The 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference has been a truly historic meeting, and the Alzheimer’s Drug Discovery Foundation (ADDF)’s role in bringing about a new era of research was evident throughout.
The ADDF moderated a session on promising Alzheimer’s research focused on diverse drug targets and led an informative roundtable on venture-minded drug development, commercialization, and the path forward for the Alzheimer’s field. Our presence at the conference included 15 ADDF-funded scientists, who presented the latest updates on their groundbreaking research informed by the biology of aging.
“There is perhaps no area of medical research more exciting right now than Alzheimer’s. Drugs in clinical trials, the focus of CTAD, are being tested against every known underlying cause of this complex disease,” said Dr. Howard Fillit, the ADDF’S Co-Founder and Chief Science Officer. “I can’t help but come away from CTAD energized by the realization of how far we’ve come. We will soon have a portfolio of drugs that we can use to personalize treatment for patients at various stages of Alzheimer’s.”
Two phase 3 trials demonstrate hope and limitations of amyloid-clearing treatment
Data presentations on amyloid-clearing monoclonal antibodies reinforced Dr. Fillit’s observation that “if you’ve seen one monoclonal antibody, you’ve seen on monoclonal antibody,” a theme that was echoed by many other experts in attendance.
Phase 3 lecanemab data presented on Tuesday confirmed earlier reports that the drug cleared brain amyloid and slowed cognitive decline, albeit modestly. Lecanemab is on track for likely FDA approval early next year. While several media reports have called attention to safety concerns, the data shows lecanemab was generally well tolerated. It will require close monitoring, particularly in patients at higher risk such as those taking anticoagulants, but overall these results are starting us down a promising path.
On Wednesday, phase 3 gantenerumab data showed this drug, which also targets amyloid, neither reduced brain amyloid levels nor slowed cognitive decline. Two drugs, one class, different results.
In a late-breaking oral presentation, topline data was also presented on donanemab, indicating donanemab-treated patients were significantly more likely to reach amyloid plaque clearance with higher amyloid reductions compared to aducanumab-treated patients and that it likely also reduced levels of tau tangles in the brain. This ongoing trial will report additional results early next year.
The ADDF is looking to the future
The themes the ADDF and Dr. Howard Fillit have been talking about for years are all now center stage. Disease modification is possible, but lecanemab and amyloid clearing drugs in general are only the first part of the combination therapies needed to put the brakes on Alzheimer’s and extend patients’ independence.
The ADDF will continue its unique and vital role in the Alzheimer’s research ecosystem. As Dr. Susan Catalano pointed out during the ADDF’s roundtable, “the ADDF has been incredible at supporting companies that would not exist without its funding.” This support is a large part of the reason today’s pipeline is incredibly diverse, with three of four drugs in clinical developing being tested against targets other than amyloid and tau.
We have made tremendous strides, but far from slowing down, the research field is picking up steam for what comes next.
ADDF-led session explores biology of aging and novel Alzheimer’s drug targets
In his introduction to the session, Beyond Amyloid and Tau: Emerging Solutions, Dr. Fillit said even if lecanemab routinely slows cognitive decline by 20, 25 or even 30%, there is a long way to go to the ultimate goal of slowing cognitive decline by 100%. “We need to be able to tell patients that 1, 2 and 3 years later, they will be the same, not getting progressively worse.” The answer lies in precision medicine and combination therapy aimed at targets beyond just amyloid and tau.
Among the data shared during the session was a pilot study presented by Dr. Mitzi Gonzales, in collaboration with Dr. Miranda Orr of the Wake Forest School of Medicine, showing two repurposed drugs (called senolytics) used in combination appear to penetrate the blood-brain barrier where they can clear senescent “zombie” cells that cause brain injury that contributes to Alzheimer’s. Because repurposed drugs are already proved safe in humans, this early clinical trial, and the larger senolytics trial now enrolling, can move more quickly than trials testing new drug compounds.
This is also true for the antioxidant therapy edaravone, which was presented by Treeway. Already approved to treat ALS as an IV infusion, edaravaone has been reformulated and is being tested as an oral treatment for Alzheimer’s disease. This is the first study to investigate the effect of an antioxidant treatment for early-stage Alzheimer’s. Both trials are supported by funding from the ADDF.
Biomarkers were a common thread through the three-day conference
As Dr. Fillit said during CTAD, “imagine trying to develop a hypertension drug without having a blood pressure cuff.” That’s how important biomarkers are, and their value is no less for Alzheimer’s than for heart disease.
In the days leading up to the CTAD conference, the ADDF hosted its annual Diagnostics Accelerator Investigator Day, which gathers all of the innovative scientists receiving ADDF support for their promising work developing blood tests, eye scans, and digital technologies to detect Alzheimer’s earlier, more accurately, and in more accessible ways than ever before. The investigators presented exciting updates on their work, as well as sharing ideas on how to collaborate to speed the development of promising diagnostics and treatments for this disease.
One panel at CTAD debated a topic that was not possible just a few years ago: Are blood-based amyloid and tau biomarker tests advanced enough that they can replace spinal taps and PET scans as enrollment tools for clinical trials? According to Dr. Fillit, there is a “fair consensus” that we are at that point. The next step will be to keep up a full-court press to develop biomarkers for all of the underlying causes of Alzheimer’s.
If exercise alone helps, multi-domain lifestyle interventions may hold even more promise
In her keynote talk, ADDF-funded investigator and 2021 Goodes Prize Winner Dr. Miia Kivipelto reviewed findings from the groundbreaking FINGER prevention trial and talked about what comes next. FINGER showed that lifestyle interventions can prevent cognitive decline and have a clear brain benefit as we age. Up next for this trial is FINGER 2.0, supported by the ADDF, testing a combination of lifestyle interventions plus the widely used diabetes drug metformin.
People who followed 50% of the lifestyle modification advice in the FINGER trial did significantly better than people who did less, which Kivipelto hopes will motivate people. “You don’t need to do everything to get the benefit,” she said. “Following just 50% of the advice mattered and any type of regular and supervised exercise can help.”
“Hot off the press” results from another multi-domain lifestyle intervention presented by ADDF-funded Dr. Kristine Yaffe, called the SMARRT trial, showed the benefit of tailored, individualized lifestyle interventions. Participants who received personalized lifestyle interventions performed better on tests of memory, attention, verbal fluency, and other cognitive measures, and also reported a higher quality of life in this two-year NIH-funded study compared to patients who received standard one-size-fits-all educational materials. Much like the 50 percenters in Kivipelto’s trial, participants in the SMARRT trial did not need to work on every risk factor to have a positive effect.
Current success in drug development creates need for even more funding
The ADDF participated in a roundtable, Investments in Innovation: Advancing the Path Forward to New Alzheimer’s Treatments. Moderated by Dr. Niranjan Bose, Managing Director, Health & Life Sciences at Gates Ventures, venture capital and venture philanthropy funders discussed the exciting news that came out of CTAD, what’s next for the field, and what it will take to get there.
“This is an exciting time for the field, the community and especially for patients,” said Dr. Bose “In this session, we’re going to talk about how to catalyze the current excitement to inspire more interest and bring more resources to Alzheimer’s research.”
With the incredible amount of exciting research presented at CTAD, we are ending 2022 on a hopeful note for the Alzheimer’s field. There is even more to look forward to in 2023, with potential FDA approval of lecanemab on the horizon, donanemab expected to read out results early next year, and continued progress in development of cutting-edge biomarkers and drugs aimed at diverse targets. All of this combined is bringing us closer than ever to finding effective treatments for Alzheimer’s disease.