Helus Pharma Eyes Q4 Phase III Data for HLP-003 in Major Depression

Key Points

• Helus Pharma expects top-line Phase III results for HLP-003 in the fourth quarter from the APPROACH trial, which tests two 16-milligram doses as an add-on treatment for moderate-to-severe major depressive disorder.
• The trial’s primary endpoint is depression improvement at six weeks, with a 12-week assessment measuring durability. Helus plans to seek FDA approval in 2028 if its broader Phase III program succeeds.
• HLP-003 is a deuterated psilocin designed to improve brain exposure and delivery efficiency, while Helus is also advancing HLP-004 for generalized anxiety disorder and an earlier-stage HLP-005 program.

Helus Pharma, formerly known as Cybin NASDAQ: HELP, outlined its late-stage development plans for HLP-003 in adjunctive major depressive disorder (MDD) and discussed its broader pipeline of serotonergic agonists during TD Cowen’s Novel Mechanisms in Neuropsychiatry virtual summit.

Michael Halstead, who joined Helus as chief executive officer in early August, said the company is developing several programs intended to address mental health conditions. Its most advanced candidate, HLP-003, is deuterated psilocin and is in Phase III development as an add-on treatment for patients with MDD who have not adequately responded to background antidepressant medication.

Halstead said the company expects top-line results from its first Phase III trial, called APPROACH, in the fourth quarter. Helus anticipates filing a New Drug Application for HLP-003 in 2028, supported by its broader Phase III program.

HLP-003 Phase III trial design

Amir Inamdar, Helus Pharma’s chief medical officer, described APPROACH as a placebo-controlled study evaluating two 16-milligram doses of HLP-003 administered three weeks apart. The study’s primary endpoint is at six weeks, while a secondary endpoint at 12 weeks is intended to assess durability of effect.

The trial enrolls patients with moderate-to-severe MDD who are receiving stable doses of antidepressants but remain inadequately responsive. Helus raised the minimum Montgomery-Åsberg Depression Rating Scale, or MADRS, score for enrollment to 24 from 21 in its Phase II trial.

Participants may remain on background selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. However, monoamine oxidase inhibitors and tricyclic antidepressants are excluded, as are antipsychotics and mood stabilizers. Inamdar said antipsychotics could interfere with the pharmacodynamic effects of psychedelic compounds, while use of mood stabilizers may indicate conditions other than unipolar depression.

Helus has not disclosed the statistical power of APPROACH. Halstead said the company believes the study is powered comparably with other late-stage trials in the drug class.

Prior findings and expectations

Inamdar said that in the company’s Phase II study, a single dose of HLP-003 produced an approximately 13-point effect on MADRS, followed by an additional roughly 5.5-point benefit after a second administration. He said the Phase III design incorporates the second dose into the six-week primary endpoint.

Halstead cautioned against comparing the adjunctive MDD study directly with monotherapy trials or studies in other conditions. He said currently marketed adjunctive antipsychotic therapies have shown roughly two to three points of improvement in some trials and four to five points for the strongest products, while carrying cardiometabolic and sexual-dysfunction side-effect burdens.

The company expects to report the six-week primary efficacy endpoint, 12-week data, and customary safety and adverse-event information in its top-line update. Additional data are expected to be presented later at medical conferences, Halstead said.

Deuterated psilocin and safety considerations

According to Inamdar, HLP-003 differs from psilocybin-based products because it is deuterated psilocin, the active metabolite formed after psilocybin is converted in the body. Helus believes deuteration may improve stability and delivery efficiency while reducing drug load.

Inamdar said preclinical studies indicated HLP-003 entered the brain about twice as fast as psilocin derived from psilocybin and reached higher brain exposure. He also said a 16-milligram dose of HLP-003 produced a peak plasma concentration about 1.5 times higher and overall exposure about 2.5 times higher than 25 milligrams of psilocybin in comparisons cited by the company.

For treatment-day monitoring, Inamdar said clinicians would assess physiological measures including blood pressure and heart rate, as well as mental status, before determining whether a patient is ready for discharge. He said post-treatment discharge timing could vary by patient.

Regarding suicidality, Inamdar said it is an important clinical feature of MDD and may occur in depression trials. He said regulators and key opinion leaders would assess any events in the context of baseline severity, timing, treatment relationship, and whether there is an imbalance between active treatment and placebo groups.

Beyond HLP-003, Halstead said Helus is developing HLP-004, a deuterated DMT candidate in Phase II for generalized anxiety disorder, and an earlier-stage HLP-005 program. The company expects to advance a lead HLP-005 candidate in 2027.

About Cybin (NASDAQ:HELP)

Cybin Inc is a clinical-stage biopharmaceutical company focused on developing psychedelic-based therapeutics for the treatment of mental health conditions. The company combines drug discovery, clinical development and proprietary formulation technologies to design potentially more efficient and scalable psychedelic treatments.

Cybin's development programs have included CYB003, an investigational deuterated psilocybin analog being studied for major depressive disorder, and CYB004, an investigational deuterated DMT molecule being evaluated for generalized anxiety disorder and other mental health indications.

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