NeuroPerspective has released its Fall 2024 issue, featuring our annual comprehensive review of Alzheimer’s, as well as of Anxiety and TBI. Our Alzheimer's review appraises the current, minuscule impact of the commercial advents of Eisai/Biogen’s lecanemab and Lilly’s donanemab. They are more similar than different, providing barely (if that) perceptible slowing of disease progression and a rare but not inconsequential risk of ARIA, that may prove to be deadly for .5-1% of patients, a seemingly small percentage that would translate into very noteworthy casualties given the size of the patient population. Other amyloid mAbs, including Lilly’s remternetug and programs from Acumen, AbbVie, and ProMIS hope to improve the risk/benefit profile, via augmenting anti-amyloid impact and/or reducing the risk of ARIA. But they are still three or more years away from potential approval. Hopes for tau as a target for monoclonal antibodies have been largely dashed due to limited BBB access and even less, if any, intracellular access. There are active vaccine and antibody fragment programs that hope to improve on the original mAb legacy. The most promising programs appear to be in the neuroinflammation and cellular waste disposal categories. The neuroimmunological space has just started to mature, with clinical stage programs underway from Alector/GSK and Alector/AbbVie. This type of midstream focus offers the prospect of disease modification without having to precisely identify the upstream molecular culprit that initiates the disease process. However, the popular TREM2 target appears linked to ARIA as well. There is also a slew of small companies whose programmatic execution has been sloppy and their hyperbole excessive, with Cassava, Anavex, and Annovis prominent in that group, Cognition Therapeutics and Athira having recently flamed out. Among the 200+ programs assessed are those from: AbbVie/Alector, AC Immune, Actinogen, Advantage, Alnylam, Allyx, Anavex, Athira, Attralus, Biogen, BMS, Casma, Cognition Therapeutics, Cyclerion, Eisai/BioArctic, JNJ, Lexeo, Lilly, Merck, Monument Bioscience, Muna, Myrobalan, Neumora, Neurocrine/Nxera, ProMIS, Prothena, Roche, Takeda, Therini, and Vigil. The issue also includes a full review of Anxiety, where the pervasive prevalence of the disorder has far eclipsed the paltry resources devoted to bettering the limited generic options currently available. More selective GABAergic programs are underway at AbbVie/Cerevel and Engrail, with public speaking models serving as proxies for Social Anxiety in trials being conducted by Bionomics and Vistagen. Psychedelics are being developed for GAD by MindMed and Cybin. CRF antagonism has been revived by HMNC. The third therapeutic area reviewed is TBI, another high-prevalence disorder with little available therapeutically, and with Biogen having exited, the developmental candidate roster has shrunken still further. SanBio has obtained provisional approval in Japan for its cell therapy, the potential of ibogaine as a TBI treatment is being explored by Soneira. The Fall issue includes an overview of Gain Therapeutics, focused on Gcase enhancement in the treatment of Parkinson’s. The Psychedelics Update section critically reviews the FDA’s mishandling of the Lykos Therapeutics application for the use of MDMA in PTSD. As always, there is coverage of significant clinical, fiscal, and partnering events. 112 pages. NeuroPerspective is the quarterly review of the neurotherapeutics area offering essential, 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 Fall issue is being made available as a single issue purchase, US$900.

NeuroPerspective has released its Winter 2025 issue, featuring our comprehensive Review of 2024 and Preview of 2025 for the neurotherapeutics area. In terms of 2024, the availabilities of Eisai/Biogen’s Leqembi and Lilly’s Kisunla constitute a dress rehearsal, for the eventual availability of genuinely impactful disease-modifiers for Alzheimer’s. The risks are more easily quantified than their benefit, which we believe will be captured by the modal familial assessment:’ I can’t tell if it’s helping or not.’ Otherwise, disease-slowing in neurodegeneration is still a work in early process, with yet-to-be-validated research in neuroinflammation and protein clearance standing out. We had been anticipating 2024’s PhII readouts from AbbVie/Alector in Alzheimer’s, and Roche/Prothena in Parkinson’s, and while both studies failed, Roche and Prothena believe some signal was seen in the latter. FTD-GRN may be the next high-profile context for disease-modifier development, with GSK/Alector producing important results at year-end or early in 2026. Programs from Vesper Bio, Takeda/Denali, Astellas, Passage Bio, and Arkuda/JNJ are earlier stage. The highest level drama in neurotherapeutics is coming from Psychiatry. The Winter issue explores the dfferences between some of the muscarinic compounds in pursuit of BMS/Karuna’s Cobenfy, in light of the failure of AbbVie/Cerevel’s emraclidine in schizophrenia and Neurocrine’s PhII positive findings. We continue to believe that, over the next two to four years, the clinical practice of Psychiatry is going to be revolutionized, first in schizophrenia, but then in depression. The failure of Neumora’s first PhIII for navacaprant, and Alto’s PhII for ALTO-100, are a reminder that the barrier to entry remains quite high, but several programs are going to report results this year, including JNJ and Autobahn. Other areas where significant progress has been made include severe epilepsies, with PhII success reported for Lundbeck/Longboard’s bexicaserin, and for the lead assets from Neurvati/GRIN Therapeutics and Praxis Therapeutics. Despite the very skimpy funding available to novel pain therapy programs, Vertex’s VX-548 appears on track to approval as a useful nonopioid acute pain option. 2024 saw the inevitable failures of some neurodegeneration programs based on fictitious (Cassava and Athira) or dubious premises (Annovis), though developer denial is still in full stride for the latter. The Winter Issue includes our customary ‘Psychedelics Update’, as that sector encounters resistance from regulators ill-equipped to assess therapeutics that rely so heavily upon synergistic combinations of drug and psychotherapy. The FDA’s rejection of Lykos’ NDA signals a backlash of sorts, and psychedelic drug developers have scrambled to avoid the pitfalls that swallowed up the Lykos application: Compass will have critical PhIII results for psilocybin by mid-year, MindMed has moved into PhIII with LSD, Cybin, Gilgamesh, Reunion, and Atai are among several which have important datasets coming over the next eighteen months. There are some ‘Lowlights’ also discussed in the Winter Issue, among them the failure of core programs from Sage Therapeutics and Sage’s surprising passivity in the face of these setbacks. The companies covered in the Winter Issue are include those that represent the best and most accomplished of current neuroscience, some that epitomize the risks and aspirations of R&D, and the inevitable bevy of companies for whom ‘post hoc’ is a way of life. Just a few of the 200+ programs with summaries of their progress and prospects are: AbbVie, Acadia, Alector, Anavex, Atai, Biogen, Biohaven, Bionomics, Boehringer Ingelheim, BMS, Cassava, Cybin, Engrail, Denali, Eisai, Harmony, HMNC, Intra-Cellular, Janssen/JNJ, LillyLundbeck, Maplight, Merck, MindMed, Neumora, Neuren, Neurocrine, Noema, Nxera, Otsuka, Ovid, Prothena, Remedy, Roche, Sage, Seaport Therapeutics, Takeda, Transposon, UCB. There are reviews of significant clinical, fiscal, partnering/acquisition events and trends, valuation winners and losers. 42 pages. Published since 1995, NeuroPerspective is the quarterly review of the neurotherapeutics area offering essential, unique, and comprehensive coverage of developments in the science and the business of the CNS sector. Among our 2025 Feature Reviews will be Schizophrenia, ALS, Parkinson’s, and Alzheimer’s. A one-year (1-5 user) subscription to NeuroPerspective is $3300. A 6-10 user subscription is $5500. Other customized user base and startup pricing options are available. Orders with immediate download availability can be made at our website, https://www.niresearch.com/onlinestore.html. The Winter issue is being made available as a single issue purchase, US$900.

NeuroPerspective Reviews Psychedelics, Epilepsy, FTD 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 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 that is at least a year away. 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 also 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 has 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 programs 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 offering 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. To activate a subscription and download the new issue, go to https://www.niresearch.com/onlinestore.html. The Summer issue is being made available as a single issue purchase, US$900.

NeuroPerspective Reviews Depression, PTSD, and Stroke The Spring 2024 issue of NeuroPerspective features three comprehensive therapeutic area reviews. First is Depression, an area on the cusp of being transformed as Psychiatry adds new therapeutic tools, and begins to meaningfully parse large patient populations based on phenotypic or biomarker differentiators. New mechanisms are in clinical stage, ranging from the kappa opioid antagonists from JNJ and Neumora; to Psychedelic (e.g. Compass, Atai, Cybin, Beckley, many others) and psychoplastogen (Delix, Onsero, Intra-Cellular) to novel approaches from Xenon, HMNC, Gate Neuro, Alto Neuro, Actinogen, Boehringer Ingelheim, Engrail, Evecxia, and others. Second is PTSD, where human foibles guarantee an ever-expanding patient pool. The entactogen category looms large, with Lykos (MAPS) having submitted the NDA for MDMA-assisted psychotherapy. How the FDA handles this complex filing will say a lot about how psychedelic programs will be regulated. MDMA variants are in development by Atai, MindMed, and Tactogen. Bionomics hopes to take BNC210 into PhIII, though there are dosing and safety concerns to be sorted out. Third is Stroke, still off-menu for most larger companies, but attracting more interest from small companies based on seeking complementary roles alongside mechanical thrombectomy and thrombolysis. NoNO Therapeutics has compelling evidence of partial neuroprotection for nerinetide, hints-of-concept have been seen in programs from Acticor, Lumosa, AptaTargets, Revalesio, and Acticor. AbbVie should have results soon for elezanumab, a regenerative therapy. The Spring issue includes a cursory overview of Longboard, with promising PhII data supporting bexicaserin in the treatment of DEE’s like Dravet and Lennox-Gastaut. The Psychedelics Update section reviews GAD data from MindMed, depression results for Cybin and Atai/Beckley, as well as a healthy flow of funding into the more advanced companies in the sector. As always, there is coverage of significant clinical, fiscal, partnering, and regulatory events, including a very impressive 1Q in terms of investor funding for CNS. 72 pages. NeuroPerspective is the quarterly review of the neurotherapeutics area offering essential, 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 Spring issue is being made available as a single issue purchase, US$900.

NeuroPerspective has released its Spring 2023 issue, featuring comprehensive reviews of neurotherapeutics programs addressing Schizophrenia, ALS, and Addiction. The Schizophrenia area had been relatively moribund since the field became dominated by Second Generation (‘atypical’) antipsychotics, but that is now changing, as novel mechanisms aimed at the three domains of schizophreniform illness are maturing. The most tangible advance is in the slow-to-arrive début of muscarinic agonists, with Karuna‘s KarXT having performed strongly in two PhIII trials. While the second PhIII saw the readout for negative symptoms slip below statistical significance at one timepoints, Karuna is preparing to file the NDA midyear, and we have no doubt as to KarXT’s approvability. Negative symptom impact will not be part of the label, since the protocols used thus far could be at risk of pseudospecificity, but the negative sx data will be usable in marketing KarXT. Somewhat behind time wise are a flock of muscarinic agonists which hope to emulate KarXT by being highly selective for M4 or M1/M4 subtypes: Cerevel, Neurocrine/Sosei, and Maplight stand out in this group. New approaches to broad spectrum antipsychotic impact are also coming to fruition, with Otsuka/Sunovion‘s ulotaront finishing PhIII during 3Q:23. Cognitive impairment has been a challenging indication, one of the more intriguing programs is Neurocrine‘s DAAO inhibitor, licensed from Takeda, in PhII, while Boehringer Ingelheim has gone all in on iclepertin, in PhIII. Neurostructural interventions that might have a disease-modifying component are much more preliminary in their development, though Oryzon Genomics has their epigenetic modulator vafidemstat in PhII. ALS has been the neurodegenerative disorder where FDA standards have traditionally been relatively lax, as was the case for Amylyx‘s Relyvrio, whose approval was largely attributable to coaching by the then-head of neuroscience for the FDA. The next example of Agency flexibility is like to be Biogen/Ionis‘ tofersen, for the rare SOD1 mutation form of ALS. Genetically defined subgroups have been more difficult targets than expected, and midstream disease-modifiers may be relatively more accessible: Programs from QurAlis, AbbVie/Calico, Denali, Sanofi/Denali, and Annexon are in the clinic, preclinical programs of interest include those from Libra Therapeutics, NRG Therapeutics, and Aclipse Therapeutics. Addiction receives less pharma investment and attention than even stroke/TBI, and this has not really changed despite the onslaught of the opioid epidemic, exacerbated by the toxic potency of fentanyl. Orexin-1, GPR139, and mGluR5 inhibitors are three next-gen mechanisms of interest. Psychedelic compounds, particularly ibogaine and/or its analogs, are intriguing candidates for addiction disorders as well. The issue also includes a Company Spotlight appraisal of Noema Pharma; a Company review sample from NeuroLicensing 2023, and a review of significant clinical, fiscal, partnering, and regulatory events from 1Q:23. A one-year (1-5 user) subscription to NeuroPerspective is $3100. A 6-10 user subscription is $5250. Other customized userbase and startup pricing options are available. The Spring issue is being made available as a single-issue purchase, for $850. 100 pages.