Slide 1: PIVOT-HD Topline Results
PTC Therapeutics PIVOT-HD Phase 2 Readout 1 Matthew B. Klein, MD CEO May 2025 PIVOT-HD Topline Results
Slide 2: Forward Looking Statements
PTC Therapeutics PIVOT-HD Phase 2 Readout 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-
Slide 3: PIVOT-HD Study Design
PTC Therapeutics PIVOT-HD Phase 2 Readout PIVOT-HD Study Design 3 *Placebo subjects randomized 1:1 to 5 mg or 10 mg for OLE and all subjects remain blinded to initial treatment assignment Primary Endpoint: Reduction in Blood HTT protein (Week 12) 12 Weeks Placebo-Controlled PTC518 5 mg PTC518 10 mg
Slide 4: Dose-Dependent mHTT Lowering and Safety Confirmed with Signals of Longer-term Effect
PTC Therapeutics PIVOT-HD Phase 2 Readout Dose-Dependent mHTT Lowering and Safety Confirmed with Signals of Longer-term Dose-Dependent Biomarker and Clinical Effect 4 Continued favorable safety and tolerability profile with no treatment-related NfL spikes Favorable and dose-dependent trends on clini
Slide 5: 12-Month Topline Results
PTC Therapeutics PIVOT-HD Phase 2 Readout 5 12-Month Topline Results
Slide 6: Baseline Characteristics of Enrolled Subjects
PTC Therapeutics PIVOT-HD Phase 2 Readout Baseline Characteristics of Enrolled Subjects * Includes 2 participants initially randomized to Stage 2 but reassigned to Stage 3 based on TFC 6 Baseline Characteristic Stage 2 Stage 3 Placebo (N=29) PTC518 5 mg (N=27) PTC518 10 mg (N=25) Placebo (N=24) PTC5
Slide 7: PTC518 Treatment Resulted in Dose-Dependent Blood HTT Lowering
PTC Therapeutics PIVOT-HD Phase 2 Readout PTC518 Treatment Resulted in Dose-Dependent Blood HTT Lowering 7 Biomarker Month 12 Mean (SD) Treatment Effect PTC518 5 mg PTC518 10 mg mHTT Blood (95% CI) -23.3% (-33.4, -13.2) -36.1% (-45.9, -26.4) Biomarker Month 12 Mean (SD) Treatment Effect PTC518 5 mg
Slide 8: Favorable Trends of NfL Lowering and no Treatment-Related Spikes
PTC Therapeutics PIVOT-HD Phase 2 Readout Favorable Trends of NfL Lowering in Stage 2 Subjects and no Treatment-Related Spikes 8 Stage 3 Mean plasma NfL % change from baseline to Month 12 Stage 2 Mean plasma NfL % change from baseline to Month 12 -15 -10 -5 0 5 10 15 Placebo PTC518 5 mg PTC518 10 mg
Slide 9: Caudate Brain Volume Changes Across Treatment Groups
PTC Therapeutics PIVOT-HD Phase 2 Readout Caudate Brain Volume Changes Across Treatment Groups 9 Based on exploratory analysis Stage 2 Stage 3 0 -5 -10 -15 -20 Placebo PTC518 5 mg PTC518 10 mg Mean (SD) % change from baseline to Month 12 -4.6 % -4.4 % -4.9 % Placebo PTC518 5 mg PTC518 10 mg 0 -5 -10
Slide 10: Early Signals of Favorable Effect on Clinical Scales in Stage 2 Subjects
PTC Therapeutics PIVOT-HD Phase 2 Readout Early Signals of Favorable Effect on Clinical Scales in Stage 2 Subjects 10 Clinical Scale Mean (SD) Change Baseline to Month 12 Placebo (N=29) PTC518 5 mg (N=27) PTC518 10 mg (N=25) cUHDRS -0.49 (1.25) -0.41 (0.70) -0.27 (0.99) TFC -0.3 (0.78) -0.2 (0.49) -
Slide 11: PTC518 Treatment Showed Favorable Safety and Tolerability Profile at Month 12
PTC Therapeutics PIVOT-HD Phase 2 Readout PTC518 Treatment Showed Favorable Safety and Tolerability Profile at Month 12 11 Most common adverse events were nasopharyngitis, influenza, headache and falls Similar adverse event profile across all treatment groups and disease stages, including placebo PT
Slide 12: PTC518 Treatment Showed Favorable Safety and Tolerability Profile at Month 12
PTC Therapeutics PIVOT-HD Phase 2 Readout 12 AE Category Stage 2 Stage 3 Placebo (N=29) PTC518 5 mg (N=27) PTC518 10 mg (N=25) Placebo (N=24) PTC518 5 mg (N=25) PTC518 10 mg (N=29) TEAEs, n (%) 26 (89.7) 22 (81.5) 22 (88.0) 20 (83.3) 21 (84.0) 27 (93.1) TESAEs,* n (%) 3 (10.3) 1 (3.7) 1 (4.0) 1 (4.2
Slide 13: 12-Month Results Confirm Dose-Dependent mHTT Reduction, Safety and Early Trends
PTC Therapeutics PIVOT-HD Phase 2 Readout Month 12 Results Confirm Dose-Dependent mHTT Reduction, Safety and Early Trends of Favorable Clinical Effect Dose-dependent and durable lowering of HTT protein in blood Favorable safety profile with no treatment-related NfL spikes Early trends of favorable e
Slide 14: 24-Month Interim Results
PTC Therapeutics PIVOT-HD Phase 2 Readout 14 24-Month Interim Results
Slide 15: Baseline Characteristics of Subjects Included in 24-Month Interim Results (Stage 2)
PTC Therapeutics PIVOT-HD Phase 2 Readout Baseline Characteristics of Subjects Included in 24-Month Interim Results (Stage 2) 15 Baseline Characteristic PTC518 5 mg (N=10) PTC518 10 mg (N=11) Age (years) Mean 44.7 46.8 Gender, n (%) Male Female 5 (50.0) 5 (50.0) 6 (54.5) 5 (45.5) CAG length Mean (SD
Slide 16: Natural History Comparative Analysis Utilizing ENROLL-HD Disease Registry
PTC Therapeutics PIVOT-HD Phase 2 Readout Natural History Comparative Analysis Utilizing ENROLL-HD Disease Registry 16 • Age ≥ 25 years • CAG between 40 and 50 • TFC score of 13 • IS score of 100 • PINHD score between 0.18 to 4.93 • Propensity score weighting analysis applied to compare PTC518 treat
Slide 17: Favorable Effect on cUHDRS at Month 24 Relative to Natural History
PTC Therapeutics PIVOT-HD Phase 2 Readout -1.2 -1 -0.8 -0.6 -0.4 -0.2 0 Favorable Effect on cUHDRS at Month 24 Relative to Propensity-Matched Natural History Nominal p values from ad hoc natural history 17 comparator analysis -0.85 -0.80 PTC518 5 mg PTC518 10 mg cUHDRS Change from Baseline at Month
Slide 18: Dose-Dependent NfL Lowering From Baseline at Month 24
PTC Therapeutics PIVOT-HD Phase 2 Readout -25% -20% -15% -10% -5% 0% 5% 10% 15% Dose-Dependent NfL Lowering From Baseline At Month 24 * Change relative to subject baseline 18 % Change from Baseline in Mean plasma NfL -13.9% -9.0% PTC518 5 mg PTC518 10 mg p = 0.12* p = 0.03* Worsening Plasma NfL incr
Slide 19: PTC518 Continues to Show Favorable Safety and Tolerability Profile at Month 24
PTC Therapeutics PIVOT-HD Phase 2 Readout PTC518 Treatment Continues to Show Favorable Safety and Tolerability Profile at Month 24 19 Adverse event profile remains consistent through Month 24 No reported treatment-related SAEs nor NfL spikes at Month 24 PTC518 was well tolerated, with no dose-limiti
Slide 20: Favorable Trends of Slowing of Progression and NfL Lowering at Month 24
PTC Therapeutics PIVOT-HD Phase 2 Readout Favorable Trends of Slowing of Progression and NfL Lowering at Month 24 20 Dose-dependent clinical trends of disease slowing relative to matched natural history at Month 24 Continued favorable safety and tolerability profile Dose-dependent NfL lowering at Mo
Slide 21: Summary and Next Steps
PTC Therapeutics PIVOT-HD Phase 2 Readout 21 Primary endpoint reached with durable mHTT lowering, safety and signals of clinical effect in Stage 2 patients Summary and Next Steps Complete data analyses and plan for development and regulatory discussions Dose-dependent trends on clinical scales and N
Slide 22: PTC Therapeutics PIVOT-HD Phase 2 Readout
PTC Therapeutics PIVOT-HD Phase 2 Readout