Lilly's latest BACE setback embodies obstacles in Alzheimer's R&D

Eli Lilly
The news comes about five months after Lilly and AstraZeneca pulled the plug on two phase 3 trials of lanabecestat after an independent interim analysis deemed they “were not likely to meet their primary endpoints.” (Eli Lilly)

Eli Lilly is dropping a BACE inhibitor that was being tested in Alzheimer’s disease in combination with a second drug, a monoclonal antibody that binds to amyloid deposits in the brain. The news, disclosed in the company’s third-quarter earnings presentation, comes after the termination of two phase 3 studies evaluating a different BACE inhibitor, lanabecestat. 

The Big Pharma wasn’t forthcoming on specifics, referring only to the first drug as BACE IV, or LY3202626, and the second as LY3002813, or N3pG mAb. The pair were being evaluated as a combination in the TRAILBLAZER-ALZ study, which is also assessing N3pG alone in the treatment of Alzheimer’s disease, said Nicole Hebert, an adviser at Lilly R&D Communications, via email. 

The company’s decision to dump the BACE inhibitor is “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.” 

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It comes about five months after Lilly and AstraZeneca pulled the plug on two phase 3 trials of lanabecestat after an independent interim analysis deemed they “were not likely to meet their primary endpoints.” 

Lilly’s setbacks are not unique in the BACE space or Alzheimer’s R&D. Just this year, Eisai and Biogen’s BACE inhibitor reduced amyloid plaques but failed to improve clinical symptoms, while Merck’s BACE1 inhibitor verubecestat earned a negative interim review, leading the company to end a phase 3 study. Janssen also halted trials of its BACE inhibitor atabecestat. But it didn’t do so because of poor efficacy; in this case, liver safety issues made the drug's benefit-risk ratio “no longer favorable to continue development of atabecestat for people who have late-onset preclinical stage Alzheimer’s disease.” 

“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.”

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The mid- and late-stage failures of several BACE inhibitors echo a trend in the Alzheimer’s field, in which drugs that show early promise end up crashing in phase 3. There is a grave need for new hypotheses, as Alzheimer’s research has relied on amyloid plaques and tau tangles as targets, but has not seen a new treatment approved in more than 15 years. Denali Therapeutics, for one, is working on a RIPK1 inhibitor for the treatment of Alzheimer’s. But, as a Stat News article pointed out, academics pursuing new approaches often struggle to obtain funding and get their work published.