Roche, AC Immune’s Alzheimer’s Drug Joins Long List of Trial Flops
By T. Chakraborty, Ph.D.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by dementia. Approximately 5.8 million people are living with this disease in the USA alone. With a lack of disease-modifying therapies, and with the global aging population on the rise, biopharmaceutical giants have been scrambling for a long time to find cures .
One of the key pathological hallmarks of AD is the formation of neurofibrillary tangles (NFT). The major constituent of NFT’s is hyperphosphorylated tau. According to the tau hypothesis, tau, a cytoskeletal protein, is soluble in its native form. Mutation in tau leads to hyperphosphorylation, leading to the formation of aggregates and NFT, which can cause neurodegeneration. Based on this hypothesis, multiple biopharmaceutical giants have developed drugs targeting tau.
One of the major drugs targeting Tau is Semorinemab, an anti-tau IgG4 antibody. This drug was developed as a collaboration between Genentech and AC immune, a swiss company. On September 23rd, 2020, Genentech announced that the drug failed to meet its primary endpoint and secondary endpoint in Phase II clinical trial (TAURIEL) . This puts enormous pressure on the entire tau hypothesis.
TAURIEL is a Phase II randomized multicenter clinical trial to test if Semorinemab can inhibit the cognitive decline in early AD patients. This 73-week long study enrolled 457 patients across 97 centers. The drug failed to reach the primary endpoint, reducing the decline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) as well as two secondary endpoints, Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13) and Alzheimer’s Disease Cooperative Study Group – Activities of Daily Living Inventory (ADCS-ADL). The study did meet the safety endpoint as well. Additional analysis is underway, while the comprehensive data remains unreleased, but will be presented in the upcoming medical congress.
Andrea Pfeifer, CEO of AC Immune, commented, “Today’s news is surprising and disappointing, given what we as a field know about Tau and its strong spatiotemporal correlation with both symptoms and pathology in AD. We believe the full data analysis of this first-of-its-kind study will yield information about this promising target that will advance our understanding and inform future efforts to successfully develop effective therapeutics for neurodegenerative diseases. We would like to thank the patients, caregivers, and investigators who participated in this important, ground-breaking trial and look forward to the final results from our partner, Genentech.” 
Consequences of This Failure
This failed clinical trial came at a high cost to AC immune, with its stock plummeting by almost 50%. Also, Roche, Genentech’s sister company, had its stock decrease by 3.13 %. This failure may well have a domino effect on the industry, as multiple therapies targeting tau are in development. Currently, Roche has an ongoing trial LAURIET, with Semorinemab in moderate AD patients. Still, given that the patients are more advanced than in the TAURIEL study, it is unlikely to succeed. AbbVie’s antibody treatment, ABBV-8E12, is in Phase II and is targeting abnormal tau tangles. Roche has also partnered with UCB, UCB0107, which aims to block tau protein buildup in patients.
TAURIEL is not the first failure of its kind. Last year, Biogen’s humanized monoclonal antibody targeting tau also failed in a clinical trial. Further, LMTX, an inhibitor of Tau aggregation, flunked in the Phase III clinical trial in 2016. With the tau hypothesis still unproven, these failed clinical trials may lead to a change in strategy. In early 2018, biopharmaceutical giant Pfizer stopped all work in neurodegeneration, including AD. This move showed that clinical trial failures could be a huge financial burden to the companies forcing them to take drastic steps .
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