Over the past year, we have had many reasons to be proud of the promising work supported by the ADDF. The following is a summary of what I see as the ADDF’s most important science and research involvements of 2019. As we close out the decade, I am encouraged that we are moving closer to viable therapies and prevention strategies for Alzheimer’s disease.
1. Diverse Approaches Gain Traction
While the primary focus of the Alzheimer’s drug discovery field over the past two decades has been the beta amyloid target, the ADDF has kept its eye on the research and development pathways of a diverse pipeline of drugs aimed at novel targets and aging malfunctions. We have long held a belief that aging is the leading risk factor for Alzheimer’s, and as such, we have continued to increase our support for the development of drugs that address the multitude of aging-related biological changes that may contribute to this complex disease. Today, we provide support to more than 25 drugs currently in clinical trials targeting novel mechanisms, such as neuroinflammation, epigenetics, and neuroprotection.
These alternative research approaches are finally gaining ground as potential therapies for the prevention and treatment of Alzheimer’s. It is exciting and very encouraging to see that several of the drugs we have supported entered phase 2, and even phase 3, trials this past year.
To name a few, Oryzon Genomics developed a novel epigenetic inhibitor ORY-2001, called vafidemstat, with several investments from the ADDF, including support to expand the European-based, phase 2a clinical trial to several sites in the United States to evaluate the safety and efficacy of ORY-2001 in patients with mild to moderate Alzheimer’s.
We are currently funding the first non anti-amyloid combination therapy program, the Amylyx trial called PEGASUS that examines AMX0035 in Alzheimer’s patients. This trial is exploring a proprietary two-drug combination therapy to prevent nerve cell death and degeneration and is the first trial to target two novel mechanisms at once. This year we saw promising results from Amylyx Pharmaceuticals’ CENTAUR trail, which demonstrated that AMX0035 had clinically significant benefits for patients with ALS. These early results not only bring promise to the ALS community, but also to the Alzheimer’s community.
The incredibly high costs—and long timeframes—associated with traditional regulatory drug development make repurposing drug programs, testing whether already FDA-approved drugs for other conditions might work as potential treatments for Alzheimer’s, a promising area of drug development. This past year, an ADDF-funded clinical trial of rasagiline, a Parkinson’s disease treatment that may limit cognitive decline in those with mild-to-moderate Alzheimer’s disease, reported positive Phase 2 findings at our 20th International Conference on Alzheimer’s Drug Discovery and at CTAD.
Earlier this year, AgeneBio announced the start of “HOPE4MCI,” a phase 3 clinical trial evaluating the efficacy of AGB101, a once-a-day investigational medication to treat amnestic Mild Cognitive Impairment due to Alzheimer’s disease. The ADDF has been supporting AgeneBio for several years to develop their drug.
The promise of a multi-pronged approach makes me even more certain that the treatment of Alzheimer’s will likely follow the path set by cancer treatment, where ultimately a precision medicine approach using biomarkers and combination therapies based on the biology of aging will provide individualized, targeted therapies for patients.
2. Moving Closer to Blood Tests and Other Biomarkers
Biogen received much attention from the medical and patient communities when the company announced it would seek regulatory approval for their previously discontinued phase 3 trial of aducanumab. While I believe more data will be needed to demonstrate this drug’s meaningful clinical effect, it is noteworthy that the Biogen study was one of the first to use the amyloid PET imaging biomarker that the ADDF helped to develop to ensure the study participants had beta-amyloid plaques in their brains, confirming a diagnosis of Alzheimer’s disease. Studies have indicated that up to 30 percent of those enrolled in previous clinical trials didn’t have plaques and possibly didn’t have Alzheimer’s – contributing to many past failures of drug trials. The brain scan was also used to demonstrate that aducanumab worked to remove beta-amyloid plaques from patients in the trial, demonstrating that the drug actually hit its target. Whether or not the FDA approves aducanumab, the Biogen trial is a step forward in advancing clinical research.
As more therapies with novel drug targets other than amyloid are developed, we need better biomarkers that can measure effectiveness. Advanced research is underway to develop such tests. The ADDF announced its first investments this year with 10 new research awards totaling $10 million through its Diagnostics Accelerator, a $50 million research initiative supported by Bill Gates and other philanthropists, designed to advance the development of simple and inexpensive biomarkers for Alzheimer’s and related dementias. These current awards include research for blood tests in various stages of development, with one close to becoming a viable diagnostic tool for early detection of Alzheimer’s disease.
Such biomarkers will further revolutionize how we approach Alzheimer’s disease by allowing us to simplify diagnosis, improve clinical trial design, and pave the way for disease monitoring and treatment for Alzheimer’s and related dementias.
3. Heightened Support for Frontotemporal Degeneration (FTD) Research
This past year, we intensified our commitment to finding answers to related dementia conditions. Frontotemporal Degeneration (FTD) is the most common form of dementia for individuals under age 60, and to date, no approved treatments exist.
The ADDF partnered with The Association for Frontotemporal Degeneration (AFTD) to fund a study led by Italian researcher Barbara Borroni, M.D. to determine whether non-invasive brain stimulation can restore brain activity in patients with FTD. Results presented at our international conference gave us hope that this type of brain stimulation is effective to improve cognition in patients with FTD.
The ADDF and AFTD also announced an award to the Bluefield Project to Cure FTD as part of our Diagnostics Accelerator partnership. The program is directed towards early diagnosis of FTD and predicting who will advance to dementia in the coming years. Since it takes an average of four years before the diagnosis of FTD is confirmed by symptoms, I believe this investment in novel FTD biomarkers, including blood tests, will be crucial in advancing our ability to make earlier diagnoses and accelerate clinical drug trials.
4. Mounting Evidence Supports Prevention and Brain Health
As the evidence mounts that personalized lifestyle interventions may improve cognitive functions and memory, particularly in people at risk for Alzheimer’s, it’s never too early for all of us to start taking action to preserve our cognitive vitality.
Yuko Hara, Ph.D., the ADDF’s Director of Aging and Alzheimer's Prevention, highlighted the findings of a recent study, published in October 2019 in the journal Alzheimer's and Dementia, reporting on personalized interventions that may improve cognitive function and reduce risk. The ADDF offers a wealth of information and continues to enhance its CognitiveVitality.org website—an educational resource designed to help consumers and healthcare providers make informed decisions about brain health.
This year I was happy to serve as an expert contributor to several reports and roundtables, including the Global Council on Brain Health (GCBH), a collaborative from AARP that addressed the issue of dietary supplements and brain health, and UsAgainstAlzheimer’s Brain Health Partnership advocating for better brain health care in the U.S.
5. Venture Philanthropy Funding Is Paying Off
The ADDF has long followed a venture philanthropy model, whereby philanthropic capital is used to advance bold ideas in drug development and the ADDF then receives a return on investment that can go towards funding additional research.
In 2019, Rodin Therapeutics became one of the ADDF’s venture philanthropy success stories. Roughly five years ago, we invested $420,000 in Rodin for preclinical work for their novel epigenetic drug that affects gene expression as a treatment for neurodegenerative disorders such as Alzheimer’s. The company now has a drug in Phase 1 research and was acquired by Alkermes in November 2019 for $950 million. It is evident that our small investment helped to lessen the risk associated with this program early on, thereby propelling other investors to help fund clinical trials. In turn, the ADDF will reap financial returns on its investment, which will be re-invested in future research.
What Comes Next?
The field is finally shifting toward more innovative targets for treating Alzheimer’s and related dementias. Each year brings us closer to achieving our mission and maintaining our singular focus on the science that’s needed to conquer Alzheimer’s disease. As we begin the next decade, there are many exciting advancements in drug development and biomarkers that I am hopeful will lead to new and effective ways to prevent and treat Alzheimer's disease.