On Tuesday, Compass Pathways released the much-anticipated topline results1 from their Phased IIb trial of COMP360 (psilocybin) for Treatment Resistance Depression (TRD).
The anticipation for this trial was high. The results would be viewed as a bellwether of sorts for the “psychedelics as medicine” thesis because it is the largest double-blinded randomized, placebo-controlled trial (DB-RCT) to date of psilocybin with 233 participants. Before this study, only 151 participants had been evaluated in DB-RCT psilocybin trials—which was surprising to me when I recently learned this.
Since this trial yielded positive topline results but also worrisome safety data—which caused psychedelic stocks to fall and an uptick in commentary about safety concerns—some preliminary analysis and sensemaking at this stage could be helpful.
To that end, I started a thread of the useful perspectives I found online:
Compared to other development-stage biotech companies, psychedelic stocks are overwhelmingly held by the public. Usually, at this stage of drug development, institutional capital will make up about 80% of shareholders—psychedelic companies, like Compass, are a complete reversal with approximately 80% of shares publicly held.
These investors are presumably less educated about the drug development process, bought into the promise of enormous effect sizes, minimal safety concerns, and the novelty of psychedelics as medicine—thus, even positive topline results can’t match the hype.
The Long Shadow of MAPS
One reason the results are considered disappointing—even as they indicate rapid and statistically significant treatment responses to a condition, which is by definition resistant to treatment—is because of the instinct to compare them to MAPS Phase III results.
Wit which set a very high bar of “67% of participants in the active group no longer qualifying for PTSD and a clinically meaningful reduction in symptoms in 88%2”.
Compare this to the headline numbers of 36.7% (contol=17.7%) response at week three and 24.1% (control=10.1%) at week 12.
Safety Four Ways: Toxicity, addictive potential, and existential destabilization & hopelessness
A vital feature of the Psychedelics as Medicine thesis is the safety narrative, precisely, the favorable toxicity profile and the characterization of being non-addictive—therefore, how can safety concerns peg back otherwise excellent results?
This depends on what do you mean by ‘safe.’
Even though psychedelics are currently considered non-toxic and non-addictive, the safety risk comes in the form of what might be called existential destabilization and hopelessness.
In my opinion, the biggest question raised by these results is “to what extent are such risks mitigated by psychotherapy—as implemented in the MAPS protocol— but not “psychological support” as in the Compass protocol?”
In other words, what happens as Psychedelic Assisted Therapy becomes unbundled?
“Largest randomised, controlled, double-blind psilocybin therapy study ever completed shows rapid and sustained response for patients receiving a single dose of COMP360 psilocybin with psychological support…
…phase IIb clinical trial of COMP360 psilocybin therapy for treatment-resistant depression has achieved its primary endpoint for the highest dose, with a 25mg dose of COMP360 demonstrating a highly statistically significant and clinically relevant reduction in depressive symptom severity after three weeks, with a rapid and durable treatment response…
At least twice the number of patients in the 25mg group showed response and remission* at week 3 and week 12, compared with the 1mg group. The protocol-defined sustained response* up to week 12 was double, with 20.3% of patients in the 25mg group vs 10.1% in the 1mg group…
The trial was powered to compare two active doses of COMP360, 25mg and 10mg, against a comparator 1mg dose…
There were 12 patients who reported treatment-emergent serious adverse events (TESAEs). These TESAEs included suicidal behaviour, intentional self-injury, and suicidal ideation, which are regularly observed in a treatment-resistant depression patient population, and which occurred more frequently in the 25mg group than in the 10mg or 1 mg groups.
Where are the Diamond Hands?
Despite the headline positive news that the 25 mg dose elicited a robust, statistically significant response in the primary endpoint—combined with the adverse events data— it wasn't enough to convince shareholders, and the Compass stock price took a hit—as did other psychedelic stocks, Atai and MindMed.
This thread from Andy Coravos offered a salient hypothesis:
~80% of psychedelic stocks are held by retail investors.
This is a complete inversion of the convention for biotech companies in phase II/III trials which insiders and institutions usually hold the majority of shares.
Urogen, for example, is a biopharmaceutical company developing treatments for urothelial and specialty cancers; over 85% of shares are owned by institutions and insiders.
Ultimately, the narrative which that retail investors bought into and is now challenged by these results hinged on two plot lines:
The phenomenal results from MAPS’ Phase III results were a harbinger of the future of the entire field
Psychedelics are non-toxic and non-addictive,, and so safety is not a concern
The Long Shadow of MAPS Phase III
If I think back on the MAPS phase III results of the MDMA for PTSD trial, the number that I remember is 67%:
“67% of participants who received three MDMA-assisted therapy sessions no longer qualified for a PTSD diagnosis and 88% experienced a clinically meaningful reduction in symptoms.”
When I hear people talk about MDMA for PTSD, they use this number. When the mainstream press talks about MDMA for PTSD, they use this number.
What was the takeaway for the Compass Phase II trial? 36%.
Compared to the MAPS trial, these results from the Compass phase IIb seem lackluster, even if they’re not.
Even though it is inappropriate to compare them (preliminary data, different trials, different conditions, different primary endpoints) I think this is half of what spooked investors.
If we think about the natural history of this field, early programs such as those at Johns Hopkins and MAPS, which paved the way, used a more cautious study design that leaned heavily on the psychotherapeutic alliance and was optimized for results, safety, and to satisfy cautious regulators.
Compass now has the tricky task of making psychedelic-assisted therapy more scalable and stepping out beyond this established format.
The main differences between the MAPS and Compass trials include:
the number of dosing sessions—the MAPS trial consisted of three therapist-supported dosing sessions while the Compass trial was a single dose of psilocybin with psychological support
The extent of psychotherapeutic support—MAPS’ protocol consisted of three preparation sessions and nine psychotherapy sessions in addition to the three dosing sessions. It is unclear what psychological support in the Compass trial looks like, hopefully we’ll learn more in the published results.
A third consideration is the qualitative differences between MDMA and psilocybin. The classic psychedelics induce subjective experiences like ego dissolution, mystical experiences, and an overall higher level weirdness than MDMA. In contrast, MDMA produces higher good drug effects like a high, openness, and connection than classic psychedelics.
It could bethat more frequent, less ego-dissolving experiences, with more significant support, would produce better results with fewer adverse events. However, the Compass trial is probably more realistic in terms of what the practice of psychedelic medicine will look like in medical settings.
In reality, I should have made this part III of the Unbundling Psychedelic Therapy series because it is not only the largest psychedelic trial to date but also a test of the efficacy of a single dose and the safety when intense psychotherapy protocol is removed.3
What We Talk About When We Talk About Drug Safety
This tweet from James Kent captures the safety concern well:
Again from the press release:
“There were 12 patients who reported treatment-emergent serious adverse events (TESAEs). These TESAEs included suicidal behaviour, intentional self-injury, and suicidal ideation, which are regularly observed in a treatment-resistant depression patient population, and which occurred more frequently in the 25mg group than in the 10mg or 1 mg groups.”
The narrative about psychedelics as medicine includes a nod to their great safety profile, primarily related to two great features:
Their toxicity profile—psychedelics seemingly have no upper toxicity threshold. This is excellent news since drug toxicity is a cause of iatrogenic harm in healthcare, anything that can reduce such damages is clearly a good thing.
Their profile as non-addictive substances is also excellent, especially in light of the opioid epidemic and the steep rise in drug-related overdose deaths.
“Although there is a general public perception that psychedelic drugs are dangerous, from a physiologic standpoint they are in fact one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline.”—Nichols 2016
What this does not include is what I have heard Matthew Johnson call “Behavioral Toxicity,” which I took him to mean the risk of psychedelics lies not in their toxicity or their addictive capacity but in the potential for someone to hurt themself or another while tripping.
Another form of risk might be called emotional or psychological overwhelm—for many, psychedelic trips are journeys into longstanding emotional wounds; this terrain is dark, scary, embarrassing, and shameful—when such aspects of our psychede are revealed it can, as they say, “fuck with you.”
Finally, there is the sense of hopelessness that can be strengthened when one has exhausted all treatment options, especially the most promising ones.
“My great concern right now is not that people are going to dismiss psychedelics not that people are going underestimate psychedelics, my concern, and I've seen this happen… the desire for a means of salvation is so powerful in human beings and the hope for some sort of ultimate cure or final answer, my greatest fear is that its so profound is that these agents are being oversold and when people realize they're not going to solve all of life's problems,or they may introduce new problems like you go to the Mountain Top and now you gotta come back down and your totally disillusioned and you go the other way.”
Policy Reform
Finally, what does this mean for policy reform efforts?
The grassroots and local efforts lean heavily on the same narrative that commercial proponents do—psychedelics are non-toxic, non-addictive, and have massive therapeutic potential; therefore they should be decriminalized.
As research continues, safety concerns will become more manifest and they will not only affect share prices but also policy reform.
These results from Compass are the starkest challenge to the safety narrative that we’ve seen—along with recent allegations of sexual abuse within the underground psychedelic therapy circles—these two narrative corrections could give pause to not only to retail investors but voters and politicians as well.
“Topline results of Phase 2 trials are typically first disclosed through press releases so that key stakeholders (patients and their advocacy groups, physicians, clinical trials practitioners, investors, etc.) can have timely access to a high-level summary of the important findings. The sponsors of the trials often will save more detailed findings for future medical conference presentations and/or peer-reviewed journal publications, and as a result, there may be an extended period of time where only the topline results are available on which stakeholders can rely. It is therefore critical for trial sponsors to release objective findings and avoid selective disclosure of favorable results.”
AFAIK we don’t know what psychological support actually looked like in this trial - but if we compare the visit schema from the MAPS protocol to this, it seems pretty dramatic—Psychotherapy played a massive role in the MAPS trial with 12 total therapy sessions, while ‘psychological support’ in the Compass trial is unclear:
Great breakdown as always!