Another Beta-Secretase 1 (BACE) Inhibitor Phase 3 Trial Stopped


A trial of investigational drugs LY3202626 and LY3002813 (also known as N3pG mAB) (BACE IV; Eli Lilly, Indianapolis, IN) in combination for patients with Alzheimer’s disease (AD) has been terminated by the manufacturer of the drugs. Termination of the this arm of TRAILBLAZER-ALZ trial (NCT03367403) was disclosed in Eli Lilly’s third-quarter earnings presentation. The trial was testing LY3002813, a beta-secretase (BACE) inhibitor in combination with the monoclonal antibody to amyloid (N3pG) and N3pG alone. The trial arm of N3pG alone versus placebo will continue. 

Specific reasons for terminating the trial were not given; the company instead stated that it was “based on several factors, including the totality of Lilly and non-Lilly evidence related to the safety and efficacy of BACE inhibitors as a class,” Hebert said. “In this context, the potential risk-benefit profile has evolved since the decision to include BACE IV in this study. While the trial will continue with N3pG as monotherapy vs. placebo, it is unfortunate that this BACE IV dosing regimen used in combination isn’t an option for patients.” 

Several other phase 3 trials of BACE inhibitors were terminated for lack of results or safety issues this year, including lanabecestat (Eli Lilly and AstraZeneca,Cambridge, MA), verubecestat (Merck, Kenilworth, NJ) and atabecestat (Janssen, Malvern, PA). In a clinical trial of E2609 (Eisai, Woodcliff Lake, NJ and Biogen, Cambridge, MA), another BACE inhibitor a reduction in amyloid plaques was seen but without meaningful clinical change.  

“Regarding the BACE class, there was significant scientific presentation and discussion at the CTAD meeting in late October about the class,” Hebert said. “There are many variabilities at play with the class and recent findings from Lilly and others have challenged the BACE hypothesis, and as a field we are still evaluating the BACE class. We look forward to continued robust scientific discussion with others in the field about the viability of this class.”

Many companies are continuing trials of monoclonal antibodies to amyloid in its multiple forms, and some researchers suggest new or modified pathophysiologic hypotheses are needed to increase the number of drugs in development. Others are focusing on the need to understand the course and pathophysiology of AD earlier, before clinical symptoms are seen, in order to develop new and better therapeutic targets. 


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