While competitor Eli Lilly has abandoned commercialisation of its Alzheimer’s therapy solanezumab due to lack of efficacy in a pivotal Phase III study, Genentech has tabled data supporting further development of its Phase III drug crenezumab. The anti-Abeta antibody is highly homologous to solanezumab.
Mixed results have shaken confidence in Amyloid-beta antibodies designed to slow neurodegeneration in Alzheimer’s patients. According to Geoffrey Porges, analyst at Leerink Swann & Co, “the failure of Eli Lilly’s solanezumab in patients with mild Alzheimer’s disease has reduced confidence in the amyloid hypothesis”. He downgraded the probability of Amyloid-beta therapies to reach the market from 65% to 35%. As a reaction, developers of the remaining Amyloid-beta antibodies in Phase III development, Genentech (crenezumab) and Biogen (aducanumab, BIIBO37) have presented data that suggest safety and efficacy of their compounds.
At the 9th Clinical Trials on Alzheimer’s disease Conference (CTAD) in San Diego, Genentech presented data from a Phase Ib safety study and an exposure-response model that suggest an improved outcome of the CREAD Phase III trial in patients with mild Alzheimer’s forms by using a dose of 60mg/kg of crenezumab. This dose has been used since January 2016, when Phase III trails with the humanised antibody that binds Abeta40-42 oligomers started. Data from the two first cohorts of an crenezumab dose escalation study showed no dose-limiting toxicities and no occurence of Amyloid Related Imaging Abnormality-Edema (ARIA-E). According to Genentech, there were no discontinuations related to the antibody, licenced from AC Immune in 2006.
Prior to Genentech’s announcement, Biogen presented new analyses of Phase Ib data at the same meeting suggesting that aducanumab cleared amyloid plaques and improved cognition. All doses of aducanumab being tested within the study significantly reduced amyloid plaques vs. placebo after 54 weeks. The highest dose of the human antibody significantly improved Clinical Dementia Rating-Sum of Boxes, the endpoint Biogen had chosen for its ongoing Phase III trail. However, three deaths and five ARIA-E cases were reported from the study, which enroled 197 Alzheimer’s patients. Aducanumab is thought to target aggregated forms of amyloid-beta, including soluble oligomers and insoluble fibrils deposited into amyloid plaques.
