NeuroVoices: Gennero Pagano, MD, MSc, PhD, on Prasinezumab for Parkinson Disease

Gennero Pagano, MD, MSc, PhD

At the International Parkinson and Movement Disorder Society (MDS) Virtual Congress 2021, September 17-22, investigators presented part 2 of the phase 2 PASADENA study (NCT03100149), which evaluated the efficacy and safety of prasinezumab (Roche) in patients with early-stage Parkinson disease (PD). Overall, 316 participants were recruited into the study, 309 of which started Part 2 and were included in the analysis. Patients were randomized 1:1:1 to receive intravenous prasinezumab every 4 weeks (low dose [1500 mg] or high dose [3500 mg] for body weight <65 kg or 4500 mg for body weight ≥65 kg) for 2 years (early-start group, n = 204) or placebo for 1 year, followed by prasinezumab (low or high dose) for 1 year (delayed-start group, n = 105).

Prasinezumab, an investigational humanized monoclonal antibody, resulted in a slight delay of motor progression, leading to more favorable trajectories among these patients. In April 2020, Roche announced that the trial had missed the primary efficacy outcome on the MDS-Unified Parkinson’s Disease Rating Scale but generated positive signals on multiple secondary and exploratory end points. Roche’s other study, PADOVA (NCT04777331), is an ongoing phase 2b study that will study prasinezumab over an 18-month period.

Gennero Pagano, MD, MSc, PhD, expert medical director, Roche, sat down with NeurologyLive for a new segment of NeuroVoices to discuss the results. He provided context on the mechanistic action of prasinezumab and his perspective on whether the drug would be more effective if used concomitantly with another approved medication.

NeurologyLive: Can you detail your results at MDS 2021 Virtual Congress? What stood out the most to you?

Gennero Pagano, MD, MSc, PhD: At MDS Virtual Congress, we had the opportunity to present data from PASADENA, a phase 2 trial that tested the safety and efficacy of prasinezumab. This was the first time we presented data from part 2 of the study. Part 1 is the randomized controlled part with placebo, whereas in part 2, everyone on placebo moved to study drug. We showed that people who started prasinezumab early, at the beginning of the 2 years, were on a better trajectory compared to patients who started prasinezumab later, after the first year. That group was first on placebo and then the drug. These results tell us that prasinezumab could have some potential on the delay of motor production, although this was not the primary end point of the study.

Why is the mechanistic action of this drug advantageous?

Prasinezumab is a humanized, monoclonal antibody that binds to aggregated alpha synuclein. Alpha synuclein is the protein that is considered one of the drivers of neurodegeneration in Parkinson disease. The opportunity to bind aggregated alpha synuclein has shown potential to slow disease progression. In preclinical models, it has had an impact on the neurons, particularly on preserving the synapses, and on ameliorating modern and cognitive behavior. With prasinezumab, we’re testing the hypothesis that binding these aggregates would have an impact on the long-term progression of the disease. Unfortunately, in Parkinson disease, the current available treatments can improve the symptoms for a little while. The potential of this treatment is going off its [Parkinson disease] underlying mechanisms.

Could this drug be even more effective if paired with an FDA-approved PD treatment?

What we showed at MDS Virtual Congress was that in a subgroup of patients on monoamine oxidase B inhibitors, the signal of efficacy was slightly bigger. Our explanation is not linked to the concomitant medication, but it’s the fact that patients in the early stage who require more symptomatic therapy and who are probably more slightly more advanced than the ones doctors have faced. They require some treatment and are basically on the verge of progression. One of the interesting characteristics about a drug that could affect the disease progression is that you need patients during the trial who progress. Those on monoamine oxidase B inhibitors showed that greater signal, even though they were in the same treatment arm. For the new studies, we are planning to use this paradigm by staying in the early stage but focus on patients that need more symptomatic therapy.

Is there anything else you’d like to mention about the drug or its clinical program?

In Parkinson disease drug development, we’re facing a big challenge because we’re moving away from a symptomatic to a disease-modifying therapy. This has been proven to be difficult, not only in identifying the right drug with the right mechanism, but also to clearly show that this is having an effect on the patient. The progression takes time. This is a disease that takes 10 years sometimes, and we have a short time to show some effect. This is the challenge we are facing now. The stakeholders, community, patients, investigators, and all the drug companies are trying to agree what are the right end points to measure these drugs and make sure that this drug can be transformational.

Transcript edited for clarity. For additional segments of NeuroVoices, click here.

REFERENCE

Pagano G, Zanigni S, Monnet A, et al. Delayed-start analysis of PASADENA: a randomized phase 2 study to evaluate the safety and efficacy of prasinezumab in early Parkinson’s disease; Part 2 week 104 results. Presented at: MDS Virtual Congress; September 17-22, 2021. Poster LBA 5