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The agency’s letter of support for using the α-synuclein seed amplification assay biomarker was supported by data observed in the Parkinson's Progression Markers Initiative cohort study.
Todd Sherer, PhD
(Credit: MJFF)
According to a new announcement, the FDA has issued a letter of support for using the α-synuclein seed amplification assay (αSyn-SAA) biomarker in clinical trials for Parkinson disease (PD) and related diseases. This decision comes following a multi-stakeholder collaboration between The Michael J. Fox Foundation for Parkinson's Research (MJFF) and the Critical Path Institute (C-Path) to advance PD therapeutics using this recently discovered biomarker.1
In the letter, the agency highlighted that its support comes from evidence gathered in the Parkinson's Progression Markers Initiative (PPMI), a longitudinal observational study sponsored by MJFF. The FDA noted that its decision to encourage use of αSyn-SAA also relied on other global studies across industry and academia, which represented the large amount of data as well as the applied collaboration used to validate the tool.
“The biomarker, now with the support of the FDA, will lead to faster, more effective clinical trials for Parkinson’s disease. Researchers can design trials that target specific aspects of disease biology with confidence that participants in the study have similar, important biological features. We anticipate this will speed along potential therapies already in early stages of the pipeline, while also attracting new or sustained interest from drugmakers. Our laser-focused goal remains the same — placing better therapies and a cure in the hands of people and families with Parkinson's," Todd Sherer, PhD, MJFF's chief mission officer, told NeurologyLive®. "Working collaboratively together with partners — people and families living with PD, neuroscience and clinical leaders, industry experts, federal research funders (i.e., the National Institutes of Health), disease-focused nonprofit organizations and regulatory authorities — we are able to leverage the incredible amount of knowledge and expertise in the space. We believe bringing the field together is the fastest way to improve its outcomes.”
Published in The Lancet Neurology, the PPMI study showed that use of an αSyn-SAA technique had high diagnostic accuracy of PD, distinguished molecular subtypes, and detected the disease before primary symptoms.2 In total, data on αSyn-SAA was collected from 1123 participants from the PPMI cohort, including patients with a diagnosis of PD and at-risk patients with gene variants (GBA and LRRK2) linked to the disease. In the large-scale analysis, αSyn-SAA was shown to differentiate PD from controls with a sensitivity of 88% and specificity of 96%.
The research was co-led by authors Andrew Siderowf, MD, PPMI investigator and director, PD and Movement Disorders Center at the University of Pennsylvania, and Luis Concha, PhD, director, research and development at Amprion. In the study, samples of cerebrospinal fluid surrounding the brain and spinal cord were analyzed from each participant using αSyn-SAA.
In the study, approximately 93% of patients with no known genetic cause had a positive αSyn-SAA result. Results varied for patients with genetic forms of PD, with 96% having the GBA variant and a positive αSyn-SAA result, compared with 68% of patients with LRRK2. Most prodromal patients had positive αSyn-SAA results, suggesting they had α-synuclein aggregates despite no PD diagnosis. Fifty-five percent of women with PD with the LRRK2 variant had a positive αSyn-SAA result compared with 72% of men with PD who had the same the variant. Patients with the LRRK2 variant and a negative αSyn-SAA result tended to be older compared with than those with positive αSyn-SAA results.
Loss of sense of smell was the most strongly predicted clinical feature of a positive αSyn-SAA result. Among all participants with PD who had loss of smell, 97% had positive αSyn-SAA compared with 63% of patients whose sense of smell was unchanged. Also, in patients with REM sleep behavior disorder, positive αSyn-SAA results were present in 85% (28 out of 33 patients) of participants. There were no other clinical features associated with a positive αSyn-SAA result.
Patients who carried the LRRK2 or GBA variants but had no PD diagnosis or prodromal symptoms, nonmanifesting carriers (NMCs), had positive αSyn-SAA results (LRRK2, 9% [14 out of 159 patients]; GBA, 7% [11 out of 151 patients]). Most prodromal participants and NMCs with positive αSyn-SAA had brain scans that did not show a decline in the expected number of dopamine-producing nerve cells, suggesting buildup of α-synuclein aggregates could be an early mark of disease onset.
Since the tool can detect early biological changes related to PD and related diseases before symptoms appear, it could potentially enhance trials assessing therapies that are aimed at delaying or preventing disease onset. Additionally, it supports research into personalized therapies for patients at all stages of these conditions. The biomarker can further accelerate and streamline these trials by providing objective end points, ensuring participants have the relevant pathology, and tracking therapy-induced changes. This efficiency can reduce the risk for industry investment in developing potential blockbuster therapies, including preventive treatments.
Diane Stephenson, PhD
(Credit: C-Path)
“The new biomarker findings that have just emerged in the last two years are truly transforming how we're going to be doing drug development for the future of Parkinson's. We all know that this is a very complex neurodegenerative disease that has so much rapid progression and a huge unmet need for disease-modifying therapies," Diane Stephenson, PhD, executive director of Critical Path for Parkinson's Consortium at C-Path, told NeurologyLive. "We now have a molecular tool that looks at a signature of what's going on in living individuals that tells you what is the underlying biology of the disease. Very similar to cancer, where we know the molecular features of the disease. We can now do this in Parkinson's where just two years ago, it was only possible by having autopsy postmortem tissues."
"With these new tools, we're able to identify a light that shows us who are the right people to treat with promising new disease-modifying therapies, not only when they're diagnosed, but years before the onset of symptoms," Stephenson said. "This landmark milestone that we achieved through this letter of support was so fast because of the data that was shared thanks to the generous support of The Michael J. Fox Foundation and thousands of patients from around the world who generated their samples. We pulled all that data together in a comprehensive submission to the FDA, and within three months they issued a letter of support. The data was reliable, robust, and showed consistency across multiple studies around the world.”
In January 2024, a multistakeholder team made up of academic researchers and clinicians, industry, nonprofits, regulators, and patients published the first biological staging system for Parkinson known as the neuronal alpha-synuclein disease integrated staging system (NSD-ISS).3 Published in The Lancet Neurology, the system relies on the biomarker detected by SAA to identify the evolution of NSD into progressive stages.4 The agency’s letter of support recognizes the potential of NSD-ISS with data produced by αSyn-SAA to speed up the success of therapeutic development in PD.
Led by Tanya Simuni, MD, FAAN, the proposed system is currently intended for research use only, with the goal to enhance trial design and improve drug development. Simuni, a professor of neurology and head of the division of movement disorder at the Northwestern University Feinberg School of Medicine, sat down with NeurologyLive® to discuss the long-term impacts this staging system has on the PD research community. She provided clarity on the purpose behind the paper, the role of α-synuclein in PD, and the next steps in expanding drug development.
