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2022 has provided mixed fortunes for companies aiming to slow Alzheimer’s disease. Ulrich Dauer, CEO of the German biotech Vivoryon, explains the lessons these events provide. The quest for a treatment to slow the progression of Alzheimer’s disease has endured decades of disappointments. The most common treatment strategy -- clearing up harmful deposits, or “plaques,” of the protein amyloid beta (Abeta) from the brain -- has yielded many clinical failures. Even when Biogen’s Abeta-clearing antibody Aduhelm was controversially approved by the U.S. Food and Drug Administration (FDA) in 2021, the U.S. Centers for Medicare and Medicaid Services (CMS) restricted reimbursement of Aduhelm to patients with Alzheimer’s that are enrolled in clinical trials. This vastly limited the profitability of the drug. “Aduhelm was approved based on a surrogate [endpoint], which is the plaque-removing potential,” noted Ulrich Dauer, CEO of the German biotech Vivoryon Therapeutics, which is developing a small molecule drug to slow Alzheimer’s disease. “It has not been proven yet whether this really translates into patient benefit.” The field faces mixed clinical results After disappointing clinical outcomes in the Alzheimer’s field, 2022 saw a positive development when the antibody drug lecanemab slowed clinical decline in patients with Alzheimer’s disease in a phase 3 trial in September. The phase 3 results, released by Biogen and Eisai, were statistically significant and were observed using an established clinical endpoint called the clinical dementia rating sum of box score (CDR-SB). The CDR-SB is a composite metric of cognition and the ability of the patient to live independently. Dauer explained that this trial was a vital sign that targeting Abeta can improve the progression of patients with Alzheimer’s disease. In addition, it is notable that lecanemab targets Abeta at an earlier stage of the Abeta pathology than other drugs, before the protein aggregates into plaques. “We are excited to see what the authorities will make of it,” said Dauer. “I can only hope that it is approved and breaks the ice because what we really believe is that the Alzheimer's field will develop in a similar way to the cancer field: different approaches and combinations. But we first need a successful frontier.” However, the Alzheimer’s Abeta antibody space was hit with another clinical failure in November 2022. Roche’s gantenerumab failed to slow the progression of Alzheimer’s disease in two phase 3 trials. Though the results were a big setback for Roche, they could inform future efforts to tackle the complex condition. “It is critical for all of us in the field to learn from each other, whether it’s from successes, like the lecanemab data, or from challenges and setbacks, such as the recent gantenerumab readout report,” said Dauer. He added that gantenerumab acts on the Abeta pathology at a later stage than lecanemab, which could partially explain the different outcome. Vivoryon’s candidate in the race Vivoryon has its own lead candidate drug for Alzheimer’s, called varoglutamstat. Unlike many antibodies in late-stage clinical trials for treating Alzheimer’s disease, the small molecule drug is designed to slow the disease by acting on multiple biological pathways, not just Abeta. Varoglutamstat also blocks the pathology earlier in the process than leading antibody candidates, and can be taken orally -- a more convenient drug delivery than injecting or infusing antibody drugs. “We haven't seen any kind of amyloid-related imaging abnormality (ARIA), a limiting side effect of these plaque-removing antibodies which leads to microbleeding,” added Dauer. “The application of those antibodies is really limiting.” Vivoryon is testing varoglutamstat in two late-stage clinical trials. One phase 2b study is being carried out in Europe, and a full data readout is expected in early 2024. Another phase 2a/b study is recruiting patients in the U.S., with updates pending next year. While Vivoryon’s focus is on developing the drug as a monotherapy, Dauer explained that the drug could also be used in conjunction with emerging antibody treatments. Image/Shutterstock Lessons from Alzheimer’s drugs’ clinical performances One of the main results from Aduhelm’s controversial approval is a debate about the most relevant endpoints to use in clinical trials. In the case of Aduhelm, the FDA accepted the plaque-removing potential of the drug as a surrogate endpoint for clinical benefits. However, the industry is revisiting the most appropriate endpoints to use in clinical trials in Alzheimer’s disease. One endpoint pursued by Vivoryon is the CDR-SB. While Dauer sees the endpoint as a good composite metric, it has its downsides. “For the CDR-SB, you need raters,” he said, adding that most raters are physicians in clinical trials. “The larger the trial is, the more raters you need. You have to make sure that they are really aligned with the criteria.” Another key debate from the mixed clinical results from the Alzheimer’s field is: are we intervening too late for these patients? “When you look at Alzheimer's disease pathology, it starts to kick in even years before you see the first symptoms,” observed Dauer. “This is a challenge because that's the basic principle of treatment of all these diseases: the earlier you intervene, the higher the chances that you get efficacy.” While intervening years earlier in the pathology seems a simple concept, identifying people that will develop Alzheimer’s disease in the future is a complex puzzle. Patients are currently detected when they start presenting symptoms. “The principle of an earlier intervention is still attractive and will increase with growing progress in diagnosis,” said Dauer. “For the time being, we have to focus on those patients that are ready to see the doctor and try to treat them.” The positive impact While clinical results in 2022 have been mixed for the Alzheimer’s field, they have also benefited companies in the sector. Amid troubled public markets, firms like Vivoryon have been able to bankroll their clinical development as lecanemab buoyed investor interest. “If you look back three years ago, no investor was even convinced that it's possible to get a drug approved in Alzheimer's disease,” said Dauer. “This certainly has changed with Aduhelm and lecanemab.” Additionally, Eli Lilly’s antibody donanemab could intrigue more investors, as it is in a phase 3 trial with results expected in 2023. This upswing in investor interest coincides with big pharma’s determination to be in the race to an effective Alzheimer’s treatment. Whichever company unlocks this goal could tap into a market of a similar size to that of cancer treatment, but with much fewer approved treatments. Obstacles and excitement There remain challenges for companies like Vivoryon in the development of Alzheimer’s treatments. For example, large patient cohorts need to commit to clinical trials of up to 96 weeks, which can be difficult. “It's a merciless disease with a merciless progression, but the progression is relatively slow and you need those long treatment times,” said Dauer. In addition, infectious diseases like COVID-19 can threaten patients, who are typically more vulnerable to these infections than the general population. In spite of the challenges and mixed results, however, Dauer sees a lot of progress on the horizon for the Alzheimer’s field. This is particularly the case for alternative approaches to Abeta, such as targeting inflammation in the brain and harmful forms of the protein tau. “Alzheimer's is a complex disease,” said Dauer. “It's not just one particular pathology that promises a successful strategy. You have to understand the disease as a whole.”

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