The world's first Phase 3 psilocybin clinical trial is about to commence

Research into clinical uses for psychedelics has proliferated in recent years, but despite the constant stream of "psychedelic renaissance" news, the vast majority of studies remain in early, preliminary stages. Apart from one notable modality (MDMA-assisted psychotherapy for post-traumatic stress disorder), no psychedelic clinical trial has progressed further than Phase 2.

A recent announcement from Compass Pathways is set to change that, with the world's first Phase 3 human trial for day psilocybin therapy with psychological support due to commence by the end of 2022. The trial will enroll close to 1,000 participants and Compass is looking to FDA approval by the end of 2025.

The landmark Phase 3 trial follows the company's announcement of successful Phase 2B results late last year. Those results encompassed 233 patients with treatment-resistant depression randomly split into three dosage arms: 25 mg, 10 mg, and 1 mg. Over the 12-week follow-up, Compass reported statistically significant improvements in measures on a depression scale after a single 25-mg psilocybin dose, compared to the two lower dose groups.

The Phase 2B data, which has yet to be formally published in a peer-reviewed journal, was not entirely positive with five patients (6.3%) in the 25-mg group and six patients (8%) in the 10-mg group experiencing serious adverse events during the follow-up period. These adverse events included suicidal ideation and suicidal behavior, however, in a statement at the time Compass indicated it is unclear whether the adverse reactions were causally related to the psilocybin treatment.

"… of the 12 patients experiencing serious adverse events, only 1 of them occurred within 24 hours of the dosing. The other 11 experienced theirs up to 62 days later. Therefore it is not clear that there is a direct link with administration of the drug," Compass stated to New Atlas late in 2021.

Following discussions with the US Food and Drug Administration (FDA) regarding these Phase 2B results, Compass has now revealed its Phase 3 program which spans three parts: two clinical trials and one long-term follow-up.

The first Phase 3 trial has been dubbed Pivotal 1 and it will enroll 378 participants to compare a single 25 mg psilocybin dose to placebo. The choice of using a placebo control stands apart from the Phase 2B design which evaluated three different doses.

Some psychedelic clinical researchers have recently suggested the nature of a psychedelic experience is so powerfully obvious that it is impossible to effectively blind a trial with a regular placebo. The argument suggests since every participant will immediately know whether they have been given a psychedelic or placebo, the ultimate results may be inflated by expectancy effects.

Not only could those in the psychedelic group report greater improvements knowing they have been given the active drug, but those in the placebo group could report greater disappointment. And this discordancy could lead to large differences between placebo and psilocybin groups.

Guy Goodwin, Compass Pathways' chief medical officer, said the choice of a placebo control in Pivotal 1 is designed to help clearly elucidate the safety profile of psilocybin.

"We are using a placebo in our phase 3 program, because it is necessary to understand the true safety profile of COMP360 psilocybin therapy at our preferred dose of 25 mg," Goodwin explained in a statement to New Atlas. "The psychedelic experience necessarily leads to some unblinding, whatever the comparator. Since it reflects the mechanism of drug action, it is important that we also confirm the dose response effects seen in our phase 2b study."

The second part of the Phase 3 program has been dubbed Pivotal 2 and it more directly replicates the three-tiered (25mg/10mg/1mg) design of the 2B trial. But in this instance the goal is to explore the efficacy of a second psilocybin dose administered three weeks after the first dose. Pivotal 2 will look to enroll 568 participants.

Smaller early trials looking at psilocybin's effect on depression has found two 25-mg doses to be safe and effective. According to Goodwin, one of the key reasons for the two-dose design of Pivotal 2 is to explore whether two 10-mg doses are effective at reducing the symptoms of depression considering transitory benefits were detected a few weeks after the smaller psychedelic dose.

"We found that the 10-mg dose produced intermediate effects between the 25-mg and 1-mg dose in phase 2b (at a level found with some existing antidepressants)," Goodwin explained. "We don’t know yet what the effects of two doses of 10-mg will be, and we’re going to look at this as part of our phase 3. It would increase patient options if two 10-mg doses prove to give good outcomes."

Both Pivotal trials will focus solely on patients with treatment-resistant depression. So although there are other Phase 2 psilocybin trials currently underway exploring the treatment for patients with major depressive disorder, this Phase 3 is only targeting those patients with severe depression that haven't responded to antidepressants or psychotherapy.

As with most psychedelic clinical research, this trial will follow a protocol of pre- and post-drug psychotherapy. However, the therapy part of Compass' protocol is reasonably pared back compared to some other psychedelic-assisted therapy trials employing more comprehensive therapeutic oversight.

"The psychological support consists of preparation, which will consist of three sessions, supervision on the day of drug administration for 6-8 hours and two integration sessions," according to Goodwin. "The preparation includes time for explanation of the purpose and design of the study."

Aside from the long-term follow-up part 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–Åsberg Depression Rating Scale (MADRS), six weeks after the first drug dose.

Interestingly, Goodwin does suggest patient responses for 25-mg psilocybin doses should be reproducible in the case of depression relapse, despite there being no real clinical evidence to back this up. While the long-term efficacy of this kind of psychedelic-assisted psychotherapy treatment has not been completely established, Goodwin envisages some patients could require two to three psilocybin doses per year to maintain treatment efficacy.

Compass expects the first wave of data from Pivotal 1 to come late in 2024. And moves to apply to the FDA for market approval could come as soon as the following year. So if successful, this could be the clinical evidence that leads to psilocybin becoming a FDA-authorized medicine within three to four years.

Source: Compass Pathways