Another Alzheimer's Drug Fails in Phase III Trials as Biogen and Eisai Halt Aducanumab Studies

Following Roche’s announcement more than a month ago that it was terminating the two Phase III CREAD I and CREAD 2 clinical trials of crenezumab for the treatment of early Alzheimer’s disease (prodromal or mild AD), yet another AD drug has failed to pass Phase III clinical trials.

On March 21, Biogen and its partner Eisai announced the termination of two global Phase III clinical trials of the Alzheimer’s disease drug aducanumab, codenamed ENGAGE and EMERGE. After a comprehensive analysis of the data from these trials, the independent Data Monitoring Committee concluded that aducanumab did not demonstrate improvement in mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s dementia, and was unlikely to meet the primary efficacy endpoints.

Biogen stated in a press release that the two companies made this decision primarily due to insufficient efficacy, rather than safety concerns. Detailed data from the ENGAGE and EMERGE studies will be presented at an upcoming conference.MedicineAnnounced at the conference.

Industry insiders have stated: "This disappointing news once again underscores the complexity of treating Alzheimer’s disease, succinctly capturing a major bottleneck in current Alzheimer’s research and development. As the most common neurodegenerative disease worldwide, the societal impact of Alzheimer’s is self-evident. Yet, for a condition with such profound consequences, we have not even fully elucidated its etiology and pathogenesis."

Alzheimer’s disease has long been a major challenge in new drug development, with a clinical failure rate as high as 99.6%. Over the past two decades, research efforts in this field have met with near-total failure; multiple monoclonal antibody drugs from pharmaceutical giants such as Roche, Eli Lilly, AstraZeneca, Johnson & Johnson, and Pfizer have all failed in Phase III clinical trials, casting a heavy shadow over the landscape of Alzheimer’s drug discovery.

Some argue that the failure of new Alzheimer’s drugs in mid-to-late-stage clinical trials cannot be simply attributed to flaws in scientific theory. Rather, it indicates problems in other areas, such as the characterization of disease progression, the design of clinical trials, and patient heterogeneity.

Although the development of drugs for Alzheimer’s disease remains a long and arduous journey, it is worth noting that China’s original novel anti-Alzheimer’s drug, GV-971, has successfully completed Phase I, II, and III clinical trials. According to information released on the Green Valley Pharmaceutical website, GV-971 can target multiple links in the pathogenesis of Alzheimer’s disease (AD). First, GV-971 targets beta-amyloid (Aβ), a major factor in the brain involved in the onset of AD. In this process, GV-971 simultaneously inhibits the formation of fibrils from Aβ monomers and promotes the depolymerization of already formed Aβ fibrils. Further studies have found that GV-971 can reduce neuroinflammation in the brain, regulate neurotransmitter homeostasis, and improve cognitive dysfunction and neuropsychiatric symptoms, thereby playing a series of important therapeutic roles in AD. Phase I and II clinical studies demonstrated its favorable safety profile and showed a promising trend in improving patients’ cognitive dysfunction, while the results of its Phase III clinical trial were even more encouraging.

The results of the Phase III clinical study of GV-971 demonstrated that GV-971 significantly improved cognitive impairment in patients with Alzheimer’s disease (AD). Compared with the placebo group, the mean improvement in the ADAS-cog12 score was 2.54, which was highly statistically significant (p<0.0001). The therapeutic effect was particularly pronounced in the subgroup with more severe disease (MMSE scores of 11–14), where the mean improvement in the ADAS-cog12 score was 4.55 compared with the placebo group. GV-971 showed a clear trend toward improvement in the secondary efficacy endpoint, CIBIC-plus (p=0.059); however, no statistically significant differences were observed for the ADCS-ADL scale or the NPI questionnaire. There were no significant statistical differences in the incidence of adverse events or serious adverse events between the GV-971 group and the placebo group, indicating that GV-971 has a favorable safety profile and is well tolerated.

On October 16, 2018, Green Valley Pharmaceuticals submitted a New Drug Application (NDA) for the indication of mild-to-moderate Alzheimer’s disease. The application has been accepted and processed by the Center for Drug Evaluation (CDE), and the company plans to conduct global clinical trials in the future. Analysts predict that GV-971 is poised to become the world’s first innovative multi-target oligosaccharide drug for the treatment of Alzheimer’s disease.