Slide 1: PADOVA: Topline results from a Phase IIb study of prasinezumab in early-stage Parkinson's disease
PADOVA: Topline results from a Phase IIb study of prasinezumab in early-stage Parkinson’s disease participants on stable symptomatic treatment Tania Nikolcheva,1 Gennaro Pagano,2,3 Judith Anzures-Cabrera,4 Tanya Simuni,5 Kenneth Marek,6 Nicola Pavese,7 Klaus Seppi,8 Fabrizio Stocchi,9 Ronald B. Post
Slide 2: Affiliations
Affiliations 1. Product Development Neurology, F. Hoffmann-La Roche Ltd, Basel, Switzerland 2. Roche Pharma Research and Early Development (pRED), Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, Switzerland 3. University of Exeter Medical School, London, UK 4. Roche Products Ltd, Welwyn Ga
Slide 3: Disclosures
Disclosures § Tania Nikolcheva, Gennaro Pagano, Nathalie Pross, Annabelle Monnet, Gesine Respondek, Loes Rutten-Jacobs, Valerie Schlegel, Lauren Boak, Geoffrey A. Kerchner, Patrik Brundin, Hanno Svoboda, and Azad Bonni are full-time employees and own shares of F. Hoffmann-La Roche Ltd. § Judith Anzu
Slide 4: Prasinezumab is a humanised IgG1 monoclonal antibody that selectively binds aggregated α-synuclein
Prasinezumab is a humanised IgG1 monoclonal antibody that selectively binds aggregated α-synuclein1,2 Prasinezumab’s proposed mode of action for the treatment of Parkinson’s disease1 Prasinezumab selectively binds aggregated α-synuclein Proposed effects: § Reducing neuronal toxicity § Preventing cel
Slide 5: Global Phase IIb PADOVA study design
Global Phase IIb PADOVA study design Novel time-to-event approach allows measuring treatment effect on top of standard-of-care symptomatic therapies 110 sites in Austria, Canada, France, Italy, Luxembourg, Poland, Spain, UK and US Key inclusion criteria Stratification Idiopathic PD L-DOPA or MAO-Bi
Slide 6: PADOVA endpoints
PADOVA endpoints Time-to-event (TTE) Continuous (Change from baseline) § ≥5 points in MDS-UPDRS Part III OFF* Primary (confirmed motor progression) § ≥3 points in MDS-UPDRS Part II in the presence § MDS-UPDRS Part III OFF (76 weeks) of confirmed motor event (motor function) § MDS-UPDRS Part III OFF
Slide 7: Well-conducted study with high rate of retention
Well-conducted study with high rate of retention Participant disposition Randomised N=586 Placebo Prasinezumab n=293 (100%) n=293 (100%) Randomised, not treated Randomised, not treated n=1 (0.3%) n=3 (1.0%) Entered DB period Entered DB period n=292 (99.7%) n=290 (99.0%) Discontinued Discontinued n=1
Slide 8: Baseline characteristics well balanced across arms
Baseline characteristics well balanced across arms Population consistent with early-stage PD; 74% of participants on L-DOPA Key baseline demographic and disease Placebo Prasinezumab All characteristics n=293 n=293 N=586 Age (yr) mean (SD) 64.4 (7.5) ` 64.2 (7.3) Sex, male n (%) 189 (64.5%) 183 (62.5
Slide 9: Prasinezumab continues to have a favourable safety & tolerability profile
Prasinezumab continues to have a favourable safety & tolerability profile Safety summary § IRRs comparable between groups (11% prasinezumab vs 12.8% placebo); no serious IRRs § Three deaths: two in placebo, one in prasinezumab arm; the latter due to sinus adenocarcinoma and deemed unrelated to study
Slide 10: PADOVA primary endpoint focuses on meaningful motor progression
PADOVA primary endpoint focuses on meaningful motor progression Time to confirmed motor progression event defined as ≥5 points on MDS-UPDRS Part III in OFF medication state# A threshold of meaningful motor progression in early-stage PD was defined1 Threshold of 5 points on MDS-UPDRS Part III Time to
Slide 11: Primary endpoint
Primary endpoint Time to confirmed motor progression event Motor progression event definition § ≥5 points in MDS-UPDRS Part III OFF § Confirmation: ❑ Sustained over two consecutive visits OR ❑ Levodopa equivalent daily dose (LEDD) increase prior to visit following the event Estimand strategy for oth
Slide 12: Primary endpoint
Primary endpoint Time to confirmed motor progression event Motor progression event definition § ≥5 points in MDS-UPDRS Part III OFF § Confirmation: ❑ Sustained over two consecutive visits OR ❑ Levodopa equivalent daily dose (LEDD) increase prior to visit following the event Statistical analysis § Pr
Slide 13: Primary endpoint
Primary endpoint Time to confirmed motor progression event Motor progression event definition § ≥5 points in MDS-UPDRS Part III OFF § Confirmation: ❑ Sustained over two consecutive visits OR ❑ Levodopa equivalent daily dose (LEDD) increase prior to visit following the event Statistical analysis § Pr
Slide 14: Primary endpoint: Study missed statistical significance
Primary endpoint Overall Prasinezumab showed a trend towards delaying motor progression Primary endpoint: Study missed statistical significance Time to ≥5 points on MDS-UPDRS Part III OFF Median n n events (weeks) 95% CI Placebo Prasinezumab 293 200 61.1 52.3, 71.9 100 Prasinezumab 90 Placebo 293 22
Slide 15: Primary endpoint: Trend more pronounced in prespecified L-DOPA subgroup
Primary endpoint L-DOPA Prasinezumab showed a trend towards delaying motor progression Primary endpoint: Trend more pronounced in prespecified L-DOPA subgroup Time to ≥5 points on MDS-UPDRS Part III OFF Median n n events (weeks) 95% CI Placebo Prasinezumab 218 145 64.4 55.3, 81.1 100 Prasinezumab 90
Slide 16: Secondary endpoint: trend towards delaying the decline of function
Secondary endpoint Overall Prasinezumab showed a trend towards delaying the decline of function Time to ≥3 points on MDS-UPDRS Part II in the presence of Median n n events (weeks) 95% CI a confirmed motor event Prasinezumab 293 142 112.1 81.1, NE Placebo 100 Prasinezumab 90 Placebo 293 163 88.3 62.7
Slide 17: Consistent trends in favour of prasinezumab across TTE endpoints
Primary and secondary endpoints Overall Consistent trends in favour of prasinezumab across TTE endpoints Forest plot of primary and secondary TTE endpoints Time to ≥5 point in MDS UPDRS Part III OFF Primary endpoint (confirmed) ≥3 points in MDS-UPDRS Part II in the presence of confirmed motor event
Slide 18: Prasinezumab showed no effect on motor progression at 76 weeks
Secondary endpoint Overall Prasinezumab showed no effect on motor progression at 76 weeks Change from baseline to Week 76 on MDS-UPDRS Part III OFF 6 5 Difference in adjusted means (SE) change from baseline 4 –0.39 (0.74); 95% CI (–1.84 to 1.05) Adjusted mean 3 No difference vs placebo p=0.5994* 2 1
Slide 19: Trend towards reduction of motor progression at 104 weeks
Exploratory endpoint Overall Prasinezumab showed a trend towards reduction of motor progression at 104 weeks Treatment duration longer than 18 months may be needed to measure treatment effect Change from baseline to Week 104 on MDS-UPDRS Part III OFF 7 n=326 (56%) with double-blind data at 104 weeks
Slide 20: Trend towards reduction of motor progression at 104 weeks in L-DOPA-treated population
Exploratory endpoint L-DOPA Prasinezumab showed a trend towards reduction of motor progression at 104 weeks in the L-DOPA-treated population Treatment duration longer than 18 months may be needed to measure treatment effect Change from baseline to Week 104 on MDS-UPDRS Part III OFF 7 n=242 (56%) wit
Slide 21: Trend towards reduction in neuromelanin loss in substantia nigra
Exploratory endpoint Prasinezumab showed a trend towards reduction in neuromelanin loss in substantia nigra Change from baseline to Week 76 in Neuromelanin MRI* Substantia nigra pars compacta intensity Substantia nigra pars compacta volume 0.4 p=0.079 p=0.1566 0.18 1.27 2.5 0.2 (0.185) (3.144) chang
Slide 22: Trend towards reduction in iron accumulation in putamen and substantia nigra
Exploratory endpoint Prasinezumab showed a trend towards reduction in iron accumulation in putamen and substantia nigra Change from baseline to Week 76 in Iron R2* MRI# Iron (R2*) putamen (Average) Iron (R2*) substantia nigra pars compacta (Average) 0.43 p=0.0025 0.50 p=0.1903 (0.197) 0.47 change fr
Slide 23: PADOVA: potential clinical benefit of prasinezumab in early-stage Parkinson's disease
PADOVA: potential clinical benefit of prasinezumab in early-stage Parkinson’s disease on top of symptomatic treatment While primary endpoint missed, TTE analyses showed trends towards delaying motor progression § More pronounced in L-DOPA treated population § Consistent trends across secondary endpo
Slide 24: Acknowledgements
Acknowledgements We thank all the study participants and their families, and investigators and site staff, for their time and commitment to the prasinezumab clinical development programme 24