α-Synuclein Active Immunotherapeutic Drug Appears Safe and Effective, and Generates Immune Response in Parkinson Disease

The α-synuclein active immunotherapeutic PD01A appears to be safe and well-tolerated over time among patients with Parkinson disease (PD), according to findings published in The Lancet Neurology. These findings were also presented at the International Parkinson and Movement Disorders 2020 Virtual Congress.

The authors of the study arrived at their conclusion after performing a phase 1 safety and immunogenicity study and 3 consecutive extensions of the study. A total of 24 participants who were recruited to a single private clinic in Vienna, Austria, were included in the study. Participants were aged 45 to 65 years and had a clinical diagnosis of PD for at least 4 years and were in Hoehn and Yahr Stage 1 to 2. Patients also had imaging results that were consistent with their PD diagnosis, and were being treated with stable doses of PD therapies for at least 3 months.

Participants were randomly assigned to treatment with 4 subcutaneous immunizations with 15 μg or 75 μg PD01A injections. Initial follow-up was for 52 weeks and was followed by another 39 weeks of follow-up. Subsequently, participants were randomly assigned to receive 2 booster injections of 15 μg or 75 μg PD01A. Follow-up lasted 24 weeks for the first booster dose and an additional 52 weeks for the second booster dose.

Twenty-one of 24 participants received all 6 immunizations and completed 221 to 259 weeks of the study. Ultimately, the investigators concluded that the treatment demonstrated safety and tolerability throughout the study period, and that specific active immunotherapy generated a substantial humoral immune response with target engagement among recipients of the treatment. The investigators noted that all patients in the study had experienced at least 1 adverse event, but that most of these adverse events, with the exception of temporary local injection site reactions, were likely not related to the study drug

Joohi Jimenez-Shahed, MD, Associate Professor of Neurology and Medical Director of Movement Disorders Neuromodulation and Brain Circuit Therapeutics at Mount Sinai Hospital in New York, answered our questions about the study and its implications. Dr Jimenez-Shahed was not involved in the study.

Neurology Learning Network: Could you discuss the study and its key findings?

Dr Jimenez-Shahed: This was a phase 1 study of an immunotherapy directed at α-synuclein, the protein that accumulates in neurons in PD. In the study, a peptide that is intended to generate an immune response against α-synuclein was injected into patients with PD. The study was designed in a way that all patients received active treatment, and there was a high dose (75 μg) and a low dose (15 μg). Over time, there were 2 sets of booster injections that were administered. Various levels of the immune response over time were measured through cerebral spinal fluid analyses, as well as serum markers.

This was primarily designed as a safety and immunogenicity study. It was not intended or designed to look at efficacy, but the authors did track PD motor symptoms, along with these immune markers and safety assessments.

NLN: What is the proposed mechanism for this drug in PD?

Dr Jimenez-Shahed: We know that α-synuclein accumulates in the brains of patients with PD, and we know that this process accelerates over time. What is not known, however, is whether modulating the amount or the rate of that accumulation can have a neuroprotective effect in PD. The idea here was to investigate the safety of generating an immune response against this protein. In subsequent studies, the investigators will look at the clinical efficacy of this approach to treating PD.

NLN: What areas of future research are still needed for this drug?

Dr Jimenez-Shahed: This was a very preliminary study that looked at the safety and the immune response α-synuclein active immunotherapeutic PD01A. The important findings are that this was a safe way to deliver the peptide and that an immune response was able to be generated, indicating that the mechanisms and the pathways in the brain are being successfully targeted by the delivery of the peptide.

The future work that needs to be done involves determining how exactly this will affect the course of PD among the patients who received this therapy. Whether this is a symptomatic effect, a slowing of progression, or even a neuroprotective treatment are still to be determined, but these preliminary results certainly give a positive indicator that the therapy is safe and tolerable and that these kinds of broader studies on efficacy can continue.

NLN: What key takeaways about this topic do you hope to leave with neurologists and neurology providers?

Dr Jimenez-Shahed: The immunization with the peptide was able to be delivered repeatedly in a safe manner. So, this looks like a viable way to approach patients with PD. I think the fact that the booster injections were successfully able to mount increasing immune responses is also important because this is a treatment that could potentially be maintained over a longer period of time, which is important because PD is a chronic, progressive condition. It will be important for neurologists to keep an eye on the amount of immune response that was achieved with the successive doses of the immunization, because in this study, greater immune response was associated with greater stabilization of PD symptoms as measured by the Unified Parkinson's Disease Rating Scale. There may be a reasonable chance that this treatment could have implications for long-term progression of the disease and potentially even disease management.

—Christina Vogt

Reference:
Volc D, Poewe W, Kutzelnigg A, et al. Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial. Lancet Neurol. 2020;19(7):591-600. doi:10.1016/S1474-4422(20)30136-8