New trails on anti-Amyloid drug failed
Lanabecestat is a potent inhibitor of Amyloid beta (Aβ) formation – the main component of amyloid plaques. Aβ is formed through cleavage of amyloid precursor protein (APP) by proteases known as secretases (β and γ). The Beta-site-APP-cleaving enzyme 1 (BACE1) cleaves APP at the β-secretase site, after which APP is cleaved by γ secretase to generate Aβ peptides. Lanabecestat inhibits BACE1 and was able to reduce levels of Aβ1-40 and Aβ1-42 in the brain, cerebrospinal fluid (CSF), and plasma in several animal models, as well as in human CSF and plasma. Besides that, Lanabecestat is brain permeable meaning that an adequate amount of this substance is able to reach the brain after oral intake.
Taking these facts into account, two clinical trials were designed to test if the oral administration of Lanabecestat would be effective in two different groups of patients: patients with mild cognitive impairment (the AMARANTH study) and patients with mild AD (the DAYBREAK-ALZ study). The main question in both studies was: can Lanabecestat slow the progression of cognitive deterioration?
Unfortunately, both studies had to be earlier terminated because no benefits were found in the groups using the substance compared with the group taking placebo, only side effects were noted.
The substance was able to reduce Aβ levels in CSF and was associated to a greater reduction in Aβ plaques density compared to placebo. But no positive clinical effect was shown.
Even though Lanabecestat was generally well tolerated, psychiatric adverse events were numerically greater in treatment groups compared with placebo group and were consistent with dose dependence. Lanabecestat exposure was also associated with hair color changes and weight loss.
Full text: https://jamanetwork.com/journals/jamaneurology/fullarticle/2755347
In two new, randomized clinical trials, Lanabecestat (a potent Aβ inhibitor) did not slow cognitive or functional decline of AD compared with placebo. One more hope of treatment has failed. It appears unlikely that current BACE inhibitors will be an effective disease modifying treatment for symptomatic AD but future studies are still needed to determine if reduction in Aβ production can provide meaningful clinical benefit in earlier stages of the disease continuum or in other high-risk populations.
PREVENTION is still the best solution!