Eli Lilly and AstraZeneca today announced that they will end two ongoing Phase 3 trials of lanabecestat, a small-molecule BACE inhibitor the two companies have been developing jointly since 2014. According to the program’s independent data monitoring committee, a futility analysis showed lanabecestat would most likely miss the trial’s efficacy endpoint. The companies decided to scrap both the AMARANTH trial of 2,202 people with early AD and the DAYBREAK-ALZ trial of 1,899 people with mild AD dementia.
“This is indeed bad news. Together with other recently terminated trials, it emphasizes the view that BACE inhibitors are unlikely to be effective when used to treat symptomatic individuals,” said Stefan Lichtenthaler at the German Center for Neurodegenerative Diseases (DZNE) in Munich (see full comment below).
The setback comes after liver toxicity sank Janssen’s atabecestat (May 2018 news). Merck pulled the plug on verubecestat in prodromal AD when an interim analysis showed no glimmer of efficacy (Feb 2018 news), and Lilly, Roche, Pfizer, and Boehringer Ingelheim all have axed other BACE inhibitors in Phase 1.
Researchers emphasize that it is important to evaluate these BACE inhibitors in symptomatic patients to gather evidence of whether and at what stages of Alzheimer's long disease process they work. At the same time, they say, the approach of reducing Aβ generation stands the greatest chance of success during the presymptomatic 10–15 years of amyloid plaque buildup in the brain. “BACE inhibitors are likely to be more effective when used as a preventive approach,” said Lichtenthaler.
“As with Merck’s verubecestat, it appears that late-stage, i.e. symptomatic, AD is too late for robust benefit from a BACE inhibitor,” Paul Aisen, University of Southern California, La Jolla, wrote to Alzforum. “This does not mean that BACE inhibitors will not find a place in the prevention or very early treatment of AD. Some good news is that lanabecestat—like verubecestat but in contrast to atabecestat—was apparently well-tolerated without major safety concerns. This is particularly important for very early intervention before symptoms,” Aisen wrote (see full comment below).
Does today’s news mean lanabecestat is dead? Not quite. For the time being, Lilly and AstraZeneca are maintaining the alliance they had forged around this drug. They will close the two trials and analyze their data, according to Lilly spokesperson Nicole Hebert, but have not yet decided whether to launch prevention trials with this compound.
Lilly has a different BACE inhibitor in the clinic. LY3202626 is currently being studied together with Lilly’s anti-plaque N3pG-Aβ monoclonal antibody in the first combination trial of two investigational drugs in the AD field. This Phase 2 study enrolls people with memory loss but not yet dementia, who have both a positive amyloid and tau PET scan. The study will continue, Hebert confirmed, indicating that Lilly is not retreating from BACE inhibitors as a class. Other researchers in the field praise this combination approach, but caution that the patients in this trial also have subtle symptoms, hence have likely had amyloid plaques for years.
Two other BACE inhibitors are still active in single-drug trials. Last week, Eisai and Biogen reported that elenbecestat was safe in a small Phase 2 trial (June 2018 news), though its Phase 3 MISSION AD program of two large trials enrolls people with early symptomatic AD.
Novartis, Amgen, and the Banner Alzheimer’s Institute in Phoenix are going all-out to evaluate CNP520 in a genetically defined population. “My […] colleagues and I remain excited about our ongoing collaboration […] to evaluate […] CNP520 in Alzheimer’s Prevention Initiative (API) Generation Studies 1 and 2, including a proportion of cognitively unimpaired APOE4 homozygotes who have not yet demonstrated significant amyloid plaque burden before the treatment has started,” Eric Reiman of Banner wrote to Alzforum (see full comment below).
“A BACE inhibitor might still be the best pharmacological choice for prevention of patients at risk,” agreed Jochen Herms of the DZNE in Munich. “If long-term treatment with BACE inhibitors is without side effects, then I would take them were I at risk. So these studies, even though they failed in symptomatic AD, are very important for future patients, because they allow the field to get to know the possible side effects of BACE inhibition” (see full comment below).—Gabrielle Strobel
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