- 🧭 COMPASS Pathways Amends Phase 3 Program
- 🍄 Stamets Stack Finally Patented
- 🔮 Learning from Zuranolone
and lots more…
Psychedelic Sector News
COMPASS Pathways Amends Phase 3 Program
On its Q4 2022 Earnings Call, COMPASS Pathways executives shared an important update to the company’s Phase 3 program, which is made up of two Phase 3 trials of COMP360 psilocybin therapy for treatment-resistant depression (TRD). (For a refresher, see our overview of the company’s Phase 3 program, as originally announced, in Bulletin 120.)
Reduced Sample Size in COMP 005
Most notably, CEO Kabir Nath explained that the company will reduce the sample size of its COMP 005 study, the smaller of the two Phase 3 trials which compares a single 25 mg dose of COMP360 to a true placebo. Nath explained that the decision was made following further analysis of its Phase 2b data, as well as analysis of recent data from von Rotz et al. (2023), which “led to a re-estimation of the sample size for the COMP 005 trial and a revision to a lower expected response to true placebo”.
Based on these findings, the company will reduce its COMP 005 enrolment target from 378 participants to 255. This will bring forward the completion of the trial by one or two quarters, meaning a readout could be provided as early as summer 2024.
Streamlined Long-term Follow-up, Additional Doses for Non-responders
Nath also announced that the long-term follow-up element of the Phase 3 program will now be integrated into the two Phase 3 trials, COMP 005 and 006, as opposed to being separate trials. The company will hope that this will “reduce selection bias and the implementation burden on our patients and clinicians”.
Aside from the six-week, primary outcome analysis of each trial, which the company is dubbing Part A, COMPASS intends to follow patients for a year. This could provide valuable data on the durability of COMP360 therapy, as well as the potential utility of retreating patients after the initial treatment course.
Here, Nath explained Part B of the pivotal trials, which is the period between the six-week assessment (the primary endpoint) and week 26. COMPASS announced that, during this period, patients who “meet criteria for retreatment” will be offered further COMP360 therapy. This additional treatment will be the same as what they received in their original allocation, which could include placebo for those in COMP 005 (but, only one dose, even for those in COMP 006 in which Part A consists of two doses separated by three weeks). It is unclear what the precise criteria for this retreatment is, but Nath explained that the company, “will treat people who either do not remit or who relapse after remitting”. A COMPASS representative confirmed to Psychedelic Alpha that participants, “will be offered retreatment in Part B either if they haven’t remitted following their initial treatment (one initial administration in COMP 005 or two in COMP 006) or if they have remitted but then subsequently experience a depressive relapse.” The precise criteria may be a trade secret.
The period from 26 weeks to 52 weeks, then, is Part C: the open-label component. Here, patients who meet criteria for retreatment will be offered one 25 mg dose of COMP360. This is a common tactic to incentivise non-responding patients (especially those in lower or placebo dose arms) to remain in the trial.
COMPASS has submitted the changes to the FDA, who are expected to respond to the company’s COMP 005 protocol amendments by March 20th. Nath was keen to remind listeners that, “it’s routine to have an ongoing dialogue with the FDA as we conduct the trials, especially with our breakthrough therapy designation.” It’s also worth noting that these amendments are being tabled at a time when not a single participant has dosed in the Phase 3 program.
No Data from Anorexia Nervosa Trial in 2023
Aside from its Phase 3 program for MDD, COMPASS has a range of other programs in its pipeline. One such program, COMP360 for anorexia nervosa, was plastered on the front cover of Financial Times’ Weekend supplement last week: “Anorexia is the deadliest psychiatric disorder. Could psychedelics help?”, the magazine asked.
We might have to wait longer than anticipated for an answer to that question, however. On the earnings call, Nath explained that given the dearth of evidence in the area, “we are on a steep learning curve.” He explained that the company has learned that it needs to, “make amendments to [its] protocol to better meet the needs of this highly vulnerable patient population.”
As such, COMPASS has backpedalled its expectation of topline data in 2023.
FTO Challenge Further Denied
In response to a question regarding IP updates, Nath provided an update on the post-grant reviews that challenged COMPASS’ 10,947,257 and 10,954,259 patents. As we reported last summer (Bulletin 108), COMPASS survived post-grant reviews (PGRs) from Freedom to Operate (FTO), a non-profit group founded by Carey Turnbull. After institution of FTO’s PGRs was denied, FTO filed requests for rehearing along with requests for Precedential Opinion Panel (POP) review. According to Nath, the USPTO Board denied the requests for POP review on February 10, 2023; the requests for rehearing remain pending.
Stamets Stack Finally Patented
As reported by our Editor-at-Large Graham Pechenik over on Twitter, it appears that a years-long effort “across multiple applications [and] several appeals” has resulted in success for Paul Stamets.
US Patent 11,590,120, which covers combinations of psilocybin and lion’s mane extract, alone and with niacin, has been issued. This combination is colloquially referred to as the ‘Stamets Stack’, which is now the subject of a drug development push by Stamets’ MycoMedica Life Sciences, which secured $60m in funding last summer.
Stamets’ ’120 Patent issued from one of at least ten child applications that sprouted from a first provisional application filed on July 23, 2016. Stamets’ composition claims originally fared poorly with examiners, accruing “§ 101” rejections for being “patent ineligible” naturally-occurring products, as nothing more than a combination of compounds all naturally present in Psilocybe and lion’s mane mushrooms (failing the patent office’s “markedly different characteristics” test).
Stamets appealed these rejections to administrative patent judges several times; in each case, the examiner’s rejections were affirmed (“the claims merely recite a mixture of individual naturally-occurring components, and nothing else additionally”).
In the application leading to the ’120 Patent, Stamets ultimately persuaded the examiner that his claims were to more than natural products, by amending them to recite “pharmaceutical formulations” and “pharmaceutical dosage forms” (these “are not natural phenomena” and “distinguish the claims from a mere assembly of natural products”), and by submitting an affidavit demonstrating that the combination of compounds “provides a synergistic effect that is not expected based on what is known in the prior art,” and is thus “markedly different from the naturally occurring components.”
Subsequently, after six and a half years and four Requests for Continued Examination (RCEs), a patent with composition claims covering the “Stamets Stack” finally issued. Numerous other Stamets’ applications remain pending, including one with claims on the use of psilocybin or psilocin alone to reduce symptoms of depression or anxiety (in which Porta Sophia filed a third-party submission of prior art last May).
Learning from Zuranolone
Sage Therapeutics’ major depressive disorder (MDD) and postpartum depression (PPD) drug, zuranolone, is expected to receive an approval decision from the FDA on August 5th.
In the meantime, Sage and its partner Biogen have been hammering out a commercial strategy that they hope will enable the rapid roll-out of the drug, which has a protocol characterised by short-term, episodic dosing.
Zuranolone is not a psychedelic. It’s a neurosteroid that acts as a positive allosteric modulator of the GABA-A receptor, which is the target of a variety of drugs including alcohol and benzodiazepines. Given this fact, it’s subject to scheduling by the DEA which will take place after any approval by the FDA.
But, that’s not where the similarities to potential psychedelic drug products end. Pivotal studies of zuranolone demonstrated rapid relief from depressive symptoms from a two-week, once-daily course of treatment, with Sage planning to allow for the drug to be administered on an as-needed basis.
As such, zuranolone’s intended treatment regime is more interventional, as opposed to the chronic, daily dosing regime seen in standard of care treatments like SSRIs and other oral antidepressants. This is similar to the interventional nature of psychedelic therapies, and acknowledges the often episodic nature of depression.
Given this focus on rapid-acting, short courses of treatment, Sage’s challenge is more than just commercialising another daily oral antidepressant such as Axsome’s Auvelity (which, it should be noted, is relatively rapid-acting). Rather, Sage and Biogen will have to steward a new way of how prescribers, payors and other Key Opinion Leaders think about depression and its treatment.
Given the fact that zuranolone would be offered as a two-week treatment course, it has an entirely different monitoring profile to longer-term SSRIs, too. In this more acute treatment paradigm, regular check-ins with patients might be more appropriate in both identifying response to the treatment course and intervening when a trend toward relapse is identified. This challenge is top-of-mind for many psychedelic drug developers, with COMPASS Pathways hoping to engage in this longer-term monitoring—and potential retreatment—of patients, too.
Given the fact that oral antidepressants like SSRIs can take weeks or months to have an effect, if any, Psychedelic Alpha readers will be well aware that there’s ample appetite among practitioners for rapid-acting depression drugs. But, products like Janssen’s Spravato (esketamine) nasal spray have failed to meet blockbuster drug expectations due to unfamiliar and logistically challenging administration and monitoring protocols, mixed clinical trial records and high costs; especially when compared to low-cost, orally administered take-home generic drugs that have been dominant in the treatment of depression for the better part of a half-century.
In a psychedelic drug market that’s absent any true comps, we’re adding zuranolone to our list of drugs to watch*. In particular, the elements of zuranolone’s roll-out plan that might be most informative to psychedelic drug sponsors include:
- How will payors evaluate and cover this different treatment paradigm? Will they insist on value-based models such as covering the large upfront cost of treatment on the basis of shared risk with the drug manufacturer, who would be required to reimburse them some amount if a patient requires retreatment earlier than anticipated?
- Given mixed clinical trial data on the matter, how will zuranolone perform in patients taking other antidepressants, particularly SSRIs?
- What will durability of effects look like in the real-world, and how will payors and practitioners deal with potential trade-offs between the drug’s fast-acting nature and durability?
- With short courses of treatment and potential scheduling, how will the difficulty of providing samples to physicians limit Sage’s ability to change prescribing habits from the current standard of care?
- Taken together: will zuranolone successfully carve out space in a crowded market dominated by cheap, easy-to-prescribe generics?
If Sage and Biogen are able to change the way prescribers and payors think about the treatment of depression, they may lay some of the conceptual groundwork for future psychedelic therapies. With zuranolone expected to come to market in late 2023, we will be watching closely to see how it fares.
* This list might resemble a ‘Frankenstein’ of comps that resemble psychedelic therapies to varying degrees, including Spravato, ketamine therapy, TMS, etc.
Synthesis Institute Appears to Be in Distress
Synthesis Institute is in serious financial distress, according to Tweets from current students and others close to the matter.
The company operates a psilocybin facilitator training program in Oregon, where it hoped to open a service center, along with retreats in the Netherlands.
This is a developing story.
Transcend Therapeutics Raises $40m Series A
In the largest psychedelic company raise of the year thus far, New York based Transcend Therapeutics has scored a $40m Series A led by Alpha Wave Global and Integrated.
The company is developing methylone for PTSD, and expects to launch multiple clinical trials off the back of this financing. Its first US patent application, filed under Track One, and covering methods of treatment with methylone, published on February 23rd as US20230054211A1 (coincidentally timed with the receipt of its first Office Action); a twin PCT application had published on February 9th.
Layoffs at Psychedelics Companies
A number of psychedelics companies have laid off staff in 2023, with Cybin becoming the latest to publicly announce lay-offs amidst a “streamlined clinical alignment” process. Around 15% of the company’s workforce were made redundant.
We’re hearing of lay-offs at a number of other psychedelic drug developers, too.
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Business Trip Podcast: The 2023 Psychedelic Industry Landscape with Psychedelic Alpha
In this week’s episode of Business Trip, Greg and Matias chat with Josh Hardman, the founder of Psychedelic Alpha.
Josh is a leading writer and founder at Psychedelic Alpha, an online resource, newsletter, and community covering the intersection of psychedelics and business. He regularly collaborates and writes with experts in the psychedelic field including entrepreneurs, academic researchers, non-profits, and more to provide a comprehensive understanding of the latest developments in the industry. Psychedelic Alpha recently released Psychedelics 2022: A Year in Review to comment on and analyze the industry across research, funding, and policy.
Do Mice Hallucinate? Do Humans Head-Twitch?
- How to fold Indigenous ethics into psychedelics studies. Science.
- Wall Street Backs a New Class of Psychedelic Drugs. WSJ looks at short-acting and non-hallucinogenic psychedelics drug developers, from Transcend and Gilgamesh to Small Pharma.
- Psychedelics Are a Promising Therapy, but They Can Be Dangerous for Some. The New York Times.
- Anorexia is the deadliest psychiatric disorder. Could psychedelics help? Financial Times.
- Do Psychedelics Demand an Innovative Approach to Patents? Shayla Love for Lucid.
- The Promise and Perils of Psychedelics. NEJM’s Intention to Treat podcast speaks to Roland Griffiths.
- ‘Mystical’ experience using psychedelics may improve mental health, study reveals. The Independent.
- Psychedelics may help people reinvent themselves. UC News speaks to Neşe Devenot about a new look at a 2014 psilocybin for smoking cessation study, which she co-authored.
- A Tale of Two Strategies: Does COMPASS Have the Right One? Matt Zorn for Lucid.
- This is your brain on psychedelics. POLITICO.
- I Got a Tour of the First Psychedelic Therapy Clinic in Britain. VICE.
- Where Did 2022 Take the Psychedelic Medicine Field? Josh Hardman for Lucid.
- Virtual reality plus psychedelics are being trialled in therapy. Are they effective? ABC News profiles Enosis Therapeutics.
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