Two previously failed drug candidates, Eli Lilly’s Solanezumab and Roche’s Gantenerumab, are again under clinical study for Alzheimer’s disease. Both drugs are immunotherapies targeting amyloid-beta in the brain, a target that researchers — including Dr. Michael Geschwind, who spoke with Alzheimer’s News Today — think has the potential to revolutionize Alzheimer’s treatment.
Amyloid-beta has long been the focus of Alzheimer’s research, especially over the past decade. Many of the potential treatments used an immunotherapeutic slant to stop the protein’s toxicity, and hence prevent or slow disease progression.
Solanezumab and Gantenerumab, both monoclonal antibodies against amyloid-beta, looked promising in animal studies. Yet, while clinical trials showed the drugs to be safe, results repeatedly failed to produce convincing evidence that they might alter disease progression. Both pharmaceutical companies have now re-launched efforts in new Phase 3 clinical trials.
Eli Lilly announced last year that Solanezumab successfully demonstrated an impact on disease progression in its early stages in the ongoing EXPEDITION 3 trial. A group of patients who received the drug after a waiting period had a decline that closely paralleled but remained behind those in a group receiving treatment from the start. Patients treated later never caught up with patients treated earlier in cognitive and functional assessments, and the gap remained constant over a two-year period. This finding constituted enough evidence for Lilly to remain confident about the drug’s efficiency.
Likewise, Roche has continued its efforts with Gantenerumab. In contrast to other immunotherapies targeting amyloid-beta, Roche focused on presymptomatic patients from the outset. In spite of this, Phase 3 clinical trials failed to show improved cognition and function compared to placebo, and in late 2014 the trial, called SCarlet RoAD, was discontinued.
The company, however, reassessed its efforts and announced in mid-2015 that it had determined that the lack of efficacy was due to dose levels. In a press release, Roche declared that it was developing approaches to increase doses, and would test the drug again in Phase 3 trials.
These renewed efforts were discussed at the 10th World Congress on Controversies in Neurology (CONy), held March 17–20 in Lisbon, Portugal. Alzheimer’s News Today covered the conference, and spoke about them with Michael Geschwind, professor of neurology at the Memory and Aging Center at University of California San Francisco and a renowned expert in dementia disease.
Dr. Geschwind is among the scientists enthusiastic about the potential of amyloid-beta immunotherapy, despite the difficulties to date in proving its efficacy. “Amyloid is still a viable target in Alzheimer’s disease. More than 30 clinical trials, including mostly immunotherapies have failed, but most of them have targeted patients that have moderate or severe disease,” he told Alzheimer’s News Today.
According to Dr. Geschwind, the key to success is focusing on much earlier disease stages, as subgroup analyses of the trials have indicated. “It is possible that these drugs might work but they just need to be given earlier,” he said. He also talked about trials using amyloid-beta immunotherapies on familial forms of Alzheimer’s disease to see if treating asymptomatic patients could delay the onset of a disease, whose course is typically predictable in families.
Eli Lilly, however, announced last week that the primary endpoint in the EXPEDITION 3 trial of Solanezumab is changing — a highly unusual move in an ongoing late-stage trial. The trial’s goals were initially aimed at improving both cognition and function, but Lilly claimed that emerging evidence supports cognitive decline preceding and predicting functional decline in Alzheimer’s. The new endpoint will, therefore, only encompass cognition.
In spite of this, Dr. Geschwind believes that immunotherapy approaches targeting amyloid-beta can still be considered the future of Alzheimer’s disease treatment. “At least for the near future, I believe that there is still a place for anti-amyloid therapy, but we should know this pretty soon,” he concluded.
The full interview is available at this link, or by clicking on the video below.