In patients with Parkinson disease (PD), treatment with prasinezumab has no meaningful effect on global or imaging measures of disease progression, compared with placebo, and is associated with infusion reactions. These are the findings of 2 studies published together in the New England Journal of Medicine.
Recognizing that aggregated alpha-synuclein plays a key role in the pathogenesis of PD, researchers sought to explore the effect of the monoclonal antibody prasinezumab, directed at aggregated alpha-synuclein, in patients with the neurologic disorder.
The two-part Phase 2 Trial of Anti α-Synuclein Antibody in Early Parkinson’s Disease (PASADENA; ClinicalTrials.gov Identifier: NCT03100149) was designed to evaluate the efficacy and safety of low-dose (ie, 1500 mg) prasinezumab and high-dose (ie, 4500 mg) prasinezumab in individuals with early PD. The current analysis describes the results of the 52-week, double-blind, placebo-controlled portion of the study (part 1) and an exploratory additional 52-blinded extension (part 2), in which all participants received active treatment.
Eligibility criteria included early-stage PD (stage 1 or stage 2 on the Hoehn and Yahr scale [stages range from 1-5, with higher stages indicative of greater disease severity]); findings on dopamine transporter imaging with single-photo-emission computed tomography (SPECT) with use of the tracer 123I-ioflupane that were consistent with PD; and no prior treatment for symptoms of PD.
Participants in part 1 were randomly assigned in a 1:1:1 ratio to treatment with placebo, prasinezumab 1500 mg, or prasinezumab 4500 mg (referred to as the 4500-mg group, even though the patients with a body weight <65 kg received only 3500 mg) intravenously every 4 weeks. In part 2, those participants who had been treated with placebo were randomly assigned in a 1:1 ratio to receive prasinezumab 1500 mg or prasinezumab 4500 mg.
The primary endpoint of part 1 of the trial was the difference between the prasinezumab and the placebo groups in change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS; range, 0-236, with higher scores indicative of greater impairment). Secondary endpoints included dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane SPECT.
In part 2 of the trial, prespecified exploratory analyses were performed to compare these groups:
- Participants in the early-start cohort received prasinezumab 1500 mg or prasinezumab 4500 mg for 104 weeks
- Participants in the delayed-start cohort received placebo for the initial 52 weeks (in part 1)
- Participants in the delayed-start cohort received prasinezumab 1500 mg or prasinezumab 4500 from weeks 56 through 104 (in part 2)
Between week 52 and week 56, those in the delayed-start group did not receive any treatment.
A total of 316 participants were enrolled in the study, with 105 individuals assigned to the placebo group, 105 to the prasinezumab 1500 mg group, and 106 to the prasinezumab 4500 mg group.
Baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the prasinezumab 1500 mg group, and 30.8 in the prasinezumab 4500 mg group. Mean changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the prasinezumab 1500 mg group (difference vs placebo, –2.0; 80% CI,
–4.2 to 0.2; P =.24), and 8.8±1.2 in the prasinezumab 4500 mg group (difference vs placebo, –0.6; 80% CI, –2.8 to 1.6; P =.72).
Serious adverse events were reported in 6.7% of patients in the prasinezumab 1500 mg group and in 7.5% of those in the prasinezumab 4500 mg group. Infusion reactions were reported in 19.0% and 34.0% of participants, respectively.
A key limitation of the current trial is the planned censoring of data from participants when they initiated treatment for symptoms of PD and their omission from the primary analysis. Further, the study population was not entirely representative of the wider population of patients with PD, with an underrepresentation of non-White and non-US or non-European populations because of the countries in which the trial was conducted.
“In this placebo-controlled trial, treatment with prasinezumab, a humanized monoclonal antibody targeting aggregated [alpha]-synuclein, had no meaningful effect on global clinical or imaging measures of Parkinson’s disease progression,” the researchers stated.
They concluded that future studies might be warranted that “explore the potential relationship and temporal delay between removal of aggregated [alpha]-synuclein and neuronal sparing.”
Disclosure: This research was supported by F. Hoffmann-La Roche and Prothena Biosciences. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Pagano G, Taylor KI, Anzures-Cabrera J, et al; PASADENA Investigators; Prasinezumab Study Group. Trial of prasinezumab in early-stage Parkinson’s disease. N Engl J Med. Published online August 4, 2022. doi:10.1056/NEJMoa22028