The Phase 3 trial showed Roche’s investigational anti-amyloid monoclonal antibody failed to slow clinical decline, while also showing a lower than expected level of beta-amyloid removal. And yet other late-stage Alzheimer’s drugs – such as Biogen and Eisai’s lecanemab and Eli Lilly’s Donamemab – also attack amyloid plaque and have shown much more promising results.
Roche says it will be able to deliver a 'high quality, clear and comprehensive Alzheimer’s dataset to the field' from its Phase 3 trial, promising to share its learnings in the continued search for new treatments. Full data from the 27-month long study is due to be presented at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in San Francisco next month.
Good phase 3 studies promise wealth of data
Alzheimer's associations say they are naturally 'extremely disappointed' that gantenerumab has failed to live up to expectations: but they point out that the Roche data should reveal more insights into the complex relationship between removal of beta-amyloid and reduction of clinical decline – a relationship already thrown into the spotlight by Biogen’s Aduhelm (approved by the US FDA in June 2021).
“We are seeing great progress and innovation in this class of treatment, and we learn from each trial,” notes the US-based Alzheimer’s Association. “Roche’s Graduate [Phase 3] trials were well-powered and fully-completed Phase 3 studies that will help us learn more about the impact of removing beta-amyloid on slowing clinical decline for people living with early stage Alzheimer’s.”
Dr Susan Kohlhaas, Director of Research at Alzheimer’s Research UK, adds that comparing drugs will help researchers better understand drug development.
“Gantenerumab is one of several drugs that has been designed to remove the hallmark Alzheimer’s protein, amyloid, from the brains of people in the very early stages of the disease,” she said.
“Earlier this year a final stage trial of a different anti-amyloid drug, lecanemab, successfully cleared amyloid from the brain and slowed the decline in participants’ memory and thinking skills. Looked at together, data from the lecanemab and gantenerumab trials will yield important insights as to why one anti-amyloid drug worked better than the other, and this will help further refine this approach to treating people with Alzheimer’s disease.”
- Roche’s gantenerumab is a fully-human monoclonal IgG1 antibody designed to target and bind to aggregated forms of beta-amyloid, including oligomers, fibrils and plaques, and activate immune cells in the brain (microglia) to clear amyloid plaques and prevent further accumulation.
But phase 3 trials failed to show a statistically significant slowing in clinical decline; nor the level of beta-amyloid removal that was expected.
- Biogen and Eisai’s lecanemab is an investigational anti-amyloid beta (Aβ) protofibril antibody for the treatment of early AD in the confirmed presence of amyloid pathology in the brain. A decision on the drug’s BLA is expected from the FDA in January.
- Eli Lilly’s donanemab is an investigational antibody that targets a modified form of beta amyloid called N3pG: which is currently being studied in several Phase 3 trials.
- Biogen’s Aduhelm was approved by the US FDA in June 2021. Although long-term Phase 3 data in March showed a reduction in amyloid beta plaques and p-tau181, and clinical decline was reduced in participants who had plasma p-tau181 reduction at 78 weeks, the drug has suffered from the CMS’s decision in April to only cover the drug in clinical trials.
Directing future research
Dementia is set to reach 78 million people by the end of the decade; and is already the seventh leading cause of death globally, according to the WHO.
The WHO recently set out its blueprint for dementia research: tracking current drugs in development and highlighting the potential of precision medicine, repurposed drugs and revamped clinical trials.
It identifies 143 agents in 172 clinical trials on Alzheimer’s: of which 83.2% are putatively disease modifying drugs, 9.8% cognitive enhancers and 6.9% for treatment of neuropsychiatric symptoms.
Look past Roche’s results, the Alzheimer’s organizations remain optimistic: highlighting the number of drugs now coming into late-stage development.
“We are confident in the robust and diverse Alzheimer’s drug development pipeline,” says the Alzheimer’s Association.
“The unprecedented number of Phase 3 clinical trial data reports and anticipated Food and Drug Administration (FDA) actions over the next year clearly signal that we are in a new era of expanding possibilities for Alzheimer’s disease treatment.
“The future of Alzheimer’s treatment will be a combination of drugs that target different aspects of the disease at different times, as well as lifestyle interventions. Encouraging and supporting a diverse treatment pipeline is essential to achieving the Alzheimer’s Association’s vision of a world without Alzheimer’s and all other dementia.”
Dr Susan Kohlhaas, Director of Research at Alzheimer’s Research UK, also highlights that research goes far beyond anti-amyloid drugs. “Alzheimer’s disease is complex, and potential drugs that target other aspects of the disease are also making their way through clinical trials. There are over 140 potential Alzheimer’s drugs in clinical trials – the majority of which target proteins or processes other than amyloid. While anti-amyloid drugs are perhaps the closest to making it to patients, they are not the only hope for effective new treatments.”
Accessible and affordable treatments
Furthermore, Roche’s gantenerumab could help open doors for more accessible and affordable treatments – which could prove all the more important as the impact of the disease increases on a global scale.
“There were several innovative aspects of these gantenerumab trials,” says the Alzheimer’s Association.
“For example, the treatment was delivered by injection under the skin rather than an infusion directly into a vein, and the drug was administered with half the dose delivered twice per month, rather than the whole monthly dose given at one time.
“These features could make it possible to have a more accessible and affordable treatment that can be administered in a doctor’s office and perhaps even at home. The hope is that this method, which is also being tested in other treatments, will be just as effective, more convenient and reduce potential travel-related hardships on people living with Alzheimer’s, their caregivers and family members.”
Push for funding
With Roche's news, Alzheimer's organizations are highlighting the importance of their campaigns to increase funding for dementia research and boost diversity in clinical trials.
In the US, the Alzheimer’s Association and the Alzheimer’s Impact Movement (AIM) support the bipartisan Equity in Neuroscience and Alzheimer’s Clinical Trials (ENACT) Act (S. 1548 / H.R. 3085). The ENACT Act would provide resources to increase the participation of underrepresented populations in NIH-supported Alzheimer’s and other dementia clinical trials, expand education and outreach to these populations, and encourage better racial/ethnic representation among clinical trial staff.
Over the Atlantic, Alzheimer's Research UK says it is 'now absolutely critical that the UK government delivers on its promise to double dementia research funding to £160m a year by 2024': boosting UK research and paving the way for breakthroughs.