Slide 1: PIVOT-HD Data Update – Q2 2024: Interim Results
1 PIVOT-HD Data Update – Q2 2024 Matthew Klein, M.D. CEO June 2024 PIVOT-HD Interim Results
Slide 2: Forward-Looking Statements
PIVOT-HD Data Update – Q2 2024 Forward-Looking Statements 2 This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this presentation, other than statements of historic fact, are forward-looking sta
Slide 3: Week 12 Interim Readout Met Key Objectives
PIVOT-HD Data Update – Q2 2024 Week 12 Interim Readout Met Key Objectives 3 PTC518 treatment resulted in dose-dependent lowering of HTT mRNA and protein levels in blood cells PTC518 demonstrated desired CSF exposure with higher concentrations of free drug in the CSF than plasma PTC518 was well toler
Slide 4: Key Objectives for Month 12 Interim Results
PIVOT-HD Data Update – Q2 2024 Key Objectives for Month 12 Interim Results Demonstrate durability of HTT protein lowering with PTC518 in blood cells Demonstrate continued safety and tolerability of PTC518 over 12 months Demonstrate evidence of activity on disease biomarkers Demonstrate evidence of C
Slide 5: Evidence of Durability of Effect, Safety and Dose-Dependent Benefit on Clinical Measures
PIVOT-HD Data Update – Q2 2024 Evidence of Durability of Effect, Safety and Dose-Dependent Benefit on Clinical Measures Note: Results based on interim readout Dose-dependent and durable lowering of HTT protein in blood at 12 months PTC518 was well tolerated with no evidence of treatment-related NfL
Slide 6: Study Design
PIVOT-HD Data Update – Q2 2024 PIVOT-HD Study Design 6 12 weeks 9 months PTC518 5mg R PTC518 10mg Part 1 Part 2 Placebo PTC518 5mg PTC518 10mg Week 12 Endpoints • Safety and tolerability • Blood HTT mRNA and protein lowering • CNS exposure Month 12 Endpoints • CSF HTT protein lowering • CNS biomarke
Slide 7: Cohort of Month 12 Patient Characteristics
PIVOT-HD Data Update – Q2 2024 Cohort of Month 12 Patient Characteristics 7 Category Placebo (N=10) PTC518 5mg (N=10) PTC518 10mg (N=12) Overall (N=32) Age (years) mean 47.4 45.3 46.9 46.6 Gender, n (%) Male 7 (70.0%) 4 (40.0%) 7 (58.3%) 18 (56.3%) Female 3 (30.0%) 6 (60.0%) 5 (41.7%) 14 (43.8%) CAG
Slide 8: Blood HTT Protein Lowering Results
8 PIVOT-HD Data Update – Q2 2024 Blood HTT Protein Lowering Results
Slide 9: PTC518 Treatment Resulted in Dose-Dependent Blood mHTT Protein Lowering at Week 12
PIVOT-HD Data Update – Q2 2024 -60% -50% -40% -30% -20% -10% 0% 10% 20% 30% 40% PTC518 Treatment Resulted in Dose-Dependent Blood mHTT Protein Lowering at Week 12 (June 2023) 9 Dose-dependent lowering of HTT protein +12% -21% -30% Note: Error bars represent the standard error of the mean. Mean % cha
Slide 10: PTC518 Results in Durable, Dose-Dependent Blood mHTT Protein Lowering at Month 12
PIVOT-HD Data Update – Q2 2024 -60% -50% -40% -30% -20% -10% 0% 10% 20% 30% 40% PTC518 Treatment Results in Durable, Dose-Dependent Blood mHTT Protein Lowering at Month 12 10 Note: For each subject the mean values of pre- and post-treatments are used Dose-dependent lowering of HTT protein with stead
Slide 11: Biomarker and Clinical Scale Results
11 PIVOT-HD Data Update – Q2 2024 Biomarker and Clinical Scale Results
Slide 12: Dose-Dependent CSF mHTT Protein Lowering at Month 12
PIVOT-HD Data Update – Q2 2024 -50% -40% -30% -20% -10% 0% Placebo PTC518 5mg PTC518 10mg PTC518 Treatment Results in Dose-Dependent CSF mHTT Protein Lowering at Month 12 12 -9% -21% -43% Median % change from baseline (mHTT CSF) CSF protein lowering consistent with protein lowering in blood
Slide 13: NfL Levels Consistent Across Treatment Groups With No Treatment-Related Spikes
PIVOT-HD Data Update – Q2 2024 NfL Levels Consistent Across Treatment Groups With No Evidence of Treatment-Related Spikes 13 -50% -40% -30% -20% -10% 0% -7% -3% -4% Median % change from baseline (NfL Plasma) Placebo PTC518 5mg PTC518 10mg Change in Plasma NfL Levels from Baseline to Month 12 0 5000
Slide 14: Change in Striatum Brain Volume Consistent Across Treatment Groups
14 PIVOT-HD Data Update – Q2 2024 Change in Striatum Brain Volume Consistent Across Treatment Groups -5.4% -5.2% -5.8% 0% -5% -10% -15% -20% -25% -30% -35% -40% -45% -50% Placebo PTC518 5mg PTC518 10mg Median striatum % change from baseline to Month 12
Slide 15: Trend of Dose-Dependent Improvement of Total Motor Score
15 PIVOT-HD Data Update – Q2 2024 PTC518 Treatment Demonstrated Trend of Dose-Dependent Improvement of Total Motor Score Mean Change from baseline at Month 12 0.00 2.00 4.00 6.00 8.00 10.00 12.00 Placebo PTC518 5mg PTC518 10mg 4.90 2.00 1.33 Worsening Note: Error bars represent the standard error of
Slide 16: Trends of Improvement on Other Key Clinical Measures
PIVOT-HD Data Update – Q2 2024 -2.50 -2.00 -1.50 -1.00 -0.50 0.00 Mean change from baseline at Month 12 Worsening Total Functional Capacity (TFC) -0.80 -0.30 -0.50 Placebo PTC518 5mg PTC518 10mg PTC518 Treatment Demonstrated Trends of Improvement on Other Key Clinical Measures 16 Worsening Composite
Slide 17: Safety
17 PIVOT-HD Data Update – Q2 2024 Safety
Slide 18: PTC518 Treatment Continues to be Well Tolerated
PIVOT-HD Data Update – Q2 2024 PTC518 Treatment Continues to be Well Tolerated At Month 12 18 Most common adverse events were nasopharyngitis, influenza, headache, and falls PTC518 was well tolerated, with no dose-limiting toxicities Similar adverse event profile across all treatment groups, includi
Slide 19: PTC518 Treatment Continues to be Well Tolerated at Month 12
PIVOT-HD Data Update – Q2 2024 * Unrelated to drug 19 # Judged by the investigator to be probably or possibly related to treatment Category Placebo (N=10) PTC518 5mg (N=12) PTC518 10mg (N=10) Subjects with at least one TEAE 8 (80.0) 9 (90.0) 11 (91.7) Subjects with at least one serious TEAE 2 (20.0)
Slide 20: Evidence of Durability of Effect, Safety and Dose-Dependent Benefit on Clinical Measures
PIVOT-HD Data Update – Q2 2024 Evidence of Durability of Effect, Safety and Dose-Dependent Benefit on Clinical Measures Dose-dependent and durable lowering of HTT protein in blood at 12 months PTC518 was well tolerated with no evidence of treatment-related NfL spikes at 12 months Dose-dependent lowe
Slide 21: Additional Week 12 Data
21 PIVOT-HD Data Update – Q2 2024 Additional Week 12 Data
Slide 22: Patient Characteristics of Additional Week 12 Subjects
PIVOT-HD Data Update – Q2 2024 Patient Characteristics of Additional Week 12 Subjects 22 Category Placebo (Stage 2 N=18) (Stage 3 N=11) PTC518 5mg (Stage 2 N=13) (Stage 3 N=13) PTC518 10mg (Stage 2 N=14) (Stage 3 N=12) Overall (Stage 2 N=45) (Stage 3 N=36) Age (years) mean 48.6 48.7 47.0 48.1 Gender
Slide 23: Dose-Dependent Blood mHTT Protein Lowering at Week 12
PIVOT-HD Data Update – Q2 2024 -40% -30% -20% -10% 0% 10% 20% 30% PTC518 Treatment Resulted in Dose-Dependent Blood mHTT Protein Lowering at Week 12 23 Note: Results include all subjects for whom biomarker data are available Mean % change from baseline blood mHTT (Week 12) +12% -16% -26% Dose-depend
Slide 24: PTC518 Safety Profile Consistent for Additional Week 12 Subjects
PIVOT-HD Data Update – Q2 2024 PTC518 Safety Profile Consistent for Additional Week 12 Subjects 24 Most common adverse events were nasopharyngitis, influenza, headache, and falls PTC518 was well tolerated, with no dose-limiting toxicities Similar adverse event profile across all treatment groups, in
Slide 25: Summary and Next Steps
25 PIVOT-HD Data Update – Q2 2024 25 Summary and Next Steps Evidence of favorable CNS activity with trends of improvement on key clinical measures and continued safety Continue PIVOT-HD and PIVOT-HD Open Label Extension studies Begin preparations for Phase 3 clinical trial