NeuroPerspective has released its Winter 2024 issue, featuring our comprehensive Review of 2023 and Preview of 2024 for the neurotherapeutics area. While some will consider the launch of Eisai/Biogen’s Leqembi to have been the premier event for 2023, we consider this a first step, a dress rehearsal, for the eventual availability of genuinely impactful disease-modifiers for Alzheimer’s. For the time being, lecanemab and donanemab will have their risks better 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 stage, with promising, yet-to-be-validated research in neuroinflammation and protein clearance standing out. We are looking forward to 2024 PhII readouts from AbbVie/Alector in Alzheimer’s, and Roche/Prothena in Parkinson’s. Genetically-linked disorders would seem to be more accessible, but the travails of huntingtin-targeting in Huntington’s has shown that target specificity is not the panacea that had been hoped for. Instead, the drama in neurotherapeutics is coming from an area that a decade ago, was being dismissed as hopelessly mire in genericized mediocrity, Psychiatry. December saw two major deals that were Psychiatry-centric: Bristol Myers Squibb’s $14 billion buyout of Karuna, and AbbVie’s $8.7 billion acquisition of Cerevel. While welcomed by the investors who benefited, these deals signaled a surge in the credibility and accomplishments of Psychiatry R&D, bringing back BMS, who had left Psychiatry years ago, while building upon AbbVie’s leadership role in neuroscience. Over the next two to four years, the clinical practice of Psychiatry is going to be revolutionized, first in schizophrenia, but then in depression, where treatments will be customized in a way that moves far beyond the trial-and-error of past practice. Sage/Biogen’s Zurzuvae for Post-Partum Depression is the first iteration of tailored therapies, with clinical successes for KarXT and MDMA representing the next step in Psychiatry. While the muscarinic class is front-and-center right now, there is a broad range of novel mechanisms in development. The Winter Issue looks at the companies involved and those which might constitute attractive acquisition and/or licensing opportunities for larger companies eager to not miss out. The Winter Issue includes our customary ‘Psychedelics Update’, as that sector works to earn the excitement that has been generated in recent years: The coming approval of MDMA for PTSD represents a significant landmark, Compass will have its first PhIII results for psilocybin in Treatment-Resistant Depression later this year. But this remains the turf of small companies, the only large company to actively engage with Psychedelics is Otsuka. There are some ‘Lowlights’ also discussed in the Winter Issue, none higher-profile than the devolution of Biogen’s role in CNS R&D, where their leadership in partnering from 2017-20 has vaporized as they downplay the importance of neuroscience in their history and their future. The return of large companies to prominent roles in neuroscience diminishes, but does not completely erase, the sting of Biogen’s withdrawal. It is reassuring to see companies like Teva, which had amputated its CNS R&D several years ago, citing neuro-innovation as a new focus for their resources. 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, Bayer AG, Biogen, Bionomics, BMS, Cassava, Cybin, Engrail, Denali, Eisai, Intra-Cellular, Janssen/JNJ, Lilly, Longboard, Lundbeck, Maplight, Merck, MindMed, Neumora, Neuren, Neurocrine, Noema, NoNO, Otsuka, Ovid, Prothena, Reviva, Roche, Sage, Sosei Heptares, Takeda, Transposon, UCB, and Vigil. There are reviews of significant clinical, fiscal, partnering/acquisition events and trends, valuation winners and losers, including our annual review of the IPO class of 2019-21. 43 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 2024 Feature Reviews will be Depression, PTSD, Stroke, Epilepsy, and Alzheimer’s. A one-year (1-5 user) subscription to NeuroPerspective is $3200. A 6-10 user subscription is $5450. Other customized user base and startup pricing options are available. The Winter issue is being made available as a single issue purchase, US$850.

NeuroPerspective has released its Fall 2023 issue, featuring our annual comprehensive review of Alzheimer’s, as well as Huntington’s and ADHD. It features our comprehensive annual review of the Alzheimer's space, including an appraisal of the impact that can be expected from the Leqembi launch, which may mean more to the psychology of investors in the space than to the clinical treatment of AD patients. Eisai/Biogen’s lecanemab and Lilly’s donanemab share much in common, including barely 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 earlier stage 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. 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 Denali/Sanofi, 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. The pursuit of an infection-based AD hypothesis continues with Lighthouse Pharma’s resumption of the work started by Cortexyme. 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. Among the 200+ programs assessed are those from: AbbVie/Alector, AC Immune, Alnylam, Allyx, Anavex, Athira, Attralus, Biogen, Casma, Cognition Therapeutics, Cyclerion, Denali, Eisai/BioArctic, Janssen/JNJ, Karuna, Lexeo, Lilly, Merck, Monument Bioscience,Neurocrine/Sosei, ProMIS, Prothena, Roche, Takeda, Therini, Vaxxinity, and Vigil. The issue also includes a full review of Huntington’s, where the understanding of the pathophysiological pathways triggered by mutant huntingtin has not rendered the therapeutic task nearly as straightforward as many had expected. With high-profile disappointments from Roche and Wave Life Sciences, and confusing data thus far from UniQure, walking the tightrope of reducing mutant Htt while leaving sufficient wild-type Htt has proven to be challenging. Other programs assessed include Annexon, LoQus23, Prilenia, Sage, Spark, and Takeda. The third therapeutic area reviewed is ADHD, where the industry, having failed to develop novel mechanisms with the efficacy offered by psychostimulants, failed to manufacture enough of that proven class, leaving patients to flounder without medication. Takeda’s failure to supply Vyvanse represented a surrender to the numerous generic companies waiting in the wings. The Fall issue includes a cursory overview of Neumora, whose funding prowess can support multiple clinical-stage programs. Mixed signals regarding Biogen’s path ahead are reviewed, while the Psychedelics Update section notes the start of inevitable and necessary consolidation, starting with Otsuka’s acquisition of Mindset and Cybin’s merger with Small Pharma. As always, there is coverage of significant clinical, fiscal, partnering, and regulatory events, including FDA decisions regarding Biogen/Sage’s zuranolone and Brainstorm’s erstwhile cell therapy for ALS. 108 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 $3100. A 6-10 user subscription is $5250. Other customized userbase and startup pricing options are available. The Fall issue is being made available as a single issue purchase, US$850.

NeuroPerspective has released its Summer 2023 issue, featuring comprehensive reviews of the Psychedelic Therapeutics area, as well as Parkinson's and Multiple Sclerosis. There is no area in neurotherapeutics that is in such frequent and potentially substantive transformation as Psychedelics. Along with Alzheimer's, it has become one of the two areas to which NP returns on an annual basis. MAPS has successfully completed its second PhIII trial of MDMA in PTSD, and while these studies were small scale in comparison to most pivotal studies, the pressure from advocacy groups, particularly military veterans, is so intense that we expect the FDA to approve MDMA by the end of 2024. Compass Pathways is the other PhIII-stage psychedelic company, in the wake of their PhIIb success, it has begun enrollment in two PhIII trials of psilocybin in Treatment-Resistant Depression. They are about two years behind MAPS in their clinical development timeline. There are well over 100 companies that have been founded in the Psychedelics space, some of which have already gone out of business, and with the funding spigot turned down to a trickle, culling and consolidation are major corporate trends in this area. This issue of NP focuses on fifty of the more credible entrants, including classic psychedelic companies like Atai, Beckley Psytech, Biomind, CaamTech, Compass, Cybin, Enveric, GH Research, Gilgamesh, Lusaris, MindMed, Mindset, Mydecine, Psylo, Silo, Small Pharma, Terran, and TRYP. There are also several companies in the dissociative and empathogen categories, including Tactogen and Freedom Biosciences. The issue also looks at some of the fundamental issues framing the discussion around the viability of Psychedelics from both a clinical and commercial viewpoint. None looms larger than the debate around whether the hallucinogenic experience is 'a bug, or a feature.' Some very capable companies are betting that the hallucinations associated with classic psychedelics are superfluous, that the impact of these drugs is achieved by hypercharging neuroplasticity. Delix Therapeutics (which has a Featured review), Onsero Therapeutics, and Psilera are prominent in this group, relying upon chemistry expertise to parse the neuroplastic from the hallucinogenic. Other questions addressed at length are: What role does psychotherapeutic prep and integration play in psychedelic therapies, and what protocol variants (number of doings, booster sessions) many be optimal and/or viable. 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,Treefrog) and gene therapy (e.g. Lilly/Prevail, Neurocrine/Voyager). Alpha-synuclein continues as a target of interest, though its performance as a target has been mixed at best. Roche/Prothena have launched a major PhIIb trial, Takeda/AstraZeneca are in PhII. BioArctic and Sanofi/ABL Bio, UCB/Neuropore, and AC Immune are among the numerous programs also active with this target. 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, Servier/Oncodesign). Other neuroprotective options are in development by companies including AbbVie/Mission, NRG Therapeutics, and Lucy Therapeutics. In terms of improved symptomatic options, Cerevel is well into PhIII, Cerevance, Neurolixis, and Intra-Cellular are earlier-on. Multiple Sclerosis is in some ways the success story of the neurodegeneration area, with multiple disease-modifying options, the CD20 targeting drugs (e.g. Ocrevus and Kesimpta) having attenuated the choice between efficacy and safety that characterized earlier-generation options. BTK inhibitors had been expected to be the next-gen mechanism of promise, but safety issues have cropped up with most of the leading programs. Sanofi/Principia and Merck Serono should have PhIII results during 2023-24, with Roche a year behind.Progressive MS continues to be underserved, and regenerative therapies have thus far been problematic clinically. The issue also includes a Company Spotlight appraisal of Delix Therapeutics, Pharma; commentary on lecanemab and donanemab in Alzheimer's, and regarding Acadia's pricing of Daybue for Rett Syndrome. As always, there is coverage of significant clinical, fiscal, partnering, and regulatory events from 2Q:23. 116 pages.

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.

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.