Hereditary Diffuse Leukoencephalopathy With Spheroids

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 .

Amylyx Pharmaceuticals has joined the public markets with a $190 million IPO that will support the company as it shepherds its amyotrophic lateral sclerosis drug through regulatory review, and if all goes well, a commercial launch as a new treatment for the neuromuscular disorder. Cambridge, Massachusetts-based Amylyx boosted the size of the offering by 1.25 million shares. Initially planning to offer 8.75 million shares, Amylyx ended up offering 10 million shares at $19 apiece, which was the midpoint of the targeted $18 to $20 range. Those shares began trading on the Nasdaq Friday under the stock symbol “AMLX.” There was no pop for Amylyx’s stock price, which closed its first day of trading at $18.07. Amylyx aims to treat ALS by addressing the death of neurons. The company’s drug, AMX0035, is comprised of two small molecules that each take a different approach to pathways associated with neuronal survival. The company contends that the two mechanisms combined offer the potential to help neurons live longer. In a placebo-controlled Phase 2 study, patients treated with the Amylyx drug showed improvement on measures of physical function in ALS patients. Based on those results, Amylyx submitted a new drug application to the FDA. Last week, the agency accepted that application under priority review and set a June 29 target date for a regulatory decision. Before the FDA makes a decision, it will convene an independent panel of experts to discuss AMX0035’s safety and efficacy as well as any scientific questions regarding the drug. The date for that advisory committee meeting has not yet been set. In the meantime, a larger Phase 3 study is underway. The FDA went back and forth on whether the larger study was needed to support a drug application. Though the agency ultimately concluded that Amylyx could seek approval based on the Phase 2 data, the company is proceeding with the late-stage study to generate additional data on the drug’s safety and efficacy as it pursues regulatory approvals in other markets around the world. According to the IPO filing, Amylyx traces its beginnings to a Brown University dorm room where, in 2013, co-founders Josh Cohen and Justin Klee set out to find an answer to the question of why neurons die. The duo’s research led to development of AMX0035, the company’s only drug candidate so far. Though ALS is the drug’s first disease target, Amylyx notes that improving neuron survival has potential applications in many neurodegenerative disorders. A clinical trial is already underway testing AMX0035 in Alzheimer’s disease and tests in Wolfram disease are also planned. Since its formation, Amylyx has raised about $234 million, most recently a $135 million Series C round of funding last July. Morningside Venture Investments is Amylyx’s largest stockholder, owning an 18.9% post-IPO stake, according to the prospectus. ALS Invest 1 owns 10.8%, while Viking Global Investors owns 8.8%. As of the end of the third quarter of 2021, Amylyx reported a $125.7 million cash position. Combined with the IPO proceeds, the company plans to deploy about $100 million of its capital toward the regulatory review process of AMX0035 in ALS, as well as preparation for the potential launch of the drug—if it’s approved. Another $15 million is set aside to fund the ongoing Phase 3 clinical trial through to completion; $10 million is earmarked for expanding the company’s drug pipeline to other neurodegenerative disorders. Two more biotechs joined the public markets in the first week of the new year. Here’s a look at the IPOs of CinCor and Vigil Neuroscience. CinCor’s upsized IPO brings in $194M for hypertension drug trials Patients who have high blood pressure can choose from a wide range of hypertension drugs, many of them older medicines and a few of them new. In many cases, these drugs aren’t enough to help patients control the condition. CinCor is developing a drug that offers a novel approach to hypertension and other cardiovascular and kidney conditions, and it has raised $193.6 million to clinical development of its most advanced program. Late Thursday, Boston-based CinCor priced its IPO at $16 per share, which was the midpoint of the company’s projected price range. CinCor was able to boost the size of the deal, offering 12.1 million shares, up from the 11 million shares the company had planned. CinCor began trading on the Nasdaq on Friday under the stock symbol “CINC.” Standard of care hypertension drugs include angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), both of which work by lowering levels of the blood pressure regulating hormone aldosterone. CinCor notes in its IPO filing that treatment with these drugs over a long period of time can lead to “aldosterone breakthrough,” in which levels of the hormone in the blood return to or exceed baseline levels. Mineralcorticoid receptor antagonists (MRAs) can lead to an increase in the synthesis of aldosterone, which then requires higher doses of the drug to compensate. But MRAs introduce multiple side effect risks. CinCor’s lead drug candidate, CIN-107, is a small molecule designed to block the production of aldosterone by targeting the enzyme responsible for that hormone’s synthesis in the adrenal gland. The drug has reached Phase 2 testing in patients whose blood pressure is uncontrolled despite prior treatment with three antihypertension drugs. A separate Phase 2 study is was recently started in patients with uncontrolled hypertension despite treatment with one antihypertension agent. CinCor said in the filing it is also developing the drug for primary aldosteronism, a hormone disorder that occurs when too much of the hormone is produced. Another potential application of the drug is easing the complications associated with chronic kidney disease. CinCor formed in 2018 as a subsidiary of CinRx Pharma, a Cincinnati-based biotech company whose business model is acquiring a drug assets and advance them to the point of an exit, such as a licensing deal, a joint venture, or an IPO. In 2019, CinCor spun out as an independent company and licensed its lead drug from Roche. According to the prospectus, CinCor had raised $185 million prior to the IPO. Most of that cash was raised in October when the company closed a $143 million Series B funding round. The company’s largest shareholder is Sofinnova Investments, which owns a 14.8% post-IPO stake. Sofinnova Partners and 5AM Ventures each own 10.9%, while CinRx owns 8.1%. At the end of the third quarter of 2021, the company reported a $141.7 million cash position. In its prospectus, CinCor said it planned to spend about $90 million to advance CIN-107 through the completion of Phase 2 testing in patients with uncontrolled high blood pressure. Another $37 million is budgeted for advancing that drug through a separate mid-stage testing in primary aldosteronism. CinCor also plans to start a Phase 2 test enrolling chronic kidney disease patients who have uncontrolled blood pressure. That study is expected to begin in the first half of this year. Vigil nabs $98M to test new approach to rare neuro disorder Vigil Neuroscience, a company developing a treatment for a rare inherited neurological disorder that has no FDA-approved therapies, now has $98 million to bring its drug into its first test in humans. The biotech offered 7 million shares for $14 apiece, which was below the $15 to $17 price range that the company had planned. Those shares began trading on the Nasdaq on Friday under the stock symbol “VIGL.” The disease target of Cambridge, Massachusetts-based is adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). The rare disease is a type of leukodystrophy, a disorder that leads to a wasting away of the white matter of the brain. The neurodegeneration of ALSP leads to changes in personality, cognition, and muscle function. The decline progresses to dementia and eventually, a vegetative state. According to Vigil, estimates place the affected U.S. population at 10,000 people. ALSP stems from a mutation to the gene that produces colony stimulating factor 1 receptor, a protein expressed on the surface of microglia and macrophages, both of them immune cells found in the central nervous system. In the IPO filing, Vigil notes that colony stimulating factor 1 receptor shares a downstream signaling pathway with another protein, TREM2. Vigil aims to compensate for the loss of function in microglia by targeting TREM2. Vigil’s drug, VGL101, is an antibody designed to activate TREM2. A Phase 1 test in healthy volunteers began last month. Vigil said in the IPO filing that it expects preliminary data will become available in the second half of this year. Vigil formed in 2020, co-founded by venture capital firm Atlas Venture. The company licensed intellectual property for TREM2-targeting molecules from Amgen. In addition to the antibody approach taken by VGL101, the biotech is also developing a small molecule drug to target TREM2. According to the filing, Vigil had raised $120 million prior to the IPO, most recently a $90 million Series B round in August. Atlas is Vigil’s biggest shareholder, owning an 18.7% stake, according to the prospectus. Northpond Ventures and Vida Ventures own 13.6% and 11.8% respectively. Amgen’s stake is about 11.3%. At the end of the third quarter of 2021, Vigil reported having $110.6 million in cash. Combined with the IPO proceeds, Vigil plans to spend about $105 million to advance the development VGL101 in ALSP and other rare leukoencephalopathies and leukodystrophies. Another $30 million is planned for research on small molecules that could treat neurodegenerative diseases associated with microglial dysfunction, while $20 million is set aside for additional R&D.