Interview: Are we on a path towards a cure for Parkinson’s?

The choice of April for Parkinson’s Disease Awareness Month is significant because it marks the birth month of James Parkinson (the 11^th being his birthday), the British surgeon who first described the condition in his 1817 essay, “An Essay on the Shaking Palsy” [1]. By highlighting Parkinson’s disease during this month, organisations and advocates aim to honour his contributions to neurology and further the cause of those impacted by Parkinson’s disease today. Medicom Medical Publishers had the privilege of interviewing Prof. Andrew Siderowf (Penn Medicine, Philadelphia, PA, USA), a Professor in Neurology and leading physician in Parkinson’s research, particularly in biomarker development and the future of treatment modalities for Parkinson’s disease.

What is the unmet need for biomarker development and validation in Parkinson’s disease?

“There’s a significant clinical need for better early diagnosis and prognosis for patients through the use of biomarkers,” said Prof. Siderowf. “When people are diagnosed, particularly early in the disease, misdiagnosis occurs 15–40% of the time, according to consistent research findings. Biomarkers could significantly reduce this uncertainty. An accurate clinical diagnosis usually emerges after a few years, but that’s a long time for patients to wait. So, biomarkers could certainly help with diagnosis, in addition to aiding prognosis. When patients come to my office, they often express concerns about the future, questioning what they can expect in 5–10 years,” expressed Prof. Siderowf. “Currently, we have no definitive answers due to the heterogeneity of the disease’s progression. Biomarkers could potentially provide clarity in these areas. Furthermore, in terms of research, we are very hopeful that biomarkers could accelerate drug discovery by demonstrating target engagement, the appropriate mechanistic effect, and changes in Parkinson’s physiology over time.”

Do you think biomarkers could also be beneficial for patient selection in future clinical trials?

“Absolutely, biomarkers play a crucial role in trials, especially in patient selection —sometimes referred to as stratification— and in disease monitoring as an outcome measure,” stated Prof. Siderowf. “We’ve already seen this in Alzheimer’s trials, where patients are expected to have the target pathology before enrolment, either based on blood markers for amyloid or amyloid imaging. This concept has been true for other conditions too, like high blood pressure, where the diagnosis is a prerequisite for treatment,” he continued. This approach could potentially extend to other disorders, such as REM sleep behaviour disorder, especially when the clinical symptom burden is less prominent.”

Could you talk about immunotherapy for Parkinson’s?

“Immunotherapy is categorised into active immunotherapy, with vaccines, and passive immunotherapy, with monoclonal antibodies, raised in the laboratory.” Prof. Siderowf pointed out the SPARK study (NCT03318523), which investigated cinpanemab, a monoclonal antibody targeting alpha-synuclein in Parkinson’s disease. “Unfortunately, this trial did not meet its primary or secondary endpoints [2]. On the other hand, prasinezumab, another monoclonal antibody aimed at a different target on the synuclein protein, is currently being evaluated in several clinical trials, including the PASADENA (NCT03100149) and PADOVA (NCT04777331) trials [3]. These humanised antibodies are designed to recognise certain epitopes on the synuclein molecule, embodying a passive immunotherapy strategy where the antibodies aim to clear synuclein aggregates. This mechanism is somewhat analogous to how anti-amyloid therapies work to clear amyloid aggregates in Alzheimer’s disease,” Prof. Siderowf explained.

“Despite the extensive testing, neither approach —targeting synuclein aggregates with monoclonal antibodies or vaccines— has yet demonstrated definitive effectiveness. However, there remains some optimism that prasinezumab may show positive results in ongoing trials,” said Prof. Siderowf. This cautious optimism is buoyed by the recent successes in Alzheimer’s disease immunotherapy, notably with antibodies like donanemab and lecanemab, which succeeded after initial rounds of immunotherapies failed. These precedents highlight that early failures in the development of synuclein-targeting therapies are not necessarily indicative of the approach’s ultimate viability.

“The journey of immunotherapy in neurodegenerative diseases underscores a learning process; initial failures are not uncommon and can guide subsequent efforts towards more effective treatments. The challenges encountered thus far in synuclein immunotherapy suggest that the field is still evolving, and with further refinement, these strategies may prove to be more successful,” Prof. Siderowf decided. “As such, passive immunotherapy remains a promising, albeit work-in-progress, avenue for the development of disease-modifying treatments for Parkinson’s disease.”

Any concluding remarks concerning Parkinson’s Awareness Month in April?

“As a physician treating patients with Parkinson’s disease daily, it’s clear that, while we have effective therapies like levodopa and new surgical approaches, the long-term outcomes haven’t significantly changed over the past 25 years. There remains a pressing need for disease-modifying therapies, and biomarkers could play a vital role in this endeavour. Ultimately, a deeper understanding of the causes of Parkinson’s disease, such as how synuclein aggregates and how to halt it, is essential for making significant progress in treating the disease,” concluded Prof. Siderowf.

1. Parkinson J. An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci. 2002 Spring;14(2):223-36; discussion 222.
2. Lang AE, et al. N Engl J Med 2022 Aug 4;387(5):408-420.
3. Pagano G, et al. N Engl J Med 2022 Aug 4;387(5):421-432.

 

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Posted on 2 April, 20242 April, 2024