Background

Prasinezumab is a humanized IgG1 monoclonal antibody directed against aggregated α-synuclein. Genetic and pathological evidence suggest that this protein plays a central role in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies, such as dementia with Lewy bodies (DLB). In mouse models of PD and DLB, the mouse version of PRX002, 9E4, has been reported to reduce a C-terminally truncated form of α-synuclein that is considered neurotoxic, as well as α-synuclein propagation from cell to cell, neuropathology, and behavioral endpoints (e.g. Games et al., 2013; Games et al., 2014; Masliah et al., 2011).

Prasinezumab is one of several α-synuclein antibodies being investigated for PD. Others include LU AF82422 and MEDI1341. ABBV-0805 and cinpanemab were discontinued.

Findings

In March 2014, Prothena, in partnership with Roche, began a single-center study in 40 healthy adults younger than 66 to compare the safety and pharmacokinetics of a single infusion of 0.3, 1, 3, 10, or 30 mg/kg to placebo. This trial assessed peripheral target engagement (Mar 2015 conference news; press release). At the 2015 AD/PD conference, Prothena reported that the antibody was safe, well-tolerated, and dose-dependently reduced the concentration of free α-synuclein in the blood down to 4 percent; data were subsequently published (Schenk et al., 2017).

In June 2014, an eight-center, multiple-ascending-dose trial began comparing a six-month course of prasinezumab to placebo in what was to be 64 people with idiopathic PD. The trial evaluated safety and pharmacokinetic parameters, included exploratory CSF, imaging, and clinical markers, and was completed in September 2016. At the 2017 AD/PD conference, the trial was reported to have enrolled 84 people with mild to moderate PD, and to have been safe, without anti-PRX002 antibodies or serious adverse events. Side effects included gastrointestinal complaints, infusion site rash, headaches, and peripheral edema. Prasinezumab half-life was 14 days, and the CSF/serum ratio was 0.3 percent for all dose groups at week nine. Unbound serum α-synuclein dropped by up to 97 percent at the highest dose, indicating peripheral target engagement. Antibody levels rose dose-dependently in CSF, but the amount of monomeric α-synuclein in CSF did not change. At the time, Prothena had no assay to measure the concentration of α-synuclein aggregates in CSF before and after treatment. There was no improvement on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS, see May 2017 conference news). These data were subsequently published, and the half-life estimate was revised to 10.2 days (Jankovic et al., 2018).

Notably, this trial explored the use of smartphone measures to monitor clinical changes, showing that these digital markers closely correlate with the MDS-UPDRS but may be more sensitive (May 2017 conference news; Lipsmeier et al., 2022).

In June 2017, Roche started PASADENA, a two-year Phase 2 study comparing the efficacy of monthly infusions of 1,500 or 4,500 mg prasinezumab to placebo in 316 people with newly diagnosed PD and mild symptoms. Participants must not be on dopamine replacement therapy, although they can take monoamine oxidase-B inhibitors. A one-year, placebo-controlled, double-blind period will be followed by another year in which all participants receive the antibody but are blinded to dose. The primary outcome is change on the MDS-UPDRS global score; secondary outcomes include change in dopamine transporter imaging as per DaTscan, as well as a range of clinical, safety, and pharmacokinetic measures (for details, see Apr 2018 conference news; Pagano et al., 2021). In December 2018, recruitment was completed with 316 participants enrolled at 64 study sites in the U.S. and Europe.

In April 2020, Roche announced that PASADENA had missed the primary efficacy outcome on the MDS-UPDRS, but generated positive signals on multiple secondary and exploratory endpoints (Apr 2020 news). In September 2020, the company presented one-year results at the International Congress of Parkinson's and Movement Disorders. Prasinezumab had been generally safe and tolerable in this trial, but had not significantly slowed decline on the MDS-UPDRS. The treatment showed a trend toward benefit on the UPDRS Part III, which measures decline in motor function, and on several prespecified tests of motor function, including the mobile-phone-based endpoints. The low and high dose performed similarly well. DaT-SPECT showed little change in placebo or treatment groups. An ongoing one-year blinded extension ran until early 2021, and a five-year open-label treatment with the 1,500 mg dose will continue until 2026. Results of the placebo controlled and one-year open-label phases were published after peer review (Pagano et al., 2022). According to additional analyses presented at the 2021 AD/PD conference, and subsequently published, the antibody slowed decline on the UPDRS Part III or the digital motor score by one-quarter to one-third, and participants with more severe and faster-progressing symptoms benefitted more from treatment. In a prespecified analysis of subgroups who had more symptoms, or were taking MAO-B inhibitors, the antibody reportedly cut decline between 40 and 64 percent (Apr 2021 news; Pagano et al., 2024). Roche presented results of open-label treatment in 271 patients at the March 2024 AD/PD conference. After three or four years of treatment, worsening on the MDS-UPRDS part II and III significantly lagged behind that of matched historical controls from the Parkinson's Progression Markers Initiative. Depending on the readout, rates of progression slowed between 40 and 118 percent with treatment.

In May 2021, Roche began a Phase 2b study in PD patients with more advanced symptoms than in PASADENA. Called PADOVA , this study is enrolling 575 people who are on stable dopamine replacement medication; they will receive monthly prasinezumab 1,500 mg or placebo for 18 months. The primary outcome as registered was time to confirmed motor progression on the MDS-UPDRS Part III, defined as a decline by more than 5 points in the OFF medication state. Secondary outcomes include additional measures of motor function, clinical change, adverse events, pharmacokinetics, and anti-drug antibodies. The trial will run through 2024, at more than 120 sites throughout North America and Europe. It has an optional two-year open-label extension.

A Phase 1 trial in Japan began in January 2018 to assess the safety and tolerability of single doses of prasinezumab in healthy volunteers.

For all clinical trials on prasinezumab, see clinicaltrials.gov.