BACKGROUND:Prasinezumab has previously shown potential for reducing the progression of motor signs (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III) in patients with early-stage Parkinson's disease who were treatment-naive or receiving monoamine oxidase type B (MAO-B) inhibitors. The aim of the PADOVA trial was to evaluate the efficacy and safety of prasinezumab in a broader population of patients receiving stable symptomatic medication. METHODS:This phase 2b, multicentre, double-blind, parallel-group, placebo-controlled, randomised, superiority trial recruited participants with early-stage Parkinson's disease (age 50-85 years, 3 months to 3 years from diagnosis, Hoehn and Yahr stage 1 or 2) on stable symptomatic medication from 110 centres in nine countries in Europe and North America. Participants were individually randomly assigned (1:1) via permuted blocks (stratified by symptomatic medication [levodopa or MAO-B inhibitor]) to intravenous prasinezumab (1500 mg) or placebo every 4 weeks for at least 76 weeks and until the target number of motor progression events was reached. Participants, investigators, and clinical assessors were masked to group assignment. The primary endpoint was time to a confirmed motor progression event (≥5-point increase in MDS-UPDRS Part III off-medication score), assessed in the full analysis set (all randomly assigned participants according to the treatment to which they were assigned). Safety and tolerability were assessed in all randomly assigned participants who received at least one dose of study drug, with participants grouped according to treatment received. The trial is registered with ClinicalTrials.gov (NCT04777331) and EudraCT (2020-004997-23), and is active, not recruiting. FINDINGS:Between May 5, 2021, and March 22, 2023, 787 individuals were screened. 586 were enrolled and randomly assigned (n=293 per group; mean age 64·2 years [SD 7·3]; 214 [37%] female and 372 [63%] male); 550 completed double-blind treatment (prasinezumab, n=277; placebo, n=273). The primary endpoint was not met; the primary analysis showed a non-significant delay in motor progression with prasinezumab versus placebo (hazard ratio 0·84 [95% CI 0·69-1·01]; p=0·066); median time to confirmed motor progression in the prasinezumab group was 61·1 weeks (95% CI 52·3-71·9), compared with 49·7 weeks (40·1-58·1) in the placebo group. The incidence of one or more serious adverse events was similar between groups (prasinezumab, 34 [12%] of 292; placebo, 34 [12%] of 290) and three recorded deaths were unrelated to the study drug (prasinezumab, n=1 [<1%]; placebo, n=2 [1%]). INTERPRETATION:Although PADOVA did not meet the primary endpoint, prespecified exploratory evidence suggests clinical activity of prasinezumab in early-stage Parkinson's disease, supporting continued investigation in the ongoing phase 3 PARAISO trial (NCT07174310). FUNDING:F Hoffmann-La Roche.

The use of symptomatic medications represents a challenge for clinical trials of novel medicines designed to slow Parkinson’s disease progression. A time-to-event (TTE) approach using a defined motor progression milestone may mitigate the confounding effect of symptomatic therapy on the Movement Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). This analysis uses prasinezumab- and placebo-treated groups from the PASADENA study to evaluate the impact of symptomatic medications on treatment effects by comparing a TTE approach to a change-from-baseline approach with and without censoring the population upon starting symptomatic therapy. While the TTE approach yielded consistent hazard ratios between censored and non-censored analyses, the estimated difference between treatment arms using the change-from-baseline approach was lower without censoring than with censoring, suggesting a potential masking of prasinezumab treatment effects by symptomatic therapy. Thus, the TTE approach may mitigate the potential confounding effect of symptomatic therapy on MDS-UPDRS Part III.

Introduction: Prasinezumab was shown to potentially delay motor progression in individuals with early-stage Parkinson's disease (PD) who were either treatment-naive or on monoamine oxidase type B inhibitor (MAOBi) therapy in the PASADENA study. We report the rationale, design, and baseline patient characteristics of the PADOVA study, designed to evaluate prasinezumab in an early-stage PD population receiving standard-of-care (SOC) symptomatic medications. Methods: PADOVA (NCT04777331) is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, in which individuals with early-stage PD on SOC stable symptomatic monotherapy (levodopa or MAO-Bi) receive intravenous prasinezumab 1500 mg every 4 weeks. The primary endpoint is time to confirmed motor progression, defined as >= 5 points increase from baseline on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in practically defined OFF-medication state. Results: 586 participants were enrolled between May 5th, 2021 and March 22nd, 2023. At baseline, 74.2 % and 25.8 % of participants were receiving levodopa and MAO-Bi, respectively. Mean age was 64.2 years and 63.5 % were male. Mean time from diagnosis was 18.6 months, 85 % of participants were in Hoehn & Yahr (H&Y) Stage 2, and mean MDS-UPDRS Part III score was 24.5. Compared with the PASADENA population, PADOVA participants were older (similar to 5 years), with longer disease duration (similar to 8 months), and slightly more advanced based on H&Y stage (10 % more in Stage 2) and MDS-UPDRS Part III (similar to 3 points more). Conclusions: PADOVA has successfully recruited an early-stage PD population to test the effect of prasinezumab when added to background SOC.

Background To understand changes in the underlying progression of early Parkinson's disease, it is important to derive estimates of the threshold for meaningful motor progression on the MDS-UPDRS Part III in OFF medication state. Objective To estimate this threshold using two approaches: anchor-based analyses, and clinical consensus via a modified Delphi panel. Methods For the anchor-based analyses, data from a Phase II clinical trial were used. Mean and median MDS-UPDRS Part III change scores were calculated for those participants rated as ‘Minimally worse’ on the Clinical Global Impression of Improvement (using the first visit rated as ‘Minimally worse’ or worse, and at Weeks 24 and 52). Cumulative data up to Week 104 were used to assess the difference between motor progressors’ and non-progressors’ change scores on motor-related outcomes. For the modified Delphi panel, a panel of 13 expert clinicians received an online survey in two rounds and provided responses anonymously. Results For the anchor-based analyses, estimates of meaningful change ranged from 4−6 points. Numerically worse change scores were identified on motor-related outcomes for participants who had experienced motor progression compared with those who had not. For the modified Delphi panel, consensus was reached in Round 2, with 92% agreeing that 5 points is suitable to define a clinically meaningful motor progression threshold. Conclusions Results of the anchor-based analyses and modified Delphi panel were consistent, supporting a meaningful motor progression threshold of a worsening of 5 points on the MDS-UPDRS Part III (OFF medication state) in an early Parkinson's disease population.

Digital health technology (DHT) tools for Parkinson’s disease (PD) e.g., smartphones and wearables were used for remote and frequent measurement of motor signs in the phase 2 PASADENA study of the anti-alpha-synuclein monoclonal antibody prasinezumab. 316 early-stage PD participants were randomized to placebo, 1500 mg, or 4500 mg prasinezumab for 52 weeks; placebo participants were re-randomized to prasinezumab for the ensuing 52 weeks. Patients performed daily smartphone motor “active tests”, and were passively monitored by smartphone/smartwatch throughout the day over 2 y. Change from baseline analyses censored data at dopaminergic treatment start. Bilateral speeded tapping variability and hand-turning, U-turn speed, passively monitored hand movement power, and summary Simple Sum scores progressed numerically less in prasinezumab-treated vs placebo at week 52. All findings except hand-turning persisted at week 104. DHT sensor-based outcome measures may contribute to quantifying disease progression in clinical research of early-stage, dopaminergic treatment-naïve PD. Clinical Trial Registry Name: ClinicalTrials.gov; Clinical Trial Registry ID: NCT03100149; registered 2017-03-29.

Prasinezumab, a monoclonal antibody that binds aggregated alpha-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab's potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (>= 60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (>= 60 years versus <60 years); motor subphenotypes (akinetic-rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson's disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings.

The PASADENA study is an ongoing Phase II, multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of intravenous prasinezumab, administered every 4 weeks, in early-stage Parkinson’s disease (PD). During the double-blind study period, prasinezumab-treated individuals showed less progression of motor signs (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III). We evaluated here whether the effect of prasinezumab on motor progression, assessed as change in MDS-UPDRS Part III in OFF- and ON-state, and MDS-UPDRS Part II scores was sustained over 4 years from the start of the trial. We compared participants enrolled in the PASADENA open-label extension (OLE) to an external comparator arm derived from the Parkinson's Progression Markers Initiative (PPMI) observational study. Both PASADENA delayed- (n = 94) and early-start (n = 177) groups showed a slower decline (less increase in score) on MDS-UPDRS Part III in OFF- (-51% for the delayed-start group and − 65% for the early-start group) and ON-state (-94% for the delayed-start group and − 118% for the early-start group), and on MDS-UPDRS Part II (-48% for the delayed-start group and − 40% for the early-start group), compared with the PPMI external comparator (n = 303). This exploratory analysis, which requires confirmation in future studies, suggests that the effect of prasinezumab in slowing motor progression in PD may be sustained long-term.

To compare the progression of the PASADENA population treated with prasinezumab to a matched real-world data sample from the Parkinson's Progression Markers Initiative (RWD-PPMI).

Abstract Digital health technology (DHT) tools for Parkinson’s disease (PD) such as smartphones and wearable sensors enable remote and frequent measurement of motor signs which may facilitate research on novel treatments for PD. Here, we report the effect of the anti-alpha-synuclein monoclonal antibody prasinezumab on two-year motor sign progression in an early-stage PD population as measured with the Roche PD Mobile Application DHT. 316 early-stage PD participants of the phase 2 PASADENA study (NCT03100149) were randomized to treatment with placebo, 1500 mg, or 4500 mg prasinezumab for 52 weeks (Part 1); and placebo treated patients in Part 1 were re-randomized to 1500 mg or 4500 mg prasinezumab for the ensuing 52 weeks (Part 2, delayed-start group). Patients performed daily motor ‘active tests’ on provisioned study smartphones, carried the phone and wore a smartwatch throughout the day for passive monitoring, over two years. Change from baseline on 17 pre-specified individual sensor features and a summary Simple Sum score were analyzed with linear random slope and intercept models or mixed models for repeated measures, censoring patient data following the start of dopaminergic treatment. Adherence to active testing averaged 5.7 and 5.0 days/week in Parts 1 and 2, respectively. Bilateral speeded tapping variability and hand turning, U-turn speed, the power of passively monitored non-gait hand movements, and the Simple Sum score progressed less in prasinezumab-treated vs placebo at week 52. All findings except hand turning persisted at week 104. While the primary outcome for Part 1 PASADENA (MDS-UPDRS sum of Parts I, II and III) showed no significant difference from placebo, exploratory sensor-based outcome measures showed reduced motor sign progression in prasinezumab-treated individuals with early-stage PD.

Background: Objectively measuring Parkinson’s disease (PD) signs and symptoms over time is critical for the successful development of treatments aimed at halting the disease progression of people with PD. Objective: To create a clinical trial simulation tool that characterizes the natural history of PD progression and enables a data-driven design of randomized controlled studies testing potential disease-modifying treatments (DMT) in early-stage PD. Methods: Data from the Parkinson’s Progression Markers Initiative (PPMI) were analyzed with nonlinear mixed-effect modeling techniques to characterize the progression of MDS-UPDRS part I (non-motor aspects of experiences of daily living), part II (motor aspects of experiences of daily living), and part III (motor signs). A clinical trial simulation tool was built from these disease models and used to predict probability of success as a function of trial design. Results: MDS-UPDRS part III progresses approximately 3 times faster than MDS-UPDRS part II and I, with an increase of 3 versus 1 points/year. Higher amounts of symptomatic therapy is associated with slower progression of MDS-UPDRS part II and III. The modeling framework predicts that a DMT effect on MDS-UPDRS part III could precede effect on part II by approximately 2 to 3 years. Conclusions: Our clinical trial simulation tool predicted that in a two-year randomized controlled trial, MDS-UPDRS part III could be used to evaluate a potential novel DMT, while part II would require longer trials of a minimum duration of 3 to 5 years underscoring the need for innovative trial design approaches including novel patient-centric measures.

Objective: Here, we describe the results of PASADENA Part 2 at Week 104 and Part 3 Week 52 open-label extension (OLE). Background: Prasinezumab is a humanised monoclonal antibody designed to target aggregated alpha-synuclein and slow disease progression in Parkinson's disease (PD). PASADENA (NCT03100149) is multicentre, randomised, double-blind, placebo-controlled study evaluating the efficacy of prasinezumab in participants with early-stage PD. Design/Methods: Participants with early-stage PD (diagnosis ≤2 years of age at screening; Hoehn & Yahr Stages I–II) were randomised to receive intravenous prasinezumab every 4 weeks (1500 mg or 4500 mg) for approximately three years (early-start group), or placebo for 52 weeks followed by prasinezumab (1500 mg or 4500 mg) for approximately two years (delayed-start group). All 316 PASADENA participants were considered in the analysis, with participants included regardless of change in symptomatic therapy. Motor progression and motor complications were defined, respectively, as a ≥5-point increase on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III and reaching a score ≥1 point on MDS-UPDRS Part IV, and were analysed using Cox proportional hazards models. Results: Baseline characteristics were balanced between individuals in the early- and delayed-start groups. At the end of Part 2, fewer participants in the early-start group showed motor progression (80.1%) or developed motor complications (45.0%) compared with the delayed-start group (89.5% and 55.2%) (hazard ratio: 0.77 [80% confidence interval (CI) 0.65–0.91] and 0.74 [80% CI 0.60–0.92]). One-year results from Part 3 will be further described. Conclusions: The PASADENA Part 3 OLE is currently ongoing, and we aim to describe the long-term safety and efficacy on a yearly basis. Disclosure: Prof. Pagano has received personal compensation for serving as an employee of F.Hoffmann-La Roche Ltd. Prof. Pagano has stock in F.Hoffmann La Roche Ltd. Dr. Zanigni has received personal compensation for serving as an employee of Eli-Lilly and Company. Dr. Zanigni has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd. Dr. Zanigni has stock in F. Hoffmann-La Roche Ltd. Mrs. Monnet has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd. Kirsten I. Taylor has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd. Kirsten I. Taylor has received stock or an ownership interest from F Hoffman-La Roche Ltd. Ms. Hahn has received personal compensation for serving as an employee of Excelya Germany GmbH, Freiburg, Germany. Dr. Simuni has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Acadia, Abbvie, Accorda, Adamas, Allergan, Amneal, Aptinyx, Denali, General Electric (GE), Kyowa, Neuroderm, Neurocrine, Sanofi, Sinopia, Sunovion, Roche, Takeda, Voyager, US World Meds, Parkinson's Foundation, and the Michael J. Fox Foundation for Parkinson's Research. Dr. Simuni has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuroderm and Sanofi. Dr. Simuni has received research support from NINDS, Parkinson's Foundation, MJFF, Biogen, Roche, Neuroderm, Sanofi, Sun Pharma, Abbvie, IMPAX and Prevail. . Dr. Marek has received personal compensation for serving as an employee of IND. Dr. Marek has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for invicro. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biohaven. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for takeda. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alkahest. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Denali. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astellas. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bial. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven. Dr. Marek has received research support from Michael J Fox Foundation. Dr. Postuma has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche, Biogen, Takeda, Theranexus, GE, Jazz, Curasen, Paladin, Inception Sciences, Phytopharmics, Vaxxinity, Merck. Dr. Postuma has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen/Partners. The institution of Dr. Postuma has received research support from CIHR, Weston Foundation, Webster Foundation, Roche, MJFF, Parkinson Canada, FRSQ, NIH. Dr. Pavese has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Pavese has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bial. Dr. Pavese has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AbbVie. Dr. Pavese has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Britannia. The institution of Dr. Pavese has received research support from Multiple System Atrophy Trust. The institution of Dr. Pavese has received research support from Parkinson's UK. The institution of Dr. Pavese has received research support from Independent Research Fund Denmark. The institution of Dr. Pavese has received research support from European Union. The institution of Dr. Pavese has received research support from MRC. Fabrizio Stocchi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bial, Biogen, Sunovion, Lundbeck, UCB, Zambon, Chiesi, Lusofarmaco, Abbvie, Neuroderm, Kyowa, Synegile, Roche, Britannia, Sunovion, Blue Rock. Fabrizio Stocchi has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BIAL, Zambon, Biogen, Roche, Synegile, Sunovion. Fabrizio Stocchi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bial, Zambon, UCB, Kyowa, Sunovion. Dr. Svoboda has received personal compensation for serving as an employee of Hoffmann La Roche. Dr. Svoboda has received stock or an ownership interest from Hoffmann La Roche. Dr. Fontoura has received personal compensation for serving as an employee of F. Hoffmann La Roche. Dr. Fontoura has received stock or an ownership interest from Roche Pharmaceuticals. Rachelle Doody has nothing to disclose. Dr. Kerchner has received personal compensation for serving as an employee of F. Hoffmann-La Roche, Ltd.. Dr. Kerchner has stock in F. Hoffmann-La Roche, Ltd.. Dr. Kerchner has received publishing royalties from a publication relating to health care. Dr. Bonni has received personal compensation for serving as an employee of F.Hoffmann-La Roche Ltd. Dr. Bonni has received stock or an ownership interest from F.Hoffmann-La Roche Ltd. Tania Nikolcheva has received personal compensation for serving as an employee of F. Hoffmann La Roche. Tania Nikolcheva has received stock or an ownership interest from F. Hoffmann La Roche.

BACKGROUND Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the 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 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).