The Alzheimer’s Association estimates that nearly six million Americans are living with the disease, a number that is expected to rise to 14 million by 2050. Marketed drugs such as memantine and donepezil modestly slow memory loss in some patients, but no new treatments for Alzheimer’s disease (AD) have been approved since 2003. Rather, most clinical trials of new, potentially disease-modifying therapies have failed.
Until recently, those failures were believed to include global Phase 3 trials of Biogen and Eisai’s aducanamab, an antibody designed to clear amyloid-beta from the brains of individuals affected by mild to moderate AD. The companies had prematurely halted the EMERGE and ENGAGE trials in March 2019, as well as an extension study and an early Phase 2 trial of the drug, after an independent data monitoring committee ruled that the Phase 3 trials would likely not hit their primary endpoint.
However, in late October, the two companies announced that a new analysis of the data suggested that the drug may work in a subset of patients. In this sub-population, the EMERGE study appeared to meet its goal, slowing the rate of memory decline by 23% in patients who received at least 14 weeks of the highest dose (10mg/kg) of aducanamab. However, the ENGAGE trial failed to show more than a 2% reduction and did not achieve its endpoint, although fewer patients in that study had received the high dose for 14 weeks. Biogen explained that a mid-study protocol change that allowed carriers of APOE4, a risk factor for AD affecting two-thirds of the randomized trial participants, to receive the high dose of the drug appeared to account for the positive results, along with the larger dataset that became available for analysis after the studies were halted. Biogen also said that, based on discussions with the U.S. FDA, they would seek approval of aducanamab in early 2020 without undertaking another trial.
Many experts see this decision as controversial, questioning whether the evidence is substantial enough to warrant FDA approval. While the FDA is likely to be under considerable pressure from patients, families and advocacy groups to approve a new treatment for AD, the agency could also ask Biogen for another trial.
Some question whether the successful trial outweighs the failed one in determining the drug’s success and point to the “highly selected patient population that may not be representative of the real world.” There are also concerns about the safety data for aducanamab, including a 35% incidence of brain swelling in the high dose group and a significant incidence of cerebral microhemorrhages. The director of the Alzheimer’s Disease Discovery Foundation also questioned the significance of the 23% improvement, which translated to a -0.4 absolute change on the CRD-SB dementia rating scale (a memory test). However, one clinical investigator noted that the high dose group registered a 40% improvement on a second functional rating scale (the ADCS-ADL-MCI) that was more clinically relevant, which translates into a person with mild AD who might still be able to work, shop and travel.
In November, there was further surprising news in the AD space, as China’s drug regulator granted conditional approval to Shanghai Green Valley Pharmaceuticals seaweed-derived drug, oligomannate (CV-971), designed to improve cognitive function in patients with mild to moderate AD. Green Valley is expected to launch the drug in China and is planning to initiate a global Phase 3 trial in early 2020, with sites in the United States, Europe and other parts of Asia. As part of the conditional approval, the China National Medical Products Administration is also requiring the company to conduct further post-marketing studies in China to confirm the drug’s long-term efficacy.
Oligomannate was approved based on a placebo-controlled Phase 3 trial in 818 Chinese patients showing that patients receiving the drug were performing better on a standard clinical scale of cognitive function in AD (ADAS-COG). The company said that a statistically significant improvement between the treatment and placebo groups was seen as early as week four of the trial. Positive results from the global Phase 3 trial will likely be required to win over skeptics, who have pointed out that only this single subjective measure supports oligomannate’s efficacy, while three other widely used AD assessments showed no difference between the treated patients and those receiving placebo.
Published research by oligomannate’s developers suggests that the drug works by modulating gut microbiota and by altering levels of inflammatory cytokines and pro-inflammatory T cells within the nervous system. Some scientists in the microbiome field, however, have expressed skepticism about the preclinical research concerning the mechanism of action for the drug, pointing out inconsistencies between the team’s data and other microbiome research on inflammation in the nervous system.