The world’s experts in Parkinson’s disease have arrived at a sobering juncture. After a global investment of $23 billion in the development of new therapies for Parkinson’s disease, researchers are discovering that one therapy can’t possibly cure all.
Parkinson’s disease, says Alberto Espay, MD, MSc, director of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders, is really multiple diseases. Perhaps 20 of them. Perhaps even more.
“We’re going through a transformation of how we think about Parkinson’s disease,” says Espay, a UC Health neurologist who is the author, co-author or editor of five books about movement disorders and chair of the Movement Disorders Section of the American Academy of Neurology. “It’s a folly to have assumed that Parkinson’s was a single disease.”
The type of Parkinson’s developed by an individual in her 70s, for example, might contrast greatly with the type experienced by Muhammad Ali, who was diagnosed in his 40s after – in his own estimate – taking 29,000 punches to the head.
Espay made his comments on the eve of a four-year assessment of the $45 million Parkinson’s Progression Markers Initiative (PPMI), a global, 33-site trial initiated by the Michael J. Fox Foundation. Espay is the site leader for Cincinnati’s portion of the study. Espay and his colleagues had hoped the landmark study would help them discover biomarkers that would pinpoint underlying aspects of the disease process and would help them determine whether a drug was effective in slowing or halting that process.
“PPMI was designed with the idea that we already knew the truth: the definition of Parkinson’s disease,” Dr. Espay says. “We sought to correlate biomarkers with this truth. But our analyses were biased; they assumed Parkinson’s was a single entity with clinically defined subtypes.”
One size doesn’t fit all
In reality, one set of biomarkers would not validate all cases of parkinsonism. Espay likened the situation to the field of oncology, which evolved over a period of decades from a focus on “the cure for cancer” to an understanding of cancer’s profound complexity. No single cure for cancer could be found, because there was a vast array of cancer types and subtypes, with different molecular profiles, different mutations and different vulnerabilities. A therapy that successfully treated one type of breast cancer, for example, might be completely ineffective against another type. This knowledge ushered in the age of precision medicine – the matching of drugs to molecular subtypes of disease.
“Imagine how far behind we are compared to oncology,” Espay says. “We’re still in the 1970s. Our model has been to develop therapies to cure Parkinson’s disease, and there have been 23 such drugs. When the drugs failed, we blamed a number of things. We said the study design was flawed, the patients were too advanced, or the animal models didn’t replicate the complexity of the human disease.”
In truth, some of the therapies might have helped a subset of patients; but successful responders went unrecognized amidst the overall negative results of the trials.
Similarly, Espay notes, a cystic fibrosis treatment trial of Ivacaftor failed when it included all subsets of patients with CF. But when the drug was given only to patients with a specific mutation, the trial proved successful.
Precision medicine for Parkinson’s disease
“We need to take a big step back and re-think this,” Espay says. “We need to understand that we’re going to be targeting multiple diseases. We need to ask, ‘What subset of patients will benefit from a specific mechanism of action?’ ”
Understanding the subtypes of Parkinson’s disease and finding biomarkers for those subtypes will cost money. PPMI’s $45 million budget “is a drop in the bucket” compared to the cost of an effective study of aging that could lead to a new understanding of Parkinson’s, Alzheimer’s and other neurodegenerative diseases, Espay says. Only when biomarkers drive the creation of specific disease subtypes (and not the other way around) will treatments with neuroprotective potential be effectively developed and used.
“We will need to follow a large number of aging individuals – both healthy and sick — so that we can see what signals correspond with what subtype,” Espay says. “We need to develop true phenotypes based on patterns of cognitive, motor, autonomic and sleep issues and how they differ at the molecular and biological levels.”
But amidst this sobering assessment, signs of hope are emerging. “We are at the tipping point that cancer was in the 70s,” Espay says. “We are moving from an unproductive, single-disease model for neuroprotection to an era of precision medicine, where molecularly defined subtypes of Parkinson’s will be slowed or potentially reversed, perhaps even with some of the drugs we had given up on. Neuroprotection in Parkinson’s will happen with smaller subtypes, one at a time, as has been happening in cancer treatment.”
— Cindy Starr