Amgen and Novartis Halt BACE Inhibitor Trial; Eisai/Biogen’s Elenbecestat Emerges as Last Hope in Alzheimer’s Pipeline

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Alzheimer’s disease has long been a major challenge in new drug development, with a failure rate exceeding 99%. In recent years, multiple monoclonal antibody drugs targeting beta-amyloid, backed by billions of dollars in investment from pharmaceutical giants including Eli Lilly, AstraZeneca, Johnson & Johnson, Pfizer, and Roche, all suffered dismal failures in Phase III clinical trials, casting a heavy shadow over the investment outlook in this field. Subsequently, another promising class of new drugs—BACE inhibitors—successfully replaced antibody therapies to take center stage in Alzheimer’s disease research and development.

BACE (β-amyloid cleaving enzyme) is a key enzyme in the production of β-amyloid. Targeted inhibition of BACE can reduce the production of β-amyloid, which is believed to decrease the formation of amyloid plaques in the brain caused by toxic oligomers and protofibril aggregation. This may have potential disease-modifying effects, thereby slowing the progression of Alzheimer's disease.

However, BACE inhibitors also seem unlikely to break the curse. In early 2018, Merck & Co., the leader in the BACE field, announced the termination of the Phase III clinical program for verubecestat; in June 2018, Eli Lilly and AstraZeneca jointly announced the termination of the global Phase III program for lanabecestat. The reasons for terminating both drug programs were identical: after evaluation by an independent data monitoring committee, it was concluded that these projects were unlikely to achieve their primary endpoints even if completed.

Recently, the BACE field suffered another major setback as Amgen, Novartis, and the Banner Alzheimer’s Institute jointly announced the termination of the pivotal Phase II/III clinical study of the BACE1 inhibitor CNP520 (umibecestat) in the Alzheimer’s Prevention Initiative Generations Project (APIGP). The project aimed to investigate the safety and efficacy of CNP520 in preventing or delaying the onset of Alzheimer’s disease in patients assessed to be at high risk of developing symptoms based on age and genetic status. The decision to terminate was made because an evaluation of unblinded data during a regular, pre-planned review revealed that certain measures of cognitive function declined more rapidly in the CNP520 treatment group than in the placebo group.

Amgen and Novartis entered into a strategic collaboration in August 2015 to develop innovative therapies for Alzheimer’s disease. Researchers from both companies were well aware of the issues that emerged in early clinical trials of BACE inhibitors; however, these issues were not observed in the early studies of CNP520. Regarding the termination of the APIGP program, investigators have been informed of the decision and will contact study participants to discontinue treatment and discuss next steps, including follow-up visits as appropriate. The three parties will conduct further analyses to better understand the data from the APIGP program.

In addition to CNP520, two other monoclonal antibody drugs targeting beta-amyloid—crenezumab, developed by Roche and AC Immune, and aducanumab, developed by Eisai and Biogen—also failed in Phase III clinical trials earlier this year and were subsequently discontinued. These failures appear to have clearly delineated the boundaries of the beta-amyloid hypothesis.

Currently, only one major drug program remains in the BACE inhibitor field: elenbecestat, developed by Eisai and Biogen. In a small-scale clinical study, the drug demonstrated positive effects on cognitive improvement, with no signs of neuropsychiatric symptoms or accelerated brain atrophy. In March this year, elenbecestat successfully passed its eighth safety review, allowing the Phase III program to continue advancing. The drug has been hailed as the “last hope” in the BACE inhibitor field.

According to statistics from the World Health Organization, there were more than 36 million Alzheimer’s disease patients worldwide as of 2012, and the number is projected to exceed 130 million by 2050.

Drug development in this field has been exceptionally challenging, with widespread setbacks. Yet, encouragingly, there is no evidence to suggest that the biopharmaceutical industry is poised to abandon these efforts despite the high risk of failure. These unsuccessful attempts serve as crucial stepping stones, helping to advance our understanding of highly complex neurological disorders, while providing new clues and guiding adjustments in research directions.

Currently, some companies have turned their attention to emerging fields such as immunoneurology, epigenetics, microbiomics, and gene therapy, although these efforts are still in very early stages. With the continuous advancement of science, it is firmly believed that Alzheimer's disease (AD) will eventually be conquered.

References:

1、Amgen and Novartis abandon Alzheimer’s drug after worsening symptoms

2、Amgen, Novartis And Banner Alzheimer's Institute Discontinue Clinical Research Program With BACE Inhibitor CNP520 For Alzheimer's Prevention