Michela Gallagher, CEO of AgeneBio, and her staff have given themselves a big challenge – to develop the first and only therapeutic targeting brain network imbalance and potentially the first therapeutic to slow progression to and delay the onset of Alzheimer’s dementia, which is becoming a public health crisis.
Gallagher believes the biggest roadblock to finding an effective therapy has been the previous emphasis on treating later stage patients. Based on clinical research results to date, she believes Agenebio’s Phase 3 drug AGB101 restores normal brain function and preserves memory in patients and has the potential to delay the onset of Alzheimer’s dementia. During a recent Alzheimer’s panel discussion at a Milken Global conference, Gallagher explained that a proactive approach of addressing Mild Cognitive Impairment (MCI) to delay the onset of dementia can have a measurable impact. “If you can delay progression to a diagnosis of dementia by three years you will cut the prevalence – that is the number of people with Alzheimer’s dementia – by a third,” she says. “That’s a big win.”
Gallagher, Ph.D., founded AgeneBio in 2008. Her research led to the discovery of neural overactivity in neurocognitive aging localized to specific circuits in the hippocampus. She led the Phase 2 trial of AGB101 and initiation of AgeneBio’s drug discovery program to develop selective GABA alpha 5 positive allosteric modulators.
Gallagher is the Krieger-Eisenhower professor of Psychological and Brain Science, heads the Neurogenetics and Behavior Center at Johns Hopkins University and has published over 250 peer-reviewed papers in the field of cognitive neuroscience. She is a Fellow of the American Association for the Advancement of Science, the American Psychological Association, and the American Psychological Society. Prior to joining Johns Hopkins in 1997, Gallagher rose through the faculty ranks at University of North Carolina at Chapel Hill, where she was the Kenan Professor of Psychology. She earned her Ph.D. in physiological psychology from University of Vermont and in 1968 earned her undergraduate degree from Colgate University as one of two women in the university’s first female graduating class.
As part of a new Alzheimer’s industry series, WuXi AppTec Communications spoke with Gallagher about how AgeneBio’s early stage strategy can be used to bring new therapies to a growing number of senior citizens who don’t have access to effective treatments.
WuXi: What are the causes of Alzheimer’s disease? Are they genetic or environmental?
Michela Gallagher: Alzheimer’s is a complex disease that occurs late in life. Both biology and many exposures during life contribute to risk. There are certain inherited genetics that are known to cause Alzheimer’s disease at younger ages but that only accounts for 1%-to-2% of all Alzheimer’s dementia. Aging itself is the greatest risk factor for the occurrence of Alzheimer’s disease, representing the most common form of dementia affecting one out of three persons over the age of 85.
WuXi: How has the R&D for Alzheimer’s drug discovery evolved over the past five years? What have been some of the major scientific breakthroughs?
Michela Gallagher: A singular focus of Alzheimer’s drug discovery over the past few decades has been on amyloid to treat the disease – with late stage clinical trials designed to reverse the symptoms or arrest progression in patients with dementia. Those trials have not been successful. In recent years, attention has moved to prevention of dementia with patients in earlier stages of the disease. Patients for such trials can be selected in a prodromal phase, in which the hallmark feature of memory loss is worse than would be expected for a person’s age. The ability to visualize the accumulation of pathology in the brain, either amyloid or tau, is adding to the ability to detect increasing risk before a clinical diagnosis of dementia.
WuXi: What is your company’s approach to treating Alzheimer’s disease?
Michela Gallagher: Over the past decade or so, it’s become recognized that a condition of neural overactivity occurs in specific memory-making circuits of the brain in the earliest phases of Alzheimer’s disease.
In these prodromal Alzheimer’s patients, our approach has demonstrated that our drug can normalize neural activity in the brain. Alongside our clinical studies, basic science reports in recent years have established that heightened neural activity drives the specific pathophysiology of the disease – increasing amyloid and tau accumulation, and in the latter case tracking the spread of tau which tracks the progression of symptoms and neurodegeneration in the brain. Our approach, which a small molecule, is to normalize neural activity and slow or arrest progression in the earliest stages of the disease. The Phase 3 trial is underway.
WuXi: How does it differ from other companies?
Michela Gallagher: To our knowledge we are the only company in a late stage trial for FDA registration using this novel approach. Other companies are focused primarily on amyloid or tau.5. What are the major challenges in treating Alzheimer’s disease?
Ultimately, we would like to be therapeutically treating patients at risk before any symptoms are apparent. However, we don’t yet know with certainty how to select patients for treatment who are at risk. The only studies of that type that are on a strong foundation are those that study familial risk. But that is a small sample size and you can’t know whether therapeutics used in those families, which are currently under investigation, would work on those without familial risk. And all of these clinical trials are lengthy, due to the initial slow progression relatively speaking, extending over many years. Our trial in prodromal AD has a protocol lasting 18 months.
WuXi: What are the major regulatory challenges in clinical development? Are changes in clinical trial design needed?
Michela Gallagher: Trials right now are very lengthy and clinical cognitive assessments are used as outcome measures for effectiveness rather than biomarkers that would reliably show you have actually intervened in the disease progression in a manner that would be beneficial to patients. We need biomarkers that could be used as surrogates for the patient outcomes, for example, as has been done in oncology trials for cancer treatments.
WuXi: Why are we seeing so many failures in the late stages of clinical development?
Michela Gallagher: A lot of them have been focused on a single approach trying to reverse or halt progression in a late stage of illness rather than preventing dementia. AgeneBio is focused on prevention rather than a cure.
WuXi: What more can government contribute to support R&D?
Michela Gallagher: Government has really stepped up in recent years compared to even a decade ago. I think the pace of support is commensurate with the growing need and looming public health crisis. They just need to keep it up.
WuXi: How will Alzheimer’s drug development evolve over the next five-to-10 years? What are the best treatment modalities for Alzheimer’s disease? Will combinations of modalities be necessary?
Michela Gallagher: It’s likely there will be combinations but that’s going to depend on a number of different approaches being tested. We need more shots on goal. I think that’s where the field is at right now. The companies that are investing in new research and new clinical studies are not starting new amyloid trials. There’s a lot of focus on different novel approaches.
WuXi: Is a cure possible? What scientific advances are needed to find a cure?
Michela Gallagher: There’s a difference between prevention and a cure. Based on our research I absolutely believe we will be able to stop Alzheimer’s in its tracks in the not too distant future. We need sustained support in order to continue the pace of research with different approaches designed to prevent dementia.