On the last day of 2021, we’re sending out a bulletin that touches on developments from the past fortnight in the psychedelics space.
We’re busy wrapping up our 2021 Year in Review, which we will begin publishing next week. It’s quite a lengthy piece that we’re excited to share with you all in a number of weekly releases. It will be followed by a piece that outlines some of the trends and key events we’ll be keeping an eye on in the New Year.
Psychedelic Sector News
FT-104: A Goldilocks Molecule? Field Trip Patent Application Reveals Nature of Company’s Lead Candidate
Like many psychedelics companies, Field Trip has sought to diversify itself across a number of different business areas (or, ‘value chain’ locations). As such, while many view the company as primarily operating in the clinics space, Field Trip has been keen to point to its drug development efforts, too.
Recap: What’s FT-104?
These drug development efforts are housed in Field Trip’s Discovery unit, with FT-104 being the first molecule under development.
Field Trip has previously described FT-104 as a prodrug of a synthetic 5-HT2A agonist, with a binding affinity similar to that of psilocybin. However, the company claimed that FT-104 should be expected to produce a “reliably shorter duration of psychoactivity” than psilocybin, in the region of 2-3 hours.
In September, the company announced treatment resistant depression (TRD) and postpartum depression (PPD) as lead indications for FT-104, the former of which is the focus of COMPASS Pathways’ drug development efforts, among others.
Despite these qualitative claims about FT-104, which led to some educated guesses, little was known about it. That all changed yesterday.
Patent Filing Reveals Nature of FT-104
Last week, many people woke up on Christmas morning to unwrap gifts, presumably finding a welcomed gift inside. That’s not always the case, though: sometimes what lies beneath the festive wrapping paper and tacky plastic bow is a gift that comes as a surprise, or one that’s distasteful or unwanted.
In the case of Christmas, this anticipation is an annual affair. For patent nerds, however, every Thursday approximates this experience as patent applications publish on the USPTO’s web portal. When these applications publish, it’s often the first time we get to fully unwrap the box and see inside (at risk of stretching this tenuous metaphor far beyond its utility: perhaps you can imagine companies discussing their patent filings prior to publication as being similar to a situation where someone tells you, broadly, what gift they have acquired for you. You have a general idea, and you may even be able to pick up the wrapped gift and give it a shake in an attempt to verify their claims. But, it’s not until you unwrap that gift that you can see every detail).
Yesterday’s ‘drop’ was a little thin on the psychedelics front, with Psilocybin Alpha’s eagle-eyed editor-at-large Graham Pechenik sharing a number of U.S. filings of note. Field Trip’s filing, however, lifts the shroud of secrecy from FT-104.
In a patent application titled Tryptamine Prodrugs, Field Trip claims prodrugs of a number of tryptamines and isotryptamines, with the primary focus being 4-HO-DiPT.
While the application doesn’t mention FT-104 anywhere, Pechenik correctly deduced that the molecule was, indeed, the subject of the filing. This was confirmed when Founder Ronan Levy tweeted on the matter a number of hours later.
The patent application itself covers use in treatment (of mental disorders including depression) of 4-HO-DiPT prodrugs, including via subcutaneous injection or oral tablet administration.
See Graham Pechenik’s thread for more information on the patent filing and 4-HO-DiPT, including a number of figures from the filing.
As aforementioned, Field Trips’ Ronan Levy confirmed that FT-104 refers to a prodrug of 4-HO-DiPT via Twitter: “It’s a more soluble form of 4-HO-DIPT, one of Shulgin’s favourite tryptamines.”
Levy went on to quote Shulgin, who said of 4-HO-DiPT: “I truly doubt that there is another psychedelic drug, anywhere, that can match this one for speed, for intensity, for brevity, and sensitive to dose.”
We won’t get too into the chemistry of this synthetic psychedelic, but it’s worth noting that its subjective effects are reportedly similar to those of other serotonergic psychedelics like psilocybin and LSD. That’s not surprising, given that it’s a tryptamine and a homologue of psilocin.
As alluded to, what differentiates 4-HO-DiPT, and presumably FT-104, is the brevity of the subjective effects it induces.
This fits into a broader trend we’re seeing whereby psychedelic drug developers are seeking to identify and develop shorter-acting psychedelics.
The primary motivation for this is to allow psychedelic-assisted therapy to become more congruent with the current standard of care for mental health disorders, which often includes talking therapy sessions that last for around an hour and are spread across a number of months or years.
Psychedelic-assisted therapies, meanwhile, can take the better part of a full day, which is cost- and labour-intensive, and is perhaps more akin to a procedure (such as a surgery) than traditional psychotherapy.
Noticing this potential benefit of 4-HO-DiPT, in TiHKAL Shulgin wrote:
“To be on a trip and then to be back pretty much in two hours and really baseline in another hour? Most unusual. If there will ever be an acceptance of drugs such as these, in a psychotherapeutic context, a short duration is of extreme value to both the patient & the therapist.”
A 2-3 hour trip is certainly not as short-acting as the drugs under development by other companies (like GH Research who are looking at 5-MeO-DMT, for example), or as the ketamine therapy currently administered by Field Trip at its clinics.
As such, FT-104 might represent a middle ground (or, “just right,” as Goldilocks exclaimed) between the lengthy, but apparently effective, psilocybin- and MDMA-assisted therapies and a new wave of incredibly short-acting (or even non-hallucinogenic entirely) psychedelics.
But, it’s not all rosy. Psychedelics of the DiPT class exert their effects in a primarily aural way, with some reporting that music can become less harmonious and more dissonant. We wonder how this might affect the decisions Field Trip might eventually make around set and setting in its clinics, should FT-104 make it that far. Music playlists are carefully curated in psychedelic-assisted therapy, so these aural distortions may add another layer of consideration to this process.
Writing in TiHKAL, Shulgin also reported that 4-HO-DiPT had a tendency to induce tremors.
Interestingly, 4-HO-DiPT is not scheduled at the federal level in the U.S. (though at least one state, Florida, has scheduled the substance), though DiPT-based psychedelics could be construed as analogs of 5-MeO-DiPT which would criminalise possession, purchase or sale of the drug under the Federal Analog Act.
Regarding patentability, we’d note that Field Trip filed its application “Track One” and is receiving prioritized examination. Hence, although the U.S. non-provisional application was only filed on July 30, 2021, it’s already received one substantive office action, to which Field Trip has already replied (the U.S. prosecution documents are available here). After amending the claims to exclude certain unsubstituted compounds alleged to be in the prior art, it appears that at least some claims to FT-104 will be allowed. We also note that another Field Trip application, claiming the benefit of a different U.S. provisional application, and filed on October 1, 2021, is currently pending in Canada: CA3132847, entitled “Rapid-Acting Hallucinogenic Compositions and Methods”, and said to cover “rapid-acting formulations of hallucinogenic drugs that contain excipients which modify pharmacokinetics”.
TL;DR: The shroud of mystery surrounding Field Trip’s FT-104 molecule is finally lifted. We now know that FT-104 is a prodrug of 4-HO-DiPT, a tryptamine that Shulgin spoke highly of. Importantly, 4-HO-DiPT has a relatively short duration of action at around 2-3 hours, which might make it more attractive (or, manageable) for use as a catalyst to psychotherapy.
Research that Formed Backbone of Fresh COMPASS Pathways Patent Challenge Published
In our last Bulletin, we covered a challenge to COMPASS Pathways’ “infamous” Polymorph A patent, which covers a crystalline composition of psilocybin. Make sure to (re-)read that issue for fuller context on the below. (Since then, a second post-grant review was filed by FTO, to challenge COMPASS’ ’259 patent, which issued the same day as its ’257 patent challenged in the first PGR.)
Since then, new research has been published detailing crystallographic discoveries that Usona Institute claim “bring new clarity to pharmaceutical psilocybin polymorph characterization.” In a press release that avoids mentioning COMPASS explicitly, the nonprofit described the “breakthrough research” that it claims “conclusively shows that three psilocybin polymorphs repeatedly occur from the well-known crystallization process and that they have appeared in numerous places throughout the history of synthesizing psilocybin since 1959.”
The press release goes on to suggest that “recently granted patents,” no doubt referring to COMPASS Pathways’ patents covering crystalline psilocybin mixtures, be revised.
This research, published last week, forms the backbone of the aforementioned post grant review filing by non-profit Freedom to Operate, which seeks to challenge a COMPASS Pathways patent.
CaaMTech CEO Andrew Chadeayne weighed in on the publication via Twitter. Responding to a Tweet that asked, perhaps rhetorically, “Does Compass’ “Polymorph A” not actually exist?,” Chadeayne confidently stated: “Yes. It looks like Polymorph A (or Form A) exists[,] along with several other crystalline forms of psilocybin.” Chadeayne goes on to explain that, “from what I can tell, the issue is that COMPASS Pathways made a mistake in concluding that they had a single, pure crystalline form– when they really had a mixture.”
Musical Chairs at MindMed: FDA Halts Trial; Changes at the Top
The FDA has issued a clinical hold on MindMed’s Phase 2b trial of LSD for generalised anxiety disorder, effectively pressing pause on the program. Details are characteristically scarce, but further action from the FDA should be provided by the end of January 2022.
The company also announced that Director and Chairman of the Board, Perry Dellelce, has stepped down from his role, and both the Chief Technology Officer and Chief Scientific Officer are leaving their posts.
The stock price continues its steady decline.
Bloomberg’s The Dose: Opiate Alternative Kratom Spurs Investor Interest
While the U.S. has been trying to ban kratom for years, a recent decision by the World Health Organization is being heralded as a win by its advocates. Read more in Bloomberg’s The Dose newsletter.
Reminder: atai Life Sciences’ Kures program is investigating deuterated mitragynine (the most abundant active alkaloid in the leaves of kratom) for opioid use disorder.
UK Regulator Issues Guidance on Real-World Data
The UK’s Medicines and Healthcare products Regulatory Agency (MHRA), the country’s equivalent of the FDA, has published new guidance on the use of real-world data (RWD) to support clinical trials.
What’s RWD? Find a note on RWD and Real-World Evidence (RWE) from Psilocybin Alpha’s Pharmaceutical Advisor, Michael Haichin in our July 9th issue.
At present, RWD is primarily used to monitor the safety of drugs and devices post-approval, but is rarely employed to demonstrate efficacy during clinical trials. This new guidance from the MHRA seeks to provide clarity on the regulator’s expectations around the quality of RWD for a variety of use cases, including where it’s used to support the planning of clinical trials or a regulatory submission.
MHRA Chief Executive Dr. June Raine explained that the guidance is intended to help drug developers employ RWD and RWE in ways that might make it “more feasible for trial sponsors to repurpose existing medicines for new conditions,” and address a “growing need to find more cost-effective ways of conducting clinical trials”, which regularly exceeds £1m in the UK.
A whole host of psychedelics companies are seeking to employ real-world data to augment their drug development efforts: from the larger companies like COMPASS Pathways (via collaboration with an NHS Trust) and MindMed (via agreements with companies like Forian) through to smaller players like Albert Labs.
UK-based psychedelics companies such as Clerkenwell Health have welcomed recent changes to the UK’s drug development regime in the wake of Brexit. More on this in our forthcoming Year in Review.
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