Parkinson’s Research Buoyed by Alzheimer’s Advances

 The research landscape for neurodegenerative diseases has undergone a monumental shift in the past year with the FDA approval of Eisai and Biogen’s Leqembi in Alzheimer’s disease and a regulatory decision for Eli Lilly’s donanemab expected by the end of 2023. While Alzheimer’s patients and researchers celebrate this momentum, another group is also heartened: researchers studying Parkinson’s disease.

Both Alzheimer’s and Parkinson’s are progressive diseases that affect proteins in the brain, though it’s traditionally thought that the similarities end there. But experts told BioSpace that the rising tide in Alzheimer’s research has the potential to accelerate the study and treatment of Parkinson’s disease by drilling down into biological mechanisms of neurodegeneration, mainstreaming the use of biomarker data and uncovering potential shared mechanisms. These advances, they say, could inform clinical trial design and analysis in Parkinson’s and usher in a funding environment that could spell progress for a notoriously intractable condition.

“There’s a lot of optimism now in the field that this is a breakthrough in neurodegeneration itself, not just in Alzheimer’s disease,” said Joanne Taylor, senior vice president of research at Gain Therapeutics.

Biological Cascades

Parkinson’s disease is characterized by a loss of dopamine-producing neurons in a region of the brain called the substantia nigra. Most people with Parkinson’s also have deposits of abnormal alpha-synuclein protein, which forms into clumps called Lewy bodies inside the neurons. These irregular deposits cause many of the motor and cognitive symptoms associated with the disease. Tracking disease progression quantitatively over time, however, is still an open area for research, said Akihiko Koyama, a leader at The Eisai Center for Genetics Guided Dementia Discovery.

Recently—beginning with Alzheimer’s—scientists have made progress toward a biological understanding of neurodegeneration, Koyama told BioSpace. “One big change happening . . . is that we are defining the disease biologically when before we were defining it symptomatically,” he said. This means that instead of relying exclusively on one readout, researchers can study multiple biomarkers, including amyloid beta protein, tau protein and neuroimaging results from MRI scans in the case of Alzheimer’s.

Gene Kinney

In Parkinson’s disease, one biomarker of interest is alpha-synuclein protein, Gene Kinney, CEO of Prothena, told BioSpace. This “likely plays a very important role” in the development of the disease, even before a person might present with clinical symptoms, Kinney said.

In collaboration with Roche, Prothena is testing an investigational Parkinson’s treatment, prasinezumab, that targets alpha-synuclein to stop it from spreading between neurons. Roche has fully enrolled participants for a Phase IIb study, Kinney said, with top-line data expected in 2024.

The shift from symptom- to biology-based definitions via the use of biomarkers is not exclusive to Alzheimer's and Parkinson’s. Biogen’s Qalsody (formerly tofersen) for SOD1-ALS won FDA accelerated approval in April based largely on data showing a reduction in the biomarker neurofilament light chain (NfL)—this after the drug failed to meet the clinical endpoint in Phase III. Now, Taylor said, companies with investigational Parkinson’s drugs are looking to apply these same insights.

“The availability of biomarkers is becoming very important because these diseases really start happening a long time before symptoms start to appear,” she said. Incorporating biomarker readouts into clinical trials for Parkinson’s is appealing for several reasons. One, Taylor said, is that it allows enrollment earlier in the disease process since people who develop motor and neurologic symptoms of Parkinson’s may already have had changes occurring in their brains years before the onset of these symptoms. Preventing the disease cascade may prove to be more attainable than reversing changes decades in the making, Taylor noted.

Second, she said that collecting multiple biomarkers for trial participants increases the odds that researchers can identify a significant signal that a drug is working, which can also shed light on how it works.

Finally, biomarkers can act as preliminary signals as to whether to continue a long and costly trial for a Parkinson’s drug candidate. Such encouraging preliminary signs aren’t just a boon for researchers—this feedback can also encourage investors, Taylor said. “If we can show an effect on biomarkers, it’s a reason to believe that this drug will work on the disease. We think that investors will be very excited about that.”

Shared Mechanisms

The key protein biomarkers in Alzheimer’s and Parkinson’s—amyloid beta and alpha-synuclein, respectively—likely share an important characteristic. Both are pathological, Kinney said, meaning they are each thought to drive disease progression as opposed to indicating the disease process.

While they are distinct proteins that may affect neurons in their own ways, Koyama said further research into the causes of Alzheimer’s might clarify a shared mechanism for how incorrectly folded, disease-causing forms arise and spread. While the target of the protein might be different, “There could be a very similar mechanism happening.”

The reciprocal benefits of neurodegenerative research go the other way too. Gain’s disease-modifying compounds for Parkinson’s, belonging to the class of small-molecule structurally targeted allosteric regulators (STARs), have also shown early signs of acting on Alzheimer’s, Taylor said. Because the compounds improve lysosomal health, they may act upstream of the changes that occur in both diseases. In cellular models of Alzheimer’s, Gain’s compounds prevented amyloid beta toxicity as well as tau hyperphosphorylation. 

“It could be that, just by improving the lysosomal health, we could have an effect on pretty much all of these diseases where protein misfolding is involved,” Taylor said.

A Boon for Collaborations

Success in Alzheimer’s clinical trials is a proof point not only for the basic science but also for the research collaborations behind it, Kinney said.

Massive studies under the umbrella of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) bridge academia, industry and government research institutions. The Parkinson’s Progression Markers Initiative (PPMI), led by the Michael J. Fox Foundation, aims to achieve the same level of collaboration. In 2021, the consortium announced plans to triple enrollment numbers in its longitudinal clinical study. One of the initiative’s goals is to identify biomarkers across each stage of Parkinson’s—work that Kinney said will undoubtedly help drug developers.

A final cross-therapeutic lesson, Kinney said, is that the moonshot for Parkinson’s should be a combination of effective drugs rather than any single magic bullet. The approval of a landmark Alzheimer’s therapy has sparked renewed investor interest in Parkinson’s research, with the hope that bets on multiple drugs will eventually pay off.

“When we think about medicine, that first breakthrough is a signal of good things to come,” Kinney said. “What we're seeing today is the tip of the iceberg with respect to where this field can go.”

https://www.biospace.com/article/parkinson-s-research-buoyed-by-advances-in-alzheimer-s-/