The March/April 2019 issue of NeuroPerspective has been released, offering detailed reviews of two therapeutic areas, as well as coverage and commentary regarding significant developments in the CNS therapeutics space.
The first therapeutic sector review covers Schizophrenia, the most devastating of all the psychiatric disorders, one which comprises the awkward melding of multiple schizophreniform phenotypes with very divergent symptom patterns. Affecting about 1% of the population, schizophrenia's genetic vulnerabilities are complex and contribute to schizophrenia's etiological confluence of genetic flaws, prenatal/perinatal environmental factors, and later anomalies in the formation and 'editing' of synaptic networks. At its root, schizophrenia most likely arises from neurodevelopmental failure exacerbated by the degenerative impact of aberrant adolescent synaptic 'pruning,' perhaps reflecting aberrant neuroinflammatory/immune system activity. Network deficits account for the neural dyscontrol that sets the stage for hallucinations/delusions, and for the impoverishment of cognitive capabilities and motivation. While there is promising work on neuroinflammation currently ongoing, with a predominant focus on neurodegeneration (e.g. Alector, Annexon, Denali), the potential application of that work to schizophrenia lags far behind. Symptomatic treatments for schizophrenia are still the currency of the clinical practice and clinical development realms: Current therapeutics are almost solely aimed at the so-called positive symptoms of schizophrenia, there has been no real success developing treatments for the cognitive and negative symptoms that take such a functional toll, even when the more florid symptoms of schizophrenia are relatively controlled. Some of the companies whose programs are discussed in the review include: Biogen,Intra-Cellular Therapies, Karuna Pharmaceuticals, Cerevel, Allergan, Boehringer Ingelheim, Sage Therapeutics, Lundbeck, Takeda, Acadia, Promentis, Newron, Syndesi, SyneuRx, and Sunovion.
The second 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) has been untenable in the long run. Biogen is the first of the major pharma companies to make a return to stroke, via partnerships with Remedy and TMS. There is work on extending the window for thrombolytic interventions (ActiCor, Biogen), solving the seemingly intractable puzzle of neuroprotection (NoNO, AdMIRx, Avilex, ZZ Biotech), and a growing emphasis on repair/regeneration, particularly by the several cell therapy companies engaged in that work (Athersys, SanBio, NeuralStem, ReNeuron). Programs from BioAxone and Idorsia address hemorrhagic stroke. Other companies and academic centers whose programs are discussed in this review include: UCLA, ArunA, NeurOp).
The March/April issue also includes discussion of recent clinical findings from companies addressing depression (JNJ/Janssen, Sage Therapeutics,Axsome, Blackthorn Therapeutics); high-innovation partnerships for Voyager with AbbVie and with Neurocrine, Biogen with C4T and Skyhawk, and possible salvation for the PTSD program from Bionomics. The Company Spotlight Review covers SyneuRx, which is in PhII/III trials using sodium benzoate/NaBen for schizophrenia and dementia.
The September/October 2018 issue of NeuroPerspective has been released, featuring the newest iteration of our annual candid and comprehensive review of the Alzheimer's space, including a review of the current conceptual trends vis-a-vis pathophysiology and therapeutic targets.
In particular, this year there is an expanded assessment of neuro-immunology as it pertains to Alzheimer's, including infection models of AD and tactics for modulating microglial activity.
The subtitle for the review is 'Circular Illogic', because despite our past observations of the need for recalibration in the pursuit of AD, there is still more investment in amyloid-centric programs than is warranted by the data generated thus far.
Among the 150+ programs are assessed are those from: AbbVie, Alector, AC Immune, AgeneBio, Allergan, Alkahest, Anavex, Asceneuron, Axon-Neuroscience, Biogen, Cognition Therapeutics, Cortexyme, Denali, Eisai, E-Scape, Genentech, Intra-Cellular, JNJ, Karuna, Klogene, Lilly, Lundbeck, Merck, Novartis, Oryzon, Pfizer, Probiodrug, Proclara, ProMIS, Roche, Takeda, United Neuroscience, and Voyager. Alector is the focus of the Company Review, sidebars include coverage of the current state of the AD Biomarker art and an overview of the POC timelines for major AD programs.
The Sept/Oct issue also includes a full review of Frontotemporal Dementia (FTD), including an evaluation of the complex heterogeneity within this umbrella category, with marked divergences in genotype and phenotypic signs. FTD programs are evaluated, including those from AbbVie/Alector, Biogen, Axovant/Benitec, Aquinnah, and Wave Life Sciences/Takeda.
The March/April 2018 issue of NeuroPerspective features in-depth reviews of Depression and PTSD.Depression represents a patient population whose treatment falls far short of the bucolic illustrations suggested by DTC advertising for the current crop of pharmacotherapies. 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. New drugs seem to offer the prospect of near-immediate depression relief, led by the much-publicized impact of IV ketamine. Prominent RAAD programs come from JNJ (whose Phase III results have been delayed without explanation); Allergan; the surprising SAGE Therapeutics program; and potentially, Perception NeuroScience, to name but four. Suicide risk represents a growing societal problem, as is Treatment-Resistant Depression, where nothing seems to work. SAGE has made significant progress with Post-Partum Depression, with Marinus Pharmaceuticals hoping to follow suit. Other antidepressant programs reviewed include those from Alkermes, Blackthorn Therapeutics, NeuralStem, Navitor.
PTSD (Post-Traumatic Stress Disorder) has risen in profile as a result of both natural (tsunamis, firestorms) and human-made (combat, mass shootings) disasters, and the more pervasive but lower profile scourge of sexual/physical/emotional abuse of both children and adults. 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 beginning to explore this undertreated and very large-scale domain: Aptinyx, Azevan, Marinus, Rodin, SpringWorks, Tonix Pharma. Interventions can be focused upon attenuating the limbic system hyperactivation of PTSD and/or accentuating the cognitive rewriting of traumatic memory.
The March/April issue also discusses Pfizer’s CNS retreat; Axovant’s failure; the ‘revision’ of FDA guidelines for Alzheimer’s; and the several high-quality, pioneering partnerships signed in recent months: Takeda with both Denali and Wave Life Sciences, AbbVie with Voyager Therapeutics. 55 pages.
The November/December issue of NeuroPerspective features a comprehensive review of the Pain space, divided into two major sub-sections, Nociceptive (including Inflammatory) Pain and Neuropathic Pain. Even as attention has necessarily been focused upon the Opioid Epidemic that had its roots in an overreliance upon prescription opioid analgesics, the Pain field has yet to develop non-opioid alternatives that provide sufficient analgesia for severe pain. Some companies have focused upon developing modestly-less-abuse-prone opioid reformulations, these have failed to impress regulators or prescribers. Trevena's 'biased agonists' represented an unacceptable trade-off of efficacy for safety, while NGF antibodies have had a torturous path through clinical and regulatory challenges, and are burdened by their own safety risks. Extending the range of short-acting anesthetics in order to circumvent the need for post-operative opioids is a strategy that has shown some promise. Neuropathic pain is in some ways even more ephemeral and frustrating, there has yet to be a 'gold standard' for neuropathic pain, which comes in several major sub-varieties, and for which current treatments tend to offer only partial relief to a minority of patients.
Among the 60+ programs are assessed are those from: Centrexion, Lilly/AstraZeneca, Teva/Regeneron, Trevena, Vertex, Cara Therapeutics, Wex Pharmaceuticals, Mesoblast, Adynnx, Recro, Novartis/Spinifex, Xenon, Astraea, Coda Therapeutics, Aptinyx, and Amgen. The Boehringer Ingelheim licensing agenda is excerpted from NeuroLicensing 2018-19. Sidebars include coverage of JNJ esketamine program in depression; competition rapidly pursuing Biogen's Spinraza, the ambiguity of Eisai/Biogen's BAN2401 data in Alzheimer's, and the ADCOM rebuff of Alkermes' highly flawed NDA submission for ALKS 5461. 53 pages.