NeuroPerspective on Psychedelics, Epilepsy, Rett

The Summer issue of NP has been released, evaluating the areas of Psychedelic Therapeutics, Epilepsy, and Rett Syndrome.

1)Psychedelic Therapeutics were the sole focus of the March/April 2021 edition of NP, but no area has been evolving more rapidly, or received more media coverage, the latter imbued with varying degrees of superheated hype. This return to the topic assesses the state of this nascent area as a brief flood of resources for these companies has been sharply diminished, even as the data continues to come in validating the value of these treatments for some patients, in some disorders. The Compass PhIIb results illustrated the problem of submitting real data in the face of excessive expectations: That trial showed psilocybin to be a tool, not a panacea, creating durable improvement for about 25%, while having little impact on many others.

There are several tiers of companies, defined by both their science and fiscal resources. Atai stands out for its diverse plethora of psychedelic (and other) programs under its corporate umbrella (including Perception, DeMeRx), though there seems a risk of internal redundancy, with some three distinct subcomponents each pursuing novel psychedelic molecules. Compass Pathways stands out for its groundbreaking work on systematizing psilocybin therapy, including its core psychotherapeutic components. Whether it is blazing a path too easily followed by others is a separate but pertinent issue. MindMed‘s resources continue to outpace its corporate judgment, with an excessive reliance upon LSD programs that will never have wide applicability. Gilgamesh has a variety of intriguing programs, whereas GH Research has a singular focus on 5-MeO-DMT, and needs to use its resources to branch out. Cybin, Small Pharma, and Beckley Psytech also fall under the first tier category. The second tier includes smaller companies for the most part, with more limited resources: MindSet has achieved the first psychedelic partnership with a major company (Otsuka); Reunion is the new spin-out of Field Trip‘s research programs; CaaMTech, Eleusis, Terran Biosciences, Diamond Therapeutics, are just a few of the many others. There are companies determined to parse the therapeutic from the hallucinogenic, such as Delix. There are many micro-companies that are not going to survive, this Review considers 55+ of the more tangibly constituted.

Some very basic questions remain to be answered in this new field, including the overriding lack of clarity regarding the hallucinogenic, euphoric, dissociative core experiences associated with classic, empathogen, and dissociative (e.g. ketamine) classes of drugs–are they a necessary route to therapeutic benefit, or are they side effects that can be avoided without sacrificing efficacy? Our bet is on the former, but this will be confirmed (or not) by the data as it emerges.

2) The Epilepsy review evaluates progress in the two major areas of contemporary work in the area; programs for rare genetically determined epilepsies, such as Dravet Syndrome and Lennox-Gastaut Syndrome, which is going to be the testing ground for gene therapy for disease modification, via programs from Stoke Therapeutics and Encoded Therapeutics. The second area addresses novel approaches to sporadic epilepsy, with an eye towards the treatment-refractory patient population for whom current anti seizure medications have not provided sufficient control. The review includes 35+ programs, with particular attention to multiple programs from Xenon, as well as the utilization of more selective GABAergic molecules (e.g. Cerevel, Engrail) and neurosteroids (Praxis,Marinus).

3) Rett Syndrome is the third therapeutic area covered in the Summer issue. Rett Syndrome is an orphan disorder but is not rare, and even though the most common etiology is a monogenic mutation, Rett has shown the challenges of safely remediating even this kind of single gene target, for too much MeCP2 is as pathological as too little. This defeated the first gene therapy program from Novartis/Avexis, which had seemed promising. At this point, trofinetide from Acadia/Neuren is the most advanced treatment, the NDA should be filed soon, and should have no problem with approval.

Spotlight assessments are included for Engrail Therapeutics and Gilgamesh Pharma.

The Summer issue also considers the continuing dilemma posed by Biogen even as it finally moves on from Aduhelm; the mixed record of neurosteroids (e.g. Sage, Praxis, Eliem, Marinus) Cassava‘s deterioration; Centrexion’s disingenuous lack of basic disclosure, and more.

70 pages. The Summer issue of NP is being made available as a single-issue purchase for $750.