Slide 1: PTC518 Huntington's Disease Program Update
PTC518 Huntington’s Disease Program Update September 23, 2021
Slide 2: Forward Looking Statements
Forward Looking Statements: This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including statements regard
Slide 3: Small Molecule Splicing Modulation Platform
MAPT-Tauopathies ATXN3-SCA3 Undisclosed target 1 Undisclosed target 2 Undisclosed target 3 Undisclosed target 4 Undisclosed target 5 5’ Splice Site 3’ Splice Site 3 HTrnaSeq HTSpliceoseq Nanostring Plex Screen Identify Splice Site targets Identification of splicing compounds Preclinical Pipeline Cli
Slide 4: Evrysdi (risdiplam) Roadmap to Success
Evrysdi™ (risdiplam) Roadmap to Success 4 Highly selective Orally bioavailable and penetrates blood brain barrier Broad tissue distribution in animal models Defined blood to brain exposure ratio Proof of splicing mechanism demonstrated in P1 HV Evrysdi™ clinical benefit established
Slide 5: Agenda
PTC518 Huntington’s Disease Program Update Agenda 5 Huntington’s Disease Program PTC518 Phase 2 Study Design Splicing and Huntington’s Disease PTC518 Phase 1 Study Results
Slide 6: Huntington's Disease Is a Debilitating Neurodegenerative Disorder with No Disease Modifying Treatments
Huntington’s Disease Is a Debilitating Neurodegenerative Disorder with No Available Disease Modifying Treatments Huntington’s Disease • Caused by a monogenic defect; autosomal dominant inheritance • Leads to movement, psychiatric and cognitive disorders • 135,000 patients worldwide Current Treatment
Slide 7: HD Is a Monogenic Gain of Function Disorder and Lowering HTT Targets The Root Cause
HD Is a Monogenic Gain of Function Disorder and Lowering HTT Targets The Root Cause of Pathogenesis Modified from Tabrizi,S. Cell.2019. 7 Toxic gain of function mutation Expansion of CAG repeat in huntingtin (HTT) gene Huntington’s disease Whole brain atrophy HTT protein aggregates Therapeutic appro
Slide 8: Partial reduction of wild type HTT is well tolerated; HTT reduction correlates with clinical benefit
Multiple models demonstrate partial reduction of wild type HTT is well tolerated HTT reduction correlates with clinical benefit Modified from Tabrizi,S. Cell.2019. 8 Toxic gain of function mutation Expansion of CAG repeat in huntingtin (HTT) gene Huntington’s disease Whole brain atrophy HTT protein
Slide 9: Novel Splicing Mechanism that Leads to Degradation of Mutant HTT mRNA
Identification of a Novel Splicing Mechanism that Leads to Degradation of Mutant HTT mRNA 9 With PTC518 Pseudoexon is spliced in; Nonsense mutation leads to mRNA degradation No compound Pseudoexon is not spliced in; full length HTT protein is produced Exon 49 Exon 50 psiExon 5’ss 3’ss Exon 49 Exon 5
Slide 10: Characteristics of PTC518 Demonstrated in Preclinical Studies
Characteristics of PTC518 Were Demonstrated in Preclinical Studies 10 Orally bioavailable and penetrates blood brain barrier Reduces HTT mRNA and protein in the CNS and periphery Reversible and titratable Uniform lowering in key regions of the brain Not effluxed Highly selective
Slide 11: PTC518 Phase 1 Healthy Volunteer Study
PTC518 Phase 1 Healthy Volunteer Study
Slide 12: The PTC518 Phase 1 Trial Was a 4-Part Study
The PTC518 Phase 1 Trial Was a 4-Part Study 12 Phase 1 trial in healthy volunteers Multiple ascending dose longer duration: HTT mRNA splicing & protein lowering CSF sampling: Evaluate pharmacokinetics of PTC518 in the CSF Compare drug levels in CSF with plasma compartment Food effect: Evaluate the e
Slide 13: Proof of Mechanism Confirmed By Dose-Dependent HTT mRNA Splicing
Data on file PTC518- CNS- 001- HD 13 Proof of Mechanism of PTC518 Was Confirmed By Dose- Dependent HTT mRNA Splicing in Healthy Volunteers • Whole blood HTT splicing in humans • Doses evaluated = 15 mg and 30 mg • Time – Day 14; multiple doses; splicing evaluated 6h post dose on day 14 MAD Study Pla
Slide 14: Phase 1 SAD & MAD Interim Results Showed Dose-Dependent HTT mRNA Reduction
MAD showed long drug half-life with maintenance of splicing up to 72 hours following last dose Dose-dependent splicing of HTT mRNA Predictable pharmacology Well tolerated Phase 1 SAD & MAD Interim Results Showed That PTC518 Reduced HTT mRNA in a Dose-Dependent Manner 14
Slide 15: Decay Rates Can Be Modeled To Predict Decrease in mRNA and Protein
Decay Rates Can Be Modeled To Predict Drug-Dependent Decrease in mRNA and Protein Concentration Over Time 15 time concentration 1 Initial steady state: 100% HTT mRNA & protein 4 New steady state reached: 50% HTT mRNA & protein 3 50% HTT protein produced: HTT protein T½ is longer than T½ HTT mRNA 2 A
Slide 16: PTC518 Predicted to Achieve Equivalent HTT mRNA and Protein Reduction at Steady-State
PTC518 Is Predicted to Achieve Equivalent HTT mRNA and Protein Reduction at Steady-State 16 0 2 4 6 8 10 12 14 16 18 20 22 0 20 40 60 80 100 HTT mRNA abundance Steady state lowering should reach within 1 week Days % o f b a s e l i n e H T T R N A 0 7 14 21 28 35 42 0 20 40 60 80 100 HTT protein abu
Slide 17: PTC518 Predicted to Achieve Equivalent HTT mRNA and Protein Reduction at Steady-State
0 7 14 21 28 35 42 0 20 40 60 80 100 HTT protein abundance Steady state lowering should take ≥6 weeks Days % o f b a s e l i n e H T T P r o t e i n PTC518 Simulation PTC518 Is Predicted to Achieve Equivalent HTT mRNA and Protein Reduction at Steady-State Data on file 17 0 2 4 6 8 10 12 14 16 18 20
Slide 18: The PTC518 Phase 1 Trial Was a 4-Part Study
The PTC518 Phase 1 Trial Was a 4-Part Study 18 Phase 1 trial in healthy volunteers Multiple ascending dose longer duration: HTT mRNA splicing & protein lowering CSF sampling: Evaluate pharmacokinetics of PTC518 in the CSF Compare drug levels in CSF with plasma compartment Food effect: Evaluate the e
Slide 19: PTC518 Crosses the Blood Brain Barrier in Non-Human Primates and Humans
PTC518 Crosses the Blood Brain Barrier in Non-Human Primates and Humans Data on file 19 1.0 1.5 2.0 2.5 2 4 6 8 10 Human plasma-CSF correlation Free drug plasma concentration (ng/mL) C S F ( n g / m L ) 0 5 10 15 20 25 0 5 10 15 20 25 Monkey plasma-CSF correlation Free drug plasma concentration (ng/
Slide 20: The PTC518 Phase 1 Trial Was a 4-Part Study
The PTC518 Phase 1 Trial Was a 4-Part Study 20 Phase 1 trial in healthy volunteers Multiple ascending dose longer duration: HTT mRNA splicing & protein lowering CSF sampling: Evaluate pharmacokinetics of PTC518 in the CSF Compare drug levels in CSF with plasma compartment Food effect: Evaluate the e
Slide 21: The PTC518 Phase 1 Trial Was a 4-Part Study
The PTC518 Phase 1 Trial Was a 4-Part Study 21 Phase 1 trial in healthy volunteers Multiple ascending dose longer duration: HTT mRNA splicing & protein lowering CSF sampling: Evaluate pharmacokinetics of PTC518 in the CSF Compare drug levels in CSF with plasma compartment Food effect: Evaluate the e
Slide 22: Phase 1 Results: Dose-Dependent Reduction of HTT mRNA and Protein, Passed Blood Brain Barrier
PTC518 levels in the CSF are equal to or greater than levels observed in blood Dose-dependent reduction of HTT mRNA and Protein Phase 1 Results Showed That PTC518 Reduced HTT mRNA and Protein in a Dose-Dependent Manner and Passed the Blood Brain Barrier 22 Predictable pharmacology Well tolerated
Slide 23: Results Confirm Exposure Can Lead to Clinically Meaningful HTT Reduction
Results Confirm Exposure of PTC518 Can Lead to Clinically Meaningful HTT Reduction mRNA and Protein 23 What is the Dose? What is the Exposure? What is the Level of HTT Reduction? Demonstrate Clinical Benefit
Slide 24: PTC518 Phase 2 Study Design
PTC518 Phase 2 Study Design PIC)
Slide 25: Phase 2 Study Objectives
Phase 2 study objectives 25 Demonstrate safety, tolerability and pharmacology of PTC518 and HTT mRNA and protein reduction in HD patients Demonstrate PTC518 effect on blood based, CSF-based and radiographic biomarkers of Huntington’s disease to support potential accelerated approval
Slide 26: Strategies For Potential FDA Approval
Strategies For Potential FDA Approval 26 Sub Part H Part D Biomarker Path Clinical Data Path
Slide 27: PTC518 Phase 2 Study – PIVOT HD Planned Study Design
27 PTC518 Phase 2 Study – PIVOT HD Planned Study Design 12 weeks 1 year Open Label Extension • Double blind, multiple dose, 12-week placebo- controlled study with a long-term open label extension • Global clinical trial • N~100-150 patients • Trial to initiate by YE2021 Placebo Dose Level 1 Dose Lev
Slide 28: PIVOT HD Endpoint Strategy
PIVOT HD Endpoint Strategy 28 • Safety and tolerability of PTC518 in Huntington’s disease patients • Percent reduction in HTT mRNA and protein in blood Primary endpoints • Percent reduction in HTT protein in CSF • Changes in neurofilament light chain (NfL) in plasma and CSF • Change in caudate, puta
Slide 29: Identifying Optimal Clinical Trial Population
Identifying Optimal Clinical Trial Population Finding the Goldilocks Population 29 • Use natural history to analyze markers of disease progression • Identify best indicators of earlier stage/modifiable disease • Determine target patient population • Select endpoints to capture meaningful clinical be
Slide 30: Optimal Endpoints Vary by Disease Stage
30 Optimal Endpoints Vary by Disease Stage Percentile of measurement relative to controls TFC Stage 1 0 50 100 5 SDMT TMS Stage 3 Stage 2 Schematic adapted from Natural History Analyses Brain Volume Target Population Too Advanced
Slide 31: PIVOT HD Inclusion Criteria
31 PIVOT HD Inclusion Criteria Age 25 years and older Ambulatory CAG repeat 42-50 inclusive Specific clinical and radiographic parameters o Brain volumetric MRI values o Total motor score (TMS) o Cognitive score o Prognostic index of Huntington’s disease (PINHD)
Slide 32: Summary
32 Summary Phase 1 completed with achievement of all study objectives including protein reduction and projected CSF exposure Phase 2 trial to be initiated by YE 2021 • Multiple dose placebo-controlled trial of PTC518 in HD patients • Study designed to capture biomarker effects that could potentially
Slide 33: Questions
Questions PIC)