Progressive Supranuclear Palsy Atypical

iStock, Nathan Devery The investigational injection fosgonimeton appeared to have better efficacy in patients with more severe disease, according to post-hoc subgroup analyses, though none resulted in statistically significant effects. Athira Pharma announced on Tuesday that its investigational injection fosgonimeton failed the Phase II/III LIFT-AD trial , unable to significantly boost cognition or function in patients with mild-to-moderate Alzheimer’s disease. Topline data from LIFT-AD showed that fosgonimeton improved scores on the Global Statistical Test—which combines results from cognition and function measures—by 0.08 points. However, this effect fell short of statistical significance, with a p-value of 0.7, according to Athira. Fosgonimeton also had slightly beneficial effects on cognition and function when measured individually, but the magnitude of its effect on either metric also did not reach statistical significance. “These are not the results we hoped for,” Athira Chief Medical Officer Javier San Martin said in a statement, noting that the “lack of clinical decline in the placebo group” and the overall short study duration “may have impacted the trial’s ability to translate the effect of fosgonimeton treatment into meaningful clinical benefit.” Still, San Martin said that “the totality of the data continues to suggest that positive modulation of the HGF pathway has the potential to translate into improvement in parameters of neuronal health and may mitigate disease progression.” LIFT-AD also assessed the effects of fosgonimeton on biomarkers and found significant improvements in various indicators of neurodegeneration, inflammation and protein pathology. A subgroup analysis showed that fosgonimeton resulted in a “greater numerical treatment effect” in patients with more advanced disease. Post-hoc subgroup analyses likewise revealed better outcomes for patients with worse disease severity or those who had clinical dementia at baseline, and this beneficial effect was driven by cognitive improvements. However, none of these sub-analyses found statistically significant effects for fosgonimeton. Still, Anton Porsteinsson, director of the Alzheimer’s Disease Care, Research and Education Program at the University of Rochester, said in a statement that these biomarker and subgroup findings are “remarkably consistent not only across endpoints but also with our understanding of fosgonimeton’s neuroprotective mechanism of action.” Porsteinsson is an investigator for LIFT-AD. Designed to be administered via a simple subcutaneous injection, fosgonimeton is an investigational small molecule drug that works by boosting the activity of the neurotrophic hepatocyte growth factor system, which could potentially protect or promote the repair of neuronal networks. Through this mechanism of action, fosgonimeton has therapeutic potential for several neurodegenerative disease. In addition to Alzheimer’s disease, Athira is developing fosgonimeton for Parkinson’s disease dementia and dementia with Lewy bodies. The biotech released exploratory Phase II data for these in December 2023, noting that the drug candidate had overall positive effects on cognition.

Pictured: A brain hovers over a hand against a yellow-striped background/Taylor Tieden for BioSpace The first half of 2024 was filled with ups and downs for patients and researchers in the neurological disease space. The amyotrophic lateral sclerosis community took a hit when Amylyx’s Relyvrio failed its confirmatory Phase III trial and was subsequently withdrawn from the market. Huntington’s disease patients saw new hope in the form of positive mid-stage data from Wave Life Sciences. The second half of the year kicked off with the approval of a novel disease-modifying treatment for Alzheimer’s disease, only the second such option now available to patients. The next six months are shaping up to be just as eventful in clinical research, with key data readouts expected in Alzheimer’s, schizophrenia, depression and a couple of rare diseases. Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, noted several key upcoming data readouts in both the neuropsychiatric and neurodegenerative spaces. Here are five BioSpace is keeping a close eye on. Athira Pharma’s Fosgonimeton Alzheimer’s disease Recently approved medicines Leqembi and Kisunla command the most attention in the Alzheimer’s disease treatment space as the first anti-amyloid antibodies on the market, but the experimental Alzheimer’s pipeline is still robust. One candidate with a different mechanism of action is fosgonimeton, currently in a Phase II/III trial. Topline data from the trial, which includes around 550 patients, are expected in the second half of this year. Developed by Athira Pharma, fosgonimeton is designed to modulate the HGF/MET system to activate neuroprotective and anti-inflammatory pathways in the central nervous system. Athira presented data from the Phase II SHAPE trial in Parkinson’s disease dementia and dementia with Lewy bodies at the AD/PD 2024 International Conference in March, showing “encouraging safety and pro-cognitive measures.” These results “underscore confidence” in the Phase II/III LIFT-AD trial in Alzheimer’s disease, according to the company’s press release. In 2022, fosgonimeton combined with standard-of-care acetylcholinesterase inhibitors missed the primary endpoint in Athira’s Phase II ACT-AD study, failing to best placebo in ERP P300 latency, a measure of working memory processing speed. However, a planned analysis of subgroup data showed cognitive and functional improvements through the drug’s modulation of the HGF/MET system, and Athira moved forward investigating fosgonimeton as a monotherapy for Alzheimer’s. AbbVie/Cerevel’s Emraclidine Schizophrenia In December 2023, AbbVie invested nearly $9 billion in the schizophrenia space with the acquisition of Cerevel Therapeutics and its late-stage asset emraclidine. (This deal has not yet closed.) Later this year, the company will learn whether its investment has paid off. Two Phase II trials, EMPOWER-1 and EMPOWER-2, comprise approximately 750 individuals in total and are projected to read out by the end of 2024. In these trials, AbbVie is seeking the rapid improvement of schizophrenia symptoms. The trials’ primary endpoint is change from baseline after six weeks on the Positive and Negative Syndrome Scale (PANSS) scale. The studies are also evaluating the safety and tolerability of emraclidine, a positive allosteric modulator of the muscarinic M4 receptor. AbbVie will need strong data from the EMPOWER trials to keep pace with Bristol Myers Squibb, which is expecting an FDA decision in September on its own novel schizophrenia treatment, KarXT, which also targets the M4 as well as M1 muscarinic receptors. BMS obtained KarXT in its December acquisition of Karuna Therapeutics. “[Emraclidine] is behind,” Suvannevejh said. “Cerevel knew that they needed to play catch-up versus Karuna,” so they tried to design the Phase II studies to be large enough and robust enough to be considered by the FDA as Phase III studies. “We don't know if FDA is going to agree to that, [but] that’s what their hope is going to be.” Neumora Therapeutics’ Navacaprant Major depressive disorder Also in the neuropsychiatric space, Watertown, Mass.–based Neumora Therapeutics is expecting the first Phase III data for its lead asset navacaprant, a Kappa-opioid receptor (KOR) antagonist in development for major depressive disorder (MDD), in the fourth quarter of this year. The KOR system is a “well-characterized pathway known to mediate depressive-like states, and modulating this system represents a novel approach to treating MDD and other major neuropsychiatric disorders,” according to Neumora’s website. Mizuho is “bullish” on navacaprant’s prospects, due to “de-risking” Phase II data, validation from a competitor program, a positive reception from key opinion leaders on the KOR class and a large, addressable MDD market, Suvannevejh wrote in a July 8 investor note. “This represents a brand-new class for depression,” Suvannevejh said, adding that there is a “fair amount of industry excitement” around KOR antagonists due to the less-than-ideal side effects associated with currently marketed antidepressants. Neumora launched the Phase III trial in July 2023 after navacaprant monotherapy demonstrated “statistically significant and clinically meaningful reductions in symptoms of depression and anhedonia” in Phase II trial participants with moderate-to-severe MDD. If these studies are successful, Neumora intends to New Drug Application with the FDA for navacaprant in 2025. Amylyx’s AMX003 Wolfram syndrome A week after announcing the voluntary withdrawal of recently approved ALS treatment Relyvrio (AMX0035) from the U.S. and Canadian markets, Amylyx received a glimmer of hope for the drug—a combination of sodium phenylbutyrate and taurursodiol—in another neurodegenerative condition: Wolfram syndrome. Wolfram syndrome is characterized by childhood-onset insulin-dependent diabetes mellitus and progressive optic atrophy, with many patients also developing diabetes insipidus, sensorineural hearing loss and autonomic nervous system degeneration. The multi-organ disease is caused by mutations in the WFS1 gene that lead to endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which causes “lack of function across many different cell types, and ultimately, cell death across multiple cell types, starting with beta cells in the pancreas and then moving to parts of the nervous system,” explained Justin Klee, co-CEO of Amylyx. “AMX0035 targets ER stress and mitochondrial dysfunction.” Interim results from the ongoing Phase II HELIOS trial showed AMX0035 improved pancreatic function and glycemic control in adult patients with the rare, inherited disease. Treatment with Amylyx’s drug led to an increase in total C-peptide response, an established marker of pancreatic beta cell function and glycemic control and the trial’s primary efficacy measure. With these data, from eight patients who had completed 24 weeks of treatment, Amylyx co-CEO Josh Cohen told BioSpace that the company plans to engage with regulators on a possible development path for AMX0035 in Wolfram syndrome. Amylyx expects topline data from all 12 trial participants after 24 weeks of treatment during the second half of 2024. Vigil Neuroscience’s Iluzanebart ALSP Another company anticipating mid-stage data for a rare disease candidate is Vigil Neuroscience. Vigil is developing iluzanebart for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), an inherited, autosomal dominant neurological disease affecting approximately 10,000 people in the U.S. Phase II data are expected in the third quarter of 2024. ALSP is caused by loss-of-function mutations in the CSF1R gene, leading to microglial dysfunction. Iluzanebart is designed to increase signaling through DAP12/SYK to mitigate microglial dysfunction, according to Vigil. In preclinical studies, iluzanebart has “demonstrated sub-nanomolar potency and selective target engagement with TREM2,” which activates the cascade of downstream signals to mediate neuroprotective and homeostatic functions of the microglia. “It's important for Vigil and it's important for patients with this disease because there are no FDA-approved treatments . . . and Vigil is the only game in town for this disease,” Suvannevejh said. “It’s a very novel agent targeting this TREM2 mechanism of action,” and for investors, the jury is still out on whether this is an effective approach, he said. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

Phase 2b RewinD-LB trial of neflamapimod for the treatment of dementia with Lewy bodies is fully enrolled with topline data expected in December 2024 BOSTON, July 11, 2024 (GLOBE NEWSWIRE) -- CervoMed Inc. (NASDAQ: CRVO), a clinical stage company focused on developing treatments for age-related neurologic disorders, today announced that it will host a virtual key opinion leader (KOL) event on Tuesday, July 23, 2024 at 10:00 AM ET. Company’s management will be joined by John-Paul Taylor, MBBS (hons), MRCPsych, PhD (Newcastle University), who will discuss the unmet need and the role of loss of integrity of the cholinergic system in dementia with Lewy bodies (DLB), and Ralph A. Nixon, MD, PhD (New York University Grossman School of Medicine), who will focus on the mechanistic and preclinical data with neflamapimod, an oral p38α inhibitor that targets the molecular mechanisms underlying degeneration and dysfunction in the basal forebrain cholinergic system. Agenda Topics: Right Disease, Right Drug, Right Patient, Right Trial Overview of the DLB disease state, unmet need and current treatment landscape for patients Understanding the role of the basal forebrain cholinergic system in clinical disease expression and progression in patients with DLB Neflamapimod mechanism of action and therapeutic potential to reverse disease progression in the basal forebrain cholinergic system Understanding the role of plasma phosphorylated tau in the selection of patients for inclusion in DLB clinical trials Overview of CervoMed’s Phase 2b RewinD-LB trial design in DLB, which is optimized for success and with a positive result is expected to provide a clear path to market in this high value indication A live question and answer session, moderated by John Alam, MD, Chief Executive Officer of CervoMed, will follow the formal presentation. Attendees will be required to register in advance for the webcast. To register, click here. For those who are unable to attend, a replay will be made available through CervoMed’s website following the event. About John-Paul Taylor, MBBS(hons), MRCPsych, PhD John-Paul Taylor, MBBS(hons), MRCPsych, PhD is Professor of Translational Dementia Research, Institute of Neuroscience, at Newcastle University and Honorary Consultant in Old Age Psychiatry, Northumberland, Tyne and Wear NHS Trust. He specialises in understanding the causes and symptoms of DLB and is a world leading authority in that arena. Professor John-Paul Taylor graduated with honors and distinction from the University of Newcastle upon Tyne having completed an intercalated MD PhD programme in 2001. He subsequently worked in the Institute of Psychiatry at the Maudsley Hospital in London, before completing clinical academic training in Newcastle upon Tyne. In 2010 he was awarded a Wellcome Trust Intermediate Clinical Fellowship and was appointed in 2019 as Professor of Translational Dementia Research at Newcastle University. Dr. Taylor has published over 200 peer reviewed articles, numerous book chapters and has edited two books in the field of dementia and old age psychiatry. Dr Taylor’s research focuses on the application of neuroimaging and neurophysiological approaches in understanding symptom aetiology in DLB and Parkinson’s disease dementia as well as developing better management approaches for people with Lewy body disease. Clinically he leads a specialist Lewy body dementia clinic in Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust. About Ralph A. Nixon, MD, PhD Ralph A. Nixon, MD, PhD is Professor of Psychiatry and Cell Biology at New York University Grossman School of Medicine and the Director of the Center for Dementia Research at the Nathan S. Kline Institute. He received his PhD in Cell and Developmental Biology from Harvard, MD from University of Vermont, and internship/residency training in medicine and psychiatry at Massachusetts General Hospital. Dr. Nixon’s research focuses on the biology of protein clearance by endosomal-lysosomal, autophagy, and calpain-calpastatin systems and addresses molecular defects in these clearance mechanisms driven by genetic and environmental factors as a basis for Alzheimer’s disease and related disorders and as promising therapeutic targets. A second major research effort focuses on the axonal transport, assembly, and turnover of cytoskeletal proteins and their dysregulation within synapses in relation to dementing diseases. Dr. Nixon has >300 scientific publications (H-index, 108) and eight issued patents. Dr. Nixon’s awards include the MERIT, Leadership and Excellence in Alzheimer Research, and Academic Career Leadership Awards from NIH and the Zenith, Temple Discovery, and Khachaturian Awards from the Alzheimer’s Association. He is past fellow of the A.P. Sloan Foundation and current fellow of the American College of Neuropsychopharmacology. About the RewinD-LB Phase 2b Study in Dementia with Lewy Bodies CervoMed’s ongoing Phase 2b study, RewinD-LB, is a randomized, 16-week, double-blind, placebo-controlled clinical trial evaluating oral neflamapimod (40mg TID) in up to 160 patients with very mild or mild dementia due to DLB. Patients completing the 16-week placebo-controlled study period will be able to continue in the study while receiving open label neflamapimod treatment for an additional 32 weeks. Patients with Alzheimer’s Disease-related co-pathology, assessed by a blood biomarker (plasma ptau181), will be excluded. The primary endpoint in the study is change in the Clinical Dementia Rating Sum of Boxes, and secondary endpoints include the Timed Up and Go test, a cognitive test battery, and the Clinician’s Global Impression of Change. The RewinD-LB study is funded by a $21.0 million grant from the National Institutes of Health’s National Institute on Aging, which will be disbursed over the course of the study as costs are incurred. The study includes 43 sites (32 in the United States, eight in the United Kingdom, and three in the Netherlands), all of which have been initiated, and CervoMed announced the completion of enrollment in the study in June 2024. More information on the RewinD-LB study, including contact information on active clinical trial sites, is available at clinicaltrials.gov. About CervoMed CervoMed Inc. (the “Company”) is a clinical-stage company focused on developing treatments for age-related neurologic disorders. The Company is currently developing neflamapimod, an investigational, orally administered small molecule brain penetrant that inhibits p38MAP kinase alpha. Neflamapimod has the potential to treat synaptic dysfunction, the reversible aspect of the underlying neurodegenerative processes that causes disease in DLB and certain other major neurological disorders. Neflamapimod is currently being evaluated in a Phase 2b study in patients with DLB. Forward-Looking Statements This press release includes express and implied forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, regarding the intentions, plans, beliefs, expectations or forecasts for the future of the Company, including, but not limited to, the Company’s planned KOL event and the subject matter to be discussed thereat, the therapeutic potential of neflamapimod, and the anticipated timing and achievement of clinical and development milestones, including the completion and achievement of primary endpoints of the RewinD-LB Phase 2b clinical trial and the Company’s announcement of topline data therefrom. Terms such as “believes,” “estimates,” “anticipates,” “expects,” “plans,” “aims,” “seeks,” “intends,” “may,” “might,” “could,” “might,” “will,” “should,” “approximately,” “potential,” “target,” “project,” “contemplate,” “predict,” “forecast,” “continue,” or other words that convey uncertainty of future events or outcomes (including the negative of these terms) may identify these forward-looking statements. Although there is believed to be reasonable basis for each forward-looking statement contained herein, forward-looking statements by their nature involve risks and uncertainties, known and unknown, many of which are beyond the Company’s control and, as a result, actual results could differ materially from those expressed or implied in any forward-looking statement. Particular risks and uncertainties include, among other things, those related to: the Company’s available cash resources and the availability of additional funds on acceptable terms; the results of the Company’s clinical trials, including RewinD-LB; the likelihood and timing of any regulatory approval of neflamapimod or the nature of any feedback the Company may receive from the U.S. Food and Drug Administration; the ability to implement business plans, forecasts, and other expectations in the future; general economic, political, business, industry, and market conditions, inflationary pressures, and geopolitical conflicts; and the other factors discussed under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2023 filed with the U.S. Securities and Exchange Commission (SEC) on March 29, 2024, and other filings that the Company may time to time with the SEC. Any forward-looking statements in this press release speak only as of the date hereof (or such earlier date as may be identified). The Company does not undertake any obligation to update such forward-looking statements to reflect events or circumstances after the date of this press release, except to the extent required by law. Investor Contact: PJ Kelleher LifeSci Advisors Investors@cervomed.com 617-430-7579