NeuroPerspective has released its Fall 2025 issue, featuring our annual comprehensive review of Alzheimer’s, as well as reviews of Depression and Narcolepsy. Our Alzheimer’s review appraises the impact of the commercial advents of Eisai/Biogen’s Leqembi/lecanemab and Lilly’s Kisunla/donanemab. They provide an imperceptible 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 could translate into noticeable casualties given the size of the patient population. That risk could be reduced if genetic screening and exclusion of APOE4++ patients were mandated in the US, as is the case in the EU, but neither the companies nor regulators have taken that step, leaving the weighing of risk vs. benefit up to patients and their families. But the launch of two ostensible disease-modifiers has provided the medical/insurance system with the opportunity to develop treatment and payor infrastructure that will serve future, more effective options, and has reawakened the pharma industry to the commercial potential to be found here. Other amyloid mAbs, including Lilly’s remternetug, Roche’s trontinemab and programs from Acumen, AbbVie/Aliada, and ProMIS, hope to improve the risk/benefit profile, but they are years away from potential approval. The quest to improve BBB access has led to multiple partnerships for BBB-transit programs: During 2025 alone, Novartis has added two to its developmental repertoire via licensing/option deals with BioArctic and Sironax; GSK partnered with ABL Bio; Acumen licensed a JCR Pharma program; and Lilly licensed a Sangamo asset Hopes for tau as a target for monoclonal antibodies have been thus far 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, including BMS/BioArctic, JNJ/AC Immune, and Nuravax. Beyond amyloid and tau, the most promising programs appear to be in the neuroinflammation and cellular waste disposal categories. We have been intrigued by TREM2 as a means of modulating microglial activity. But the unexpected demise of the Takeda/Denali lead mAb due to safety issues, in conjunction with evidence that TREM2 activation can itself lead to ARIA, complicates the picture. AbbVie/Alector’s AL002 failed, Novartis is in PhII. The small molecule TREM2 activator in development by Sanofi/Vigil may have an advantage in the TREM2 domain, at least until Muna Therapeutics advances its program. There are downstream mediators that may be alternative targets, including PLCG2 and SHIP1, and NLRP3 inflammasome inhibitors (Halia and Cerevance) . The wait for Novo Nordisk’s semaglutide PhIII trials should be approaching its end. The recent work on the link between AD and lithium depletion is considered. Symptomatic approaches could play a more important clinical role than the crop of very limited disease modifiers. But there has been complete silence regarding AbbVie/Syndesi’s ABBV-552 PhII data, which likely means bad news. Bristol Myers Squibb is assessing a number of KarXT dosing combinations for AD-psychosis, and first data should come soon. But tolerability issues in elderly patients leave the door ajar for other muscarinic candidates, including those from Neurocrine/Nxera, Neumora, and Maplight. Syndeio has developed a considerable body of evidence for its premise that there is an optimal level, and frequency, of NMDA upregulation for procognitive impact, and that historically it has often been exceeded, with negative results. A PhII in AD is being planned. Lighthouse Pharmaceuticals has obtained NIH funding for a definitive trial of its p.gingivalis infection hypothesis. AgeneBio continues to look for a partner to complete development of AGB101 as a treatment for non-APOE4 patients. There is also a slew of small companies whose programmatic execution has been as sloppy as their hyperbole, with Cassava, Anavex, Alzheon, Annovis prominent in that group. Among the 200+ programs assessed are those from: AbbVie/Aliada, Acumen, AC Immune, Actinogen, AgeneBio, Alnylam, Allyx, Alzamend, Anavex, BioArctic, Biogen, BMS, Eisai, GSK/Alector, JNJ, Klothea, Kynexis, Leal, Lexeo, Lighthouse, Lilly, Merck, Monument Biosciences, Muna, Myrobalan, Neumora, Nuravax, ProMIS, Prothena, Roche, Sironax, Syndeio, Takeda, TrimTECH, and Sanofi/Vigil. The second major review is of Depression, an area being transformed as Psychiatry adds new therapeutic tools, and begins to meaningfully parse patient populations based on phenotypic or biomarker differentiators. New mechanisms are in clinical stage, including novel approaches from Xenon, HMNC, Syndeio, Alto Neuro, Actinogen, Autobahn, Engrail, Evecxia, and many others. There have been disappointments, such as the kappa opioid antagonists from JNJ and Neumora. With the growing positive data for Psychedelic options (e.g. Compass, Atai/ Beckley, Cybin, MindMed, Reunion, GH Research), and AbbVie’s partnership with Gilgamesh on GM-2505, the psychoplastogen wing (e.g. Delix, Onsero) has lost some momentum. The third therapeutic area reviewed is Narcolepsy, the first time NP has reviewed that area since 2006. The timing is auspicious, as the highly successful oxybate franchises (Jazz, Avadel), which have shared the spotlight with H3 antagonist drugs (Harmony, Suven), now must contend with the prospect of orexinergic drugs that for the first time address the core deficit of narcolepsy. Major OX2-agonist programs come from Takeda, Alkermes, Centessa, Jazz, and Harmony Biosciences. The Fall issue includes an overview of Saniona, the inheritor of NeuroSearch’s ion channel expertise, which has signed epilepsy drug partnerships with Acadia and Jazz Pharmaceuticals. The Psychedelics Update section appraises Reunion’s successful PhII in Post-Partum Depression and the recently disclosed CRL previously issued by the FDA to Lykos (now rebranded as Resilient Therapeutics) regarding the use of MDMA in PTSD. There is nothing there that would not be solvable by a comprehensive REMS program, and with the FDA’s current receptivity to Psychedelics, that possibility could re-emerge. As always, there is coverage of significant clinical, fiscal, and partnering events. 125 pages.

NeuroPerspective has released its Spring 2025 issue, featuring comprehensive reviews of neurotherapeutics programs addressing Schizophrenia, ALS, and Addiction. The Schizophrenia area is on the verge of its most significant transformation in decades, as the pharma industry is seeing a heated competition between companies attempting to ride the new wave of novel and refined mechanisms aimed at the trifecta of schizophreniform symptoms. Once dismissed as a backwater of generic antipsychotic me-too options, pharma companies have begun to invest heavily, with Bristol Myers Squibb's acquisition of Karuna, and JNJ's purchase of Intra-Cellular Therapies, each with a $14 billion pricetag. From a commercial perspective, the clash of Cobenfy and Caplyta, with two massive marketing efforts behind them, will be one of the fascinating stories of 2025. The degree to which the return justifies the outlay will be a major factor in modulating the return of Big Pharma to Psychiatry, already underway. Caplyta falls under the overly broad category of second-generation antipsychotics, its tolerability profile and effect on both positive and negative symptoms having set the stage for Intra-Cellular to have achieved an impressive launch on its own. Cobenfy is KarXT, the first muscarinic agonist to make it to the Market, with impact upon both positive and negative symptoms as well. KarXT has a flock of muscarinic hopefuls coming up behind it, with Neurocrine/Nxera having shown a signal in PhII. The challenge of this area was epitomized by the shocking failure of AbbVie/Cerevel's emraclidine, which had hoped to achieve through selectivity what KarXT had managed by using a peripheral blocker. One potentially crucial differentiator is the orthosteric vs. allosteric activation, both Cobenfy, the Neurocrine/Nxera program, and an earlier-stage entrant from Maplight, fall into the former category. Emraclidine was an allosteric modulator, as are programs owned by Neumora and Neurosterix, which could signal trouble ahead for them. CIAS, the cognitive impairment seen with schizophrenia, has been a difficult area to treat, but there are a number of intriguing novel mechanisms in clinical testing, from Kynexis, Atai/Recognify, Neurocrine/Nxera, Oryzon, Cerevance, and Alto Neuroscience. ALS has been a neurodegenerative disorder where FDA standards have traditionally been relatively lax, as was the case for Amylyx's Relyvrio, whose accelerated approval was largely attributable to coaching by the then-head of neuroscience for the FDA. With that miscarriage of regulatory oversight eventually corrected, and Relyvrio pulled from the Market (after $400 million in futile sales), we are back to two mediocre therapies for ALS in the US. The hope that ATXN or EIF2b might be workable access points has been dashed, the most widespread question in the field is whether targeting TDP-43 dysfunction can be directly or indirectly workable. UNC13A has been attracting attention, with programs in progress by QurAlis/Lilly and Trace Neuroscience; SARM1 inhibitors are in development by Lilly, Nura Bio, and Asha; TRPML1 is targeted by Libra Therapeutics, Samsara, and Denali spin-out Tenvie. We do not take seriously generic workarounds like NeuroSense, or failed neurotrophic cell therapy (Brain Storm). Addiction receives less pharma investment and attention than even stroke/TBI, and with NIH/NIDA now being subjected to experiments in institutional vivesection, that deficit will only worsen. Orexin-1 inhibitors and the mega-enterprise of GLP-1 agonism are two next-gen mechanisms of interest. Psychedelic compounds, including ibogaine and/or its analogs, are intriguing candidates for addiction disorders as well, and the early data in Opioid and Alcohol Abuse are promising. The issue also includes a Company Spotlight appraisal of Neumora, which has entered a new era of existential risk following the failure of the first navacaprant PhIII; a review of significant clinical, fiscal, partnering, and regulatory events from 1Q:25, with particular attention to some unusual positive developments in the Pain space, and the damage done to the kappa-opoid thesis in depression.

Psychedelics constitute a novel and heterogeneous class of therapeutic candidates that is starting to take shape via clinical data. Just in the past few days, critical and successful clinical readouts have been announced by Compass Pathways and Atai Beckley, recently Gilgamesh and Transcend had positive clinical results. Cybin has data coming soon. Lykos Therapeutics, whose FDA rejection colored the view of the field last year, is birthing a new iteration with new management and funding. The current federal administration has surprisingly embraced the concept of psychedelic therapies, and the push for accelerated reviews is likely to benefit this class. This review assesses over fifty companies, including Atai Beckley, Compass, Gilgamesh, Cybin, Enveric, GH Research, Lykos, Reunion, Terran, Freedom, and MindMed. Pain programs from Ceruvia and Sonic Therapeutics are included, Psychoplastogen programs, from companies like Delix, Psilera, AbbVie/Gilgamesh, JNJ/Intra-Cellular, and more, are also included. The Summer issue includes an updated review of Compass Pathways, whose limited data reveal from its first PhIII was misinterpreted by many observers. The Parkinson’s area continues to be the domain in neurodegeneration where the most mundane (but meaningful) of symptomatic therapies are being developed alongside the most adventuresome and risky interventions, including cell therapies (Aspen, Bayer) and gene therapy (e.g. Lilly/Prevail, Neurocrine/Voyager). Alpha-synuclein continues as a target of interest, though its service as a target has been disappointing, with Roche/Prothena continuing down the mAb road to disappointment. GBA (e.g. Lilly/Prevail, BIAL, and Vanqua) and LRRK2 may be the most promising genetic targets, and LRRK2 appears to be potentially relevant to idiopathic PD as well (e.g. Biogen/Denali, Neuron23, ). Other neuroprotective options are in development by companies including AbbVie/Mission, NRG Therapeutics, and Lucy Therapeutics. In terms of improved symptomatic options, AbbVie’s tavapadon appears very promising. 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, and is now working on a tPA-friendly next iteration: Programs from AptaTargets, Revalesio, and Simcere have shown potential. The Summer issue also comments on Supernus’ acquisition of Sage Therapeutics, Alto Neuroscience’s several announcements and program developments, Coya’s interim data in FTD, and much more. 110 pages.

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.