Lilly and Roche's Anti-Amyloid Antibodies Fail to Meet Primary Endpoint in DIAN-TU Phase II/III Trial for Autosomal Dominant Alzheimer’s Disease

Compiled by Keke

On February 10, Eli Lilly and Roche separately announced that studies of Solanezumab and Gantenerumab for symptom improvement in patients with autosomal dominant Alzheimer’s disease (ADAD) failed to meet their primary endpoints.

This study, named DIAN-TU, is a Phase II/III randomized, double-blind, placebo-controlled trial. It evaluated Eli Lilly’s solanezumab and Roche’s gantenerumab versus placebo in slowing the rate of cognitive decline and improving disease-related biomarkers in individuals with known genetically determined Alzheimer’s disease. The primary endpoint was a novel composite measure—the DIAN Multivariate Cognitive Endpoint—which includes the Logical Memory Delayed Recall from the Wechsler Memory Scale–Revised, the Cogstate International Shopping List Task, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale–Revised, and the Mini-Mental State Examination, aiming to assess cognitive performance in patients with autosomal dominant Alzheimer’s disease (ADAD).

Autosomal Dominant Alzheimer’s Disease (ADAD), also known as familial AD or dominantly inherited Alzheimer’s disease (DIAD), is a rare genetic form of AD caused by single-gene mutations in the APP, PSEN1, or PSEN2 genes. Patients with AD caused by such genetic mutations account for less than 1% of all AD patients worldwide.

The DIAN-TU study followed 194 participants for up to 7 years, with a mean follow-up duration of approximately 5 years, across 24 study sites in the United States, Canada, France, and other countries. In this study, 52 participants were randomized to the gantenerumab group, 50 to the solanezumab group, and 40 to the placebo group. All participants were from families carrying genetic mutations that cause autosomal dominant Alzheimer’s disease (ADAD). The study included both presymptomatic individuals and those with mild symptoms at enrollment. During the minimum four-year treatment period, participants’ cognitive function was assessed annually, and these results were combined to derive a composite score.

Roche stated that in this study, the rate of cognitive decline in patients treated with gantenerumab, as measured by the novel DIAN Multivariate Cognitive Endpoint, was not significantly slowed. Overall, the safety profile of gantenerumab in the DIAN-TU-001 trial was consistent with other clinical trials of the investigational drug, with no new safety issues identified. The most common adverse events associated with gantenerumab were injection site reactions, nasopharyngitis, and amyloid-related imaging abnormalities (ARIA), manifesting as brain edema or microhemorrhages, most of which were asymptomatic.

Eli Lilly noted that 36 patients in the solanezumab group completed at least four years of treatment. The initial study dosage was 400 mg every four weeks; after dose adjustment, only 25% of patients received the higher dose. Nevertheless, solanezumab failed to meet the primary endpoint of the study. This marks Eli Lilly’s fourth attempt to demonstrate that this experimental drug can slow cognitive decline in patients with neurodegenerative diseases, and, as with the previous three trials, it has once again failed. Eli Lilly is conducting additional analyses on secondary endpoints and biomarkers, with results scheduled to be presented at the “Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting” in April this year. Based on the primary endpoint results, Eli Lilly currently does not plan to continue solanezumab treatment for patients with autosomal dominant Alzheimer’s disease (ADAD).

Solanezumab is an investigational anti-amyloid monoclonal antibody that binds to amyloid beta peptides, preventing their aggregation and plaque formation in the brain. The drug is being evaluated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a clinical trial involving preclinical Alzheimer’s disease patients receiving anti-amyloid therapy. The A4 study aims to test solanezumab treatment in older adults who have amyloid plaques in the brain but show no signs of memory decline.

Gantenerumab is an investigational drug designed to bind to aggregated forms of beta-amyloid and remove beta-amyloid plaques, which are believed to cause brain cell death. Previous clinical studies have shown that the drug can reduce beta-amyloid plaques in patients with the common form of Alzheimer’s disease (AD), which is not directly caused by genetic mutations. Roche is currently conducting two Phase III studies (NCT01224106 and NCT02051608) to evaluate the safety and efficacy of gantenerumab in patients with prodromal and mild-to-moderate AD.

References:

1、Lilly and Roche's antibodies fail late-phase Alzheimer's test

2. Official websites of Eli Lilly and Roche, etc.