Analysis: COMPASS Pathways Phase 2b Psilocybin Trial Published in... https://psychedelicalpha.com/news/breaking-compass-pathways-phase-...

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Psychedelic Bulletin #122:

Lusaris Raises $60m to
Develop 5-MeO-DMT; First

Analysis: COMPASS Take-Home Psilocybin Trial

in N. America; COMPASS

Pathways Phase 2b Phase 2b Published in

NEJM

Psilocybin Trial Published (https://psychedelicalpha.c

om/news/psychedelic-

in NEJM bulletin-122-lusaris-raises-
60m-to-develop-5-meo-
dmt-first-take-home-
psilocybin-trial-in-
 November 2, 2022 -
n-america-compass-phase-
 Analysis (https://psychedelicalpha.com/news/category/analysis)
2b-published-in-nejm)

COMPASS Pathways
COMPASS Pathways’ Phase 2b trial of COMP360 psilocybin Announces Third Quarter
therapy for treatment-resistant depression (TRD) has been 2022 Financial Results and 

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Analysis: COMPASS Pathways Phase 2b Psilocybin Trial Published in... https://psychedelicalpha.com/news/breaking-compass-pathways-phase-...

published in the New England Journal of Medicine Business Highlights

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(https://psychedelicalpha.c
(https://www.nejm.org/doi/full/10.1056/NEJMoa2206443). It
om/news/compass-
becomes the largest published psilocybin trial to date (N=233),
pathways-announces-
knocking NYU’s psilocybin for alcohol use disorder study (read Companies +
third-quarter-2022-
(https://psychedelicalpha.com)
our deep dive (https://psychedelicalpha.com/news/psychedelic- financial-results-and-
business-highlights)
bulletin-117-a-deep-dive-into-psilocybin-for-alochol-use- Psychedelic Careers
disorder-former-mindmed-cmo-alleges-ip-was-syphoned-off- Psychedelic Research

to-competitor-ark-discusses-psychedelics)) off its perch after just Bulletin: October 2022

Contact
(https://psychedelicalpha.c
a couple of months.
om/news/psychedelic-
research-bulletin-
This is the second major psilocybin study to be published in the
october-2022)
prestigious journal (see our coverage
Analysis: COMPASS
(https://psychedelicalpha.com/news/psychedelic-research-and-
Pathways Phase 2b
clinical-trials-in-2021#:~:text=most%20notable%20publications Psilocybin Trial Published in
%E2%80%A6-,Psilocybin,-Goes%20Head%2Dto) of the psilocybin vs. NEJM

escitalopram study from 2021), which comes a year after the (https://psychedelicalpha.c
om/news/breaking-
company published topline results from the trial (we won’t revisit
compass-pathways-phase-
the topline data in detail; see our deconstruction of the results
2b-psilocybin-trial-
(https://psychedelicalpha.com/news/psychedelic-bulletin- published-in-nejm)
deconstructing-compass-pathways-phase-2b-results) here).

In terms of the headline findings, 37% of those in the 25mg group

Search
were responders at week 3, which (as the paper points out) “is
lower than that described for first-line treatment of major
depressive disorder in several large trials of citalopram”, and Stock Quotes

other conventional antidepressants. This figure is higher, though,

than second-line treatments (see the STAR*D trial ATAI $3.01
(USD) $0.03
atai
NasdaqGM
Life Sciences 1.01%
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314062/)).
But, we know that psilocybin would likely not be a first-line
CMPS
$10.00
(USD) $0.27
treatment; indeed, in this trial it was generally a third, fourth or COMPASS
NasdaqGS
Pathways 2.63%

fifth-line treatment.
MNMD
$2.66 $0.22
Beyond response, remission rates at week 3 were 29% in the 25mg (USD)
NasdaqCM 7.64%
MindMed
group. At week 12, 20% of this group were sustained responders.
This figure appears to be down from the one circulated in topline
CYBN
$0.4579 $0.0101 
results and touted by management, which was 24.1%
(USD) NYSE 2.16%

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Cybin
American
Inc.
(https://psychedelicalpha.com/news/psychedelic-bulletin-
Insights + Data +
deconstructing-compass-pathways-phase-2b-
results#:~:text=nearly%20a%20quarter%20(-,24.1%25,-)%20of%20pati
Quick Links
ents%20in). The reason, it seems, is because COMPASS decided Companies +
 Psychedelic Stocks &
(https://psychedelicalpha.com)
not to go with the definition of “sustained response that is
Companies (/psilocybin-
consistent with other TRD studies” when publishing the trial in a Psychedelic Careers
stocks-shroom-stocks)
peer reviewed journal, instead opting to use the protocol-defined  Latest Psychedelic Stock
definition. News (/news)
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Remember: we’re only looking at 12 week follow-up data here. (https://jobs.psychedelicalpha.com/

Results from longer-term follow-up with these patients will be  Follow us on Twitter

critical. Establishing the durability of the psilocybin therapy’s (https://twitter.com

/Psyched_Alpha)
effects will determine the clinical and health economic utility of
the treatment.
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Head-to-head trials comparing psilocybin therapy to existing

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protocols, such as CBT, will also be important endeavours. NYU’s
Rick Zeifman noted that (https://twitter.com/RickZeifman/status
SI GN UP
/1587944245268193289) CBT has been shown to have a 26 %
remmision rate in TRD patients at a 12-month follow-up, for
example.

Achieving sustained remission in 20% of patients is certainly

promising, given the treatment-resistant nature of the
participants’ diagnoses. But, is it the blockbuster result that many
had hoped for?

“The findings were positive, but not what I could call

‘spectacular’, UCL’s Dr Ravi Das told Science Media Centre
(https://www.sciencemediacentre.org/expert-reaction-to-phase-
iib-clinical-trial-of-single-dose-psilocybin-for-a-treatment-
resistant-episode-of-major-depression/). Das takes issue with
the uneven proportions of severely depressed people in different
arms of the experiment, noting that there were “significantly
fewer severely depressed people in the apparent ‘effective’ (25mg)
dose group”, which is not addressed in the paper. Dr. Matthew


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Johnson dismissed the critique (https://twitter.com

Insights + Data +
/Drug_Researcher/status/1587937887420829697), suggesting it’s
not significant.
Companies +
Last year, upon publication of the topline results from this trial,
(https://psychedelicalpha.com)
the company’s stock took a serious tumble, presumably due to
Psychedelic Careers
investors’ perception of these results as lacklustre, especially
when coupled with adverse events.
Contact

On that topic, we discussed and contextualised adverse events in

our deconstruction of the initial results
(https://psychedelicalpha.com/news/psychedelic-bulletin-
deconstructing-compass-pathways-phase-2b-results), but since
this peer-reviewed publication a number of experts have come to
the fore to discuss the matter once again.

Dr Natalie Gukasyan started an interesting discussion on Twitter

(https://twitter.com/N_Gukasyan/status/1587927092510961666)
around how adverse events are defined in the context of
psychedelics, and how we can understand their significance in a
relatively small sample of people with TRD. Gukasyan supposed
that higher rates of suicidal ideation, for example, might be
reflective of the desperation seen in patients who didn’t respond
to the treatment, especially given the amount of hype around
psilocybin for depression. As Johns Hopkins’ Sandeep Nayak
notes (https://twitter.com/sdpnayak/status
/1587934158554177537), supplemental data showed that the 3
patients that displayed suicidal behaviour in the 25 mg group
were all non-responders, supporting this thesis.

We do glean some additional information from this publication.

Notably, we learn more about what COMPASS means by
“psychological support”, a phrase that the company prefers to use
as opposed to “therapy”. Some have suspected that COMPASS
will seek to achieve reduced labour intensity in its protocol vs.,
say, MAPS’ MDMA-assisted therapy for PTSD which sees two


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therapists engaging with patients at each session.

Insights + Data +

The publication sets out the number of sessions and the

therapist:patient ratio at each. At least three preparatory Companies +
meetings between one therapist and(https://psychedelicalpha.com)
the patient take place prior
to the psilocybin session. During the 6-8 hour psilocybin session,
Psychedelic Careers
the lead therapist (who engaged with the patient during the
preparatory sessions) is accompanied by a second therapist. After
Contact
the psilocybin session, participants receive two integration
sessions with the same two therapists. Here, therapists were
instructed to avoid actively guiding participants; but rather to
remain “open and supportive”. 

Of course, one arm of COMPASS’ Phase 3 program will evaluate

two doses of COMP360 psilocybin, which will increase the
number of therapist hours (and thus costs) associated with the
protocol. But, the company will hope that this additional may
boost the portion of sustained responders.

The publication is accompanied by an editorial from Dr. Bertha

Madras (https://www.nejm.org/doi/full/10.1056
/NEJMe2210975), who expresses a broad range of concerns
surrounding the trials and potential roll-out of psychedelic
therapy. Some readers won’t be too surprised here: Madras has
been a prominent critic of marijuana policy reform, claiming that
(https://www.dana.org/article/drug-facts-week-interview-
bertha-madras/) marijuana is profoundly dangerous if used for
non-medical purposes. Notably, she served as deputy director for
demand reduction for the Office of National Drug Control Policy
under George W. Bush.

In this editorial, Madras expresses concern with the standard of

evidence in trials (which may be compromised by expectancy
bias, selection bias, etc.); the efficacy displayed in these trials; the
ability to scale up psychedelic therapy while retaining fidelity to
the protocols used in clinical trials; and, concerns around


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“unregulated clinics” and a broader push to increase access to

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psychedelics.

While some of Madras’ points are valid (notably, those on the Companies +
pitfalls of psychedelics clinical trial (https://psychedelicalpha.com)
designs and the difficulties
that will present themselves when these protocols are to be scaled
Psychedelic Careers
up and rolled out to broader patient populations), it is our
opinion that others are unreasonable.
Contact

For example, Madras expresses concern that we may see a

proliferation of “unregulated clinics, as has happened with
ketamine clinics.” Ketamine clinics have been able to operate
with relative ease due to the fact that they’re using ketamine off-
label. Psychedelics, if and when approved by the FDA, will
almost certainly be subject to strict Risk Evaluation and
Mitigation Strategies (REMS) which will stipulate many elements
of how they are prescribed and delivered, and to whom. This
would make “unregulated” practices, akin to ketamine clinics in
Madras’ example, untenable. Oddly enough, Madras explains
this in the sentence which immediately precedes her comparison
to ketamine clinics. 

Specifics aside, this Phase 2b trial leaves us all with many

questions. Now, as explained in our mid-October Bulletin
(https://psychedelicalpha.com/news/psychedelic-bulletin-120-
beckley-psytech-acquires-eleusis-a-look-at-compass-phase-
3-design-new-psychedelic-drug-dev-scoops-22m-series-a), the
company will attempt to answer some of the most pertinent
questions in its ambitious Phase 3 program.

TAGS: COMPASS PATHWAYS (HTTPS://PSYCHEDELICALPHA.COM/NEWS/TAG

/COMPASS-PATHWAYS)

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