Alzheimer’s disease (AD) is an irreversible degeneration of the brain and the most common form of dementia. Globally, more than 50 million people are living with AD, and without a medical intervention those rates could more than triple by 2050. AD is marked by two main detectable changes in the brain: plaques resulting from the accumulation of the protein fragment beta-amyloid that form outside neurons; and tangles, accumulations of an abnormal form of the protein tau that collect inside neurons. These changes disrupt neuronal function and contribute to gradual damage to brain tissue. These formations can be identified and monitored by observing changes in levels of beta-amyloid and tau in cerebrospinal fluid (CSF) and positron emission tomography (PET) scans.
Research to find drugs to treat AD has mostly focused on ways to reduce or remove amyloid plaques, but recent studies target tau as well. One such candidate is the antibody gosuranemab (previously known as BIIB092), which binds to a specific domain in the tau protein called the N-terminus. Biogen reported in June that it was ending its clinical trial for gosuranemab after it failed to meet its primary and exploratory efficacy goals in the TANGO Phase 2 study.
TANGO’s primary objective was to evaluate the safety and tolerability of gosuranemab. Its secondary goals were focused on efficacy and included measuring the drug’s ability to slow cognitive and functional impairment, as measured by changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores. Researchers enrolled 654 patients, aged 50 to 80, who had experienced mild but progressive impairment in memory function for more than six months attributed to AD. The patients were randomly assigned to receive three intravenous doses — a low, medium, or high dose — of either gosuranemab or a placebo, administered once every four weeks.
The results demonstrated a reduction of N-terminal tau in CSF. However, there were no statistically significant changes in tau tangles for any dose groups, as observed using PET imaging scans at week 78. The results also showed that all the three gosuranemab dose groups did not meet the study’s endpoint for changes in CDR-SB scores compared with the placebo group. In addition, no benefits were observed on other efficacy endpoints, including the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog 13), the Alzheimer Disease Cooperative Study Activity of Daily Living (ADCS-ADL), the Mini-Mental State Examination (MMSE), and the Functional Assessment Questionnaire (FAQ). In fact, results reported at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in November showed that all three gosuranemab groups declined more on the ADAS-Cog13 than the placebo group.
Gosuranemab also failed to show efficacy in the PASSPORT Phase 2 study in 2019. That trial involved participants with progressive supranuclear palsy, an atypical form of Parkinson’s disease, which also is characterized by the accumulation of tau tangles.
In what may be considered a glimmer of hope for the tau approach, AC Immune and Genentech announced Phase 2 trial results at CTAD for semorinemab, a monoclonal tau-targeting antibody evaluated among people with mild-to-moderate AD. Based on results of the ADAS-Cog11, participants showed a statistically significant decrease in cognitive decline of 43 percent at week 49, compared to placebo. That said, the study did not find significant changes on other endpoints, including functional decline.
Taking the Amyloid Approach
Biogen’s amyloid-targeting drug aducanumab, marketed as Aduhelm™, received accelerated approval from the FDA in June, becoming the first drug approved for treating AD. The approval was controversial because it went against the FDA advisory panel’s recommendation, prompting three members of the panel to resign from the advisory committee in protest amid widespread criticism of the accelerated approval, efficacy and safety data and steep price (which the company subsequently cut in half later that year). Medicare just announced a preliminary decision that coverage for Aduhelm™ (and all drugs in the same class) is restricted to those participating in clinical trials unless there is documented clinical benefit. This was almost immediately followed by an announcement from the Alzheimer’s Association that they will be aggressively fighting Medicare’s proposal. Meanwhile, the European Medicines Agency has rejected Biogen’s marketing application.
As therapies targeting tau, amyloid, or both continue through the pipeline, the public anxiously hopes for progress against this memory-stealing disease, especially as the population within the age group most at risk is growing. With new developments in understanding the disease happening all the time – such as last week’s announcement of an additional 42 genes determined to be connected to AD – the scientific community is optimistic that, despite the disappointment of recent clinical trial results, there is still room to explore multiple approaches to treating, and possibly even preventing, AD.
QPS is a GLP- and GCP-compliant contract research organization (CRO) delivering the highest grade of discovery, preclinical and clinical drug research development services. Since 1995, it has grown from a tiny bioanalysis shop to a full-service CRO with 1,100+ employees in the U.S., Europe and Asia. Today, QPS offers expanded pharmaceutical contract R&D services with special expertise in neuropharmacology, DMPK, toxicology, bioanalysis, translational medicine and clinical development. An award-winning leader focused on bioanalytics and clinical trials, QPS is known for proven quality standards, technical expertise, a flexible approach to research, client satisfaction and turnkey laboratories and facilities. Through continual enhancements in capacities and resources, QPS stands tall in its commitment to delivering superior quality, skilled performance and trusted service to its valued customers. For more information, visit www.qps.com or email [email protected].