Novel Serotonergic Agonist, HLP003, Targets the Adjunctive MDD Treatment Gap

Ken Kramer, PhD, shared background and updates on phase 2 and phase 3 data for HLP003, an investigational novel serotonergic agonist being developed as an adjunctive treatment for major depressive disorder (MDD). In the phase 2 trial, patients received either HLP003 or placebo during an initial double-blind, placebo-controlled period; all participants then had the opportunity to receive active medication, with a subset followed for up to 12 months.

"What we saw was the 3 Rs: a rapid response, a robust response, and over time a very resilient response," Kramer said. Reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS) at week 3 was substantially greater with HLP003 than placebo, and the gap between the placebo group at 3 weeks and the HLP003 group at 12 weeks reached nearly 13 points on the MADRS—compared with a typical 4- to 5-point difference in adjunctive MDD trials.¹ "At 12 months we still had response rates over 70%, with some patients at 100%, after just 2 treatments given 3 weeks apart," Kramer noted.

These phase 2 findings informed the phase 3 program, a classical adjunctive MDD study in which patients stable on a background antidepressant but showing only partial response receive up to 5 doses of HLP003 over 1 year.² The program includes a 12-week study, a companion 12-week study, and a long-term extension study designed to assess speed of onset, robustness of response versus placebo, and durability of effect. Exploratory endpoints will capture comorbid anxiety and quality-of-life outcomes. Because current adjunctive antipsychotics require daily administration, Kramer said an intermittent dosing schedule—potentially once every 3 months or longer—could ease the daily pill burden associated with existing options and support better long-term adherence. Trial participants entered at a baseline severity of approximately 4 out of 10 on a 0-to-10 scale, leaving room for improvement over existing options. Kramer positioned HLP003 as an alternative to current standard-of-care adjunctive options—atypical antipsychotics—which require daily dosing and carry substantial tolerability and safety burdens.

Dr Kramer is senior vice president and head of medical affairs at Helus Pharma.

References

1. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166(9):980-991.

2. Helus Pharma completes enrollment in phase 3 APPROACH study of HLP003 in adjunctive treatment of major depressive disorder ahead of schedule. Press release. July 21, 2026. Accessed August 27, 2026. https://ir.helus.com/news-releases/news-release-details/helus-pharma-completes-enrollment-phase-3-approach-study-hlp003