BioArctic’s drug candidate, BAN2401 (out-licensed to Eisai), was discussed at the AAIC digital conference. Dr. Paul Aisen presented the design of AHEAD 3-45, a platform study of two clinical trials to test whether the antibody reduced amyloid levels in preclinical pre-symptomatic AD (Alzheimer’s disease) populations. Two groups of patients were tested: the A45 population of cognitively normal individuals with elevated amyloid beta (>40 centiloids*), pre-clinical, and the A3 population of cognitively normal individuals with intermediate amyloid (20-40 centiloids), early pre-clinical. The study is conducted as a public-private partnership with the Alzheimer’s Clinical Trials Consortium (ACTC) and Eisai.
Amyloid accumulation in the brain drives the initial spread of AD and monoclonal antibodies such as aducanumab, BAN2401, gantenerumab, donanemab, designed to target the aggregated forms of amyloid-beta, can slow down disease progression. The hypothesis is that if treatments start early before irreversible damage is done to the brain, the disease can be delayed.
The study is phase 2 and the treatment period is 4 years. Initially, for the first two years, patients are treated every 2 weeks, after year 2, once in 4 weeks with dose titration to minimise side effects. BAN2401 dosing is designed to halt amyloid accumulation (A3, phase 2 study) and reduce amyloid below threshold (A45, phase 3 study) during the first 2 years. The objective is to maintain normal amyloid levels for the duration with a clinical effect.
The study is designed to demonstrate a clear amyloid reduction and show an effect in the early stages of AD as measured by cognitive tests, biomarkers and PET imaging.
Other interesting contributions were the presentation about gosuranemab, a tau-targeting antibody from Biogen. The antibody has been developed to halt the spread of extra-cellular tau that causes the degeneration of neurons, in patients with early AD. Also, two amyloid-beta targeting antibodies in a clinical-stage of development: solanezumab (Eli Lilly) targeting soluble amyloid-beta monomers (did not meet primary endpoints, but showed efficacy signals at low doses for mild AD), and gantenerumab (Eli Lilly), a fully human antibody, with high affinity to aggregated amyloid-beta. Gantenerumab did not slow cognitive decline in symptomatic patients and had an inconclusive effect on asymptomatic participants. Also, we listened in a live session on aducanumab, Biogen’s antibody currently reviewed by the FDA.
In conclusion, the key takeaway is that the targeting profile and the stage of intervention seem to be the decisive factors in the success of an AD antibody (showing clinical effect measured by a variety of biomarkers), and also making sure that the antibody is administered to the right patient population. Whether the antibody targets amyloid-beta or tau, the earlier the intervention starts, the higher probability it has to show clinical effect.
Based on the results presented so far, we believe that BAN2401 has the best profile and clinical outcome, with very precise targeting, fast onset, no need for titration and only mild side-effects. However, our impression is that since 80% of clinical trials in AD have been affected by the c-19 crisis, the clinical study Clarity AD can possibly also be delayed (patients cannot get to the clinic, the medicine cannot be administered, etc). A solution could be mobile testing, where hospital staff visits the patients in their homes.
This confirms our view that the market underestimates BioArctic as a company, and that the stock is presently undervalued.
*a centiloid is a standardised measure for the presence of amyloid in the brain in PET scans, where a value of less than 10 reflects the absence of plaque (no Alzheimer’s) and a value higher than 50 confirms the diagnosis of Alzheimer’s disease.
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