Who Ever Said It Would Be Easy? Reflecting on Two Clinical Trials Targeting α-Synuclein

Two recent, high-profile manuscripts reported negative results with two parallel approaches of passive immunization targeting alpha-synuclein in a population of patients with early Parkinson's disease (PD). These phase II studies failed to show a bona fide disease-modifying neuroprotective effect on PD progression, despite the evidence that these antibodies effectively bind native alpha-synuclein in human serum. Here, we discuss the possible reasons that could help explain the lack of clinical efficacy. In particular, we highlight (1) the wealth of evidence supporting the notion of alpha-synuclein as a valid therapeutic target; (2) the lack of evidence of target engagement in the aforementioned studies, especially of the elusive oligomeric species, the likely culprits in disease pathogenesis and/or its propagation; (3) the limitations, especially in terms of timing passive immunization, of preclinical models, where the same alpha-synuclein antibodies succeeded in mitigating disease manifestations; (4) the consideration of possibly intervening at an even earlier stage of disease in future trials; and (5) the multitude of strategies beyond passive immunization that could be used to combat alpha-synuclein-mediated neurodegeneration, if in the end the current approach is not fruitful. Overall, our perception is that converging developments in the field, among them novel bioassays and biomarkers, improved cellular and animal models and objective measurements of motor activities integrated into clinical trials, if further optimized, will gradually move the momentum of the field forward. This, to better test the concept of whether alpha-synuclein-targeting therapies can indeed deliver the holy grail of neuroprotection to the benefit of the PD community.(c) 2023 The Authors.

Automated summary

Two recent manuscripts have reported negative results in parallel approaches of passive immunization targeting alpha-synuclein in early Parkinson's disease patients. Despite effectively binding to native alpha-synuclein in human serum, these phase II studies failed to show a disease-modifying neuroprotective effect on PD progression. The reasons for the lack of clinical efficacy are discussed, including the need for evidence of target engagement, the limitations of preclinical models, the consideration of earlier intervention, and the exploration of alternative strategies beyond passive immunization. Overall, further developments in the field, such as improved bioassays and biomarkers, better models, and objective measurements, are necessary to test the concept of alpha-synuclein-targeting therapies in PD.