The trial will enroll nearly 1,000 participants, and Compass hopes to gain approval from the U.S. Food and Drug Administration (FDA) by the end of 2025.
The landmark Phase 3 trial follows the company’s announcement of successful Phase 2B results late last year. These results included 233 treatment-treated depression patients randomized into three dose groups: 25 mg, 10 mg, and 1 mg. During the 12-week follow-up, Compass reported a statistically significant improvement in measures on the Depression Scale after a single dose of 25 mg of psychedelic compared to the two lower-dose groups.
Phase 2B data, which have not been formally published in a peer-reviewed journal, are not entirely positive, with 5 patients (6.3%) in the 25 mg group and 6 patients (8%) in the 10 mg group experiencing severe disease during follow-up. of adverse events. These adverse events included suicidal ideation and suicidal behavior, however, in a statement at the time, Compass said it was unclear whether these adverse events were causally related to psychedelic treatment.
“…of the 12 patients who experienced a serious adverse event, only 1 occurred within 24 hours of taking the drug. The other 11 did so after 62 days. Therefore, it is unclear whether it was related to the dosing There is a direct connection,” Compass said in late 2021.
After discussions with the U.S. Food and Drug Administration (FDA) about these Phase 2B results, Compass has now disclosed its Phase 3 plan, which consists of three parts: two clinical trials and a long-term follow-up.
The first Phase 3 trial, dubbed “Pivotal Phase 1,” will enroll 378 participants and compare a single 25 mg dose of psychedelic to a placebo. The option to use a placebo control differs from the Phase 2B design that evaluated three different doses.
Some psychedelic clinical researchers have recently suggested that the nature of the psychedelic experience is so powerful and obvious that it is impossible to effectively blind trials with ordinary placebos. The argument argues that since each participant would immediately know whether they were given a psychedelic or a placebo, the end result could be exaggerated by the desired effect.
Not only were people in the psychedelic group likely to report greater improvement knowing they had been given the active drug, but those in the placebo group were also likely to report greater disappointment. And this incongruity could have contributed to the huge difference between the placebo group and the psychedelic group.
Guy Goodwin, chief medical officer at Compass Pathways, said the placebo control was chosen in Pivotal 1 to help clarify the safety profile of psychedelics.
“We used a placebo in the Phase 3 program because it was necessary to understand the true safety of COMP360 psychedelics at the preferred dose of 25 mg,” Goodwin explained in a statement to New Atlas. “The psychedelic experience is bound to lead to some shedding, no matter what kind of comparison is made. Since it reflects the mechanism of action of the drug, we also had to confirm the dose-response effect seen in our phase 2b study.”
The second part of the Phase 3 program, called Pivotal 2, more directly replicates the three-tier (25mg/10mg/1mg) design of the 2B trial. But in this case, the goal was to explore the efficacy of a second dose of psychedelics administered three weeks after the first. Pivotal 2 will recruit 568 participants.
Smaller early trials looking at the effects of psychedelics on depression found two 25 mg doses to be safe and effective. One of the key reasons for the two-dose design of Pivotal 2, according to Goodwin, was to explore whether two 10-mg doses would be effective in reducing symptoms of depression, as it was found in the weeks following the smaller psychedelic dose. Temporary benefit.
“We found that the 10 mg dose produced an intermediate effect (levels found in some existing antidepressants) between the 25 mg and 1 mg doses in Phase 2b,” explains Goodwin. “We don’t yet know what effect two doses of 10-mg will have, and we’ll be looking into this as part of Phase 3. If two 10-mg doses prove to have good effects, this will increase The patient’s choice.”
The two pivotal trials will focus only on patients with treatment-resistant depression. Therefore, while there are other Phase 2 psychedelic trials currently exploring treatment in patients with major depressive disorder, this Phase 3 trial is only for patients with major depressive disorder who do not respond to antidepressants or psychotherapy.
As with most clinical studies of psychedelics, this trial will follow a pre- and post-drug psychotherapy regimen. However, the treatment portion of the Compass regimen was reasonably downsized compared to some other trials of psychedelic-assisted therapy that used more comprehensive treatment supervision.
“Psychological support includes preparation, which will consist of three sessions, 6-8 hours of supervision on the day of dosing, and two integration sessions,” Goodwin said. “Preparation includes time to explain the purpose and design of the study.”
In addition to the long-term follow-up portion of the program, both parts of the Phase 3 trial will have a primary endpoint of a reduction in depression as measured by the Montgomery-Osberg Depression Rating Scale (MADRS) 6 weeks after the first dose .
Interestingly, Goodwin does suggest that in the event of a relapse of depression, the patient’s response to 25 mg of psychedelics should be reproducible, although there is no real clinical evidence to support this. While the long-term effects of this psychedelic-assisted psychotherapy have not been fully established, Goodwin envisions that some patients may need to take psychedelics two or three times a year to maintain the effects of treatment.
Compass expects the first wave of data from Pivotal 1 to appear in late 2024. And the move to apply for market approval from the U.S. Food and Drug Administration could come as soon as next year. So, if successful, this could be the clinical evidence leading to psychedelics becoming FDA-authorized drugs within three to four years.