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An Alzheimer’s disease drug developed by AC Immune and Genentech has drawn conflicting phase II results this week, raising tentative hopes for the field of treatments targeting the protein tau. For decades, the major culprit responsible for Alzheimer’s disease was suggested to be the buildup of a protein called amyloid-beta in the brain. Blocking this protein from forming ‘plaques’ should theoretically slow the cognitive decline of patients. However, a string of clinical failures — barring a controversial FDA approval of Biogen’s Aduhelm this year — cast doubt on the amyloid hypothesis. One of the most prominent alternatives to the amyloid hypothesis involves a protein called tau. Pathological forms of this protein in the brain are thought to correlate with the progression of Alzheimer’s, indicating this could be a suitable drug target. This week, the Swiss biopharma company AC Immune and its US partner, the Roche-owed Genentech, had a bittersweet experience with targeting tau. Their anti-tau antibody semorinemab yielded both positive and negative results in a phase II trial in people with Alzheimer’s disease. According to one established measure of patient cognition, the drug slowed cognitive decline by an impressive 43.6% compared to placebo. But in a measure of how independently the patient can function in their day-to-day life -- assessed by caregivers -- semorinemab had no statistically significant impact. “Alzheimer’s disease is a chronic, slow-moving, complex, multifactorial disease. Much like cancer, multiple carefully timed therapeutic interventions may be required to stop and, ultimately, reverse disease progression,” said Andrea Pfeifer, CEO of AC Immune. “So it’s not surprising that the data are not completely clear and this is not uncommon for results of studies at this early stage of development to be inconclusive.” Pfeifer also pointed out that the trial followed patients for less than a year, which could have been too short to see signals in the other endpoints. Genentech has therefore decided to proceed with an open-label extension study of undisclosed length to tease out more clues. This trial readout for semorinemab was a better outcome than the first phase II trial last year, which used a different primary measure to those of the current trial and failed to find a benefit of the drug. In response, AC Immune’s Nasdaq stock price briefly spiked by 70% on Tuesday this week, and has since returned to its original price. https://twitter.com/ka_blankenship/status/1432671256688709632 Endpoints’ Managing Editor, Kyle Blankenship, references the controversial approval of Aduhelm. AC Immune and Genentech’s latest results arrive in a time of major controversies in the Alzheimer’s field. One example is the FDA’s decision to approve Aduhelm earlier this year based on mixed clinical evidence, and another is the US biotech Cassava Sciences recently fighting claims of data manipulation surrounding its Alzheimer’s disease candidate. Pfeifer sees the FDA’s decision to approve Aduhelm as an important precedent for companies looking to navigate the complex regulatory landscape in neurodegenerative disease. “We believe it is necessary to continue to adapt as more knowledge about the disease, relevant biomarkers, and clinical endpoints become available,” she said. “The FDA’s decision signals that they are adapting and their posture significantly bolsters the opportunity for drug development in Alzheimer’s disease, which is in the best interest of patients.” Tau is a central target in a range of neurodegenerative diseases such as frontotemporal dementia and progressive supranuclear palsy. European companies targeting tau in Alzheimer’s disease include Axon Neuroscience — a Slovakian firm developing an anti-tau vaccine — and the Swiss biotech Neurimmune, whose anti-tau antibody is being developed by Biogen in phase I trials. The most advanced tau-targeting drug in development is LMTX, a small molecule developed by the Singapore- and Scotland-based TauRx Therapeutics. LMTX had its own share of mixed results in a phase III trial in 2016; the drug failed to slow the cognitive decline of Alzheimer’s patients, though the firm claimed success in a small group of patients that took no other Alzheimer’s medication. Results from another phase III trial are expected next year. One obstacle for those developing tau-based approaches to Alzheimer’s treatment is that there are many different types of tau targets that could be involved in neurodegenerative disease. “Tau forms come in many flavors in Alzheimer’s disease and other tauopathies,” said Virginie Buggia-Prevot, Senior Research Scientist at the University of Texas, US, who isn’t involved in the development of AC Immune’s antibody drug. “In addition, these tau isoforms can vary patient to patient. One hurdle to target tau therapeutically is to target the ‘right’ one.” One emerging trend in the development of Alzheimer’s treatments is to explore more holistic strategies, such as targeting inflammation in the brain or developing cocktails of drugs targeting both amyloid-beta and tau. “Many key opinion leaders have begun to support the idea that combination therapies are going to be required to successfully treat Alzheimer’s disease, a strategy that was pioneered and is now common in the treatment of cancer, HIV, and other diseases,” said Pfeifer. Others speculate that it’s better to catch Alzheimer’s disease early, before the damage becomes irreparable. The biggest challenge to this mission is the fact that a diagnosis can currently only be confirmed after death. However, more modern diagnostic techniques are in development, such as non-invasive imaging and the detection of biomarkers in the blood, cerebrospinal fluid, and saliva. In May last year, for example, the FDA approved flortaucipir, the first radiodiagnostic drug to detect tau tangles in the brain using positron emission tomography. If these early diagnostics prove effective, we could one day have a reliable starting point from which to bring in a new wave of Alzheimer’s treatments. This is an update of an article originally published on 29 September 2020. Cover image via Elena Resko

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