CYB003 for the Adjunctive Treatment of Major Depressive Disorder

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Cybin announced the initiation of PARADIGM, a phase 3 pivotal program evaluating the efficacy and safety of CYB003 for the adjunctive treatment of major depressive disorder (MDD), aptly named for the belief that CYB003 could be a paradigm shift in the treatment of depression.¹ CYB003 is a proprietary deuterated molecule related to psilocybin that was granted breakthrough therapy designation for the treatment of moderate to severe depressive disorder.²

“Just 3 years after filing an Investigational New Drug application for CYB003, the initiation of our phase 3 program is a truly significant and gratifying milestone. Following a highly collaborative and thorough design and review process with the US Food and Drug Administration, we believe that PARADIGM incorporates appropriate protocols that proactively address some of the challenges encountered by peers developing molecules with similar mechanisms of action by (1) recruiting from the larger MDD population; (2) administering CYB003 as an adjunctive treatment and not requiring patients to titrate off their existing antidepressants; and (3) utilizing a 12-week blinded period to maximize the number of patients that remain in the study through the blinded stage,” said Doug Drysdale, Chief Executive Officer of Cybin. “Our innovative approach represents a potential ‘paradigm’ shift, moving away from the daily treatment of depression symptoms and toward an intermittent, more durable treatment like CYB003 that could potentially change the course of the disease. Our clinical team has accomplished an extraordinary amount in a short time, and we are eager to continue investigating CYB003’s potential to provide long-lasting relief from depressive symptoms and disrupt the standard of care in MDD.”

The phase 3 program is comprised of 3 pivotal efficacy studies: (1) APPROACH; (2) EMBRACE; and (3) EXTEND.

In the APPROACH study, participants (n=220) will be randomized 1:1 to receive either 16 mg of CYB003 (n=110) or inactive placebo (n=110). Each study arm will evaluate a 2-dose regimen, with doses administered 3 weeks apart. The study will enroll patients with moderate to severe MDD (MADRS≥24) who are on a stable dose of antidepressant medication but are responding inadequately, at 36 clinical sites across the US and Europe. The primary endpoint will be change in depressive symptoms as measured by change in MADRS from baseline at 6 weeks after the first dose. This pivotal study has been initiated, with topline results expected in 2026.

In the EMBRACE study, participants (n=330) will be randomized 1:1:1 to receive 16 mg of CYB003 (n=110), 8 mg of CYB003 (n=110), or inactive placebo (n=110). Again, each arm will evaluate a 2-dose regimen, with doses administered 3 weeks apart. The study will enroll patients with moderate to severe MDD (MADRS≥24) who are on a stable dose of antidepressant medication but are responding inadequately, at 48 clinical sites with minimal site overlap with the APPROACH study. The primary endpoint will be change in depressive symptoms as measured by change in MADRS from baseline at 6 weeks after the first dose. This second pivotal study is expected to begin in the first half of 2025.

In the EXTEND study, participants from APPROACH and EMBRACE will roll over (up to n=550) after the completion of the 12-week, double-blind, placebo-controlled treatment periods. During EXTEND, all participants who did not respond to treatment in the APPROACH and EMBRACE studies or who relapse during the EXTEND study will be eligible to receive an additional 2 doses of CYB003 (16 mg) administered 3 weeks apart. Participants who do not respond to these 2 doses or relapse again will be eligible to receive an additional single 16 mg dose of CYB003.

Across all 3 studies, raters will be remote, independent, and blinded with no information on the dose received or the participant’s dosing experience. Effects during the dosing session will be firewalled to ensure that the study team stays blinded.

CYB003 already saw positive 4-month efficacy data in MDD in phase 2 studies. Investigators noted robust and sustained improvements in symptoms of depression with 2 doses of 12 mg or 16 mg of CYB003. The mean reduction from baseline in the MADRS total score was approximately 22 points from baseline in both dosing cohorts. Additionally, approximately 75% of the patients were responders (>/= 50% improvement in MADRS scores) following 2 doses of 16 mg, and 75% of patients on 16 mg were in remission from depression following 2 doses (MADRS score </= 10).

“Our unique phase 3 pivotal program design has been informed by the impressive phase 2 (4-month) data showing rapid, robust improvements in symptoms of depression with a single dose of CYB003, and durable effects four months after 2 doses with a 75% remission rate in the 16mg dose group. For our pivotal program, we have preserved the 2-dose regimen used in our phase 2 study, given the strong durability results seen to date,” said Amir Inamdar, Chief Medical Officer of Cybin. “The need for improved treatments for mental health disorders has never been greater. We believe that our phase 3 program can build on the positive results demonstrated in phase 2 to-date and could potentially lead to the approval and commercialization of a novel treatment modality whose effects are consistent and durable for patients with MDD.”

CYB003 was well tolerated with no drug-related serious adverse events, and all adverse events were mild or moderate in intensity. There were no incidents of suicidal ideation or behavior and no discontinuations due to adverse events.

References

1. Cybin initiates PARADIGM: a multinational pivotal phase 3 program evaluating CYB003 for the adjunctive treatment of major depressive disorder and reports second quarter financial results. News release. November 13, 2024. Accessed February 10, 2025. https://ir.cybin.com/investors/news/news-details/2024/Cybin-Initiates-PARADIGM-A-Multinational-Pivotal-Phase-3-Program-Evaluating-CYB003-for-the-Adjunctive-Treatment-of-Major-Depressive-Disorder-and-Reports-Second-Quarter-Financial-Results/default.aspx

2. Cedar Clinical Research selected as clinical research site for Cybin’s phase 3 study of CYB003. April 17, 2024. Accessed February 10, 2025. https://www.investors.numinus.com/news/news-details/2024/Cedar-Clinical-Research-selected-as-clinical-research-site-for-Cybins-Phase-3-Study-of-CYB003/default.aspx