Phase 3 PARADIGM: HLP003 (Psilocibin-d10) for Adjunctive MDD Use

Helus Pharma's phase 3 PARADIGM program is evaluating 8 mg and 16 mg doses of HLP003, a deuterated psilocin analog, as an adjunctive treatment for major depressive disorder (MDD) in adults with inadequate response to antidepressants, according to trial design data presented at Psych Congress 2026 in New Orleans, Louisiana from September 15 to 19.¹

Approximately 50% of patients with MDD do not respond adequately to first-line treatment, and adjunctive agents are often added to an antidepressant to pursue remission.¹ HLP003, previously known as CYB003, is a serotonergic agonist with activity at multiple 5-hydroxytryptamine (5-HT) receptors, including 5-HT2A, and has received US Food and Drug Administration (FDA) Breakthrough Therapy Designation for adjunctive use in MDD.¹,² Investigators positioned the program as a potential source of data for patients seeking an alternative to atypical antipsychotics.¹

“The early completion of enrollment in APPROACH brings us closer to determining whether HLP003 can provide a durable clinical benefit within a practical adjunctive treatment model for people with MDD,” said Amir Inamdar, MBBS, chief medical officer of Helus Pharma, in a July statement announcing completed APPROACH enrollment.² Inamdar was the presenting author of the Psych Congress poster.¹

HLP003 Phase 3 PARADIGM Trial Design and Eligibility Criteria

PARADIGM comprises 2 randomized, double-blind, placebo-controlled, multicenter phase 3 trials, each 12 weeks long, plus a long-term extension.¹ APPROACH randomized 223 participants 1:1 to HLP003 16 mg or placebo.¹,² EMBRACE is randomizing approximately 330 participants 1:1:1 to HLP003 16 mg, HLP003 8 mg, or placebo.¹

In both trials, participants receive a first dose on day 1 and a second dose on day 22.¹ The primary endpoint is change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at day 42, and the key secondary endpoint is the same measure at day 84.¹

Eligible adults are aged 18 to 85 years with a first MDD episode before age 60 years.¹ Participants must have a MADRS score of ≥ 24, a Clinical Global Impressions-Severity (CGI-S) score of ≥ 4, and < 50% improvement on a stable antidepressant dose.¹ Exclusions include treatment-resistant MDD (failure of ≥ 2 antidepressants), psychotic or bipolar disorders, and significant lifetime suicide risk on the Columbia-Suicide Severity Rating Scale (C-SSRS).¹

Psychedelic exposure within 12 months or 10 or more times in a lifetime, and ketamine or esketamine use within 6 months, are also exclusionary.¹ Among 202 APPROACH participants with reported baseline data, median age was 44.0 years in the HLP003 arm and 50.0 years in the placebo arm.¹ Each arm was 64.4% female, and mean baseline MADRS scores were 33.1 and 33.3, respectively.¹

EXTEND Re-Treatment Design and Phase 1/2a HLP003 Efficacy Data

EXTEND is a 43-week extension open to participants completing APPROACH or EMBRACE who continue the same antidepressant.¹ Responders who relapse may receive 2 additional HLP003 doses 21 days apart, and nonresponders receive 2 HLP003 doses on entry.¹ The primary endpoint is the probability of stable response, defined as a ≥ 50% MADRS reduction from baseline at day 84 without relapse, at week 43.¹

Key secondary endpoints include time to first relapse among participants with initial stable response and the percentage requiring 2 or 3 additional treatment sessions.¹ Safety assessments across the program include treatment-emergent adverse events, electrocardiograms, C-SSRS items 4 and 5, potential abuse-related adverse events, and sedation.¹

The program builds on a randomized, double-blind, placebo-controlled phase 1/2a trial, which found a single 16 mg dose produced a 12.99-point greater MADRS improvement versus placebo at day 21 (95% CI, −22.3 to −3.7; P =.008; effect size, 2.54).¹ After a second dose on day 22, the mean MADRS change from baseline reached −22.6 at day 364 (n = 7), with nearly all participants remaining in remission.¹

Helus Pharma expects APPROACH topline data in the fourth quarter of 2026, and EMBRACE and EXTEND are estimated to finish in 2027 and 2028, respectively.¹,² The company has stated it is targeting a potential New Drug Application (NDA) in 2028.²

References

1. Inamdar A, Kulikova A, Massa A, et al. A phase 3 clinical program evaluating the efficacy and safety of the deuterated psilocin analog HLP003 as an adjunctive treatment for major depressive disorder (PARADIGM). Presented at: Psych Congress; September 15-19, 2026; New Orleans, LA. Poster 121.

2. Helus Pharma. Helus Pharma completes enrollment in phase 3 APPROACH study of HLP003 in adjunctive treatment of major depressive disorder ahead of schedule. Published July 21, 2026. Accessed September 23, 2026. https://ir.helus.com/news-releases/news-release-details/helus-pharma-completes-enrollment-phase-3-approach-study-hlp003