NEW YORK – A recent "Letter of Support" from the US Food and Drug Administration could drive use of alpha-synuclein seed amplification assay (αSyn-SAA) testing in drug development and clinical trials for Parkinson's and related diseases.
In the letter, issued in August, the FDA encouraged "the further study and use" of αSyn-SAA testing in cerebrospinal fluid samples "to improve the efficiency of clinical trials targeting early intervention" in diseases, including Parkinson's, characterized by misfolded αSyn protein.
The letter could prove a boon for companies developing and offering αSyn-SAAs, most notably San Diego-based Amprion, which offers a laboratory-developed αSyn-SAA test called the SAAmplify-ɑSYN test (formerly SynTap).
Alpha-synuclein is a neuronal protein linked to Parkinson's and other neurological conditions including Lewy body dementia and multiple system atrophy. In Parkinson's patients, misfolded versions of αSyn form aggregates that accumulate throughout the brain in clumps called Lewy bodies that are believed to cause neuronal damage. The protein is considered both a potential drug target and a biomarker for the disease.
Alpha-synuclein seed amplification assays are premised on the observation that misfolded αSyn protein induces misfolding and aggregation in healthy αSyn protein. With αSyn-SAAs, patient cerebrospinal fluid is introduced to a collection of healthy αSyn proteins. If aggregates form, it is an indication that the patient's CSF contains the misfolded αSyn characteristic of Parkinson's.
In a study published last year in Lancet Neurology, Amprion's SAAmplify-ɑSYN test showed strong performance for detecting sporadic Parkinson's cases in patients with the olfactory deficit characteristic of the disease, a group that comprises the large majority of Parkinson's cases. In 2019, the FDA granted SAAmplify-ɑSYN breakthrough device designation for diagnosing Parkinson's.
The FDA's letter of support could boost the use of αSyn-SAAs, particularly for selecting patients for clinical trials of drugs for treating Parkinson's and other synucleinopathies. The agency issues letters of support for biomarkers it considers promising but which are not yet part of the agency's Center for Drug Evaluation and Research's (CDER) Biomarker Qualification Program. According to the FDA, letters are meant to "enhance the visibility of these biomarkers, make public FDA’s support for continued development, and encourage data sharing and collaboration."
"Essentially, it's like a proof of concept that this biomarker is working … and the goal is then to have additional conversations and additional studies," said Samantha Hutten, VP of translational biomarkers at the Michael J. Fox Foundation (MJFF). MJFF collaborated with the Critical Path Institute's Critical Path for Parkinson's consortium to request the letter. The FDA cited MJFF's Parkinson's Progression Markers Initiative (PPMI) study as providing "important supporting evidence" of the marker's potential.
She noted that while drug companies currently active in Parkinson's research are largely aware of the αSyn-SAA test and, in many cases, are already using it in their trials, companies with less experience in the space may not be as aware of the test and its uses.
She said that greater awareness of the test's existence might also boost investment in Parkinson's drug development as it could help de-risk such efforts.
"For companies that are thinking about moving into [Parkinson's], this is something that may tip the scales because it gives them confidence that there are biomarkers and tools available, which is not the case for other indications, especially in neurodegeneration," Hutten said.
She added that even at pharma companies with experience in the space, "the people on the ground with knowledge of [αSyn-SAAs] are not necessarily the same people making decisions on how to allocate budgets to Parkinson's disease versus Alzheimer's versus MS versus cancer."
"A lot of people know about [αSyn-SAAs], but having a big splash like this does really bring it to the forefront," she added.
Hutten said the letter could also streamline the process for drug companies looking to include αSyn-SAAs data in their FDA submissions.
Typically, she noted, "the onus would be on each company when they went to the FDA for approval to not only show all the drug data" but also show data supporting the use of αSyn as a biomarker. In this case, the FDA "has already issued an opinion about it in the form of this letter of support. It's one less thing these different companies have to worry about," Hutten said.
Amprion Cofounder and CEO Russ Lebovitz said that the company currently works with "most of the large- and medium-size drug developers" active in Parkinson's and added that he expects to see growth in demand for the test following the FDA letter.
"We'll see this marker being used much more for either inclusion, exclusion, or stratification in Phase III trials," he said.
The FDA has issued 25 letters of support throughout the history of the CDER program dating back to 2014. In 2015, the agency issued a letter for the use of imaging of dopamine transporter (DAT) to select patients for enrollment in Parkinson's drug trials.
Hutten said that today "most, if not all, companies are using [DAT] as part of their enrollment criteria and trials."
"That wouldn't have happened if we didn't have data from PPMI and other studies and if FDA hadn't showcased and highlighted the utility of DAT in the same way that they are for [αSyn-SAAs] now," she said.
Amprion offers the SAAmplify-ɑSYN test both for clinical trial work and as an aid for diagnosing Parkinson’s, Lewy body dementia, and Alzheimer’s with Lewy body variant. The company is the most prominent in the αSyn-SAA space, but a number of companies are pursuing other approaches to measuring αSyn as a marker of Parkinson's disease, including Scottsdale, Arizona-based CND Life Sciences, which earlier this year published data on the use of phosphorylated αSyn in patient skin biopsies to aid in the diagnosis of Parkinson's disease.
The FDA letter specifically cites CSF-based αSyn-SAAs, but blood-based αSyn assays are also drawing interest as they would be less invasive and more easily scalable than CSF assays like the SAAmplify-ɑSYN test. Last year a team led by researchers at Japan's Juntendo University detailed an αSyn-SAA capable of detecting pathological forms of the protein in patient serum.