As recently as the 1990s, it would be difficult to imagine that a psychedelic drug would potentially be a clinical option for a mood disorder like depression. But before long, data from multiple phase 3 trials will be available on psilocybin derivatives for various mood disorders.
Interim phase 2 CYB003 data as a ray of hope for treating mood disorders
Toronto, Canada–based Cybin recently unveiled upbeat interim phase 2 data related to CYB003, a proprietary deuterated psilocybin analog, in patients with moderate to severe major depressive disorder (MDD). In the randomized double-blind placebo-controlled study, CYB003 demonstrated a rapid and robust reduction in depression symptoms just three weeks after a single 12-mg dose. The study recorded a mean 14-point drop in the Montgomery-Asberg Depression Rating Scale (MADRS), a common measure of depression severity. For a patient with a moderate depression who scored 30 on the MADRS scale, a 14-point drop would bring their score down to 16, which qualifies as mild depression. Similarly, a patient with severe depression with a score of 37 would drop to 23, which qualifies as moderate depression.
For context, new generation antidepressants show an average MADRS improvement of about 2.99 points compared to placebo, according to one review.
‘Remarkable’ results in Cybin’s quest to help heal the MDD psyche
In a recent interview, Drysdale called the results following a single dose “remarkable.” A 14-point improvement in the MADRS scale is “something quite groundbreaking and really exciting for us.”
Patients in the study were taking “background, stable doses” of SSRIs, Drysdale said. “Obviously, that’s a little bit of a higher hurdle to try to show benefit on top of the background treatment,” he said.
In the context of psychedelic research, the use of placebos poses unique hurdles. Traditional placebo methods, such as the use of niacin can elicit flushing, aim to mimic the physical effects of psychedelics without inducing the psychoactive experience. Studies have found that even when participants are given a placebo, a significant percentage report experiencing effects similar to those of psychedelics. This was the case in the Cybin trial. “There were several folks in the placebo group that had visual analog scores that were up there in that psychedelic realm,” Drysdale said. “Placebo is a strange thing in depression studies.” FDA guidance also notes that placebo recipients in a psychedelic trial may experience a “nocebo” effect as they realize they didn’t receive the active treatment.
Cybin plans to use small doses of CYB003 that is subtherapeutic in a comparison arm of the phase 3 study.
The twilight of unmet needs in depression
Across the world, hundreds of millions of people suffer from depression, equating to roughly 5% of adults, according to WHO. The condition is one of the leading causes of disability. Despite the availability of a variety of treatments, many patients do not achieve full remission. One of the most influential studies of traditional antidepressants, STAR*D (Sequenced Treatment Alternatives to Relieve Depression), found that only about 33% of patients achieved remission after receiving the SSRI citalopram in the first round of treatment. Additionally, the study found that patients who did not respond to citalopram were statistically less likely to respond to subsequent treatments, which included cognitive behavioral therapy or adding additional antidepressants such as sertraline, bupropion-SR or venlafaxine-XR. The study offered additional options in subsequent rounds. For patients who have not found relief from three or more antidepressants, the cumulative remission rate was approximately 35%, according to a recent reanalysis of the STAR*D data.
In recent years, drug developers have explored a variety of approaches to developing novel antidepressants, resulting in a handful winning FDA approval, such as Spravato (esketamine) from Johnson & Johnson, Auvelity (dextromethorphan-bupropion) from Axsome Therapeutics and Zurzuvae (zuranolone) from Sage and Biogen, which scored FDA approval for postpartum depression but has thus far failed for major depressive disorder. Sage is now reviewing next steps in light of the FDA’s feedback, planning new clinical trials to address the concerns raised for MDD approval. In addition, a number of companies have performed phase 3 studies on experimental treatments, with varying degrees of success. Notable examples include Compass Pathways’ ongoing phase 3 program for psilocybin, Atai Life Sciences’ phase 2 studies on compounds such as RL-007 and VLS-01, and MAPS’ completed phase 3 studies of MDMA-assisted psychotherapy for PTSD.
Cybin’s countdown to pivotal data release and a phase 3 trial
After announcing interim data, Cybin plans to release full phase 2 topline data for its deuterated psilocybin analog in the last quarter of 2023 and is prepping for a more extensive international phase 3 trial in early 2024.
In recent years, the psychedelic industry has helped highlight the therapeutic potential of current schedule 1 substances as potentially efficacious therapies for various mood disorders. In 2021, dealmaking in the sector peaked with 14 transactions worth nearly $800 million. The situation has abruptly shifted though. In 2022, there were only five deals while some companies in the space are strategically acquiring assets from others. In 2023, several public companies in the space have witnessed significant stock price erosion.
Cybin’s strategy in a consolidating field
Meanwhile, the consolidation of the landscape continues. For instance, Cybin recently acquired Small Pharma and also acquired a significant Phase 1 DMT study from Entheon Biomedical in 2022. In addition, Otsuka Pharmaceuticals announced its acquisition of MindSet Pharma, a developer of novel psychedelic-based therapies for mental health conditions. In September 2023, Lucy Scientific Discoveries, a psychotropics contract manufacturing and research company, acquired the assets of Wesana Health, which include SANA-013, a combination of psilocybin and CBD for potential mental health treatment.
Commenting on the current state of the therapeutic landscape, Drysdale notes that the field has consolidated from dozens of companies in recent years to a handful. “That’s a good thing,” Drysdale said, adding that the companies that remain are doing “good, good scientific work.”
Drysdale notes that Cybin is recently seeing “a real shift in interest from investors” now that the company is developing deuterated psilocybin and DMT under one roof. This merger with Small Pharma unifies two significant psychedelic research portfolios. The company recently received a substantial investment from billionaire Steve Cohen’s hedge fund, Point72 Asset Management, which acquired almost 19 million shares in Cybin.
In the meantime, “the CYB003 interim data is really getting a lot of attention,” Drysdale said. “People suddenly realize that psychedelics are real. This is going to happen,” he continued.
Filed Under: Brain Breakthroughs, clinical trials, Drug Discovery and Development, Psychiatric/psychotropic drugs