Posts Tagged "Gilgamesh"

The Summer 2024 issue of NeuroPerspective has been released. It features three comprehensive therapeutic area reviews: Psychedelics, Epilepsy, and Frontotemporal Dementia.

1) There is no area of neurotherapeutics that combines promise and controversy in the same measure as Psychedelics, a novel class undergoing rapid developmental transformation. Recently, the most salient drama has involved the utilization of MDMA for PTSD. MAPS had successfully completed its second PhIII trial of MDMA in PTSD, and then spawned Lykos Therapeutics as its for-profit component. But Lykos recently had all the wrong headlines generated by its awkward encounter with the FDA’s ADCOM, a Committee which lost track of its priorities and the Agency’s scope of activity, neither of which include regulating psychotherapy, an integral component of the Lykos treatment package. The ADCOM bogged itself down with the thorny issues of functional unblinding and abuse risk, the Agency has little to offer about the former, but ample ability to reduce the latter, via a stringent REMS protocol. We suspect that the FDA’s PDUFA date of 8/11/24 may be extended, as the Agency seeks to find a resolution that would address the concerns of the ADCOM without sacrificing the patients, and the SPA in place since 2017. But in the meantime, the psychedelics field has taken a hit, the fear raised that the FDA will place unreasonable obstacles in their path. This is unfortunate, because tangible clinical progress is being made elsewhere: Compass Pathways is conducting two PhIII trials of psilocybin in Treatment-Resistant Depression; Cybin has had promising pilot data in MDD; MindMed had a successful trial of LSD in GAD; and the pace of clinical trials by companies like Gilgamesh, Beckley, GH Research, Reunion, and Atai,  is accelerating.

The other major trend of note is the psychoplastogen category, those companies who believe the therapeutic Grail is to be found in enhanced neuroplasticity, with hallucinations an unnecessary side show that can be parsed out.
AbbVie recently partnered with Gilgamesh on a psychoplastogen program, and several pharma companies have told NIR they are waiting for Delix to generate efficacy data, though formal PhII results will not come until 2026.

This review assesses over fifty companies, including Atai, Compass, Gilgamesh, Otsuka, Beckley Psytech, Cybin, Enveric, GH Research, Lykos, Reunion, and MindMed. Psychoplastogen programs, from companies like Delix, Psilera, AbbVie/Gilgamesh, Intra-Cellular, and more, are also included. The Summer issue includes a revised and updated commentary (“The Blind Leading the Unblinded’) on the Lykos NDA dilemma.

2) The second featured review covers Epilepsy, where progress is being made in addressing the sizable population (over 30% of patients with epilepsy) of Treatment-Resistant Epilepsy, and in the pursuit of genetically linked rare epilepsies like Dravet, Lennox-Gastaut, CDKL, and Tuberous Sclerosis. GABAergic tactics have long been a mainstay, albeit with significant side effect issues: Next-generation compounds are hoped to improve the risk-benefit ratio, with AbbVie/Cerevel’s darigabat in the lead,  Ovid and Saniona have earlier stage candidates. Ion channel targets are perhaps the hottest target area: Xenon/Neurocrine, Neuro3, and Praxis are among the companies pursuing sodium channel targets; potassium channels are the venue for programs from Xenon, Biohaven, Saniona, and Autifony.

Dravet Syndrome is the most heavily pursued DEE (Developmental and Epileptic Encephalopathy): Stoke Therapeutics is well underway targeting mRNA for mutant Nav1.1/SCN1A, and while the AE profile is not pristine, the data thus far have been impressive.  Longboard is going into Phase III with bexicaserin, as a safer Fintepla. While Eisai has Arena’s predecessor molecule, lorcaserin, well into PhIII for Dravet, it is unlikely to offset safety (cancer) concerns around lorcaserin, which had been withdrawn from the obesity market. Now, Harmony has clemizole (from Epygenix) in a PhIII as well. Neurvati’s subsidiary GRIN Therapeutics is testing radiprodil in a GRIN subpopulation.

Marinus’ IV ganaxolone produced a dramatic impact on patients with Refractory Status Epilepticus, which should outweigh concerns raised about the lack of clear benefit on the co-primary endpoint.

3) The third therapeutic area reviewed is Frontotemporal Dementia, a multi-faceted, heterogenous diagnostic category that includes subgroups with TDP-43 pathology, others where tau or c9orf72 aggregates are emphasized.  It is the progranulin mutation subpopulation that is seeing some of the most promising work presently underway in neurodegeneration: The therapeutic candidates include a biologic from GSK/Alector, small molecule progranulin enhancers from Vesper Bio and JNJ/Arkuda, and gene replacement programs from Prevail/Lilly and Passage Bio. FTD is also the first venue for Psilera’s neuroplastogen program.   

The Summer issue includes a succinct overview of Vesper Bio and coverage of significant clinical, fiscal, partnering, and regulatory events, including a very impressive 1H in terms of investor funding for CNS, which has matched the total invested in all of 2023. Among the higher profile developments are Puretech’s launch of Seaport
Therapeutics, Rapport Therapeutics’ IPO; positive depression results for Intra-Cellular, JNJ, and Neurocrine; and a unanimous ADCOM vote in favor of Lilly’s donanemab.

81 pages. 

NeuroPerspective is the quarterly review of the neurotherapeutics area that offers unique and comprehensive coverage of developments in the science and the business of the CNS sector. A one-year (1-5 user) subscription to NeuroPerspective is $3200. A 6-10 user subscription is $5450. Other customized userbase and startup pricing options are available. The Summer issue is being made available as a single issue purchase, US$900. To activate a subscription and download the new issue, go to https://www.niresearch.com/onlinestore.html.

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.