Hereditary Diffuse Leukoencephalopathy With Spheroids

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sclerosis community took a hit when Amylyx’s Relyvrio failed its confirmatory Phase III trial and was subsequently withdrawn from the market.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.

Opioid overdose can be quickly countered by a nasal spray administration of naloxone, a drug that reverses the depressive effects that opioids have on breathing and central nervous system function. But the product, available for more than seven years under the brand name Narcan, required a prescription. No longer. The FDA this past week approved Narcan for over-the-counter, non-prescription use. The new approval follows a unanimous FDA advisory committee vote in February that the benefits of making Narcan over the counter outweigh the risks. The regulatory decision means that in addition to pharmacies, the nasal spray could soon be available for purchase in convenience stores, grocery stores, and even gas stations. Narcan is the biggest seller for Emergent BioSolutions, but generic competition has started to erode sales of the prescription version of the product. The company reported $373.3 million in 2022 Narcan sales, down 14% compared to the prior year. The latest approval for Narcan could help bolster revenue, but Emergent has not yet disclosed a price for the OTC product. Emergent expects OTC Narcan will become available by late summer as the company changes its manufacturing to support nonprescription packaging and makes supply chain modifications. The FDA and its counterparts in other countries have been busy. Here’s a recap of some other recent regulatory news: Approved and Validated —Pharming Group drug Joenja became the first FDA-approved treatment for a rare immune disorder called activated phosphoinositide 3-kinase delta syndrome, or APDS. The disease leads to low levels of white blood cells. Joenja is a small molecule that blocks the PI3K-delta protein, an approach intended to block the signaling pathways that lead to dysregulation of immune cells. —Incyte welcomed a surprise cancer immunotherapy approval from the FDA. The agency greenlit the drug Zynyz as a treatment for Merkel cell carcinoma, a rare skin cancer. The approval comes as a surprise because the company had not previously disclosed a biologics license application or a target date for a regulatory decision. An application in squamous cell carcinoma of the anal canal was turned down by the FDA in 2021. In Merkel cell carcinoma, Incyte’s new drug will compete against Keytruda from Merck and Bavencio, marketed from partners Pfizer and EMD Serono. Pfizer is pulling out of that alliance. EMD Serono announced this week that —The Japanese Ministry of Health, Labour and Welfare approved Incyte drug Pemazyre for treating myeloid/lymphoid neoplasms characterized by a particular genetic signature. This type of cancer is characterized by the overproduction of myeloid cells and it can progress to the blood cancer acute myeloid leukemia. The FDA approved Pemazyre for the myeloid/lymphoid neoplasms indication last August. —Regulators in Japan also approved an Aurion Biotech cell therapy for bullous keratopathy of the cornea, a vision disorder affecting the innermost cells of the corneal endothelium. This therapy, brand name Vyznova, provides an alternative to corneal transplants that rely on a tight supply of donated corneas. Aurion’s technology was initially developed by scientists in Japan and then licensed by CorneaGen. That Seattle company formed Aurion Biotech, which last year raised $120 million to finance U.S. clinical trials of the cell therapy. —The European Commission approved an Amicus Therapeutics drug for Pompe disease, a rare disorder in which patients lack a key enzyme called acid-alpha glucosidase. The enzyme deficiency leads to muscle weakness and a decline in lung function. Amicus will market its new product, an infusion, under the name “Pombilti.” Amicus’s Pompe drug is part of a two medicine regimen. Prior to the infusion, patients must take a pill intended to stabilize Pombilti and improve its uptake by muscles. Amicus said it expects a European Medicines Agency committee will issue an opinion for the treatment’s pill component, called miglustat, in the second quarter of this year. Both drugs are still under FDA review. —A Cidara Therapeutics antifungal received FDA approval. The affirmative regulatory decision for intravenously infused rezfungin, brand name Rezzayo, covers the treatment of candidemia and invasive candidiasis in adults who have limited treatment options for these infections. The drug is still under regulatory review in Europe. Rezzayo will be commercialized by Melinta Therapeutics, which acquired U.S. rights to the drug in 2021. Cidara licensed drug rights to Mundipharma for all other markets. Dealing With Rejection —Incyte’s approved myelofibrosis drug, ruxolitinib, failed to secure an additional approval for an extended-release formulation. According to Incyte, the FDA said while study results met the goal of showing bioequivalence to the currently available version of the drug, marketed as Jakafi. Without disclosing specifics, Incyte said the FDA “identified additional requirements for approval.” The company said it plans to meet with the agency to discuss the next steps. —The FDA rejected AbbVie’s application for its Parkinson’s disease treatment, ABBV-951. The drug/device combination product subcutaneously administers a solution of the prodrugs carbidopa and levodopa to treat the movement problems associated with Parkinson’s. According to AbbVie, the FDA asked for more information about the pump part of the product. No questions about safety or efficacy were raised, nor did the agency did not ask for another clinical trial. AbbVie said it plans to resubmit its application as soon as possible. I Need Advice —A Brainstorm Cell Therapeutics’ amyotrophic lateral sclerosis drug application that was sent back as incomplete will get a hearing in another forum—an FDA advisory committee. Last November, the FDA sent Brainstorm a refuse-to-file letter, telling the biotech that its application for the experimental ALS therapy, Nurown, needed more data. Prior to the submission of the biologics license application, the FDA recommended that the company run another clinical trial. Brainstorm responded by asking the agency to review the application anyway, a procedure called “file over protest.” This step returns the application to active review. Brainstorm said it has submitted an amendment to the application that responds to most of the agency’s questions. The FDA said it will convene an advisory committee to weigh in on the application. The date for that meeting has not yet been set. —An experimental Biogen drug for a rare form of amyotrophic lateral sclerosis caused by mutations to the SOD1 gene received a mixed recommendation from an FDA advisory committee. The drug, tofersen, is an antisense nucleotide designed to bind to and degrade SOD1 messenger RNA. Biogen has said trial results showing reductions in SOD1 protein and neurofilaments, filaments found in neurons that could be indicative of neurodegeneration, suggest the drug is slowing the disease’s progress. The advisory committee voted unanimously that reduction in neurofilaments in the blood is reasonably likely to predict benefit in ALS patients who have the SOD1 mutation. However, on the question of whether the available clinical data provide substantial evidence of the drug’s effects on such patients, three members voted yes, five voted no, and one abstained. The FDA’s target date for a regulatory decision is April 25. No Hold on Me Anymore —The FDA lifted a partial hold that had been in place on a Phase 1/2 test of BLU-222, an experimental treatment for advanced solid tumors. The drug is designed to block CDK2, an enzyme that is associated with tumor growth. The FDA’s partial hold on the study was due to visual adverse events reported in some patients. The company said it will now work with study investigators to resume enrollment. —Vigil Neuroscience had a partial clinical hold lifted on VGL101, an antibody drug in development for treating a rare leukodystrophy called ALSP. Though the FDA cleared the biotech to begin human testing of its drug in late 2021, the agency allowed dosing only up to 20 mg per kilogram of patient weight. The partial hold applied to doses higher than that limit. The company said the FDA lifted the hold on higher doses due to supporting data from the ongoing Phase 1 study. Don’t Say I Didn’t Warn You —The FDA issued a warning letter to a website hosted in Singapore selling ivermectin pills to U.S. customers for the unapproved use of treating Covid-19.

When Vigil Neuroscience filed its IPO papers in late 2021, the biotech revealed that the FDA had just cleared its Phase I trial — but with a partial clinical hold that limited dosing to under a certain level. More than a year later, the FDA has lifted the hold. Vigil is now free to dose VGL101, an antibody targeting TREM2, at levels higher than 20 mg/kg in its ongoing and future clinical trials in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), an inherited condition that affects the brain and spinal cord. “Although we believe that 20 mg/kg is a clinically relevant dose in ALSP, we are very pleased that the hold has been lifted as we believe it’s important to maintain optionality to develop treatments that support patients suffering from both rare and common neurodegenerative indications,” president and CEO Ivana Magovčević-Liebisch said in a statement. The biotech has tested the drug among both healthy volunteers and patients with ALSP in trials conducted in the US and Australia, where it’s been exploring doses above the 20 mg/kg threshold, up to 60 mg/kg. Data from the ongoing Phase I trial helped convince the FDA, according to the company. Stifel analyst Paul Matteis noted that ultimately, the higher doses may not be necessary, but it’s hard to tell until Vigil tests it. “That said, for monoclonal antibodies in the brain, more (up to a certain point) is often better, and given the safety so far, it seems reasonable that Vigil would continue to dose escalate further as trials in ALSP/Alzheimer’s progress,” he wrote. Vigil licensed VGL101 alongside a small molecule TREM2 agonist from Amgen after the big drugmaker decided to exit neuro. TREM2, believed to be a microglia sensor involved in transmitting signals to cells, is a target also being chased by companies like Alector .