Biogen and Eisai Discontinue Elenbecestat Development as BACE Inhibitor Strategy for Alzheimer’s Disease Collapses

News Event

On September 14, Biogen and its partner Eisai announced the discontinuation of two Phase III clinical trials of their BACE inhibitor elenbecestat (E2609). Following the recommendation of the Data Safety Monitoring Board, the MISSION AD1 and AD2 trials, which involved a total of 2,100 patients with early Alzheimer’s disease, were halted because the risks outweighed the benefits. The long-term observational component of the Phase II Study 202 for this product was also discontinued. Although the Phase III Clarity AD trial of BAN2401, an anti-amyloid antibody developed by the two companies, will continue, the amyloid hypothesis has been largely falsified. This follows the successive failures of multiple anti-amyloid antibodies—including Biogen’s own aducanumab—in the Phase III Engage and Emerge trials, as well as the complete failure of BACE inhibitors.

Drug Source Analysis

BACE is a hydrolase of the amyloid precursor protein (APP) and catalyzes the first step in the generation of insoluble amyloid-beta. Under normal conditions, APP undergoes limited hydrolysis via the BACE pathway; however, certain mutations shift BACE-mediated cleavage to become the predominant pathway, thereby increasing the risk of Alzheimer’s disease (AD). To date, five BACE inhibitors have failed in mid-to-late-stage clinical trials, including CNP520 (umibecestat), which was discontinued by Novartis and Amgen two months ago. Gamma-secretase mediates the second step in amyloid-beta production; however, several gamma-secretase inhibitors not only failed to improve symptoms but also demonstrated disease exacerbation. Antibodies designed to directly clear amyloid-beta have also uniformly failed, with approximately five such antibodies failing in more than ten Phase III clinical trials. Although BAN2401 showed some efficacy in Phase II trials, it is widely believed within the industry that this outcome was largely attributable to imbalanced group allocation, and significant controversy remains regarding the continuation of the Clarity AD trial.

Of course, the amyloid-beta hypothesis is not the only theory that has failed in Alzheimer’s disease (AD) treatment. Currently, no drugs are available to slow or reverse the progression of AD. However, because the pharmaceutical industry has pinned its greatest hopes on this hypothesis and invested the most resources in it, its failures have been particularly painful. Rarely in the history of drug development has there been such a brutal battle; in most cases, companies adhere to the principle of retreating when they cannot win. Yet AD remains one of the greatest threats to human health, and the social value and market potential of drugs capable of reversing its progression are immeasurable. Furthermore, abnormalities in amyloid-beta have been shown through genetic, clinical, and preclinical studies to be intricately linked to AD. Unfortunately, not all crime bosses can be easily apprehended; even if dysregulated amyloid-beta metabolism is indeed the primary driver of AD, the pharmaceutical industry may still fail to identify an appropriate therapeutic entry point within limited investment constraints. Many believe that the industry’s investment in the amyloid-beta hypothesis has exceeded rational levels, with some even arguing that continuing to enroll patients in clinical trials borders on professional misconduct.

Therefore, a temporary withdrawal from this battlefield is inevitable, and identifying the next breakthrough point is imperative. Although amyloid-beta accumulation is one of the diagnostic criteria for Alzheimer’s disease (AD), amyloid-beta abnormalities are not the sole cause of AD; indeed, 30% of clinically asymptomatic individuals also show signs of amyloid-beta accumulation. A prevailing hypothesis now is the Tau propagation theory, which posits that Tau and amyloid-beta jointly regulate iron ion metabolism. Neurofibrillary tangles formed by hyperphosphorylated Tau within neurons constitute another major pathological feature of AD and may mediate amyloid-beta toxicity. Tau tangles typically originate in specific brain regions and then spread, causing damage. Drugs inhibiting Tau propagation are currently in clinical trials.

Another hypothesis is the central inflammation theory. Professor Tanzi of Harvard University believes that some individuals accumulate amyloid protein but remain asymptomatic because their amyloid has not yet triggered central nervous system inflammation. Of course, the mechanisms of inflammation are complex, and identifying beneficial anti-inflammatory targets is a daunting task requiring round-the-clock effort. Although epidemiological analyses have shown an association between broad-spectrum anti-inflammatory drugs, such as NSAIDs, and a reduced risk of Alzheimer’s disease (AD), prospective clinical trials have failed to demonstrate efficacy. The biological mechanisms underlying pathological changes occurring decades after the reproductive period have likely not been subjected to evolutionary pressure for selection and optimization. Consequently, curing age-related neurodegenerative diseases remains extremely challenging given the current limits of human intellect.

Original Title: Biogen and Eisai Halt Development of BACE Inhibitors