AXON Neuroscience Archives

AC Immune and Genentech’s drug has failed to slow the progression of Alzheimer’s disease in phase II. Is it time to look for other strategies in this failure-rife field? For decades, the major culprit responsible for Alzheimer’s disease was thought 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 resurrection of a drug by US firm Biogen -- has 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, so this could be a suitable drug target. But last week, this alternative hypothesis hit a bump in the road. The first phase II results ever for an anti-tau antibody drug against Alzheimer's disease found no benefits of the drug on the disease progression. The drug’s developers, the Swiss biopharma company AC Immune and its US partner Genentech, are reeling. AC Immune, for instance, took an almost 50% hit to its stock price. So why didn’t the drug help Alzheimer’s disease patients? “We are both surprised and disappointed by the top-line results of the trial and look forward to the detailed data,” said Andrea Pfeifer, AC Immune’s CEO. “It is still a little early to give a conclusive answer to this.” Genentech plans to reveal more in-depth data -- including medical imaging measuring tau protein levels in patients’ brains -- at an upcoming medical congress. “What I’m looking forward to learning from this presentation is how well the antibody was able to get rid of pathological tau in the brain,” said Virginie Buggia-Prevot, Senior Research Scientist at the University of Texas, US, who isn’t involved in the development of the antibody drug. “This strategy was designed to target tau when it spreads outside the cells, based on mouse model data. Was the antibody able to effectively do this in patients?” This isn’t the first clinical failure of an anti-tau drug for Alzheimer’s. The most advanced failure was that of LMTX, a small molecule developed to inhibit the aggregation of tau by the Singapore- and Scotland-based TauRx Therapeutics. According to phase III results, LMTX failed to slow the cognitive decline of Alzheimer’s patients in 2016, though it did seem to benefit a small group of patients that took no other Alzheimer’s medication. Phase III development of LMTX is still ongoing, in spite of the mixed results so far. So does the failure from AC Immune and Genentech mean that we should abandon tau approaches? Not necessarily; there are many different ‘flavors’ of tau targets that could be involved in Alzheimer’s disease. “[The failure] should motivate us to better understand which tau species we need to target therapeutically,” said Marc Aurel Busche, who leads an Alzheimer’s disease research team at University College London. Buggia-Prevot echoed this sentiment, adding that different tau types can vary from patient to patient. “In other words, this antibody may just not target the right forms of tau or may work only on a subset of patients.” There are a huge number of companies worldwide developing Alzheimer’s treatments that target tau. Examples in Europe 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 impact of AC Immune and Genentech’s disappointing phase II results on the operations of other tau-focused companies is unclear. “It could make investors a bit wary of investing in tau strategies,” noted Buggia-Prevot. “Encouraging data from this trial would have certainly increased enthusiasm.” That said, tau is also a central target in other neurodegenerative diseases such as frontotemporal dementia and progressive supranuclear palsy. Companies developing anti-tau treatments for these conditions could still bear fruit going forward. “It is important to pursue tau as a therapeutic target and I am hoping that this failure does not change things,” Busche told me. A common suggestion is that the tau and amyloid-beta hypotheses might be too limited in scope to tackle Alzheimer’s disease, which is a hugely multifaceted condition. Instead, additional strategies should be explored, such as targeting inflammation in the brain. “Most of the genetic risk factors for Alzheimer’s disease are actually modulating the inflammatory response of microglia, the immune cells of the brain,” said Buggia-Prevot. For example, the German biotech Vivoryon Therapeutics is developing a phase II-stage small molecule drug that blocks a protein called QPCT. This protein processes toxic forms of amyloid-beta and also enhances the inflammatory activity of pathological tau proteins. Blocking this protein could therefore attack Alzheimer’s on multiple fronts. “[Our drug] is, to our knowledge, the only therapeutic approach in clinical development that addresses all three of the most prominent pathological hallmarks of Alzheimer’s disease: amyloid-beta, tau, and neuroinflammation,” said Michael Schaeffer, Chief Business Officer of Vivoryon Therapeutics. Another way to hit different Alzheimer’s hallmarks at once is by combining multiple treatments together, such as cocktails of anti-amyloid-beta and anti-tau drugs. “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. “Tau is probably a very late target to intervene,” tweeted Karthikeyan Balakrishnan, Senior Scientist at the University of Ulm, Germany. “[It’s like] offering a hand during a free fall, the damage is already done.” The biggest challenge to introducing early detection and precision medicine into the treatment of Alzheimer's is the fact that a diagnosis can currently only be confirmed after death. But this situation could start to change. In May, for example, the FDA approved flortaucipir, the first radiodiagnostic drug to detect tau tangles in the brain using positron emission tomography. On top of amyloid-beta and tau, we could one day see tests for other potential Alzheimer’s indicators such as inflammation and altered iron metabolism. Efforts are even ongoing to develop a way to detect the condition in the blood. If these new diagnostics prove effective, we could one day have a reliable starting point from which to bring in a new wave of Alzheimer’s treatments. Image from Elena Resko

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