Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open-label extension of the PASADENA trial

Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open-label extension of the PASADENA trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open-label extension of the PASADENA trial Gennaro Pagano, Annabelle Monnet, Adriana Reyes, Benjamin Ribba, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4232431/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Oct, 2024 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Abstract 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. Biological sciences/Neuroscience/Motor control Health sciences/Diseases/Neurological disorders/Movement disorders/Parkinson's disease Figures Figure 1 Figure 2 Figure 3 Introduction Prasinezumab is a humanized monoclonal antibody designed to bind aggregated α-synuclein, inhibit intercellular spreading of pathogenic α-synuclein, and thus potentially protect neurons and slow Parkinson's disease (PD) progression 1 – 3 . The P hase II trial of A nti alpha- S ynuclein A ntibo D y in E arly Parki N son’s dise A se (PASADENA, NCT03100149) 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 PD 4 . The study is divided into three parts: a 12-month double-blind period during which participants were treated with prasinezumab 1500 mg, prasinezumab 4500 mg or placebo (Part 1); a 12-month period during which participants treated with placebo were re-randomized to 1500 mg or 4500 mg prasinezumab, while prasinezumab-treated participants continued on their dose of prasinezumab (Part 2); and a long-term (5 years) open-label extension (OLE) in which all participants received prasinezumab 1500 mg (Part 3). In the double-blind study period (Part 1), prasinezumab did not meet its primary endpoint (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] sum of Parts I + II + III) 4 . However, prasinezumab-treated individuals (both low-dose and high-dose) showed less motor progression on MDS-UPDRS Part III 4 . The OLE (Part 3) was implemented as an amendment to the PASADENA study after the completion of Part 1, to evaluate the long-term safety and efficacy of prasinezumab. Here, we performed an exploratory analysis comparing participants treated with prasinezumab in the PASADENA OLE to subjects enrolled in the Parkinson's Progression Markers Initiative (PPMI) observational study 5 , creating an external comparator arm by means of two independent approaches: propensity score and disease modeling. The PPMI was used to put the rates of disease progression seen in the OLE of PASADENA into context, in the absence of a placebo group beyond PASADENA Part 1 (Fig. 1 ). The main objective of the present study was to evaluate the change from baseline to year 4 in measures of severity of PD progression in the PASADENA OLE versus the external comparator PPMI population. Results Baseline characteristics of the PASADENA and PPMI cohorts were well balanced after weighting with propensity scores (Table 1 ) . Table 1 Baseline characteristics before and after weighting with propensity scores Characteristic Before weighting After weighting PASADENA N = 271 EC PPMI N = 303 SMD PASADENA N = 271 EC PPMI N = 270 SMD Age (years) (mean [SD]) 59.98 (9.00) 62.11 (8.53) 0.243 59.98 (9.00) 61.20 (9.28) 0.133 Sex = Male, n (%) 188 (69.4) 202 (66.7) 0.058 188.0 (69.4) 189.3 (70.1) 0.017 MDS-UPDRS Part III (mean [SD]) 21.15 (8.96) 21.17 (8.85) 0.003 21.15 (8.96) 21.13 (9.71) 0.001 Hoehn and Yahr = 2, n (%) 201 (74.2) 183 (60.4) 0.297 201.0 (74.2) 205.7 (76.2) 0.047 PD Diagnosis (months) (mean [SD]) 9.89 (6.34) 4.87 (5.36) 0.855 9.89 (6.34) 9.20 (5.61) 0.115 Years of education ≥ 12, n (%) 244 (90.0) 279 (92.1) 0.072 244.0 (90.0) 236.2 (87.5) 0.080 Montreal Cognitive Assessment (MoCA) (mean [SD]) 28.17 (1.79) 27.23 (2.26) 0.462 28.17 (1.79) 28.02 (1.89) 0.082 DaT-SPECT putamen bilateral (mean [SD]) 0.92 (0.26) 0.81 (0.28) 0.436 0.92 (0.26) 0.92 (0.31) 0.018 Note: SMD ≤ 0.2 indicates balance between groups. DaT-SPECT, dopamine transporter imaging with single photon emission computed tomography; EC, external control; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; PD, Parkinson’s disease; PPMI, Parkinson's Progression Markers Initiative; SD, standard deviation; SMD, standardized mean difference. In comparison with the PPMI cohort, at year 4, the PASADENA delayed- and early-start groups both showed: lower MDS-UPDRS Part III progression in OFF-state, with − 51% relative difference (mean [80% confidence interval (CI)], -5.73 [-7.33 to -4.14] points) for the delayed-start group and − 65% relative difference (mean [80% CI], -7.26 [-8.59 to -5.93] points) for the early-start group (Fig. 2 A); lower MDS-UPDRS Part III progression in ON-state, with − 94% relative difference (mean [80% CI], -3.71 [-5.41 to -2.01] points) for the delayed-start group and − 118% relative difference (mean [80% CI], -4.69 [-6.09 to -3.3] points) for the early-start group (Fig. 2 B); and lower MDS-UPDRS Part II progression, with − 48% relative difference (mean [80% CI], -2.20 [-2.96 to -1.45] points) for the delayed-start group and − 40% relative difference (mean [80% CI], -1.82 [-2.44 to -1.2] points) for the early-start group (Fig. 2 C). Disease progression modeling showed similar findings to those obtained with the propensity score method. Progression of MDS-UPDRS Part III (OFF) and Part II in the PASADENA delayed- and early-start groups was slower than the PPMI 90% CI (Fig. 3 ). Separation from the PPMI-based prediction occurred from year 2 onwards for MDS-UPDRS Part III and during year 4 for MDS-UPDRS Part II. In the analysis of MDS-UPDRS Part III in OFF-state, we found that 55% of the PASADENA scores were below the median PPMI predictions during year 2, and 64% and 66% were below the median PPMI predictions during years 3 and 4, respectively. For MDS-UPDRS Part II, the percentage of PASADENA scores below the median of PPMI predictions was close to 50% during years 2 and 3 (51% and 53%, respectively), but reached 56% below the median during year 4, which is comparable to the deviation of Part III in OFF-state during year 2. The percentage of MDS-UPDRS Part II scores below the median of PPMI predictions continued to increase thereafter, reaching 59% after year 4. The PASADENA arm showed no difference in MDS-UPDRS Part IV progression in comparison with the PPMI cohort ( Supplementary Table S1 ). The odds ratio of having reached stage ≥ 3 in Hoehn and Yahr (H&Y) at year 4 was 0.26 (80% CI: 0.04 to 0.42) in the PASADENA delayed-start group and 0.3 (80% CI: 0.13 to 0.47) in the PASADENA early-start group, in comparison with the PPMI cohort ( Supplementary Figure S1 ). The PASADENA delayed- and early-start groups showed numerically lower LEDD intake at year 4 in comparison with the PPMI cohort: mean − 120.83 (80% CI: -187.68 to -53.99) mg for the delayed-start group and mean − 85.08 (80% CI: -140.01 to -30.16) mg for the early-start group ( Supplementary Figure S2 ). For MDS-UPDRS Part I total, the PASADENA delayed- and early-start groups showed a mean progression after 4 years of 6.28 (80% CI: 5.67 to 6.89) and 6.39 (80% CI: 5.87 to 6.91) points, respectively, while the PPMI cohort showed a mean progression of 8.34 (80% CI: 7.91 to 8.77) points ( Supplementary Figure S3 ). The PASADENA delayed- and early-start groups also both showed lower MDS-UPDRS Part I Sleep progression (items 7 and 8) in comparison with the PPMI cohort, with − 47% relative difference (mean [80% CI], -0.24 [-0.39 to -0.09] points) for the delayed-start group and − 61% relative difference (mean [80% CI], -0.31 [-0.43 to -0.19] points) for the early-start group after 4 years. Notably, the PASADENA delayed- and early-start groups showed no difference in MDS-UPDRS Part I Fatigue (item 13) progression in comparison with the PPMI cohort after 4 years: mean − 0.11 (80% CI: -0.2 to -0.02) points for the delayed-start group and mean − 0.06 (80% CI: -0.13 to 0.01) points for the early-start group. In comparison with the PPMI cohort, the PASADENA delayed- and early-start groups showed no difference in dopamine transporter imaging with single photon emission computed tomography (DaT-SPECT) putamen or caudate striatal binding ratio progression over 4 years: mean 0.02 (80% CI: 0 to 0.06) points for the delayed-start group and mean 0.03 (80% CI: 0 to 0.05) points for the early-start group for putamen bilateral striatal binding ratio. Discussion In this exploratory analysis of the PASADENA study, people with PD treated with prasinezumab showed slower motor progression, measured by MDS-UPDRS Part III (total and subscores) in OFF and ON medication state and Part II over 4 years, when compared to an external comparator cohort derived from the PPMI observational study and a mathematical model of PD progression. Despite the low number of participants reaching H&Y stage 3 (mild to moderate bilateral involvement, some postural instability but physically independent), prasinezumab-treated individuals showed a lower risk of developing balance issues at year 4. During the past two decades, evidence from genetic, neuropathological and experimental models has suggested that α-synuclein aggregates play an important role in the pathogenesis of PD 6 . The observation that α-synuclein aggregation may spread intercellularly and contribute to neurodegeneration supported the development of immunotherapies targeting α-synuclein aggregates. Prasinezumab is a humanized monoclonal antibody directed against aggregated α-synuclein and its impact on PD progression was studied in the PASADENA Phase II study 4 . Although PASADENA did not meet its primary endpoint (change from baseline in the sum of MDS-UPDRS Part I + II + III scores) at week 52, prasinezumab reduced the decline of motor function, as measured by changes from baseline in the MDS-UPDRS Part III score and using digital readouts at week 52 4 . The PASADENA OLE provided the opportunity to study the long-term effect of prasinezumab. Notably, over 85% of PASADENA participants elected to enroll in the OLE and continued with monthly infusions of prasinezumab for 4 years. Obviously, a major limitation of the OLE is the lack of a placebo arm. We utilized the PPMI observational arm as a suitable comparator to enable quantification of treatment effects in the absence of a placebo arm beyond the first 52 weeks of the study. Using a well-established method of propensity score balancing of baseline characteristics, we matched the trial and comparator groups 7 , 8 . Using weighting allows the use of more covariates (including continuous ones) and includes all participants in the analysis. To ensure comparability, we applied the full PASADENA inclusion/exclusion criteria when we selected the PPMI cohort, and we next applied weighting (as opposed to matching) due to its flexibility in handling covariates. The validity of this approach for this study was confirmed by similar baseline characteristics and progression over 52 weeks between the PASADENA Part 1 placebo cohort and the weighted PPMI cohort. As expected, in the present study, the PPMI cohort exhibited a rate of progression consistent with previous publications 9 . By contrast, the PASADENA delayed- and early-start prasinezumab-treated groups showed less worsening of MDS-UPDRS Part III in OFF-state total score, and subscores, MDS-UPDRS Part III in ON-state, and MDS-UPDRS Part II. We confirmed this using a disease modeling approach, where we compared PASADENA OLE data with a hypothetical population created by using the characteristics of PASADENA and a model of progression 10 . We did not observe a difference in the rate of change of the DaT-SPECT measures. There could be a number of explanations for this. It is plausible that prasinezumab may preserve dopaminergic synaptic function, thus translating in the observed clinical benefit, but not impact transporter function measured by DaT-SPECT. DaT-SPECT availability is also influenced by compensatory down-regulation, which can mask the effective progressive loss of terminals. The DaT-SPECT findings could also be explained by suboptimal matching of the DaT-SPECT signal in the putamen. The matching of the PPMI and PASADENA groups was only partially achieved for the DaT-SPECT signal. Although the baseline difference was balanced (standardized mean difference [SMD] < 0.2), there was a significant difference in 1-year decline between the PPMI and PASADENA delayed-start group (placebo). Thus, the PPMI and PASADENA cohorts were not fully matched on DaT-SPECT progression. It is unclear what drove the 1-year differences between the cohorts, but substantial variability of progression rates of DaT-SPECT signal among cohorts has been reported 11 , 12 . We did not observe a difference in MDS-UPDRS Part IV, but participants started symptomatic therapy at different points, contributing to variability. A longer follow-up on stable symptomatic therapy is needed to assess a potential effect of prasinezumab on motor complications. At the 4-year time point, people with PD treated with prasinezumab had progressed less regarding non-motor symptoms, as measured by MDS-UPDRS Part I (total and sleep subscores), when compared with the external comparator cohort derived from the participants selected from the PPMI cohort. However, at the 1-year time point, the PASADENA delayed-start group (placebo until the end of year 1) already displayed a lower total score in MDS-UPDRS Part I compared with the selected PPMI cohort, and therefore the difference seen at 4 years has to be interpreted with great caution. Among the non-motor symptoms of PD, sleep items were pre-specified in this analysis because sleep problems are among the most specific non-motor symptoms of PD and associated with poor quality of life 13 . Both the PASADENA and PPMI studies enrolled treatment-naïve participants, and PASADENA also included participants on stable doses of monoamine oxidase type B inhibitors (MAO-Bi) at baseline. While participants in both studies were instructed not to start or change symptomatic therapy for the first 6 months (PPMI) or 12 months (PASADENA), all participants were expected to be on symptomatic treatment eventually. A change in medication represents one of the strongest confounders when assessing PD progression, due to its effect on motor outcome measures. Therefore, we compared the types and doses of symptomatic medications across the PASADENA and PPMI cohorts. Despite slight differences between the two studies during the first 12 months, by year 2 both cohorts were similar in terms of types of PD medications and Levodopa Equivalent Daily Dosage (LEDD), suggesting that this is unlikely to explain the differences in trajectories of progression of the MDS-UPDRS Part III and Part II scores. At year 3 and 4, when more than 90% of the participants of PASADENA and PPMI were receiving L-DOPA and/or dopamine receptor agonists, the prasinezumab-treated participants exhibited lower MDS-UPDRS Part III motor scores in ON, both compared to the PPMI cohort and to their own scores at baseline. This suggests that prasinezumab could potentially synergize with dopaminergic medications. It has previously been proposed that removal of extracellular α-synuclein aggregates might improve synaptic transmission in the nigrostriatal system, in addition to reducing the spread of protein aggregates between neurons 6 . There was a gap between the completion of Part 2 and the initiation of the OLE phase of the study, which averaged 7.4 months, largely driven by COVID-19-induced delays and other study operational aspects. Nevertheless, there was a clear separation between both PASADENA groups and the PPMI cohort on MDS-UPDRS Part III in both OFF and ON, starting from months 12 and 24, respectively, and increasing up to the 4-year timepoint. This finding suggests that, once it is established, the prasinezumab effect may be persistent, at least for the duration of the washout period, and argues against a symptomatic effect of prasinezumab. Taken together, our results suggest consistently that prasinezumab may slow motor progression and functional decline long-term in early-stage PD. We have identified several shortcomings in this exploratory analysis. Some of these are related to potential differences between the external observational PPMI cohort and the PASADENA participants. First , although the PASADENA and PPMI cohorts are comparable, there is a potential calendar time bias. The PASADENA study started in 2017, and the participants’ assessment up to the year 4 data cut snapshot occurred in the third quarter of 2023, whereas the initial PPMI cohort was enrolled between 2011 to 2018. Despite a gap of 6 years on initiation, there is a large overlap between the studies. Second , the PPMI study was conducted in North America, Europe, Israel, and Australia, and PASADENA is being conducted in North America and Europe. This difference in regional bias is considered low. Third , selection bias, which refers to the enrolment of people in clinical trials that are different from those in clinical practice, is limited because PASADENA had similar inclusion and exclusion criteria to the PPMI study. Fourth , participants in the OLE of PASADENA and the PPMI cohort may also differ due to the clinic visit frequency. The PASADENA study required a visit to the clinic every month to receive an infusion while in the PPMI study, participants visit their clinic approximately every 3 months. Our findings need confirmation in another long-term trial. The PADOVA study (NCT04777331) is an ongoing Phase IIb, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of intravenous prasinezumab versus placebo, in participants with early-stage PD who are on stable symptomatic PD medication (for at least 6 months, with stable doses for 3 months prior to baseline). The double-blind part of the PADOVA study is followed by an OLE, which, like the present study, will address the long-term effects of prasinezumab treatment. In conclusion, the effect of prasinezumab on slowing motor progression in PD may be sustained long-term. The PASADENA OLE is continuing. Declarations Acknowledgements The study is sponsored by F. Hoffmann-La Roche Ltd. F. Hoffmann-La Roche Ltd was involved in the study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication. We thank the patients and their families who participated in the PASADENA study and the clinical investigators. Editorial assistance for this manuscript was provided by m X m Medical Communications funded by F. Hoffmann-La Roche Ltd. Author contributions Concept and design: GP, AM, AR, BR, TN. Acquisition, analysis or interpretation of data: AM, AR, BR, TS, KB. Drafting of the manuscript: GP, AM, AR, BR. Critical revision and final approval of the manuscript: GP, AM, AR, BR, HS, TK, TS, RBP, NP, FS, KB, KS, VG, PF, RD, GAK, PB, KM, AB, and TN. Competing interests GP, AM, AR, BR, TK, KS, PF, RD, GAK, PB, AB and TN are employees and shareholders of F. Hoffmann-La Roche Ltd. RD is also employed by Genentech. PB has also ownership interests in Acousort AB, Enterin Inc, Axial Therapeutics and RYNE Bio. HS is an employee of Roche Diagnostics GmbH Deutschland and a shareholder of F. Hoffmann-La Roche. In the past 12 months, TS has served as a consultant for AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, General Electric, Kyowa, Neuroderm/ MTPA, Prevail/ Lilly, Roche, Sanofi, Sinopia, Takeda and Vanqua Bio. TS served on advisory boards for AskBio, Amneal, Biohaven, Denali, GAIN, General Electric, Kyowa, MJFF, Neuron23, Parkinson Study Group, Prevail/ Lilly, and Roche. TS has also served as a member of the scientific advisory board of Koneksa, Neuroderm/ MTPA, Sanofi and UCB, has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche, UCB and is an investigator for NINDS, MJFF, Parkinson’s Foundation. RBP also received consulting fees from Roche for helping plan and interpret the study. NP reports participating in advisory boards for Britannia, Boston Scientific, Benevolent AI, Hoffmann-La Roche, inc., and Abbvie. NP also reports receiving honoraria from Britannia, Abbvie, GE Healthcare, and Boston Scientific, and grants from the Independent Research Fund Denmark, Danish Parkinson's disease Association, Parkinson's UK, Center of Excellence in Neurodegeneration (CoEN) network award, GE Healthcare Grant, Multiple System Atrophy Trust, Weston Brain Institute, EU Joint Program Neurodegenerative Disease Research (JPND), EU Horizon 2020 research, the Michael J. Fox Foundation for Parkinson’s Research, and Hoffmann-La Roche, inc. FS is a consultant for AbbVie, Bial Pharma, Biogen, F. Hoffmann-La Roche Ltd., H. Lundbeck A S, Mitsubishi Tanabe Pharma America, Inc., Sunovion Pharmaceuticals, Inc., Teva Pharmaceutical Industries, Zambon, and Britannia. KB has received research funding from the Michael J. Fox Foundation for Parkinson's Research, the German Society for Parkinson DPG, the Health Forum Baden Wuerttemberg, the Else Kröner Fresenius Stiftung, the University of Tuebingen, and from the German Research Foundation DFG. KB is a consultant for F. Hoffmann-La Roche Ltd., Vanqua Bio, and the Michael J. Fox Foundation for Parkinson's Research and has received speaker honoraria from Abbvie, Lundbeck, UCB and Zambon. VG is a full-time employee of Excelya Germany GmbH and was an external business partner of F. Hoffmann-La Roche Ltd. KM is a consultant for Michael J. Fox Foundation for Parkinson's Research, F. Hoffmann-La Roche Ltd UCB, Denali, Takeda, Biohaven, Neuron23, Aprinoia, Prothena, Calico, Inhibikase, Invicro, Koneksa, and Lilly. RBP reports grants and personal fees from Fonds de la Recherche en Sante, grants from Canadian Institute of Health Research, grants from Michael J. Fox Foundation, grants from Webster Foundation, personal fees from Biogen, personal fees from Curasen, personal fees from Novartis, personal fees from Eisai, other from Parkinson Canada, grants from National Institute of Health, personal fees from International Parkinson and Movement Disorders Society, personal fees from Merck, personal fees from Vaxxinity, personal fees from Bristol Myers Squibb, personal fees from Clinilabs, personal fees from Ventus, personal fees from Korro, and personal fees from Calico. References Games, D., et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J Neurosci 34, 9441–9454 (2014). Schenk, D.B., et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord 32, 211–218 (2017). Jankovic, J., et al. 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Mixed Effects Models for the Population Approach: Models, Tasks, Methods and Tools (First edition), (Chapman and Hall/CRC, New York, NY, USA, 2014). Bergstrand, M., Hooker, A.C., Wallin, J.E. & Karlsson, M.O. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. Aaps j 13, 143–151 (2011). Online Methods Ethics statement In PASADENA, the protocol and recruitment materials were approved by institutional review boards or ethics committees at each study site 4 . The trial was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines. All participants provided written informed consent before participation and also for secondary data use 4 . Similarly, the PPMI study was conducted in accordance with the Declaration of Helsinki and GCP guidelines after approval by the local ethics committees of the participating sites, and all participants provided informed consent 5 . Study design Data from the PASADENA and PPMI studies were used for this exploratory analysis, and this external comparator arm was defined retrospectively based on secondary data use. PASADENA (ClinicalTrials.gov Identifier: NCT03100149) is a randomized controlled trial evaluating prasinezumab in participants with early-stage PD, details of which have been published previously 4,14 . It is being conducted at 57 sites in Austria, France, Germany, Spain, and the United States 4 . A total of 316 participants with early-stage PD (diagnosis ≤2 years at screening; H&Y Stages I–II) were randomized to receive either intravenous prasinezumab (1500 mg or 4500 mg) every 4 weeks for 104 weeks during Parts 1 and 2 of the study (‘early-start’ group) or placebo for 52 weeks during Part 1 followed by prasinezumab (1500 mg or 4500 mg) for 52 weeks in Part 2 (‘delayed-start’ group). Following a minimum wash-out period of 3 months, participants could enter a 5-year OLE, receiving prasinezumab 1500 mg every 4 weeks (Part 3). All PASADENA participants (n=271) were considered in the analysis, regardless of change in symptomatic therapy. A total of 397 untreated individuals were enrolled in the PPMI sporadic PD cohort from July 2010 until May 2013, at 24 sites in the United States, Europe and Australia 5 . The timeframe for the current analysis is presented in Figure 1 . Covariate balancing was performed at baseline (see Data analysis below) to provide a cohort that resembled the PASADENA cohort and the endpoints were analyzed from baseline over 4 years. Study population In PASADENA, key inclusion criteria included idiopathic PD with bradykinesia and one of the other cardinal signs of PD (resting tremor, rigidity) and no other known or suspected cause of PD; age 40‒80 years; dopamine transporter imaging with DaT-SPECT consistent with PD; diagnosis of PD for 2 years or less at screening; modified H&Y Stage I or II; and either treatment naïve or on a stable dose of an MAO-Bi for at least 90 days at baseline. Key exclusion criteria included medical history indicating a Parkinson syndrome other than idiopathic PD; known carriers of certain familial PD genes ( Parkin , PINK1 , DJ1 ); Mini Mental State Examination (MMSE) ≤25; use of catechol-O-methyl transferase inhibitors, amantadine, anticholinergics, or dopaminergic medication for more than a total of 60 days or within 60 days of baseline; and prior participation in any prasinezumab study 4,14 . In the PPMI study, key inclusion criteria for those with PD included age ≥30 years; DaT-SPECT or vesicular monoamine transporter (VMAT-2) imaging (Australia only) consistent with PD; untreated with PD medications (levodopa, dopamine agonists, MAO-Bis, or amantadine) within 2 years of diagnosis; H&Y Stage I or II; and presence of either at least two of resting tremor, bradykinesia, or rigidity (must have either resting tremor or bradykinesia) or a single asymmetric resting tremor or asymmetric bradykinesia 5 . Key exclusion criteria for PD participants included a clinical diagnosis of dementia or the taking of PD medications within 60 days of baseline or for >60 days in total 5 . For the current analysis, PASADENA inclusion criteria were applied to the PPMI study (age 40‒80 years and the presence of two motor features of which one is bradykinesia and the second either resting tremor or rigidity). Follow-up assessments were performed at 3-month intervals during the first year of participation, and every 6 months thereafter, up to 11 years after inclusion. Data sample In PASADENA, a total of 271/316 (85.8%) participants rolled over into the 5-year OLE after an average wash-out period of 7.4 months and median of 6.5 months (early-start group, n=177/211; delayed-start group, n=94/105). The clinical data cut-off representing a minimum of 4 years of follow-up occurred in July 2023, with a snapshot taken on 02 October 2023. The PPMI study is an observational study sponsored by The Michael J. Fox Foundation, launched in 2010 to identify biomarkers of PD onset and progression, and enrolling individuals with early-stage PD in 12 countries, in partnership with more than 30 biotech and pharmaceutical, non-profit and private funders. We elected to use the PPMI observational study as our external comparator for PD progression because it is contemporary to PASADENA and runs in similar clinical sites. We undertook several steps to include only individuals in PPMI who closely matched the PASADENA OLE participants. We also developed a disease-modeling quantitative approach to complement the external comparator analysis. From the August 2021 version of the Analytic Dataset, the original PPMI population included 397 PD participants. Following the application of the PASADENA inclusion criteria employed in this analysis, 303 PD participants from the PPMI cohort were included (see Supplementary Figure S4 for details of attrition). For all the participants, any dosages of reported symptomatic PD treatments were converted into LEDD using the methods described by Jost 15 and Tomlinson 16 . Study endpoints Outcomes were compared between the PASADENA early-start group, PASADENA delayed-start group, and external comparator PPMI cohort. The primary endpoints of this analysis were: the change from baseline to year 4 in the severity of motor progression (irrespective of starting of symptomatic treatment) as measured by the change in the MDS-UPDRS Part II, Part III in ON- and OFF-state, motor subscores (bradykinesia, rigidity, resting tremor), axial signs, tremor motor severity subscore, and non-tremor motor severity subscore in PASADENA 4 years OLE participants compared to the propensity score-weighted PPMI cohort. The secondary and exploratory endpoints were: the change from baseline to year 4 in LEDD, MDS-UPDRS Part I sleep-related subscores (i.e., items 7 and 8 for sleep and item 13 for fatigue), the severity of motor complications as measured by MDS-UPDRS Part IV, and DaT-SPECT in the bilateral putamen and bilateral caudate (secondary), and the odds of having H&Y ≥3 versus <3 (exploratory) in PASADENA 4 years OLE participants compared to the PPMI cohort. DaT-SPECT analysis was conducted as previously described 4,5 . Data analysis Two independent data analysis approaches were implemented: one based on propensity score and the other based on disease modeling. Propensity Score A propensity score is defined as the conditional probability of treatment assignment based on observed baseline covariates, and a propensity score-adjusted analysis provides a technique to control for confounding bias and ensure comparability in observational studies 7,8 . Potential confounders as baseline characteristics were then considered, including age, sex, education, MDS-UPDRS Part III score in OFF state, modified H&Y stage, DaT-SPECT in the bilateral putamen, Montreal Cognitive Assessment (MoCA) score, and time since diagnosis of PD. The propensity score was estimated using a logistic regression model where group assignment (PPMI vs. PASADENA) was regressed on the final set of covariates. The propensity score was used to balance baseline characteristics of the PPMI cohort to resemble more closely those of the PASADENA cohort, by employing inverse probability of treatment weighting. Each participant in PASADENA was given an equal weight of 1, whereas participants in the PPMI arm were given weights calculated as propensity score/(1 - propensity score). The estimation obtained with this weighting is the Average Treatment effect in the Treated (ATT), a term from causal inference that refers to the treatment effect for the individuals who received the treatment. By doing so, a pseudo-population was created via weighting,where baseline covariates are balanced (i.e., independent of the treatment assignment). Balancing between the PASADENA and PPMI cohorts was assessed by evaluating the SMD and a baseline characteristic was considered balanced if its SMD following weighting was ≤0.2 17 . This process was repeated iteratively until the desired balance was achieved. The weights were included in the outcome models. A mixed model for repeated measures (MMRM) was used for the longitudinal endpoints including covariates: age, sex, education, bilateral putamen at baseline, the visit (as a categorical factor), a group-by-visit interaction and the baseline endpoint. Within each participant, the model incorporates an unstructured variance-covariance matrix for the random error terms. An analysis of covariance (ANCOVA) was used as the primary analysis for the change in DaT-SPECT areas including the same covariates as for MMRM. An MMRM was also performed post hoc . The validity of this methodology was confirmed by ensuring comparability of the baseline characteristics and the progression over 52 weeks between the PASADENA placebo group and the weighted PPMI cohort; results were also in line with published literature 9 . A logistic model was fitted to the number of participants with H&Y ≥3 versus <3 at year 4. Subjects who withdrew from the study up to year 4 were excluded. Missing values were considered events (26 records in PPMI, 12 records in PASADENA). Due to the low number of events in PASADENA, the two arms were combined. A logistic model was fitted to the number of participants with H&Y of ≥3 versus <3 at year 4, including the following covariates: age, sex, education, H&Y stage at baseline and arm. The schedule of assessments was planned for a visit every 2 months, during the first two years, and then every 3 months, during the OLE, for participants in PASADENA, while in PPMI it was every 3 months for the first year then every 6 months, with the main assessments collected yearly. Hence, we used data from the yearly visits in PASADENA (+/- 8 weeks) for this comparison to match the PPMI arm for the longitudinal endpoints. MDS-UPDRS Part IV, which measures motor complications after the start of levodopa, was explored in two ways. Firstly, MDS-UPDRS Part IV was analyzed as a continuous endpoint including participants in the PPMI cohort or those taking prasinezumab who started levodopa during the first 3 years. The index date was defined as the annual visit after which a participant started levodopa treatment. Cohorts were balanced at the index date on age, sex, education, MDS-UPDRS Part III ON, Part IV, H&Y, PD diagnosis, LEDD value on the day of MDS-UPDRS Part III ON assessment, starting of MAO-Bi (yes/no), and starting of dopamine agonist (yes/no). MMRM was used to model the change from index date up to year 4 with the following covariates: LEDD value on the day of MDS-UPDRS Part III ON assessment, months in the study before starting levodopa, months on prasinezumab, age, sex, education, catechol-O-methyltransferase-inhibitor initiation (yes/no), and amantadine initiation (yes/no). Secondly, MDS-UPDRS Part IV was analyzed as a dichotomous endpoint including participants who had been on levodopa for at least 2 years at the end of year 4. A logistic model was fitted to the number of participants with MDS-UPDRS Part IV of ≥1 versus <1 at year 4 if at least 20% of events per arm were observed, including the covariates defined before. Disease Modeling Disease modeling is a quantitative approach to predict the progression of an endpoint or measure of efficacy as a function of a population’s characteristics. As such, it has been recognized as a key approach to support the development of effective therapeutic strategies 18 . We recently developed disease models of MDS-UPDRS Part III and Part II based on PPMI data 10 . The models capture the natural progression of PD and the effect of symptomatic treatments on the progression following a population approach 19 . The effect of symptomatic treatments was modelled by means of pharmacodynamic relationships using the LEDD 15,16 as input of the models. The disease modeling complements the propensity score approach as it continuously balances the usage of LEDD at the subject level throughout the course of PD. The models were evaluated by comparing predictions to PASADENA placebo data. For this, simulations of the models using PPMI-inferred parameters at a population level, and LEDD dosing regimen as used in the PASADENA study, were performed to form a PASADENA external comparator arm. No additional parameters were considered for matching the two cohorts beyond this balancing for LEDD usage. This prediction matched the actual data from the control group of PASADENA for MDS-UPDRS Part III OFF and Part II but not for Part III ON. Indeed, over that year, 46% and 48% of the PASADENA data were below the predicted PPMI median for MDS-UPDRS Part III OFF and Part II respectively. These numbers were considered satisfactory given the theoretical expectation of 50%. However, for MDS-UPDRS Part III ON, a total of 42% was below the predicted median. Based on this and supported by the visual predictive check ( Supplementary Figure S5 ), we decided not to use the PPMI-based Part III ON disease model for further comparison with PASADENA. Predictions of MDS-UPDRS Part III OFF and Part II from the virtual control arm were then compared to empirical data from the PASADENA treatment groups. This comparison was performed qualitatively and quantitatively through prediction-corrected visual and numerical predictive checks 20 . The members of the PASADENA Investigators and Prasinezumab Study Group who are authors on this manuscript PASADENA Investigators Tanya Simuni, 4 Kathrin Brockmann 9 Prasinezumab Study Group Gennaro Pagano, 1,2 Annabelle Monnet, 3 Adriana Reyes, 3 Benjamin Ribba, 1 Hanno Svoboda, 1,10 Thomas Kustermann, 1 Krzysztof Smigorski, 1 Paulo Fontoura, 3 Rachelle Doody, 3,11 Geoffrey A. Kerchner, 1 Patrik Brundin, 1 Azad Bonni 1 , Tania Nikolcheva 3 1. Roche Pharma Research and Early Development (pRED), Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland; 2. University of Exeter Medical School, London, UK; 3. F. Hoffmann-La Roche Ltd, Basel, Switzerland; 10. Roche Diagnostics GmbH, Penzberg, Germany; 11. Genentech USA Inc., San Francisco, USA; A full list of members and their affiliations appears in the Supplementary Information. Additional Declarations Yes there is potential Competing Interest. GP, AM, AR, BR, TK, KS, PF, RD, GAK, PB, AB and TN are employees and shareholders of F. Hoffmann-La Roche Ltd. RD is also employed by Genentech. PB has also ownership interests in Acousort AB, Enterin Inc, Axial Therapeutics and RYNE Bio. HS is an employee of Roche Diagnostics GmbH Deutschland and a shareholder of F. Hoffmann-La Roche. In the past 12 months, TS has served as a consultant for AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, General Electric, Kyowa, Neuroderm/ MTPA, Prevail/ Lilly, Roche, Sanofi, Sinopia, Takeda and Vanqua Bio. TS served on advisory boards for AskBio, Amneal, Biohaven, Denali, GAIN, General Electric, Kyowa, MJFF, Neuron23, Parkinson Study Group, Prevail/ Lilly, and Roche. TS has also served as a member of the scientific advisory board of Koneksa, Neuroderm/ MTPA, Sanofi and UCB, has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche, UCB and is an investigator for NINDS, MJFF, Parkinson’s Foundation. RBP also received consulting fees from Roche for helping plan and interpret the study. NP reports participating in advisory boards for Britannia, Boston Scientific, Benevolent AI, Hoffmann-La Roche, inc., and Abbvie. NP also reports receiving honoraria from Britannia, Abbvie, GE Healthcare, and Boston Scientific, and grants from the Independent Research Fund Denmark, Danish Parkinson's disease Association, Parkinson's UK, Center of Excellence in Neurodegeneration (CoEN) network award, GE Healthcare Grant, Multiple System Atrophy Trust, Weston Brain Institute, EU Joint Program Neurodegenerative Disease Research (JPND), EU Horizon 2020 research, the Michael J. Fox Foundation for Parkinson’s Research, and Hoffmann-La Roche, inc. FS is a consultant for AbbVie, Bial Pharma, Biogen, F. Hoffmann-La Roche Ltd., H. Lundbeck A S, Mitsubishi Tanabe Pharma America, Inc., Sunovion Pharmaceuticals, Inc., Teva Pharmaceutical Industries, Zambon, and Britannia. KB has received research funding from the Michael J. Fox Foundation for Parkinson's Research, the German Society for Parkinson DPG, the Health Forum Baden Wuerttemberg, the Else Kröner Fresenius Stiftung, the University of Tuebingen, and from the German Research Foundation DFG. KB is a consultant for F. Hoffmann-La Roche Ltd., Vanqua Bio, and the Michael J. Fox Foundation for Parkinson's Research and has received speaker honoraria from Abbvie, Lundbeck, UCB and Zambon. VG is a full-time employee of Excelya Germany GmbH and was an external business partner of F. Hoffmann-La Roche Ltd. KM is a consultant for Michael J. Fox Foundation for Parkinson's Research, F. Hoffmann-La Roche Ltd UCB, Denali, Takeda, Biohaven, Neuron23, Aprinoia, Prothena, Calico, Inhibikase, Invicro, Koneksa, and Lilly. RBP reports grants and personal fees from Fonds de la Recherche en Sante, grants from Canadian Institute of Health Research, grants from Michael J. Fox Foundation, grants from Webster Foundation, personal fees from Biogen, personal fees from Curasen, personal fees from Novartis, personal fees from Eisai, other from Parkinson Canada, grants from National Institute of Health, personal fees from International Parkinson and Movement Disorders Society, personal fees from Merck, personal fees from Vaxxinity, personal fees from Bristol Myers Squibb, personal fees from Clinilabs, personal fees from Ventus, personal fees from Korro, and personal fees from Calico. Supplementary Files SupplementalmaterialPASADENAPPMI05.04.24.docx Cite Share Download PDF Status: Published Journal Publication published 08 Oct, 2024 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4232431","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":288966160,"identity":"b2b667b7-488b-442a-9cc0-bfca1aeeb78f","order_by":0,"name":"Gennaro Pagano","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYAgAGyDmIU1LGulaDhPWIu/ee+zBzz02DObsxy9+Lqg4n8/PfvbgA4Yam2hcWgzPnEs37HmWxmDZk1MsPePMbcuZPXnJBgzH0nIbcGmZkWMmwXPgMIPBgZwEad622wYGN3jMJBgbDuPWMv+NmeQfkJbzb5J/87adA2kx/4FPi7wEj5k02JYb6ceAthwA28KAT4sBT46ZtMyBNB7LGW/YrHnOJBtI9uQYSyTg8Yt8+xkzyTcHbOTM+dMf3+apsDPgZz9j+OFDjQ1uWw5AaB4DEIKDBBzKwbbAzDJgYH+AR90oGAWjYBSMZAAABs5VbeRaBq4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-6247-8988","institution":"Roche Pharma Research and Early Development (pRED), Neuroscience and Rare Diseases Discovery and Translational Area","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Gennaro","middleName":"","lastName":"Pagano","suffix":""},{"id":288966161,"identity":"4b1dc7f1-4dc1-4e8b-b0ee-ab3a902beca2","order_by":1,"name":"Annabelle Monnet","email":"","orcid":"","institution":"F. 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(A) \u003c/strong\u003eMDS-UPDRS Part III OFF delayed-start group (empirical data represented in light blue); \u003cstrong\u003e(B) \u003c/strong\u003eMDS-UPDRS Part III OFF early-start group (dark blue); \u003cstrong\u003e(C)\u003c/strong\u003e MDS-UPDRS Part II delayed-start group (empirical data represented in light blue); \u003cstrong\u003e(D)\u003c/strong\u003e MDS-UPDRS Part II early-start group (dark blue). The vertical red arrows indicate the start of prasinezumab treatment for these two groups. MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; PPMI, Parkinson's Progression Markers Initiative.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4232431/v1/4090ac028fd719a3316598b5.png"},{"id":66242767,"identity":"e1e470dd-0c17-4a12-83b6-2fef259b43c3","added_by":"auto","created_at":"2024-10-09 07:07:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":911438,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4232431/v1/054c34d7-b752-4e2e-956b-9f4204ffb8e4.pdf"},{"id":54316106,"identity":"a1093a0a-3101-4560-8819-0fcc45cf4444","added_by":"auto","created_at":"2024-04-08 17:47:33","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":299446,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementalmaterialPASADENAPPMI05.04.24.docx","url":"https://assets-eu.researchsquare.com/files/rs-4232431/v1/32afb71eb75de68654b8d130.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nGP, AM, AR, BR, TK, KS, PF, RD, GAK, PB, AB and TN are employees and shareholders of F. Hoffmann-La Roche Ltd. RD is also employed by Genentech. PB has also ownership interests in Acousort AB, Enterin Inc, Axial Therapeutics and RYNE Bio. HS is an employee of Roche Diagnostics GmbH Deutschland and a shareholder of F. Hoffmann-La Roche. In the past 12 months, TS has served as a consultant for AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, General Electric, Kyowa, Neuroderm/ MTPA, Prevail/ Lilly, Roche, Sanofi, Sinopia, Takeda and Vanqua Bio. TS served on advisory boards for AskBio, Amneal, Biohaven, Denali, GAIN, General Electric, Kyowa, MJFF, Neuron23, Parkinson Study Group, Prevail/ Lilly, and Roche. TS has also served as a member of the scientific advisory board of Koneksa, Neuroderm/ MTPA, Sanofi and UCB, has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche, UCB and is an investigator for NINDS, MJFF, Parkinson’s Foundation. RBP also received consulting fees from Roche for helping plan and interpret the study. NP reports participating in advisory boards for Britannia, Boston Scientific, Benevolent AI, Hoffmann-La Roche, inc., and Abbvie. NP also reports receiving honoraria from Britannia, Abbvie, GE Healthcare, and Boston Scientific, and grants from the Independent Research Fund Denmark, Danish Parkinson's disease Association, Parkinson's UK, Center of Excellence in Neurodegeneration (CoEN) network award, GE Healthcare Grant, Multiple System Atrophy Trust, Weston Brain Institute, EU Joint Program Neurodegenerative Disease Research (JPND), EU Horizon 2020 research, the Michael J. Fox Foundation for Parkinson’s Research, and Hoffmann-La Roche, inc. FS is a consultant for AbbVie, Bial Pharma, Biogen, F. Hoffmann-La Roche Ltd., H. Lundbeck A S, Mitsubishi Tanabe Pharma America, Inc., Sunovion Pharmaceuticals, Inc., Teva Pharmaceutical Industries, Zambon, and Britannia. KB has received research funding from the Michael J. Fox Foundation for Parkinson's Research, the German Society for Parkinson DPG, the Health Forum Baden Wuerttemberg, the Else Kröner Fresenius Stiftung, the University of Tuebingen, and from the German Research Foundation DFG. KB is a consultant for F. Hoffmann-La Roche Ltd., Vanqua Bio, and the Michael J. Fox Foundation for Parkinson's Research and has received speaker honoraria from Abbvie, Lundbeck, UCB and Zambon. VG is a full-time employee of Excelya Germany GmbH and was an external business partner of F. Hoffmann-La Roche Ltd. KM is a consultant for Michael J. Fox Foundation for Parkinson's Research, F. Hoffmann-La Roche Ltd UCB, Denali, Takeda, Biohaven, Neuron23, Aprinoia, Prothena, Calico, Inhibikase, Invicro, Koneksa, and Lilly. RBP reports grants and personal fees from Fonds de la Recherche en Sante, grants from Canadian Institute of Health Research, grants from Michael J. Fox Foundation, grants from Webster Foundation, personal fees from Biogen, personal fees from Curasen, personal fees from Novartis, personal fees from Eisai, other from Parkinson Canada, grants from National Institute of Health, personal fees from International Parkinson and Movement Disorders Society, personal fees from Merck, personal fees from Vaxxinity, personal fees from Bristol Myers Squibb, personal fees from Clinilabs, personal fees from Ventus, personal fees from Korro, and personal fees from Calico.","formattedTitle":"Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open-label extension of the PASADENA trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrasinezumab is a humanized monoclonal antibody designed to bind aggregated α-synuclein, inhibit intercellular spreading of pathogenic α-synuclein, and thus potentially protect neurons and slow Parkinson's disease (PD) progression\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eP\u003c/span\u003ehase II trial of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eA\u003c/span\u003enti alpha-\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eS\u003c/span\u003eynuclein \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eA\u003c/span\u003entibo\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eD\u003c/span\u003ey in \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eE\u003c/span\u003early Parki\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eN\u003c/span\u003eson\u0026rsquo;s dise\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eA\u003c/span\u003ese (PASADENA, NCT03100149) 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 PD\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The study is divided into three parts: a 12-month double-blind period during which participants were treated with prasinezumab 1500 mg, prasinezumab 4500 mg or placebo (Part 1); a 12-month period during which participants treated with placebo were re-randomized to 1500 mg or 4500 mg prasinezumab, while prasinezumab-treated participants continued on their dose of prasinezumab (Part 2); and a long-term (5 years) open-label extension (OLE) in which all participants received prasinezumab 1500 mg (Part 3).\u003c/p\u003e \u003cp\u003eIn the double-blind study period (Part 1), prasinezumab did not meet its primary endpoint (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] sum of Parts I\u0026thinsp;+\u0026thinsp;II\u0026thinsp;+\u0026thinsp;III)\u003csup\u003e4\u003c/sup\u003e. However, prasinezumab-treated individuals (both low-dose and high-dose) showed less motor progression on MDS-UPDRS Part III\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The OLE (Part 3) was implemented as an amendment to the PASADENA study after the completion of Part 1, to evaluate the long-term safety and efficacy of prasinezumab.\u003c/p\u003e \u003cp\u003eHere, we performed an exploratory analysis comparing participants treated with prasinezumab in the PASADENA OLE to subjects enrolled in the Parkinson's Progression Markers Initiative (PPMI) observational study\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, creating an external comparator arm by means of two independent approaches: propensity score and disease modeling. The PPMI was used to put the rates of disease progression seen in the OLE of PASADENA into context, in the absence of a placebo group beyond PASADENA Part 1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe main objective of the present study was to evaluate the change from baseline to year 4 in measures of severity of PD progression in the PASADENA OLE versus the external comparator PPMI population.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBaseline characteristics of the PASADENA and PPMI cohorts were well balanced after weighting with propensity scores (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics before and after weighting with propensity scores\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eBefore weighting\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eAfter weighting\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePASADENA\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;271\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEC PPMI\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;303\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePASADENA\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;271\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEC PPMI\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;270\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years) (mean [SD])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e59.98 (9.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e62.11 (8.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e59.98 (9.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e61.20 (9.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.133\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u0026thinsp;=\u0026thinsp;Male, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e188 (69.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e202 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e188.0 (69.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e189.3 (70.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMDS-UPDRS Part III (mean [SD])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21.15 (8.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21.17 (8.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e21.15 (8.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e21.13 (9.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoehn and Yahr\u0026thinsp;=\u0026thinsp;2, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e201 (74.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e183 (60.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e201.0 (74.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e205.7 (76.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD Diagnosis (months) (mean [SD])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.89 (6.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.87 (5.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.855\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.89 (6.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.20 (5.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYears of education\u0026thinsp;\u0026ge;\u0026thinsp;12, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e244 (90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e279 (92.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e244.0 (90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e236.2 (87.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMontreal Cognitive Assessment (MoCA) (mean [SD])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28.17 (1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27.23 (2.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.462\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e28.17 (1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e28.02 (1.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDaT-SPECT putamen bilateral (mean [SD])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.92 (0.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.81 (0.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.436\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.92 (0.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.92 (0.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eNote: SMD\u0026thinsp;\u0026le;\u0026thinsp;0.2 indicates balance between groups.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eDaT-SPECT, dopamine transporter imaging with single photon emission computed tomography; EC, external control; MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; PD, Parkinson\u0026rsquo;s disease; PPMI, Parkinson's Progression Markers Initiative; SD, standard deviation; SMD, standardized mean difference.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn comparison with the PPMI cohort, at year 4, the PASADENA delayed- and early-start groups both showed: lower MDS-UPDRS Part III progression in OFF-state, with \u0026minus;\u0026thinsp;51% relative difference (mean [80% confidence interval (CI)], -5.73 [-7.33 to -4.14] points) for the delayed-start group and \u0026minus;\u0026thinsp;65% relative difference (mean [80% CI], -7.26 [-8.59 to -5.93] points) for the early-start group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA); lower MDS-UPDRS Part III progression in ON-state, with \u0026minus;\u0026thinsp;94% relative difference (mean [80% CI], -3.71 [-5.41 to -2.01] points) for the delayed-start group and \u0026minus;\u0026thinsp;118% relative difference (mean [80% CI], -4.69 [-6.09 to -3.3] points) for the early-start group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB); and lower MDS-UPDRS Part II progression, with \u0026minus;\u0026thinsp;48% relative difference (mean [80% CI], -2.20 [-2.96 to -1.45] points) for the delayed-start group and \u0026minus;\u0026thinsp;40% relative difference (mean [80% CI], -1.82 [-2.44 to -1.2] points) for the early-start group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDisease progression modeling showed similar findings to those obtained with the propensity score method. Progression of MDS-UPDRS Part III (OFF) and Part II in the PASADENA delayed- and early-start groups was slower than the PPMI 90% CI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Separation from the PPMI-based prediction occurred from year 2 onwards for MDS-UPDRS Part III and during year 4 for MDS-UPDRS Part II. In the analysis of MDS-UPDRS Part III in OFF-state, we found that 55% of the PASADENA scores were below the median PPMI predictions during year 2, and 64% and 66% were below the median PPMI predictions during years 3 and 4, respectively. For MDS-UPDRS Part II, the percentage of PASADENA scores below the median of PPMI predictions was close to 50% during years 2 and 3 (51% and 53%, respectively), but reached 56% below the median during year 4, which is comparable to the deviation of Part III in OFF-state during year 2. The percentage of MDS-UPDRS Part II scores below the median of PPMI predictions continued to increase thereafter, reaching 59% after year 4.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe PASADENA arm showed no difference in MDS-UPDRS Part IV progression in comparison with the PPMI cohort (\u003cb\u003eSupplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). The odds ratio of having reached stage\u0026thinsp;\u0026ge;\u0026thinsp;3 in Hoehn and Yahr (H\u0026amp;Y) at year 4 was 0.26 (80% CI: 0.04 to 0.42) in the PASADENA delayed-start group and 0.3 (80% CI: 0.13 to 0.47) in the PASADENA early-start group, in comparison with the PPMI cohort (\u003cb\u003eSupplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eThe PASADENA delayed- and early-start groups showed numerically lower LEDD intake at year 4 in comparison with the PPMI cohort: mean \u0026minus;\u0026thinsp;120.83 (80% CI: -187.68 to -53.99) mg for the delayed-start group and mean \u0026minus;\u0026thinsp;85.08 (80% CI: -140.01 to -30.16) mg for the early-start group (\u003cb\u003eSupplementary Figure S2\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eFor MDS-UPDRS Part I total, the PASADENA delayed- and early-start groups showed a mean progression after 4 years of 6.28 (80% CI: 5.67 to 6.89) and 6.39 (80% CI: 5.87 to 6.91) points, respectively, while the PPMI cohort showed a mean progression of 8.34 (80% CI: 7.91 to 8.77) points (\u003cb\u003eSupplementary Figure S3\u003c/b\u003e). The PASADENA delayed- and early-start groups also both showed lower MDS-UPDRS Part I Sleep progression (items 7 and 8) in comparison with the PPMI cohort, with \u0026minus;\u0026thinsp;47% relative difference (mean [80% CI], -0.24 [-0.39 to -0.09] points) for the delayed-start group and \u0026minus;\u0026thinsp;61% relative difference (mean [80% CI], -0.31 [-0.43 to -0.19] points) for the early-start group after 4 years. Notably, the PASADENA delayed- and early-start groups showed no difference in MDS-UPDRS Part I Fatigue (item 13) progression in comparison with the PPMI cohort after 4 years: mean \u0026minus;\u0026thinsp;0.11 (80% CI: -0.2 to -0.02) points for the delayed-start group and mean \u0026minus;\u0026thinsp;0.06 (80% CI: -0.13 to 0.01) points for the early-start group.\u003c/p\u003e \u003cp\u003eIn comparison with the PPMI cohort, the PASADENA delayed- and early-start groups showed no difference in dopamine transporter imaging with single photon emission computed tomography (DaT-SPECT) putamen or caudate striatal binding ratio progression over 4 years: mean 0.02 (80% CI: 0 to 0.06) points for the delayed-start group and mean 0.03 (80% CI: 0 to 0.05) points for the early-start group for putamen bilateral striatal binding ratio.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this exploratory analysis of the PASADENA study, people with PD treated with prasinezumab showed slower motor progression, measured by MDS-UPDRS Part III (total\u003c/p\u003e \u003cp\u003eand subscores) in OFF and ON medication state and Part II over 4 years, when compared to an external comparator cohort derived from the PPMI observational study and a mathematical model of PD progression. Despite the low number of participants reaching H\u0026amp;Y stage 3 (mild to moderate bilateral involvement, some postural instability but physically independent), prasinezumab-treated individuals showed a lower risk of developing balance issues at year 4.\u003c/p\u003e \u003cp\u003eDuring the past two decades, evidence from genetic, neuropathological and experimental models has suggested that α-synuclein aggregates play an important role in the pathogenesis of PD\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The observation that α-synuclein aggregation may spread intercellularly and contribute to neurodegeneration supported the development of immunotherapies targeting α-synuclein aggregates. Prasinezumab is a humanized monoclonal antibody directed against aggregated α-synuclein and its impact on PD progression was studied in the PASADENA Phase II study\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Although PASADENA did not meet its primary endpoint (change from baseline in the sum of MDS-UPDRS Part I\u0026thinsp;+\u0026thinsp;II\u0026thinsp;+\u0026thinsp;III scores) at week 52, prasinezumab reduced the decline of motor function, as measured by changes from baseline in the MDS-UPDRS Part III score and using digital readouts at week 52\u003csup\u003e4\u003c/sup\u003e. The PASADENA OLE provided the opportunity to study the long-term effect of prasinezumab. Notably, over 85% of PASADENA participants elected to enroll in the OLE and continued with monthly infusions of prasinezumab for 4 years. Obviously, a major limitation of the OLE is the lack of a placebo arm. We utilized the PPMI observational arm as a suitable comparator to enable quantification of treatment effects in the absence of a placebo arm beyond the first 52 weeks of the study. Using a well-established method of propensity score balancing of baseline characteristics, we matched the trial and comparator groups\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Using weighting allows the use of more covariates (including continuous ones) and includes all participants in the analysis. To ensure comparability, we applied the full PASADENA inclusion/exclusion criteria when we selected the PPMI cohort, and we next applied weighting (as opposed to matching) due to its flexibility in handling covariates. The validity of this approach for this study was confirmed by similar baseline characteristics and progression over 52 weeks between the PASADENA Part 1 placebo cohort and the weighted PPMI cohort.\u003c/p\u003e \u003cp\u003eAs expected, in the present study, the PPMI cohort exhibited a rate of progression consistent with previous publications\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. By contrast, the PASADENA delayed- and early-start prasinezumab-treated groups showed less worsening of MDS-UPDRS Part III in OFF-state total score, and subscores, MDS-UPDRS Part III in ON-state, and MDS-UPDRS Part II. We confirmed this using a disease modeling approach, where we compared PASADENA OLE data with a hypothetical population created by using the characteristics of PASADENA and a model of progression\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe did not observe a difference in the rate of change of the DaT-SPECT measures. There could be a number of explanations for this. It is plausible that prasinezumab may preserve dopaminergic synaptic function, thus translating in the observed clinical benefit, but not impact transporter function measured by DaT-SPECT. DaT-SPECT availability is also influenced by compensatory down-regulation, which can mask the effective progressive loss of terminals. The DaT-SPECT findings could also be explained by suboptimal matching of the DaT-SPECT signal in the putamen. The matching of the PPMI and PASADENA groups was only partially achieved for the DaT-SPECT signal. Although the baseline difference was balanced (standardized mean difference [SMD]\u0026thinsp;\u0026lt;\u0026thinsp;0.2), there was a significant difference in 1-year decline between the PPMI and PASADENA delayed-start group (placebo). Thus, the PPMI and PASADENA cohorts were not fully matched on DaT-SPECT progression. It is unclear what drove the 1-year differences between the cohorts, but substantial variability of progression rates of DaT-SPECT signal among cohorts has been reported\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. We did not observe a difference in MDS-UPDRS Part IV, but participants started symptomatic therapy at different points, contributing to variability. A longer follow-up on stable symptomatic therapy is needed to assess a potential effect of prasinezumab on motor complications. At the 4-year time point, people with PD treated with prasinezumab had progressed less regarding non-motor symptoms, as measured by MDS-UPDRS Part I (total and sleep subscores), when compared with the external comparator cohort derived from the participants selected from the PPMI cohort. However, at the 1-year time point, the PASADENA delayed-start group (placebo until the end of year 1) already displayed a lower total score in MDS-UPDRS Part I compared with the selected PPMI cohort, and therefore the difference seen at 4 years has to be interpreted with great caution. Among the non-motor symptoms of PD, sleep items were pre-specified in this analysis because sleep problems are among the most specific non-motor symptoms of PD and associated with poor quality of life\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e Both the PASADENA and PPMI studies enrolled treatment-na\u0026iuml;ve participants, and PASADENA also included participants on stable doses of monoamine oxidase type B inhibitors (MAO-Bi) at baseline. While participants in both studies were instructed not to start or change symptomatic therapy for the first 6 months (PPMI) or 12 months (PASADENA), all participants were expected to be on symptomatic treatment eventually. A change in medication represents one of the strongest confounders when assessing PD progression, due to its effect on motor outcome measures. Therefore, we compared the types and doses of symptomatic medications across the PASADENA and PPMI cohorts. Despite slight differences between the two studies during the first 12 months, by year 2 both cohorts were similar in terms of types of PD medications and Levodopa Equivalent Daily Dosage (LEDD), suggesting that this is unlikely to explain the differences in trajectories of progression of the MDS-UPDRS Part III and Part II scores. At year 3 and 4, when more than 90% of the participants of PASADENA and PPMI were receiving L-DOPA and/or dopamine receptor agonists, the prasinezumab-treated participants exhibited lower MDS-UPDRS Part III motor scores in ON, both compared to the PPMI cohort and to their own scores at baseline. This suggests that prasinezumab could potentially synergize with dopaminergic medications. It has previously been proposed that removal of extracellular α-synuclein aggregates might improve synaptic transmission in the nigrostriatal system, in addition to reducing the spread of protein aggregates between neurons\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. There was a gap between the completion of Part 2 and the initiation of the OLE phase of the study, which averaged 7.4 months, largely driven by COVID-19-induced delays and other study operational aspects. Nevertheless, there was a clear separation between both PASADENA groups and the PPMI cohort on MDS-UPDRS Part III in both OFF and ON, starting from months 12 and 24, respectively, and increasing up to the 4-year timepoint. This finding suggests that, once it is established, the prasinezumab effect may be persistent, at least for the duration of the washout period, and argues against a symptomatic effect of prasinezumab. Taken together, our results suggest consistently that prasinezumab may slow motor progression and functional decline long-term in early-stage PD.\u003c/p\u003e \u003cp\u003eWe have identified several shortcomings in this exploratory analysis. Some of these are related to potential differences between the external observational PPMI cohort and the PASADENA participants. \u003cem\u003eFirst\u003c/em\u003e, although the PASADENA and PPMI cohorts are comparable, there is a potential calendar time bias. The PASADENA study started in 2017, and the participants\u0026rsquo; assessment up to the year 4 data cut snapshot occurred in the third quarter of 2023, whereas the initial PPMI cohort was enrolled between 2011 to 2018. Despite a gap of 6 years on initiation, there is a large overlap between the studies. \u003cem\u003eSecond\u003c/em\u003e, the PPMI study was conducted in North America, Europe, Israel, and Australia, and PASADENA is being conducted in North America and Europe. This difference in regional bias is considered low. \u003cem\u003eThird\u003c/em\u003e, selection bias, which refers to the enrolment of people in clinical trials that are different from those in clinical practice, is limited because PASADENA had similar inclusion and exclusion criteria to the PPMI study. \u003cem\u003eFourth\u003c/em\u003e, participants in the OLE of PASADENA and the PPMI cohort may also differ due to the clinic visit frequency. The PASADENA study required a visit to the clinic every month to receive an infusion while in the PPMI study, participants visit their clinic approximately every 3 months.\u003c/p\u003e \u003cp\u003eOur findings need confirmation in another long-term trial. The PADOVA study (NCT04777331) is an ongoing Phase IIb, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of intravenous prasinezumab versus placebo, in participants with early-stage PD who are on stable symptomatic PD medication (for at least 6 months, with stable doses for 3 months prior to baseline). The double-blind part of the PADOVA study is followed by an OLE, which, like the present study, will address the long-term effects of prasinezumab treatment.\u003c/p\u003e \u003cp\u003eIn conclusion, the effect of prasinezumab on slowing motor progression in PD may be sustained long-term. The PASADENA OLE is continuing.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is sponsored by F. Hoffmann-La Roche Ltd. F. Hoffmann-La Roche Ltd was involved in the study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication. We thank the patients and their families who participated in the PASADENA study and the clinical investigators. Editorial assistance for this manuscript was provided by m\u003cem\u003eX\u003c/em\u003em Medical Communications funded by F. Hoffmann-La Roche Ltd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcept and design: GP, AM, AR, BR, TN. Acquisition, analysis or interpretation of data: AM, AR, BR, TS, KB. Drafting of the manuscript: GP, AM, AR, BR. Critical revision and final approval of the manuscript: GP, AM, AR, BR, HS, TK, TS, RBP, NP, FS, KB, KS, VG, PF, RD, GAK, PB, KM, AB, and TN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGP, AM, AR, BR, TK, KS, PF, RD, GAK, PB, AB and TN are employees and shareholders of F. Hoffmann-La Roche Ltd. RD is also employed by Genentech. PB has also ownership interests in Acousort AB, Enterin Inc, Axial Therapeutics and RYNE Bio. HS is an employee of Roche Diagnostics GmbH Deutschland and a shareholder of F. Hoffmann-La Roche. In the past 12 months, TS has served as a consultant for AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson\u0026apos;s Consortium (CPP), Denali, General Electric, Kyowa, Neuroderm/ MTPA, Prevail/ Lilly, Roche, Sanofi, Sinopia, Takeda and Vanqua Bio. TS served on advisory boards for AskBio, Amneal, Biohaven, Denali, GAIN, General Electric, Kyowa, MJFF, Neuron23, Parkinson Study Group, Prevail/ Lilly, and Roche. TS has also served as a member of the scientific advisory board of Koneksa, Neuroderm/ MTPA, Sanofi and UCB, has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche, UCB and is an investigator for NINDS, MJFF, Parkinson\u0026rsquo;s Foundation. RBP also received consulting fees from Roche for helping plan and interpret the study. NP reports participating in advisory boards for Britannia, Boston Scientific, Benevolent AI, Hoffmann-La Roche, inc., and Abbvie. NP also reports receiving honoraria from Britannia, Abbvie, GE Healthcare, and Boston Scientific, and grants from the Independent Research Fund Denmark, Danish Parkinson\u0026apos;s disease Association, Parkinson\u0026apos;s UK, Center of Excellence in Neurodegeneration (CoEN) network award, GE Healthcare Grant, Multiple System Atrophy Trust, Weston Brain Institute, EU Joint Program Neurodegenerative Disease Research (JPND), EU Horizon 2020 research, the Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research, and Hoffmann-La Roche, inc. FS is a consultant for AbbVie, Bial Pharma, Biogen, F. Hoffmann-La Roche Ltd., H. Lundbeck A S, Mitsubishi Tanabe Pharma America, Inc., Sunovion Pharmaceuticals, Inc., Teva Pharmaceutical Industries, Zambon, and Britannia. KB has received research funding from the Michael J. Fox Foundation for Parkinson\u0026apos;s Research, the German Society for Parkinson DPG, the Health Forum Baden Wuerttemberg, the Else Kr\u0026ouml;ner Fresenius Stiftung, the University of Tuebingen, and from the German Research Foundation DFG. KB is a consultant for F. Hoffmann-La Roche Ltd., Vanqua Bio, and the Michael J. Fox Foundation for Parkinson\u0026apos;s Research and has received speaker honoraria from Abbvie, Lundbeck, UCB and Zambon. VG is a full-time employee of Excelya Germany GmbH and was an external business partner of F. Hoffmann-La Roche Ltd. KM is a consultant for Michael J. Fox Foundation for Parkinson\u0026apos;s Research, F. Hoffmann-La Roche Ltd UCB, Denali, Takeda, Biohaven, Neuron23, Aprinoia, Prothena, Calico, Inhibikase, Invicro, Koneksa, and Lilly. RBP reports grants and personal fees from Fonds de la Recherche en Sante, grants from Canadian Institute of Health Research, grants from Michael J. Fox Foundation, grants from Webster Foundation, personal fees from Biogen, personal fees from Curasen, personal fees from Novartis, personal fees from Eisai, other from Parkinson Canada, grants from National Institute of Health, personal fees from International Parkinson and Movement Disorders Society, personal fees from Merck, personal fees from Vaxxinity, personal fees from Bristol Myers Squibb, personal fees from Clinilabs, personal fees from Ventus, personal fees from Korro, and personal fees from Calico.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGames, D., et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J Neurosci 34, 9441\u0026ndash;9454 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchenk, D.B., et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord 32, 211\u0026ndash;218 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJankovic, J., et al. Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol 75, 1206\u0026ndash;1214 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePagano, G., et al. Trial of Prasinezumab in Early-Stage Parkinson's Disease. N Engl J Med 387, 421\u0026ndash;432 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarek, K., et al. The Parkinson's progression markers initiative (PPMI) - establishing a PD biomarker cohort. Ann Clin Transl Neurol 5, 1460\u0026ndash;1477 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCalabresi, P., et al. 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Mov Disord Clin Pract 5, 47\u0026ndash;53 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRibba, B. Model PD progression. Journal of Parkinson's Disease (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColloby, SJ., Williams, ED., Burn, DJ., Lloyd, JJ., McKeith, IG., O'Brien, JT. Progression of dopaminergic degeneration in dementia with Lewy bodies and Parkinson's disease with and without dementia assessed using 123I-FP-CIT SPECT. Eur J Nucl Med Mol Imaging 32, 1176\u0026ndash;85 (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimuni, T., Siderowf, A., Lasch, S. et al. Longitudinal Change of Clinical and Biological Measures in Early Parkinson's Disease: Parkinson's Progression Markers Initiative Cohort. Mov Disord 33, 771\u0026ndash;782 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiguori, C., De Franco,V., Cerroni, R., Spanetta, M., Mercuri, NB., Stefani, A., Pierantozzi, M., Di Pucchio, A. Sleep problems affect quality of life in Parkinson's disease along disease progression. Sleep Med 81, 307\u0026ndash;311 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePagano, G., et al. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data. Front Neurol 12, 705407 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJost, S.T., et al. Levodopa Dose Equivalency in Parkinson's Disease: Updated Systematic Review and Proposals. Mov Disord 38, 1236\u0026ndash;1252 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTomlinson, C.L., et al. Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Mov Disord 25, 2649\u0026ndash;2653 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStuart, E.A., Lee, B.K. \u0026amp; Leacy, F.P. Prognostic score-based balance measures can be a useful diagnostic for propensity score methods in comparative effectiveness research. J Clin Epidemiol 66, S84-S90.e81 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStephenson, D., et al. Transforming Drug Development for Neurological Disorders: Proceedings from a Multidisease Area Workshop. Neurotherapeutics 20, 1682\u0026ndash;1691 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLavielle, M. Mixed Effects Models for the Population Approach: Models, Tasks, Methods and Tools (First edition), (Chapman and Hall/CRC, New York, NY, USA, 2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBergstrand, M., Hooker, A.C., Wallin, J.E. \u0026amp; Karlsson, M.O. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. Aaps j 13, 143\u0026ndash;151 (2011).\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"},{"header":"Online Methods","content":"\u003cp\u003e\u003cem\u003eEthics statement\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn PASADENA, the protocol and recruitment materials were approved by institutional review boards or ethics committees at each study site\u003csup\u003e4\u003c/sup\u003e. The trial was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines. All participants provided written informed consent before participation and also for secondary data use\u003csup\u003e4\u003c/sup\u003e. Similarly, the PPMI study was conducted in accordance with the Declaration of Helsinki and GCP guidelines after approval by the local ethics committees of the participating sites, and all participants provided informed consent\u003csup\u003e5\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy design\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eData from the PASADENA and PPMI studies were used for this exploratory analysis, and\u0026nbsp;this external comparator arm was defined retrospectively based on secondary data use. PASADENA (ClinicalTrials.gov Identifier: NCT03100149) is a randomized controlled trial evaluating prasinezumab in participants with early-stage PD, details of which have been published previously\u003csup\u003e4,14\u003c/sup\u003e. It is being conducted at 57 sites in Austria, France, Germany, Spain, and the United States\u003csup\u003e4\u003c/sup\u003e. A total of 316 participants with early-stage PD (diagnosis \u0026le;2 years at screening; H\u0026amp;Y Stages I\u0026ndash;II) were randomized to receive either intravenous prasinezumab (1500 mg or 4500 mg) every 4 weeks for 104 weeks during Parts 1 and 2 of the study (\u0026lsquo;early-start\u0026rsquo; group) or placebo for 52 weeks during Part 1 followed by prasinezumab (1500 mg or 4500 mg) for 52 weeks in Part 2 (\u0026lsquo;delayed-start\u0026rsquo; group). Following a minimum wash-out period of 3 months, participants could enter a 5-year OLE, receiving prasinezumab 1500 mg every 4 weeks (Part 3). All PASADENA participants (n=271) were considered in the analysis, regardless of change in symptomatic therapy. A total of 397 untreated individuals were enrolled in the PPMI sporadic PD cohort from July 2010 until May 2013, at 24 sites in the United States, Europe and Australia\u003csup\u003e5\u003c/sup\u003e. The timeframe for the current analysis is presented in \u003cstrong\u003eFigure 1\u003c/strong\u003e. Covariate balancing was performed at baseline (see \u003cem\u003eData analysis\u003c/em\u003e below) to provide a cohort that resembled the PASADENA cohort and the endpoints were analyzed from baseline over 4 years.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn PASADENA, key inclusion criteria included idiopathic PD with bradykinesia and one of the other cardinal signs of PD (resting tremor, rigidity) and no other known or suspected cause of PD; age 40‒80 years; dopamine transporter imaging with DaT-SPECT consistent with PD; diagnosis of PD for 2 years or less at screening; modified H\u0026amp;Y Stage I or II; and either treatment na\u0026iuml;ve or on a stable dose of an MAO-Bi for at least 90 days at baseline. Key exclusion criteria included medical history indicating a Parkinson syndrome other than idiopathic PD; known carriers of certain familial PD genes (\u003cem\u003eParkin\u003c/em\u003e, \u003cem\u003ePINK1\u003c/em\u003e, \u003cem\u003eDJ1\u003c/em\u003e); Mini Mental State Examination (MMSE) \u0026le;25; use of catechol-O-methyl transferase inhibitors, amantadine, anticholinergics, or dopaminergic medication for more than a total of 60 days or within 60 days of baseline; and prior participation in any prasinezumab study\u003csup\u003e4,14\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn the PPMI study, key inclusion criteria for those with PD included age \u0026ge;30 years; DaT-SPECT or vesicular monoamine transporter (VMAT-2) imaging (Australia only) consistent with PD; untreated with PD medications (levodopa, dopamine agonists, MAO-Bis, or amantadine) within 2 years of diagnosis; H\u0026amp;Y Stage I or II; and presence of either at least two of resting tremor, bradykinesia, or rigidity (must have either resting tremor or bradykinesia) or a single asymmetric resting tremor or asymmetric bradykinesia\u003csup\u003e5\u003c/sup\u003e. Key exclusion criteria for PD participants included a clinical diagnosis of dementia or the taking of PD medications within 60 days of baseline or for \u0026gt;60 days in total\u003csup\u003e5\u003c/sup\u003e. For the current analysis, PASADENA inclusion criteria were applied to the PPMI study (age 40‒80 years and the presence of two motor features of which one is bradykinesia and the second either resting tremor or rigidity). Follow-up assessments were performed at 3-month intervals during the first year of participation, and every 6 months thereafter, up to 11 years after inclusion.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData sample\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn PASADENA, a total of 271/316 (85.8%) participants rolled over into the 5-year OLE after an average wash-out period of 7.4 months and median of 6.5 months (early-start group, n=177/211; delayed-start group, n=94/105). The clinical data cut-off representing a minimum of 4 years of follow-up occurred in July 2023, with a snapshot taken on 02 October 2023. The PPMI study is an observational study sponsored by The Michael J. Fox Foundation, launched in 2010 to identify biomarkers of PD onset and progression, and enrolling individuals with early-stage PD in 12 countries, in partnership with more than 30 biotech and pharmaceutical, non-profit and private funders. We elected to use the PPMI observational study as our external comparator for PD progression because it is contemporary to PASADENA and runs in similar clinical sites. We undertook several steps to include only individuals in PPMI who closely matched the PASADENA OLE participants. We also developed a disease-modeling quantitative approach to complement the external comparator analysis. From the August 2021 version of the Analytic Dataset, the original PPMI population included 397 PD participants. Following the application of the PASADENA inclusion criteria employed in this analysis, 303 PD participants from the PPMI cohort were included (see \u003cstrong\u003eSupplementary Figure S4\u003c/strong\u003e for details of attrition).\u003c/p\u003e\n\u003cp\u003eFor all the participants, any dosages of reported symptomatic PD treatments were converted into LEDD using the methods described by Jost\u003csup\u003e15\u003c/sup\u003e and Tomlinson\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy endpoints\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOutcomes were compared between the PASADENA early-start group, PASADENA delayed-start group, and external comparator PPMI cohort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary endpoints of this analysis were: the change from baseline to year 4 in the severity of motor progression (irrespective of starting of symptomatic treatment) as measured by the change in the MDS-UPDRS Part II, Part III in ON- and OFF-state, motor subscores (bradykinesia, rigidity, resting tremor), axial signs, tremor motor severity subscore, and non-tremor motor severity subscore in PASADENA 4 years OLE participants compared to the propensity score-weighted PPMI cohort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe secondary and exploratory endpoints were: the change from baseline to year 4 in LEDD, MDS-UPDRS Part I sleep-related subscores (i.e., items 7 and 8 for sleep and item 13 for fatigue), the severity of motor complications as measured by MDS-UPDRS Part IV, and DaT-SPECT in the bilateral putamen and bilateral caudate (secondary), and the odds of having H\u0026amp;Y \u0026ge;3 versus \u0026lt;3 (exploratory) in PASADENA 4 years OLE participants compared to the PPMI cohort.\u003c/p\u003e\n\u003cp\u003eDaT-SPECT analysis was conducted as previously described\u003csup\u003e4,5\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo independent data analysis approaches were implemented: one based on propensity score and the other based on disease modeling.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePropensity Score\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA propensity score is defined as the conditional probability of treatment assignment based on observed baseline covariates, and a propensity score-adjusted analysis provides a technique to control for confounding bias and ensure comparability in observational studies\u003csup\u003e7,8\u003c/sup\u003e. Potential confounders as baseline characteristics were then considered, including age, sex, education, MDS-UPDRS Part III score in OFF state, modified H\u0026amp;Y stage, DaT-SPECT in the bilateral putamen, Montreal Cognitive Assessment (MoCA) score, and time since diagnosis of PD. The propensity score was estimated using a logistic regression model where group assignment (PPMI vs. PASADENA) was regressed on the final set of covariates. The propensity score was used to balance baseline characteristics of the PPMI cohort to resemble more closely those of the PASADENA cohort, by employing inverse probability of treatment weighting. Each participant in PASADENA was given an equal weight of 1, whereas participants in the PPMI arm were given weights calculated as propensity score/(1 - propensity score). The estimation obtained with this weighting is the Average Treatment effect in the Treated (ATT), a term from causal inference that refers to the treatment effect for the individuals who received the treatment. By doing so, a pseudo-population was created \u003cem\u003evia\u0026nbsp;\u003c/em\u003eweighting,where baseline covariates are balanced (i.e., independent of the treatment assignment). Balancing between the PASADENA and PPMI cohorts was assessed by evaluating the SMD and a baseline characteristic was considered balanced if its SMD following weighting was\u0026nbsp;\u0026le;0.2\u003csup\u003e17\u003c/sup\u003e. This process was repeated iteratively until the desired balance was achieved. The weights were included in the outcome models.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA mixed model for repeated measures (MMRM) was used for the longitudinal endpoints including covariates: age, sex, education, bilateral putamen at baseline, the visit (as a categorical factor), a group-by-visit interaction and the baseline endpoint. Within each participant, the model incorporates an unstructured variance-covariance matrix for the random error terms. An analysis of covariance (ANCOVA) was used as the primary analysis for the change in DaT-SPECT areas including the same covariates as for MMRM. An MMRM was also performed \u003cem\u003epost hoc\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003eThe validity of this methodology was confirmed by ensuring comparability of the baseline characteristics and the progression over 52 weeks between the PASADENA placebo group and the weighted PPMI cohort; results were also in line with published literature\u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eA logistic model was fitted to the number of participants with H\u0026amp;Y \u0026ge;3 versus \u0026lt;3 at year 4. Subjects who withdrew from the study up to year 4 were excluded. Missing values were considered events (26 records in PPMI, 12 records in PASADENA). Due to the low number of events in PASADENA, the two arms were combined. A logistic model was fitted to the number of participants with H\u0026amp;Y of \u0026ge;3 versus \u0026lt;3 at year 4, including the following covariates: age, sex, education, H\u0026amp;Y stage at baseline and arm.\u003c/p\u003e\n\u003cp\u003eThe schedule of assessments was planned for a visit every 2 months, during the first two years, and then every 3 months, during the OLE, for participants in PASADENA, while in PPMI it was every 3 months for the first year then every 6 months, with the main assessments collected yearly. Hence, we used data from the yearly visits in PASADENA (+/- 8 weeks) for this comparison to match the PPMI arm for the longitudinal endpoints.\u003c/p\u003e\n\u003cp\u003eMDS-UPDRS Part IV, which measures motor complications after the start of levodopa, was explored in two ways. Firstly, MDS-UPDRS Part IV was analyzed as a continuous endpoint including participants in the PPMI cohort or those taking prasinezumab who started levodopa during the first 3 years. The index date was defined as the annual visit after which a participant started levodopa treatment. Cohorts were balanced at the index date on age, sex, education, MDS-UPDRS Part III ON, Part IV, H\u0026amp;Y, PD diagnosis, LEDD value on the day of MDS-UPDRS Part III ON assessment, starting of MAO-Bi (yes/no), and starting of dopamine agonist (yes/no). MMRM was used to model the change from index date up to year 4 with the following covariates: LEDD value on the day of MDS-UPDRS Part III ON assessment, months in the study before starting levodopa, months on prasinezumab, age, sex, education, catechol-O-methyltransferase-inhibitor initiation (yes/no), and amantadine initiation (yes/no).\u003c/p\u003e\n\u003cp\u003eSecondly, MDS-UPDRS Part IV was analyzed as a dichotomous endpoint including participants who had been on levodopa for at least 2 years at the end of year 4. A logistic model was fitted to the number of participants with MDS-UPDRS Part IV of \u0026ge;1 versus \u0026lt;1 at year 4 if at least 20% of events per arm were observed, including the covariates defined before.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDisease Modeling\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDisease modeling is a quantitative approach to predict the progression of an endpoint or measure of efficacy as a function of a population\u0026rsquo;s characteristics. As such, it has been recognized as a key approach to support the development of effective therapeutic strategies\u003csup\u003e18\u003c/sup\u003e. We recently developed disease models of MDS-UPDRS Part III and Part II based on PPMI data\u003csup\u003e10\u003c/sup\u003e. The models capture the natural progression of PD and the effect of symptomatic treatments on the progression following a population approach\u003csup\u003e19\u003c/sup\u003e. The effect of symptomatic treatments was modelled by means of pharmacodynamic relationships using the LEDD\u003csup\u003e15,16\u003c/sup\u003e as input of the models. The disease modeling complements the propensity score approach as it continuously balances the usage of LEDD at the subject level throughout the course of PD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe models were evaluated by comparing predictions to PASADENA placebo data. For this, simulations of the models using PPMI-inferred parameters at a population level, and LEDD dosing regimen as used in the PASADENA study, were performed to form a PASADENA external comparator arm. No additional parameters were considered for matching the two cohorts beyond this balancing for LEDD usage. This prediction matched the actual data from the control group of PASADENA for MDS-UPDRS Part III OFF and Part II but not for Part III ON. Indeed, over that year, 46% and 48% of the PASADENA data were below the predicted PPMI median for MDS-UPDRS Part III OFF and Part II respectively. These numbers were considered satisfactory given the theoretical expectation of 50%. However, for MDS-UPDRS Part III ON, a total of 42% was below the predicted median. Based on this and supported by the visual predictive check (\u003cstrong\u003eSupplementary Figure S5\u003c/strong\u003e), we decided not to use the PPMI-based Part III ON disease model for further comparison with PASADENA. Predictions of MDS-UPDRS Part III OFF and Part II from the virtual control arm were then compared to empirical data from the PASADENA treatment groups. This comparison was performed qualitatively and quantitatively through prediction-corrected visual and numerical predictive checks\u003csup\u003e20\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe members of the PASADENA Investigators and Prasinezumab Study Group\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ewho are authors on this manuscript\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePASADENA Investigators\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTanya Simuni,\u003csup\u003e4\u003c/sup\u003e Kathrin Brockmann\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrasinezumab Study Group\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGennaro Pagano,\u003csup\u003e1,2\u003c/sup\u003e Annabelle Monnet,\u003csup\u003e3\u0026nbsp;\u003c/sup\u003eAdriana Reyes,\u003csup\u003e3\u003c/sup\u003e Benjamin Ribba,\u003csup\u003e1\u003c/sup\u003e Hanno Svoboda,\u003csup\u003e1,10\u003c/sup\u003e Thomas Kustermann,\u003csup\u003e1\u003c/sup\u003e Krzysztof Smigorski,\u003csup\u003e1\u003c/sup\u003e Paulo Fontoura,\u003csup\u003e3\u003c/sup\u003e Rachelle Doody,\u003csup\u003e3,11\u003c/sup\u003e Geoffrey A. Kerchner,\u003csup\u003e1\u003c/sup\u003e Patrik Brundin,\u003csup\u003e1\u003c/sup\u003e Azad Bonni\u003csup\u003e1\u003c/sup\u003e, Tania Nikolcheva\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e1. Roche Pharma Research and Early Development (pRED), Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. University of Exeter Medical School, London, UK;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. F. Hoffmann-La Roche Ltd, Basel, Switzerland;\u003c/p\u003e\n\u003cp\u003e10. Roche Diagnostics GmbH, Penzberg, Germany;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e11. Genentech USA Inc., San Francisco, USA;\u003c/p\u003e\n\u003cp\u003eA full list of members and their affiliations appears in the Supplementary Information.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4232431/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4232431/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe 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\u0026rsquo;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\u0026thinsp;=\u0026thinsp;94) and early-start (n\u0026thinsp;=\u0026thinsp;177) groups showed a slower decline (less increase in score) on MDS-UPDRS Part III in OFF- (-51% for the delayed-start group and \u0026minus;\u0026thinsp;65% for the early-start group) and ON-state (-94% for the delayed-start group and \u0026minus;\u0026thinsp;118% for the early-start group), and on MDS-UPDRS Part II (-48% for the delayed-start group and \u0026minus;\u0026thinsp;40% for the early-start group), compared with the PPMI external comparator (n\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e","manuscriptTitle":"Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open-label extension of the PASADENA trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-08 17:47:28","doi":"10.21203/rs.3.rs-4232431/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5a6cae05-164d-4b70-b83c-43e26ea7cea9","owner":[],"postedDate":"April 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":30426004,"name":"Biological sciences/Neuroscience/Motor control"},{"id":30426005,"name":"Health sciences/Diseases/Neurological disorders/Movement disorders/Parkinson's disease"}],"tags":[],"updatedAt":"2024-10-09T07:06:59+00:00","versionOfRecord":{"articleIdentity":"rs-4232431","link":"https://doi.org/10.1038/s41591-024-03270-6","journal":{"identity":"nature-medicine","isVorOnly":false,"title":"Nature Medicine"},"publishedOn":"2024-10-08 04:00:00","publishedOnDateReadable":"October 8th, 2024"},"versionCreatedAt":"2024-04-08 17:47:28","video":"","vorDoi":"10.1038/s41591-024-03270-6","vorDoiUrl":"https://doi.org/10.1038/s41591-024-03270-6","workflowStages":[]},"version":"v1","identity":"rs-4232431","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4232431","identity":"rs-4232431","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}