NeuroPerspective capsules

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.

NeuroLicensing 2023 has been released. It is completely revised and updated, featuring:

1. Analysis of current trends in CNS deal activity and parameters
2. Candid assessments of the major and midsize companies involved in CNS inlicensing: Who is seeking assets in which therapeutic areas, and their exclusions; Which companies are the strongest inlicensing candidates in specific areas. 
3. Corporate licensing agendas and performance are reviewed and appraised. 
4. Companies with full licensing appraisals: AbbVie, Biogen, Boehringer Ingelheim, BMS, Ipsen, JNJ, Lilly, Lundbeck, Mitsubishi Tanabe, Neurocrine Biosciences, Novartis, Otsuka, Roche, Sanofi, Servier, Sunovion, Takeda, UCB Pharma. 
5. Watch List: Biohaven, Karuna.
6. NL 2023 also appraises the licensing appeal of programs loosely categorized under the ‘Psychedelics’ umbrella for mid-size and large Pharma. 

NL 2023 provides a vital, comprehensive resource for teams on both sides of the transaction, both licensors and licensees.107 pages. Released February 2023. Five-user (within one Company) subscription license:$4500.

The Winter issue of NeuroPerspective has been released. This is the Overview Issue, which assesses the past year, with a particular eye to how the Alzheimer’s landscape has (and hasn’t evolved), and looks ahead to forecast key developments that can be expected in 2023. 2023 begins a two to three year sequence of trial completions that will transform the CNS space. The issue includes:

1. Highlights and Lowlights from 2022, with due consideration of Leqembi/lecanemab, Amylyx, Biogen’s new CEO, and much more. 
2. Key questions and anticipated data reveals for 2023.
3. Fiscal parameters from 2022, trends in fundraising via both institutional investors and pharma partnering, the latter down 75% compared with 2021.
4. Corporate capsule summaries covering 180+ CNS companies, some in considerable depth.
5. Psychedelic Update: The status of this highly hyped subsector is reviewed, with particular attention to key questions facing the Psychedelics field, and how they are being handled by Compass Pathways, Atai, MindMed, Small Pharma, Delix, Onsero, and their peers, including an assessment of which companies appear to have the necessary fiscal resources to achieve POC, and which ones do not.

The impact of Karuna’s PhIII success on the general perception of the Psychiatry field and the prospects for novel therapeutics. Promising new programs are in development by larger companies ranging from Merck to Sunovion to Neurocrine, as well as a host of small companies, including Cerevel, Neumora, Engrail, and Gate Neurosciences.

NeuroPerspective is a quarterly review of the neurotherapeutics area offering essential, unique, and comprehensive coverage of developments in the science and the business of the CNS sector. 1-5 reader subscriptions are US$3100 per year, 6-10 user subscriptions are $5250. Startup pricing options and other customized userbase alternatives are available.   The Winter 2023 issue is being made available as a single-issue purchase: $750. Online orders with instant downloads can be completed at https://www.niresearch.com/onlinestore.html.

The Fall 2022 issue of NeuroPerspective has been released. It features our comprehensive annual review of the Alzheimer’s space, including an assessment of the current conceptual trends vis-a-vis pathophysiology and therapeutic targets. One major theme is the resuscitation of the amyloid antibody space by the FDA, initially led by Biogen‘s Aduhelm, which was derailed by discord around data and sticker-shock from the egregious pricing. Eisai/Biogen’s lecanemab does not show superior efficacy, but the data is consistent, and it appears somewhat safer, though the risk of ARIA remains significant. With gantenerumab results coming at the end of November, and a donanemab readout next year, it is easy to foresee two or three amyloid antibodies approved. Whether they will be reimbursed by CMS Medicare will depend on whether any of these companies learned anything about pricing from the Aduhelm debacle.

Hopes for tau as a target for monoclonal antibodies have been largely dashed. 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. There are also a slew of small companies whose programmatic execution has been sloppy and their hyperbole excessive, with Cassava and Annovis prominent in that group, the former well on its way to oblivion.

Among the 200+ programs assessed are those from: AbbVie/Alector, AC Immune,  Alex, Anavex, Athira, Biogen, Casma, Cognition Therapeutics, Cyclerion, Denali, Eisai, Karuna, Lexeo, Lilly, NervGen, ProMIS, Roche, 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. But more selective GABAergic programs are underway at Cerevel, Engrail, and GABA Therapeutics, with other novel mechanisms being explored by Bionomics, JNJ, and Idorsia.

The third therapeutic area reviewed is TBI, another high-prevalence disorder with little available therapeutically. There are programs well into clinical development by SanBio and Biogen, with TBI a possible expansion target for NoNO Therapeutics if nerinetide is successful in its stroke trial.

The Fall issue includes a focused review of Gate Neurosiences and their promising approach to neuroplasticity. The approval of Amylyx‘s ALS drug is examined. Our Psychedelics update section notes updated information regarding the erstwhile benefits of ‘microdosing’, MindMed‘s attempts to correct course before it is too late; questions the premise of psychedelics in neurodegeneration; as well as incipient signs of a backlash to the rapid growth of the sector.

The Fall 2022 issue is being made available for single-issue purchase: $800.

106 pages.

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.

The Spring 2022 issue of NeuroPerspective has been released, featuring in-depth reviews of Depression, PTSD and Stroke. 

Depression continues to be a frustratingly incomplete success for psychopharmacology. The majority of patients do not find adequate relief from their first trial, and 25% do not find sufficient benefit from any of the antidepressants they try. Aversive side effects, including weight gain and sexual dysfunction, form a significant barrier to utilization, and the long delay to relief is counter-therapeutic. There have been advances in the search for a Rapid-Acting-Antidepressant,  an increased commercial deployment of off-label, IV ketamine, the commercially unrewarding advent of JNJ’s intranasal esketamine. There are several programs that claim to have potential as RAADs, with generally mixed efficacy findings from Axsome, Relmada, and Sage Therapeutics. Sage’s zuranolone features anxiolysis, somnolence, and an intermittent dosing paradigm. Compass Pathways’ psilocybin program is getting ready for PhIII, at the head of a burgeoning array of psychedelic and dissociative candidates, for which an optimal protocol is far from having been defined. These include programs from Atai/Perception, Delix, Field Trip Health,MindMed, Mindset/Otsuka, Beckley Psytech, and Small Pharma.

 The almost ubiquitous prevalence of sexual dysfunction as a consequence of depression and SSRI/SNRI has been a significant deterrent to treatment and compliance, with several new-generation entrants appearing to avoid this AE, and Fabre-Kramer’s Exxua demonstrating a beneficial impact on sexual functioning in depression. Other antidepressant programs discussed in the review include those from Atai/Perception,  Supernus/Navitor,  Novartis/Cadent, multiple candidates from Janssen/JNJ, and more than seventy others. At least eight novel mechanisms will report POC results in the next two years.

PTSD (Post-Traumatic Stress Disorder) has risen in profile, as a result of the Covid-19 pandemic, and most recently the war in Ukraine. Therapeutic interventions can be focused upon attenuating the limbic  system hyperactivation of PTSD and/or accentuating the cognitive rewriting of traumatic memory in a reconsolidation paradigm.  The pharma industry has generally taken a passive approach to PTSD, leaving the funding of research to the DoD and VA in the US, but small companies are working in this undertreated and very large-scale domain, including  Aptinyx, Alto, and Bionomics. PTSD is also the arena where MAPS’ MDMA program showed impressively solid PhIII results, and other ‘psychedelics/empathogens’ companies are working as well, including Atai, Gilgamesh, and MindMed.

The third therapeutic sector review covers Stroke, an area which became anathema to the pharma industry after a series of clinical failures 15-20 years ago. With almost 800,000 stroke cases annually in the US alone, this neglect (which had left stroke R&D primarily the province of endovascular device companies) became untenable in the long run. Biogen is the first of the major pharma companies to make a return to ischemic stroke, via its partnering of TMS’ promising new thrombolytic.  There is progress on solving the seemingly intractable puzzle of neuroprotection (NoNO, Avilex, ZZ Biotech), with NoNO wrapping up PhIII with nerinetide. 

Spotlight assessments are included for NoNO and the NeuroLicensing 2022 review of Lilly.

The Spring issue also considers the grim fiscal start to 2022; the FDA and Amylyx; a second ASO failure in neurodegeneration; partnering/acquisitions by AbbVie, Biohaven, Sanofi, and Acadia. 

It is being made available as a single-issue purchase for $750.