Aims

Objectives: Digital health technologies (DHTTs) enable remote and frequent monitoring of motor symptoms in Parkinson’s disease (PD), and may more readily detect effects of disease modifying therapies compared to infrequently administered clinical scales. We report the effects of prasinezumab, an anti-alpha synuclein monoclonal antibody, on motor disease progression measured with the Roche PD Mobile Application v2 in the phase 2 PASADENA study (NCT03100149).

Methods

Methods: 316 individuals recently diagnosed with PD were randomized to placebo, low and high dose groups. All received a smartphone/watch, performed daily active motor tests, and carried/wore devices throughout the day. 17 pre-specified sensor features were aggregated over fortnights. Linear mixed effect models with random slopes fit each feature’s change from baseline. Random mixed effects models modeled nonlinear data. Effects of interest were defined as p<0.2, and multiple comparison correction was applied at 15% false discovery rate.

Results

Results: 75% of patients had mean adherence >75.9% (median adherence=93.1%). 5/17 sensor features showed treatment effects favoring prasinezumab: speeded tapping variability of most, least affected sides; maximum speed of pronation/supination most affected side; passively-monitored spontaneous gesture power; maximal turn speed on U-turn test. 1 feature (spiral drawing accuracy/time) showed an effect favoring placebo. Two analyses survived FDR-correction, both favoring prasinezumab: speeded tapping least affected side, power of gestures in daily life (see Figure).

Conclusions

Conclusions: Daily quantification of motor severity via a DHTT in early-stage PD demonstrated a divergence of slopes in bradykinesia progression, consistent with a disease-modifying effect of prasinezumab.

Aims

This study aimed to evaluate the efficacy and safety of prasinezumab, a monoclonal antibody which targets extracellular α-synuclein, following 52 weeks of treatment in early PD.

Methods

A 52-week randomised, double-blind, placebo-controlled study (PASADENA Part 1) was performed to assess efficacy and safety of prasinezumab (low or high dose) in early PD (N=316, diagnosis ≤2 years; Hoehn & Yahr Stages I–II). The primary endpoint was the change in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total score (Parts I + II + III) from baseline to Week 52. Secondary and exploratory endpoints included: changes in MDS-UPDRS Part III, MDS-UPDRS Part III subscores, other clinical and digital endpoints and imaging biomarkers.

Results

At Week 52, MDS-UPDRS Total score was –1.30 (–14%; 80% CI: –3.18, 0.58) for pooled doses versus placebo; –2.02 for low dose (–21.5%; 80% CI: –4.21, 0.18) and –0.62 for high dose (–6.6%; 80% CI: –2.82, 1.58). MDS-UPDRS Part III was –1.88 (–35.0%; 80% CI: –3.31, –0.45) for pooled treatment groups versus placebo; –2.44 for low dose (–45.4%; 80% CI: –4.09, –0.78) and –1.33 for high dose (–24.7%; 80% CI: –2.99, 0.34). MDS-UPDRS Part III site rating, MDS-UPDRS Part III bradykinesia subscore, digital motor endpoints, and time to worsening of motor symptoms supported the MDS-UPDRS Part III positive motor signals. There were no life-threatening adverse events or immunogenicity concerns.

Conclusions

Prasinezumab had a favourable safety profile and is the first potentially disease-modifying, anti-α-synuclein antibody to show efficacy signals on clinical progression of core motor features of PD. Further studies are warranted.

Aims

To investigate time to a clinical meaningful change of 4 points on the Unified Parkinson’s Disease Rating Scale motor score (UPDRS-Motor)¹ and a clinical meaningful change of 2 points on the UPDRS-ADL.²

Methods

This is a secondary analysis of placebo arm data from the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1 (NET-PD LS-1) trial, conducted from 2007-2013.³ Trial eligibility criteria included a PD diagnosis within 5 years and dopaminergic therapy use (minimal 90 days, maximal 2 years, adjustments permitted during trial). UPDRS-Motor (ON-state) and UPDRS-ADL were assessed annually up to 72 months. Using Kaplan-Meier analysis, median time to event was calculated for: 1) UPDRS-Motor +4 points from baseline (motor event); 2) motor event co-occurring with UPDRS-ADL +2 points from baseline (combined motor/ADL event).

Results

This analysis included 248 levodopa treated individuals (mean age 66.4 years, 65.3% men). Median time to the motor event was 24 months and median time to the combined motor/ADL event was 36 months. Comparing those with a motor event versus no motor event during the first 24 months, 24-months UPDRS-ADL mean (SD) change from baseline was 3.5 (4.7) and 0.3 (3.5) respectively.

Conclusions

Among levodopa treated individuals with PD, median time to reaching a clinical meaningful change on UPDRS-Motor was 2 years, which coincided with a clinical meaningful decline of daily life functioning.

References

1 Horvath K et al. Parkinsonism Relat Disord. 2015;21(12):1421-6.

2 Martinez-Martin et al. Value Health. 2006;9(6):386-93.

3 Kieburtz, K et al. JAMA. 2015;313(6):584-93

Aims

This study aimed to evaluate the efficacy and safety of prasinezumab, a monoclonal antibody which targets extracellular α-synuclein, following 52 weeks of treatment in early PD.

Methods

A 52-week randomised, double-blind, placebo-controlled study (PASADENA Part 1) was performed to assess efficacy and safety of prasinezumab (low or high dose) in early PD (N=316, diagnosis ≤2 years; Hoehn & Yahr Stages I–II). The primary endpoint was the change in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total score (Parts I + II + III) from baseline to Week 52. Secondary and exploratory endpoints included: changes in MDS-UPDRS Part III, MDS-UPDRS Part III subscores, other clinical and digital endpoints and imaging biomarkers.

Results

At Week 52, MDS-UPDRS Total score was –1.30 (–14%; 80% CI: –3.18, 0.58) for pooled doses versus placebo; –2.02 for low dose (–21.5%; 80% CI: –4.21, 0.18) and –0.62 for high dose (–6.6%; 80% CI: –2.82, 1.58). MDS-UPDRS Part III was –1.88 (–35.0%; 80% CI: –3.31, –0.45) for pooled treatment groups versus placebo; –2.44 for low dose (–45.4%; 80% CI: –4.09, –0.78) and –1.33 for high dose (–24.7%; 80% CI: –2.99, 0.34). MDS-UPDRS Part III site rating, MDS-UPDRS Part III bradykinesia subscore, digital motor endpoints, and time to worsening of motor symptoms supported the MDS-UPDRS Part III positive motor signals. There were no life-threatening adverse events or immunogenicity concerns.

Conclusions

Prasinezumab had a favourable safety profile and is the first potentially disease-modifying, anti-α-synuclein antibody to show efficacy signals on clinical progression of core motor features of PD. Further studies are warranted.