Small Molecule · CYB003

CYB003 (deupsilocin)

Phase 3Helus Pharma (HELP)
  • Breakthrough Therapy

Oral, proprietary deuterated analog of psilocin (deupsilocin / psilocin-D10, the d10 isotopomer of psilocin, the active metabolite of psilocybin). A serotonin 5-HT2A receptor agonist ('novel serotonergic agonist') being developed as an intermittently dosed (two doses ~3 weeks apart) adjunctive treatment for major depressive disorder in patients inadequately responding to standard antidepressants. Deuteration is intended to improve pharmacokinetics (reduced variability, shorter/more predictable psychoactive duration) versus psilocybin. Granted FDA Breakthrough Therapy Designation (Mar 2024); in the Phase 3 PARADIGM pivotal program. Originated at Cybin Inc., which now does business as Helus Pharma (and refers to the compound as HLP003).

Also known as: CYB003, CYB-003, HLP003, HLP-003, deupsilocin, Psilocin-D10, deuterated psilocin, 1435934-64-7, 4-hydroxy DMT-d10

Data current as of

Modality
Small molecule
Chemical class
tryptamine, Substituted tryptamine
DEA schedule
Schedule I
Chemistry
Achiral · Deuterated
Mechanism
5-HT2A agonist
Highest phase
Phase 3
Lead indication
Major depressive disorder
Developer
Helus Pharma (HELP)
Designations
Breakthrough Therapy
Trials
4 tracked · 3 recruiting · 136 sites
Next catalyst
Q4 2026 — Topline data (Major depressive disorder)

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.

TargetActionAffinity
5-HT2AprimaryHTR2AAgonist—ⓘ

Formulations

FormulationRouteRegimenPharmacokinetics
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——

Development timeline

Phase 3Nov 2024 – Dec 2026
  1. UpcomingpendingPhase 3 APPROACH topline data expected in Q4 2026.↗
  2. 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.↗
  3. 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.↗
  4. metPhase 2 12-month durability: 100% response, 71% remission, ~23-pt MADRS reduction after two 16 mg doses.↗
  5. 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.↗
Phase 2Nov 2023 – Mar 2024
  1. 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).↗
  2. 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 1/2Oct 2023
  1. 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.

CYB003 (deupsilocin) for Major depressive disorder

Phase 3ActiveMajor depressive disorder indication →

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).

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

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

Started Dec 2025· Primary completion Mar 2027· 📍 67 sites across 8 countries (United States, United Kingdom, Poland, Australia)

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

Started Jul 2025· Primary completion Mar 2028· 📍 19 sites across 1 country (United States)

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

Started Dec 2024· Primary completion Aug 2026· 📍 47 sites across 1 country (United States)

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)

Started Aug 2022· Primary completion Oct 2023· 📍 3 sites across 1 country (United States)

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.

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Other 5-HT2A compounds

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Identifiers

Sources

  1. 5-HT2A receptor (HTR2A), GtoPdb object 6 — IUPHAR/BPS Guide to Pharmacology
  2. A Study of a Deuterated Psilocin Analog (CYB003) in Humans With Major Depressive Disorder (PARADIGM Phase 3) — ClinicalTrials.gov
  3. APPROACH: Phase 3 trial of CYB003 in MDD (NCT06564818) — ClinicalTrials.gov
  4. Cybin doing business as Helus Pharma; commences trading on Nasdaq (ticker HELP) (6-K exhibit, 5 Jan 2026) — SEC EDGAR / Cybin Inc. (Helus Pharma)
  5. Cybin initiates PARADIGM Phase 3 program for CYB003 in MDD (6-K exhibit, 13 Nov 2024) — SEC EDGAR / Cybin Inc.
  6. Cybin receives FDA Breakthrough Therapy Designation for CYB003 and reports 4-month durability data (6-K exhibit, 13 Mar 2024) — SEC EDGAR / Cybin Inc.
  7. Cybin reports positive Phase 2 12-month efficacy data for CYB003 in MDD (6-K exhibit, 18 Nov 2024) — SEC EDGAR / Cybin Inc.
  8. Cybin Reports Positive Phase 2 Data for CYB003 — Cybin / Helus Pharma (IR)
  9. Cybin reports positive Phase 2 topline data for CYB003 in MDD (6-K exhibit, 30 Nov 2023) — SEC EDGAR / Cybin Inc.
  10. EXTEND: Phase 3 long-term extension of CYB003 in MDD (NCT06605105) — ClinicalTrials.gov
  11. 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.)
  12. Phase 1/2a study of CYB003 in healthy participants with and without MDD (NCT05385783) — ClinicalTrials.gov