Gregory A. Rippon, MD, MS
Chief medical partner of neurology, ophthalmology, and internal medicine
I’ve recently returned from San Diego and the Alzheimer’s Association International Conference (AAIC). AAIC represents the best blend of scientific research, community input and collaboration that are essential to make progress against this devastating disease. It was wonderful to see friends, colleagues, community members and researchers I’ve long admired to share learnings from our collective Alzheimer’s research programs.
Through my conversations and the scientific presentations at the meeting, I am struck by the magnitude, excitement and – if I’m honest – tense anticipation we all feel at this pivotal time in Alzheimer’s research. As we look forward to a number of much-anticipated Phase III anti-amyloid clinical trial results in the months to come, it’s an ideal time to reflect on how much we’ve learned about the disease and how our persistent work, research, and even setbacks, have built the foundation of the field today.
The nuanced and important task of interpreting and translating learnings from the outcomes of prior research programs has advanced our understanding, and even our definition, of Alzheimer’s disease. We have listened closely to the clinicians and people living with Alzheimer’s disease as well as their loved ones, patient advocacy groups -- and importantly, we have thoughtfully incorporated insights from clinical setbacks, which are reflected in the way we design and administer our clinical trials, how our medicines are dosed and the ways we are working to provide support beyond our medicines. We’re hopeful that by employing these learnings and a purposeful approach, we’re getting closer to being able to answer important scientific questions that translate to meaningful learnings for the field – with our ultimate goal of making a positive impact for people living with Alzheimer’s disease.
For us at Genentech and Roche, our approach to Alzheimer’s disease is fueled by our commitment to transform how the disease is detected, diagnosed and treated. Throughout more than two decades of dedication to Alzheimer’s disease, we have made contributions to the field – from driving understanding of the biology and pathophysiology of the disease, to advancing the identification and application of biomarkers in neuroscience research, and refining study population selection and optimizing clinical trial design. There has been a lot to learn and designing studies that can capture the slowing of cognitive decline and functional decline, take time. The more we discover about the pathophysiology of Alzheimer’s disease, the more I am convinced that producing a significant clinical impact and demonstrating a meaningful change will require intervening with the right therapeutic agent in the appropriate patient population at the optimal time in the disease course.
The Right Patient
More than a decade ago, we didn’t have the technology or confirmatory testing capabilities needed as part of standard clinical trial inclusion criteria. The introduction of positron emission tomography (PET) was a critical step in ensuring clinical trials evaluated people with confirmed beta-amyloid. As a field, we are now looking to expand beyond PET to include more accessible methods of detection, such as cerebrospinal fluid (CSF) and blood-based biomarkers (BBBM), to help democratize the ability to diagnose people across geographies and socioeconomic status.
As science evolved, Genentech and Roche were the first to use a fluid biomarker for amyloid as an option in our Alzheimer’s clinical program, providing flexibility while ensuring we evaluate the right patients. Further, Roche Diagnostics is developing a comprehensive biomarker platform to aid in the detection of amyloid pathology in early stages of Alzheimer’s disease. These include a CSF test with high amyloid PET concordance as well as minimally invasive blood test, which has the potential to select patients requiring further confirmatory procedures. Once available and used in clinical practice, the CSF and blood biomarker tests would allow for a more timely and accessible evaluation of patients suspected of Alzheimer’s disease.
But the “right patient” goes well beyond confirmed disease pathology. At Genentech, we are committed to advancing inclusive research and addressing barriers to ensure future safety and efficacy data will be more reflective of the population at large. We are planning our studies in collaboration with the Alzheimer’s disease community to better meet the needs of people living with the disease, now and in the future. We are driving progress in areas beyond clinical research and partnering to forge new collaborations to collectively address health disparities to ensure more people receive appropriate Alzheimer’s disease diagnoses, treatment and care.
The Right Time
The concept of time in Alzheimer’s disease is much different from the way we understand and view other progressive diseases, like cancer. Whereas cancer progression is often measured in months or years from the time of symptom onset to diagnosis, Alzheimer’s disease impact in the brain is measured in decades. Changes in the brain, such as the accumulation of beta-amyloid and tau, begin forming 10-20 years before a person may start to present with noticeable cognitive, functional or behavioral symptoms. Moreover, Alzheimer’s disease may be driven and propagated by different mediators (e.g., beta-amyloid, tau) at different stages of the disease course. This notion is supported by the rapidly advancing understanding of Alzheimer’s disease fluid biomarkers and their subtypes over the past decade, which I believe shows tremendous promise to advance a more personalized approach to treatment of Alzheimer’s disease in the future.
The majority of neurodegenerative disease research suggests that intervening in the earlier stages of neurological disorders like Alzheimer's disease provides the greatest chance to slow or halt the progression of cognitive and functional decline in patients. This year we initiated a secondary prevention study called SKYLINE to examine that premise. The study will evaluate the potential to slow the onset and progression of Alzheimer’s disease to ease in cognitively unimpaired people with the earliest biological signs of the disease.
The Right Medicine
Unfortunately, despite the incredible amount of effort, time and resources invested in Alzheimer’s research, there is still no fully approved treatment to slow or stop the progression of the disease -- otherwise known as a disease-modifying therapy. In the last two decades alone, clinical trials evaluating more than 200 molecules in Alzheimer’s disease treatment have been initiated and discontinued.
While these figures on the surface may seem discouraging, with each medicine and each trial we have carried forward insights to optimize future programs, and I am confident that the upcoming scientific and therapeutic milestones will improve our understanding of the disease and how we as a society view Alzheimer’s disease.
At Genentech, our approach has always been to follow the science and explore multiple therapeutic approaches that address key pathways of Alzheimer’s, including beta-amyloid and tau. Fortunately, science never stops and there are a number of emerging and evolving areas of therapeutic research. Important questions around possible treatment interventions that target beta-amyloid, tau and other targets are still being explored. In the end, it is likely to require a multi-targeted approach to stop the disease fully in its tracks, ideally targeted to specific drivers of pathophysiology at the appropriate times in the disease course.
Where We Go From Here
We believe to successfully address the profound Alzheimer’s disease need we must balance rigorous, informed and evolving science with the holistic, comprehensive support for those diagnosed, their families and care partners who are also impacted. We have to think bigger and bolder -- and we are.
We must follow the science as we seek to uncover connection points across neurological disorders that may unlock critical clues to slow, stop and one day reverse neurodegeneration and its associated and irreversible disability. Relevant biomarkers of neurodegeneration across neurological disorders – like amyloid, tau and neurofilament light chain – may offer the potential to not only clarify complex neurodegenerative disease pathophysiology, but also to standardize the approach to measuring disease progression and better assess the potential of new treatments. We are also exploring blood-brain barrier research, potential ways to travel across it and the important role it plays.
We are committed to doing what’s right – through our science, in our approach and by our actions. It feels as though we are standing together with the Alzheimer’s community at the doorstep of a new era in Alzheimer’s disease research. I’m hopeful this scientific moment in history will create the momentum for progress in treating Alzheimer’s disease and neurodegenerative disorders broadly.