Lilly and Genentech Therapies Fail in Trial as Treatments for Rare Form of Alzheimer’s Disease

Rare Daily Staff

Roche subsidiary Genentech and Eli Lilly each reported that their experimental therapies did not meet the primary endpoint in a phase 2/3 study of patients who have an early-onset, inherited form of Alzheimer’s disease.

The rare form of Alzheimer’s disease (AD) known as autosomal dominant AD (ADAD) accounts for less than 1 percent of all cases of the disease that results in dementia, and eventually death. It is caused by single gene mutations in the APP, PSEN1, or PSEN2 genes. It can have a much earlier onset than the more common sporadic AD, with symptoms developing in people in their 30s to 60s. If an individual has one of these mutations, there is a 50 percent chance they will pass it on to each of their children.

The DIAN-TU-001 study, which was sponsored by Washington University School of Medicine in St. Louis, did not show a significant slowing of the rate of cognitive decline in people treated with Genentech’s experimental medicine gantenerumab or in people treated with Lilly’s solanezumab compared with placebo.

The DIAN-TU study was established in 2010 and funded by Lilly, Roche and Genentech, National Institutes of Health, and other donors. It was the first disease prevention trial to test experimental AD compounds with different mechanisms of action from two pharmaceutical companies. The collaboration between Lilly, Washington University, Roche and Genentech combined research, resources, and expertise to determine if either of the treatments could slow the rate of cognitive decline and improve disease-related biomarkers in people who are known to have a genetic mutation for inherited AD. The study also had a novel outcome measure that was designed to assess cognitive performance in people with ADAD.

The global study followed 194 participants for up to seven years; the average was about five years. It included people who did not yet have symptoms of AD at the time of enrollment as well as people who already had mild symptoms of the disease.

While Genentech and Roche say they will conduct additional analyses to understand the data from the trial, Lilly said it stop development of solanezumab as a treatment for this patient group.

Neither company is giving up on their compounds however. Genentech’s gantenerumab, which is designed to bind to aggregated forms of beta-amyloid and remove beta-amyloid plaques, continues to be studied in two large global phase 3 studies in the broader population of people with AD that is not directly caused by gene mutations. Genentech said that every person with ADAD who received gantenerumab in DIAN-TU-001 started on a lower dose and only started titrating to a fivefold higher target dose approximately halfway through the trial, prompted by observations from other studies of gantenerumab. The ongoing late-stage studies have been designed from the outset to maximize exposure to gantenerumab, bringing all patients to target dose with minimal or no dose interruption within the study period.

“Although DIAN-TU didn’t reach its primary endpoint, the trial represents the first of its kind and a bold undertaking by all partners involved,” said Levi Garraway, chief medical officer and head of global product development at Genentech. “Given its experimental nature, we are unable to draw firm conclusions about the impact of gantenerumab in autosomal dominant Alzheimer’s disease.”

As for Lilly, the company will continue a study of the anti-amyloid monoclonal antibody in preclinical Alzheimer’s disease that is testing solanezumab in older individuals who have evidence of amyloid in their brains, but do not show symptoms of memory impairment. Solanezumab had already failed in two late stage trials among patients with mild to moderate AD.

Daniel Skovronsky, chief scientific officer and president of Lilly Research Labs, said the company will continue to analyze the data from the DIAN-TU trial and remains positive about the potential of its medicines under development for AD.

Both companies will present results from the trial at the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting in April of 2020.

Photo: Levi Garraway, chief medical officer and head of global product development at Genentech

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