Roche's 'high risk' failure has industry circling the wagons on future of Alzheimer's research

Another failure of an amyloid medicine for Alzheimer’s disease has companies, analysts and patient advocacy groups circling the wagons to once again defend the theory and the future of research into the devastating neurological disorder.

The theory that reducing or preventing amyloid plaques in the brain can slow cognitive decline has time and time again failed in the clinic, with the very notable exception of one recent effort, that is: Eisai and Biogen’s lecanemab scored a surprise win in a phase 3 study in late September by proving it could slow cognitive decline by 27% compared to placebo.

But now, Roche has added a second failure in Alzheimer's to its tab this year, this time for gantenerumab, which did not improve the rate of cognitive and functional decline in two phase 3 clinical trials from the Graduate program. This follows the June disclosure that crenezumab had failed in a study of pre-symptomatic Alzheimer’s patients.

Roche CEO Severin Schwan called gantenerumab “a high-risk project” when reporting second-quarter earnings in July, and suggested that the company “plan for a situation where it doesn’t come through.”

GlobalData Senior Neurology Analyst Pippa Salter called the gantenerumab failure surprising, particularly that the med also did not seem to clear amyloid plaques as much as expected. She doesn’t see a path forward for the therapy.

“Its failure will be a significant blow to Roche, which had gambled on continued development of the product despite a previous phase 3 failure in 2014,” Salter said in a Tuesday note. “Although Roche is yet to announce future plans for gantenerumab, these results, combined with previous failures, make it challenging to see a path forward for the product.”

If gantenerumab were to be abandoned, Salter said Roche could pivot away from the amyloid hypothesis and towards other potential mechanisms of action for Alzheimer’s disease. The company has two much earlier-stage assets in its pipeline for Alzheimer’s including the anti-tau agent semorinemab in partnership with AC Immune and RG6289, which is listed as in very early development. There’s also crenezumab, which the Swiss pharma has not yet abandoned after the pre-symptomatic failure, although parts of the therapy’s development program have been shelved before.

Alzheimer's Association’s Chief Science Officer Maria Carrillo, Ph.D., also flagged an updated version of gantenerumab that Roche is developing that uses “brain shuttle technology” to move the drug across the blood-brain barrier and boost concentrations of the active ingredient in the brain.

As always, the company, analysts and patient advocates pointed to the small positives and learnings for the broader Alzheimer’s research community that were revealed in the gantenerumab study.

Despite the fact that gantenerumab did not significantly lower amyloid, Carrillo said the studies “further illustrate the relationship between the removal of beta-amyloid and reduction of clinical decline.” She explained that the studies prove that amyloid must be targeted earlier in the disease’s course to see improvements in cognition. That theory was put to the test in the earlier crenezumab failure as well.

“Each anti-amyloid treatment is being tested in a different way and may act differently on the protein that is one of the hallmarks of Alzheimer’s,” Carrillo said. “Research into their effectiveness and safety must continue. It is important to evaluate each new treatment independently.”

Alzheimer’s Drug Discovery Foundation Co-Founder and Chief Scientific Officer Howard Fillit, M.D., also stressed that the Roche data does not mean it’s time to abandon the amyloid theory but acknowledged that there are other targets to be researched.

“If you’ve seen one anti-amyloid therapy, then you’ve seen one anti-amyloid therapy,” he said in a Monday statement. “The results we’ve seen from drugs in this class points to the urgent need to bring a range of amyloid and non-amyloid therapies to market to slow the course of Alzheimer’s disease.”

Lecanemab rises

Salter and Carrillo pointed to the use of subcutaneous injection as a plus, as this has previously not been done in Alzheimer’s trials. Medications have typically been delivered intravenously, which is more invasive. This administration method would have differentiated Roche’s therapy and provided a “competitive edge” over Biogen and Eisai’s lecanemab if the study had been successful.

But the study was not successful, so that pushes lecanemab even further to the front of the line after the surprise success in September.

“With gantenerumab no longer looking like a promising candidate, lecanemab could become the market-leading [monoclonal antibody] for AD,” Salter said.

Lecanemab has shown strong results on safety and of course efficacy compared to the only currently approved monoclonal antibody, Aduhelm, which was also jointly developed by Eisai and Biogen but has been sidelined after gaining approval last year. The therapy ran into Medicaid coverage troubles after launch and has mostly been set aside by Biogen, which led development.

Another option is Eli Lilly’s donanemab, which is due to readout soon as well. But Salter believes lecanemab could have the edge, as a phase 2 study showed a higher incidence of safety issues with Lilly’s candidate.

Lilly for its part called the Roche news disappointing but said the company is focused and confident in donanemab.

Carrillo, Lilly and Fillit’s group look forward to the release of the full dataset, which Roche intends to do at the Clinical Trials on Alzheimer’s Disease conference later this month. Carrillo is particularly interested in the secondary endpoints that include additional cognitive and functional assessments, which did not read out Monday.

In an interview with Fierce Biotech earlier this month, Mark Mintun, M.D., SVP of pain and neurodegeneration R&D at Lilly, underscored the difficulty in nailing phase 3 results in light of lecanemab's win.

"Alzheimer's is a very, very tricky business with lots of people who think they know what's going on, only to be fooled by phase 3 data," he said. The company's own phase 3 results are slated for the middle of 2023.

Eisai's response to the gantenerumab situation was short and sweet: "Lecanemab and gantenerumab are different antibodies. Each potential therapy should be evaluated on its individual efficacy and safety profile."