Donanemab

The FDA has required additional three-month immunogenicity data for Eisai and Biogen's subcutaneous Leqembi given as a weekly maintenance treatment for Alzheimer's disease. What analysts viewed as a potential “inflection point” for Eisai and Biogen’s slow-footed Leqembi is facing a delay with the FDA. That inflection point industry watchers have been waiting for is a more convenient injectable version of the two firms’ currently infused Alzheimer’s disease drug. But Eisai has been forced to delay filing of the subcutaneous formulation as the FDA is asking for more data that the company can’t immediately provide. The FDA has required additional three-month immunogenicity data for subcutaneous Leqembi given at a maintenance dose of 360 mg weekly, Eisai and Biogen said Monday. Eisai, which leads Leqembi efforts, first planned to start a rolling submission in March as it collects the additional data. But the FDA told the company that a fast-track designation for the under-the-skin formulation—separate from the infused version’s—is needed to enjoy rolling review. So Eisai had to first request that new designation, which the FDA will decide on within 60 days from the company’s March submission. Leqembi’s launch has been slow so far because of its complicated logistics related to diagnosis and treatment. The antibody drug currently needs to be infused every two weeks, a requirement that poses a burden on the healthcare infrastructure and the patients. As establishing those practices takes longer than expected, Eisai earlier this year said Leqembi likely won’t meet the goal to reach 10,000 patients by the end of March. Eisai and Biogen hope to alleviate the situation with less frequent infusions or a subcutaneous version. For the first part of that plan, Eisai on Monday filed with the FDA for approval of Leqembi as a monthly intravenous maintenance treatment after a biweekly-dosed initiation phase, the exact length of which remains under discussion with the FDA. For the injectable version, the two companies had hoped that bioequivalence on pharmacokinetics and similar brain plaque reduction would suffice for an FDA application. However, the agency is now asking for more immunogenicity analyses. The partners have also been expecting a separate filing for the subcutaneous formulation as a full treatment, including the initiation phase, in 2025. Back in October, data from an extension of the phase 3 Clarity AD trial showed that a subcutaneous injection of Leqembi cleared 14% more amyloid plaque in the brain of Leqembi-naïve patients at six months, although the rate of the side effect amyloid-related imaging abnormalities was slightly higher for the injectable. The subcutaneous delay is a “technicality,” William Blair analysts said in a Monday note to clients. Still, this will push back a potential filing to the second half of 2024—or even longer if the FDA denies it the fast-track designation, the team noted. In another recent setback, drug reviewers at the European Medicines Agency couldn’t discuss Leqembi’s application at a scheduled meeting last month because of “procedural reasons.” “[T]hese are technicalities in our view and do not undermine the potential of Leqembi,” the William Blair analysts said, “but they are disappointing delays for Biogen, which clearly needs to demonstrate better execution to improve investor sentiment.” At least Eisai and Biogen don’t have to worry about any immediate threat from a competitor. The FDA also postponed its ruling on Eli Lilly’ rival anti-beta-amyloid antibody donanemab. Rather than delivering a verdict by March, the FDA is now plotting an adivosry committee meeting to disuccss the Lilly drug’s data, and an exact date has not been provided. 

Pictured: Fractured time and melting clock/Taylor Tieden for BioSpace While the past few decades have seen a focus on treating Alzheimer's disease at the source, which is widely considered to be the build-up of amyloid fibrils and tau tangles, many companies are also chasing the first approval of a drug to treat the related psychosis. Anti-amyloid drugs like Eisai and Biogen’s Leqembi and Eli Lilly’s donanemab represent a leap forward, but many experts say success rates are modest, and Aduhelm, Biogen and Eisai’s first anti-amyloid treatment, was discontinued in January. Against this backdrop, companies are increasingly focusing on symptomatic treatments, said Graig Suvannavejh, a senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas. Using a financial model, Suvannavejh estimated that 35% of Alzheimer’s patients have psychosis. Even discounting patients who may not be diagnosed or have access to treatments, this translates to roughly 1 million patients in the U.S. alone, making for a large market opportunity, he told BioSpace. Unconventional Targets According to ClinicalTrials.gov, there are more than 600 active trials studying interventional treatments for Alzheimer’s disease, but fewer than 30 that focus on Alzheimer’s-related psychosis. Given the lack of options, Alzheimer’s patients who experience psychosis may be prescribed off-label antipsychotics approved for schizophrenia, said Christoph Correll, a professor of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. Most antipsychotics target the receptors of dopamine and serotonin, neurotransmitters that are common to many processes in the body. Because of this overlap between molecular pathways in the brain and the rest of the body, the drugs can cause side effects like excessive sleepiness, swallowing difficulties and uncontrolled movements. These effects make compliance an issue for Alzheimer’s patients in particular, who are likely on other medications and may be unwilling to tolerate additional side effects, Correll said. Christiana Bardon, a co-managing partner at MPM BioImpact, told BioSpace that the side effects associated with all antipsychotics are a significant complaint. “Patients who need the antipsychotics discontinue the drugs because of the intolerable side effects,” she said, and the dearth of tolerable treatments for Alzheimer’s patients with psychosis is “a huge unmet medical need.” This is particularly true as the prevalence of the condition increases. “We're having more and more patients develop not just agitation but also psychosis,” Bardon said. With this in mind, many companies are working to make better schizophrenia medicines, and some are repurposing these candidates for Alzheimer's-related psychosis. Karuna Therapeutics is developing KarXT for both schizophrenia and Alzheimer’s-related psychosis. KarXT combines xanomeline, which activates muscarinic receptors, and trospium, which prevents xanomeline from affecting muscarinic receptors outside the brain. This combination helps to prevent side effects like nausea, vomiting and diarrhea, according to the company. Having shown positive clinical trial results in schizophrenia, KarXT is now being tested in Phase III trials for Alzheimer’s-related psychosis. Andrew Miller, Karuna’s founder and president of research and development, told BioSpace the company has seen a “broad spectrum of benefits,” in Alzheimer’s patients, including a lessening of hallucinations and delusions and a reduction in aggression and vocal outbursts. Cerevel Therapeutics’ emraclidine also targets the muscarinic pathway. The candidate selectively binds only one type of muscarinic receptor and, like KarXT, affects the balance of neurotransmitters in the brain. Emraclidine is currently in Phase II trials for schizophrenia and is also in development for Alzheimer’s-related psychosis. A third candidate with an unconventional target is Axsome’s AXS-05, a combination of two drugs: dextromethorphan, which blocks NMDA receptors, and bupropion, which increases the bioavailability of dextromethorphan. Originally conceived as an antidepressant, AXS-05 is now in Phase III trials for Alzheimer’s-related agitation. Agitation usually comes across as physical restlessness or aggression, whereas psychosis involves hallucinations and delusion. The two can often overlap in Alzheimer’s patients but cannot be treated alike, Bardon said. “Agitation is the broader subset that we have to address, and then as the disease progresses, psychotic features may emerge as well,” she explained. Clinical Development Considerations A key sticking point when developing drugs for Alzheimer’s-related psychosis is a lack of biological information. “We don’t really know what the underlying biological mechanism of psychosis and Alzheimer’s is,” Correll said. Unlike in Alzheimer’s disease, there are no clear or unique molecular targets for the related psychosis, according to a 2022 article published in Nature Reviews Neurology. Some studies suggest that genes like APOEε4 and SUMF1 may be involved, but these links have not been substantiated. A lack of good animal models compounds this difficulty, hindering basic research, Bardon said. These uncertainties mean that drug-makers have no concrete targets to aim for. Even when repurposing known antipsychotics, companies must cater to older patients, who have different metabolic rates, require more tightly controlled doses and often have lower tolerability, Bardon explained. It is paramount to ensure safe side effect pro especially because older patients are more likely to also be on other medications, she said. Suvannavejh added that it is also imperative in developing these therapies to recruit a patient population that is as homogeneous as possible, whether by age or the severity of their Alzheimer’s disease or psychosis. When it comes to evaluating the endpoints of a trial, placebo effects are a major concern, Suvannavejh said. This is especially true for neuropsychiatric conditions, as patients may be more suggestible than in other disease areas. Companies must ensure that raters, who track patient responses and behaviors, are trained well and follow the same protocols across sites, Suvannavejh said. Finally, when using existing or new antipsychotics to treat Alzheimer’s-related psychosis, physicians must look closely at the trial data. Correll prioritizes safety and efficacy and then looks at the effect size, which he said is an indicator of the study’s strength. He is also keen to explore new mechanisms that can sidestep the rather overused dopamine and serotonin pathways. A drug with a novel mechanism may be worth testing even if it comes with some side effects, Correll said, as it would allow physicians to tackle the issue from new angles. Correll noted three key aspects of clinical trials in this space: testing drugs first on a small scale, selecting sites and patient populations to reflect the actual medical need and performing thorough follow-ups. These precautions inevitably translate to reliable and sound results, allowing physicians and regulatory bodies to make informed decisions, he said. Precedent Needed The increase in drug development in this space is emblematic of a renewed interest in neuroscience overall, Suvannavejh said. Small companies can focus exclusively on specific problems yet pivot when needed. This combination of focus and flexibility allows them to pursue neglected questions, he noted, paving the way for larger companies to take the solutions forward. Frontrunners Karuna and Cerevel have each been acquired by pharma giants, with Bristol-Myers Squibb paying $14 billion for Karuna and AbbVie putting up $8.7 billion for Cerevel in December 2023. Despite the increased activity, regulatory guidelines are still being established in this space. Although the FDA is working closely with companies, Miller said there is room for improvement. “I think having more clarity and understanding when you work with [regulators] is really important,” he said. Miller looks forward to seeing the first drug approval for Alzheimer’s-related psychosis. “It would establish a clear clinical trial and endpoint precedent,” he said. “I think it would also, importantly, be an example of success.” Sruthi S. Balakrishnan is a freelance academic editor, science writer and fact-checker based in Santa Barbara, California. She can be reached at sruthisb@sciscriber.com.