Slide 1: PIVOT-HD Interim Data Update
Patient Living with HD Matthew Klein, M.D. CEO June 2023 PIVOT -HD Interim Data Update
Slide 2: Forward-Looking Statements
2 PIVOT-HD Interim Data Update Forward-Looking Statements 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 state
Slide 3: PTC518 Program Developed from PTC's Validated Splicing Platform
Novel Chemical Library HTSpliceseq Databases of Splicing Targets PTC518 developed from PTC's validated splicing platform PTC518 Program Developed from PTCs Validated Splicing Platform PTC518 Program Leveraged Learnings from Successful Development of Evrysdi 3 PIVOT-HD Interim Data Update • Importanc
Slide 4: Key Objectives for 12-Week Interim Data Readout
4 PIVOT-HD Interim Data Update Key Objectives for 12-Week Interim Data Readout Confirm the relationship of HTT mRNA to protein lowering at steady state Define CSF/plasma drug exposure in Huntington’s disease patients Determine HTT protein lowering after 12 weeks of treatment with PTC518 at 5mg and 1
Slide 5: 12-Week Interim Data Met Key Objectives
12-Week Interim Data Met Key Objectives 5 PIVOT-HD Interim Data Update 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 tolerated
Slide 6: PIVOT-HD Study Design
PIVOT-HD Study Design 6 PIVOT-HD Interim Data Update 12 weeks 9 months PTC518 5mg PTC518 10mg PTC518 20mg R Part 1 Part 2 Placebo PTC518 5mg PTC518 10mg PTC518 20mg Primary Endpoints • Safety and tolerability of PTC518 • Percent reduction in HTT mRNA and protein in blood Secondary Endpoints • Percen
Slide 7: PIVOT-HD Trial Populations
PIVOT-HD Trial Populations 7 PIVOT-HD Interim Data Update • Ambulatory Huntington’s patients age 25 and older • CAG repeats 40-50 inclusive • Motor and Cognitive Function: - UHDRS-IS score of 100 - UHDRS TFC score of 13 • PINHD score of 0.18 - 4.93 - Multivariate calculation including SDMT, TMS, age
Slide 8: PIVOT-HD Interim Analysis Patient Characteristics
PIVOT-HD Interim Analysis Patient Characteristics 8 PIVOT-HD Interim Data Update Category PTC518 5mg (N=13) PTC518 10mg (N=11) Placebo (N=9) Overall (N=33) Age (years) mean 46.2 47.4 46.9 46.8 Gender, n (%) Male 5 (38.5%) 6 (54.5%) 6 (66.7%) 17 (51.5%) Female 8 (61.5%) 5 (45.5%) 3 (33.3%) 16 (48.5%)
Slide 9: PTC518 Treatment Resulted in Dose-Dependent Blood HTT Protein Lowering at Week 12
PTC518 Treatment Resulted in Dose-Dependent Blood HTT Protein Lowering at Week 12 9 PIVOT-HD Interim Data Update -40% -30% -20% -10% 0% 10% 20% Placebo PT518 5mg PTC518 10mg Mean % change from baseline blood mHTT (Week 12) +12% Mean % change from baseline mRNA (Week 12) -27% -29% -21% -30% Dose-depe
Slide 10: PTC518 CSF Drug Levels Confirm Targeted CNS Exposure at Week 12
PTC518 CSF Drug Levels Confirm Targeted CNS Exposure at Week 12 10 PIVOT-HD Interim Data Update Ratio of CSF to Free Plasma Treatment Concentration Group Mean CSF Concentration (ng/mL) Mean Free Plasma Concentration (ng/mL) 5mg 0.923 0.917 10mg 2.037 1.402 5mg 1.1 to 1 10mg 1.5 to 1
Slide 11: PTC518 Treatment Demonstrated to Be Well Tolerated
PTC518 Treatment Demonstrated to Be Well Tolerated 11 PIVOT-HD Interim Data Update Most common adverse events were upper respiratory tract infection and headache PTC518 was well tolerated, with no treatment-related serious adverse events and no adverse events leading to discontinuation Similar adver
Slide 12: PTC518 Treatment Demonstrated to Be Well Tolerated
PTC518 Treatment Demonstrated to Be Well Tolerated 12 PIVOT-HD Interim Data Update Category PTC518 5mg (N = 13) PTC518 10mg (N=11) Placebo (N=9) Overall (N=33) Subjects with at least one TEAE 9 (69.2) 7 (63.6) 6 (66.7) 22 (66.7) Subjects with at least one serious TEAE 0 0 0 0 Subjects with at least
Slide 13: CSF NfL Levels Trended Lower in Subjects Treated with PTC518
CSF NfL Levels Trended Lower in Subjects Treated with PTC518 13 PIVOT-HD Interim Data Update Mean Change in CSF NfL Levels from Baseline to Week 12 Note: One patient excluded due to non-treatment related viral syndrome. Note: Error bars represent the standard error of the mean. -20 -15 -10 -5 0 5 10
Slide 14: Summary and Next Steps
Summary and Next Steps 14 PIVOT-HD Interim Data Update Dose-dependent lowering of HTT protein levels, safety, and CNS biodistribution objectives achieved Share safety data with FDA to support US enrollment in PIVOT-HD Continue enrollment in Stage 2 and early Stage 3 patient cohorts