doses administered three weeks apart (second dose at Week 3). Phase 2 also evaluated a 12 mg dose. | Oral | — | — |
Mechanism of action
CYB003 is a deuterated analog of psilocin (the psychoactive metabolite of psilocybin) and acts as an agonist at the serotonin 5-HT2A receptor (gene HTR2A), the canonical molecular target of classic serotonergic psychedelics; agonism of cortical 5-HT2A receptors is hypothesized to drive rapid, durable antidepressant effects via enhanced neuroplasticity. Cybin/Helus describes CYB003 as a 'novel serotonergic agonist.' As with other tryptamine psychedelics it also engages other serotonin receptor subtypes (e.g., 5-HT2C, 5-HT1A) to varying degrees, but 5-HT2A agonism is regarded as the primary therapeutically relevant action.
| Target | Action | Affinity |
|---|---|---|
| 5-HT2AprimaryHTR2A | Agonist | —ⓘ |
← Full CYB003 compound page (identity, identifiers, all indications)
Sources
- 5-HT2A receptor (HTR2A), GtoPdb object 6 — IUPHAR/BPS Guide to Pharmacology
- A Study of a Deuterated Psilocin Analog (CYB003) in Humans With Major Depressive Disorder (PARADIGM Phase 3) — ClinicalTrials.gov
- APPROACH: Phase 3 trial of CYB003 in MDD (NCT06564818) — ClinicalTrials.gov
- Cybin doing business as Helus Pharma; commences trading on Nasdaq (ticker HELP) (6-K exhibit, 5 Jan 2026) — SEC EDGAR / Cybin Inc. (Helus Pharma)
- Cybin initiates PARADIGM Phase 3 program for CYB003 in MDD (6-K exhibit, 13 Nov 2024) — SEC EDGAR / Cybin Inc.
- Cybin receives FDA Breakthrough Therapy Designation for CYB003 and reports 4-month durability data (6-K exhibit, 13 Mar 2024) — SEC EDGAR / Cybin Inc.
- Cybin reports positive Phase 2 12-month efficacy data for CYB003 in MDD (6-K exhibit, 18 Nov 2024) — SEC EDGAR / Cybin Inc.
- Cybin Reports Positive Phase 2 Data for CYB003 — Cybin / Helus Pharma (IR)
- Cybin reports positive Phase 2 topline data for CYB003 in MDD (6-K exhibit, 30 Nov 2023) — SEC EDGAR / Cybin Inc.
- EXTEND: Phase 3 long-term extension of CYB003 in MDD (NCT06605105) — ClinicalTrials.gov
- Helus Pharma announces US$50M underwritten offering; Phase 3 APPROACH data expected Q4 2026 (6-K exhibit, 24 Jun 2026) — SEC EDGAR / Helus Pharma (Cybin Inc.)
- Phase 1/2a study of CYB003 in healthy participants with and without MDD (NCT05385783) — ClinicalTrials.gov