Harnessing the Power of Biomarkers for Neurodegenerative Diseases

Innovation in CNS, Oncology, Inflammation/Immunology: Primed for Growth

This year’s World Medical Innovation Forum delved into three key areas of biomedical innovation and healthcare: CNS/Brain Health, Oncology, and Immunology and Inflammation (I&I). Here, we highlight emerging themes in these areas that showcase the efforts of trailblazing faculty members across the Mass General Brigham system and underscore the impact of discovery and development throughout the healthcare innovation ecosystem. The themes described below also represent fields that are on the cusp of significant growth, both from the standpoint of clinical care and healthcare investment.

Parkinson’s disease affects some 10 million people worldwide. The disease emerges because of a shortage of dopamine, an important signaling molecule for neurons in the brain that helps control movement. The dopamine-producing neurons slowly degenerate and die, for reasons that are not entirely clear but likely involve a mix of genes and environmental factors. Although drugs can help restore dopamine levels, they often cause a range of side effects and are often not effective in patients with advanced disease.

Therapeutic development in neurodegenerative disease is at a watershed moment. With recent FDA approvals in both amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), there are now a small handful of treatment options that can, in some individuals, slow the course of disease. Mass General Brigham faculty have been a driving force in this effort, unraveling the biology of disease and its clinical manifestations, and translating that knowledge into groundbreaking therapeutics.

At the same time, the field is also rethinking its approach to drug discovery and development for neurodegenerative diseases. That includes the identification of robust molecular markers that can enable clinicians to diagnose disease at its earliest stages — before outward symptoms emerge — and also help monitor disease progression and response to therapy.

“The problem now is that neurodegenerative diseases typically aren’t diagnosed until the brain has deteriorated to the point of irreversible dysfunction,” said Rudolph Tanzi, PhD, Director of the Genetics and Aging Research Unit, Co-director of the McCance Center for Brain Health and Co-Director of the Mass General Institute for Neurodegenerative Disease at Massachusetts General Hospital and Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. “So, the future is really about developing methods to support early disease detection and early intervention.”

Incorporating biomarkers into clinical development is a critical step that underpins recent therapeutic approvals in ALS and AD. Biomarkers provide an alternative readout to outcome-directed measures, allowing an early readout of whether a drug is likely to provide therapeutic benefit. This, in turn, reduces the likelihood of failure in an outcomes-directed trial.

A recently approved gene-based therapy for a rare genetic form of ALS caused by mutations in the SOD1 gene demonstrates the power of such biomarker-focused clinical trials. This new therapy, an antisense oligonucleotide known as tofersen, was shown in clinical trials to reduce the levels of a biomarker of neuronal injury by 50 percent; about 40 percent of patients showed functional improvements. Tofersen was approved under the FDA’s accelerated approval pathway, and a large phase three confirmatory study based on outcomes is now underway to enable full approval of the drug for this indication.

“Only about two percent of ALS patients carry mutations in the SOD1 gene,” said Merit Cudkowicz, MD, Chair of the Neurology Department and Director of the Sean M. Healey & AMG Center for  ALS at Massachusetts General Hospital and Julieanne Dorn Professor of Neurology at Harvard Medical School. “But this drug really is a miracle for some of them.”

She added, “With our FDA approval based on the use of a biomarker, this could help carve a path for future therapeutic innovations in neurodegenerative disease.

About the World Medical Innovation Forum
The World Medical Innovation Forum was established in 2015 in response to the intensifying transformation of health care and its impact on innovation. The Forum is rooted in the belief that no matter the magnitude of change, the center of health care needs to be a shared, fundamental commitment to collaborative innovation – industry and academia working together to improve patient lives. In 2022, Bank of America joined with Mass General Brigham as presenting sponsor of the Forum, bringing together two leading organizations with extensive healthcare expertise and a shared commitment to support Boston’s continued growth as a global biotech and investment hub.