Ptc Therapeutics, Inc. · NASDAQ:PTCT
Ptc Therapeutics — Technical Presentation (April 2021)
70 slides from Ptc Therapeutics's technical presentation, Apr 15, 2021
Slide 1: PTC518 Huntington's Disease Deep Dive
PTC518 Huntington’s Disease Deep Dive April 15th, 2021
Slide 2: Forward Looking Statements
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 release, other than statements of historic fact, are forward -looking statements, including statements with r
Slide 3: Diversified Platform Drives Strong Portfolio
Diversified Platform Drives Strong Portfolio 3 Clinical Commercial Research Nonsense Mutation LatAm Commercial Deflazacort Gene Therapy Bio-e Metabolic Oncology US Dystrophin PTC-AADC PTC299 AML PTC596 DIPG PTC596 LMS Vatiquinone ME Vatiquinone FA PTC923 PKU PTC299 COVID-19 SCA-3 Undisclosed MAP-Tau
Slide 4: Agenda
PTC518 Huntington’s Disease Deep Dive Agenda 4 Preclinical Development of PTC518 Anu Bhattacharyya, Exec. Director, Biology PTC518 Huntington Deep Dive Splicing Platform and Huntington’s Disease Stuart Peltz, CEO PTC518 Phase 1 Study Matthew Klein, CDO
Slide 5: PTC is the Leader in Splicing
PTC is the Leader in Splicing With 20 Years of Expertise and Proven Track Record 5 Spinal muscular atrophy Huntington’s disease Exploiting splicing Proprietary systems and specialty libraries Isoform plex HTSpliceseq Many additional targets Databases of Splicing Targets Familial dysautonomia
Slide 6: Recognition of Pre-mRNA is Mediated by U-snRNP Complexes U1 and U2
6 Recognition of Pre-mRNA is Mediated by U-snRNP Complexes U1 and U2 5’ Splice Site 3’ Splice Site 5’ Splice Site 3’ Splice Site U1 recognizes the 5’ splice site at each exon U2 recognizes the branch site near the 3’ splice site
Slide 7: Targeting Alternative Splicing of SMN2 in SMA by Targeting the U1 Site
FL mRNA Functional SMN protein Targeting Alternative Splicing of SMN2 in SMA by Targeting the U1 Site SMN1 6 8 7 mRNA 6 8 7 6 8 7 SMN2 6 8 7 6 8 CT Truncated unstable SMN protein ESE ESS U1 GA U1 GA Risdiplam stabilizes U1 Functional SMN protein FL mRNA Δ7 mRNA Activation Inhibition 7
Slide 8: The SMN2 5'-Splice Site Presents a Unique Structural Interface for Risdiplam
The SMN2 5’-Splice Site Presents a Unique Structural Interface for Small Molecule Risdiplam Canonical Duplex SMN2 Exon 7 8
Slide 9: Risdiplam Improves the Ability of the 5'-Splice Site to Promote Splicing
Risdiplam SMN2 Improves the Ability of the 5’-Splice Site to Promote Splicing Risdiplam Canonical Duplex SMN2 Exon 7 9
Slide 10: Risdiplam Increases SMN Protein in Multiple Tissues
Risdiplam Increases SMN Protein in Multiple Tissues to Near or Above Heterozygous Levels Brain Peripheral Blood Mononuclear Cells • SMN protein levels in peripheral blood cells correlate to those in brain • Similar increases in SMN observed in spinal cord, muscle, heart, liver, skin 0 1 0 0 2 0 0 3
Slide 11: Risdiplam Increases SMN Protein Levels in All SMA Types
8 6 4 2 0 SMN Protein (ng/mL) Baseline Week 4 Firefish Sunfish =<11yrs Sunfish >11yrs Jewelfish Healthy Volunteers Risdiplam Increases SMN Protein Levels in All SMA Types to the Level in Adult Healthy Subjects Healthy subjects: n=49, age 18-60 years. Patients with SMA: n=84, age 3.3 months to 52 yea
Slide 12: Evrysdi Roadmap to Success
Evrysdi™ Roadmap to Success 12 Highly selective Orally bioavailable and penetrates blood brain barrier Broad tissue distribution in animal models 1:1 ratio between blood and brain Proof of splicing mechanism demonstrated in P1 HV Evrysdi™ clinical benefit established
Slide 13: Agenda
PTC518 Huntington’s Disease Deep Dive Agenda 13 Preclinical Development of PTC518 Anu Bhattacharyya, Exec. Director, Biology PTC518 Huntington Deep Dive Splicing Platform and Huntington’s Disease Stuart Peltz, CEO PTC518 Phase 1 Study Matthew Klein, CDO
Slide 14: PTC518 Huntington's Disease Key Focus Areas
PTC518 Huntington’s Disease Key Focus Areas 14 Overview of Huntington’s Disease Different treatment modalities Why is the blood a good marker that correlates with the CNS? Can mHTT in CSF accurately verify target engagement in brain? Huntington’s Disease What evidence supports partial lowering of wi
Slide 15: PTC518 Huntington's Disease Key Focus Areas
PTC518 Huntington’s Disease Key Focus Areas 15 Overview of Huntington’s Disease Different treatment modalities Why is the blood a good marker that correlates with the CNS? Can mHTT in CSF accurately verify target engagement in brain? Huntington’s Disease What evidence supports partial lowering of wi
Slide 16: Huntington's Disease is a Debilitating Neurodegenerative Disorder
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 • Expansion of CAG trinucleotide repeat in the huntingtin (HTT) gene • Leads to movement, psychiatric a
Slide 17: Molecular Basis of Huntington's Disease is Well Understood
Molecular Basis of Huntington’s Disease is Well Understood Modified from T a b r i z i , S . C e l l . 2019. 17 Repeat Count Classification Disease Status <28 Normal Unaffected 28–35 Intermediate Unaffected 36–39 Reduced Penetrance +/- Affected 40-above Full Penetrance Affected
Slide 18: Progressive Neuronal Degeneration Occurs Throughout the Brain
18 Globus Pallidus Striatum Cortex Progressive Neuronal Degeneration Occurs Throughout the Brain HD Healthy Goh et al. Aus Psychiatry. 2018
Slide 19: HTT is Ubiquitously Expressed and Involved in Many Cellular Processes
HTT is Ubiquitously Expressed and Involved in Many Cellular Processes • Predominantly an intra- cellular protein • Required during embryonic development • Ubiquitously expressed throughout development and in all adult tissues U h l é n M e t a l . , S c i e n c e ( 2 0 1 5 ) ; www.proteinatlas.org 1
Slide 20: PTC518 Huntington's Disease Key Focus Areas
PTC518 Huntington’s Disease Key Focus Areas 20 Overview of Huntington’s Disease What evidence supports partial lowering of wild type HTT? What evidence supports partial lowering of mutant HTT? Different treatment modalities Why is the blood a good marker that correlates with the CNS? Can mHTT in CSF
Slide 21: Lowering mHTT Expression to Target Root Cause of Pathogenesis
21 Toxic gain of function mutation Huntington’s disease Whole brain atrophy HTT protein aggregates Make less HTT Lowering mHTT Expression to Target Root Cause of Pathogenesis
Slide 22: Oral Treatment has Uniform Lowering Across Key Regions of the Brain
Oral Treatment has Uniform Lowering Across the Key Regions of the Brain 22 Property Small molecules Delivery Oral CNS lowering Equal across the key areas of the brain Peripheral lowering Yes Reversible Yes
Slide 23: Antisense Oligonucleotide Treatment has More Lowering in the Cortex
23 Property ASOs Delivery Intrathecal CNS lowering Less reduction in the striatum compared to cortex Peripheral lowering No Reversible Yes Antisense Oligonucleotide Treatment has More Lowering in the Cortex Compared to the Striatum
Slide 24: Gene Therapy Treatment has More Lowering in the Striatum
24 Property RNAi Delivery Striatum/Thalamus CNS lowering Less reduction in the cortex compared to striatum Peripheral lowering No Reversible No Gene Therapy Treatment has More Lowering in the Striatum Compared to the Cortex
Slide 25: PTC518 Drug Development Objectives
PTC518 Drug Development Objectives 25 What is the Dose? 01 What is the Exposure? 02 What is the Level of HTT Reduction? 03
Slide 26: PTC518 Huntington's Disease Key Focus Areas
PTC518 Huntington’s Disease Key Focus Areas 26 Overview of Huntington’s Disease What evidence supports partial lowering of wild type HTT? What evidence supports partial lowering of mutant HTT? Different treatment modalities Why is the blood a good marker that correlates with the CNS? Can mHTT in CSF
Slide 27: Distribution Through the Blood Effectively Targets the Whole Brain
27 Purves D, Augustine GJ, et al., editors. Sunderland (MA): Sinauer Associates; 2001. Distribution Through the Blood Effectively Targets the Whole Brain
Slide 28: PTC518 Huntington's Disease Key Focus Areas
PTC518 Huntington’s Disease Key Focus Areas 28 Overview of Huntington’s Disease Different treatment modalities Why is the blood a good marker that correlates with the CNS? Can mHTT in CSF accurately verify target engagement in brain? Huntington’s Disease What evidence supports partial lowering of wi
Slide 29: The Cerebrospinal Fluid Cushions the Brain
29 In healthy people, the cerebrospinal fluid (CSF): Does • Cushion the brain • Provide immune surveillance • Remove metabolic waste Does not • Interact with most neurons directly • Contain very much protein (35 mg/dL, compared to 7000 mg/dL in serum) The Cerebrospinal Fluid Cushions the Brain Subar
Slide 30: Limitations of CSF HTT Measurement as a Pharmacodynamic Marker
Limitations of CSF HTT Measurement as a Pharmacodynamic Marker for HTT lowering 30 What We Know Unknowns The origin of CSF mHTT Specific contributions of brain regions to CSF mHTT levels Not enough data to understand a meaningful treatment related change in levels over assay variability Brain mHTT l
Slide 31: PTC518 Huntington's Disease Key Focus Areas
PTC518 Huntington’s Disease Key Focus Areas 31 Overview of Huntington’s Disease Different treatment modalities Why is the blood a good marker that correlates with the CNS? Can mHTT in CSF accurately verify target engagement in brain? Huntington’s Disease What evidence supports partial lowering of wi
Slide 32: Multiple Models Demonstrate Partial Reduction of Wild Type HTT Is Well Tolerated
Multiple Models Demonstrate Partial Reduction of Wild Type HTT Is Well Tolerated 32 Species Magnitude of wild type HTT change Phenotype Human Loss of one normal HTT allele ~50% No detectable abnormal phenotype Adult Nonhuman Primates ~50% No alterations in motor function; No abnormal histopathologic
Slide 33: HTT Reduction Correlates with Clinical Benefit
HTT Reduction Correlates with Clinical Benefit 33 Human data: ~50% reduction in HTT transcriptional activity results in mean delay of age of onset by 9.3 years Mouse data: 30-40% reduction in mHTT expression translates to beneficial effects Becanovic et. al. Nat Neurosci. 2015. doi:10.1038/nn.4014 G
Slide 34: Agenda
PTC518 Huntington’s Disease Deep Dive Agenda 34 Preclinical Development of PTC518 Anu Bhattacharyya, Exec. Director, Biology PTC518 Huntington Deep Dive Splicing Platform and Huntington’s Disease Stuart Peltz, CEO PTC518 Phase 1 Study Matthew Klein, CDO
Slide 35: Characteristics of a Promising HD Therapeutic
What are the Characteristics of a Promising HD Therapeutic? .. 35 Orally bioavailable and penetrates blood brain barrier Reversible and titratable Reduces HTT mRNA and protein in the CNS and periphery Uniform lowering in key regions of the brain Highly selective Not effluxed
Slide 36: Novel Splicing Mechanism Leads to Degradation of Mutant HTT mRNA
Identification of a Novel Splicing Mechanism that Leads to Degradation of Mutant HTT mRNA 36 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 psi Exon 5’ss 3’ss Exon 49 Exon
Slide 37: Key Preclinical Proof Points
Key Preclinical Proof Points CONFIDENTIAL. NOT FOR PROMOTIONAL USE. 37 Do the molecules lower HTT levels in cells? Do the molecules lower both HTT mRNA and protein levels? Cellular Activity Reduce cellular toxicity, mutagenicity, and key off target activity Monitor short and long-term safety in anim
Slide 38: Animal Models Were Selected to Best Show PK and PD
Animal Models Were Selected to Best Show PK and PD 38 Model Purpose Pros Cons BACHD mouse PK-PD-distribution/ HTT lowering biomarker Human Genomic Locus Full-length HTT/PsiExon target Subtle & late onset phenotype/ Increased body weight WT Mouse PK-distribution Availability; commonly used; quick PK
Slide 39: PTC518 is Orally Bioavailable and Crosses the Blood Brain Barrier
PTC518 is Orally Bioavailable and Crosses the Blood Brain Barrier After swallowing, it makes its way to the stomach Broken down in the stomach, small intestine, and liver Circulates through the bloodstream Crosses blood brain barrier to access neurons Distributed through the body 39
Slide 40: What are the Characteristics of PTC518?
What are the Characteristics of PTC518? 40 Orally bioavailable and penetrates blood brain barrier Reversible and titratable Reduces HTT mRNA and protein in the CNS and periphery Uniform lowering in key regions of the brain Highly selective Not effluxed
Slide 41: Dose Dependent HTT Lowering in the Brain of BACHD Mice
Dose Dependent HTT Lowering in the Brain of BACHD Mice 41 120 100 80 60 40 20 0 Vehicle 1 3 7 21 63 HTT Protein Levels in Brain % of baseline H TT protein Dose (mg/kg)
Slide 42: What are the Characteristics of PTC518?
What are the Characteristics of PTC518? 42 Orally bioavailable and penetrates blood brain barrier Reversible and titratable Reduces HTT mRNA and protein in the CNS and periphery Uniform lowering in key regions of the brain Highly selective Not effluxed
Slide 43: PTC518 is Highly Potent in Promoting Splicing of HTT Pre-mRNA
PTC518 is Highly Potent in Promoting Splicing of HTT Pre- mRNA and Lowering HTT Protein Levels in Human Cells 43 HTT protein lowering HTT pre-mRNA splicing RNA 0.001 0.01 0.1 1 0 20 40 60 80 100 Cpd, (M) % o f b a s e l i n e H T T R N A Protein 0.001 0.01 0.1 1 0 20 40 60 80 100 Cpd, (M) % o f b
Slide 44: PTC518 Promotes Splicing of HTT Pre-mRNA in BACHD Mouse Whole Blood
44 PTC518 Promotes Splicing of HTT Pre-mRNA in BACHD Mouse Whole Blood 0 6 12 18 24 10 20 30 40 PK Profile (Plasma_PTC518)) Time (hours) P l a s m a f r e e c o n c .. ( n g / m L ) HTT IC50 0 1 2 4 8 16 24 0 20 40 60 80 100 120 HTT RNA Levels in Blood Time (hrs) % o f b a s e l i n e H T T R N A Da
Slide 45: Strong Correlation Between HTT mRNA Splicing and Protein Lowering in Blood
45 PTC518 Showed a Strong Correlation Between HTT mRNA Splicing and Protein Lowering in Blood of BACHD Mice ➢ HTT protein lowering in BACHD white blood cells ➢ Time – 21 days; multiple doses; PD evaluated 2h post last dose Vehicle PTC518 0 20 40 60 80 100 120 HTT Protein Levels in Blood % o f b a s
Slide 46: PTC518 Uniformly Lowers HTT Protein in BACHD Mouse Brain and Blood
Vehicle PTC518 0 20 40 60 80 100 120 HTT Protein Levels in Brain % o f b a s e l i n e H T T p r o t e i n PTC518 Uniformly Lowers HTT Protein Levels in BACHD Mouse Brain and White Blood Cells 46 Data on file Vehicle PTC518 0 20 40 60 80 100 120 HTT Protein Levels in Blood % o f b a s e l i n e H T
Slide 47: What are the Characteristics of PTC518?
What are the Characteristics of PTC518? 47 Orally bioavailable and penetrates blood brain barrier Reversible and titratable Reduces HTT mRNA and protein in the CNS and periphery Uniform lowering in key regions of the brain Highly selective Not effluxed
Slide 48: HD Splicing Small Molecules Demonstrate Robust HTT Reduction in BACHD Mouse Brain
HD Splicing Small Molecules Demonstrate Robust HTT Reduction in BACHD Mouse Brain 48 Data on file from multiple studies Brain and blood HTT lowering Measurements demonstrate uniform HTT lowering across brain regions with ~1:1 brain and blood lowering effect 120 100 80 60 40 20 0 Vehicle 7 mg/kg 120
Slide 49: PTC518 Crosses the Blood Brain Barrier in Non-Human Primates
PTC518 Crosses the Blood Brain Barrier in Non-Human Primates 49 Data on file 0 5 10 15 20 25 0 5 10 15 20 25 Monkey plasma CSF correlation Calculated plasma free (ng/mL) C S F ( n g / g ) R squared 0.779 P value <0.0001
Slide 50: What are the Characteristics of PTC518?
What are the Characteristics of PTC518? 50 Orally bioavailable and penetrates blood brain barrier Reversible and titratable Reduces HTT mRNA and protein in the CNS and periphery Uniform lowering in key regions of the brain Highly selective Not effluxed
Slide 51: What are the Characteristics of PTC518?
What are the Characteristics of PTC518? .. 51 Orally bioavailable and penetrates blood brain barrier Reversible and titratable Reduces HTT mRNA and protein in the CNS and periphery Uniform lowering in key regions of the brain Highly selective Not effluxed
Slide 52: Why is it Important to Reduce Efflux?
Why is it Important to Reduce Efflux? 52 • Reducing efflux has several advantages: − Balancing the extent of peripheral vs brain lowering is critical − Increases the therapeutic window versus non target-related splicing in the periphery − Stronger correlation between blood (peripheral) and brain low
Slide 53: PTC518 is Not Effluxed, Resulting in ~1:1 Brain and Blood Lowering
PTC518 is Not Effluxed Resulting In ~1:1 Brain and Blood Lowering Effect In BACHD Mice 53 Data on file PTC518 Effluxed Molecule Peripheral ≈ Brain Peripheral >> Brain Vehicle Brain WBC 0 20 40 60 80 100 120 Effluxed molecule % o f b a s e l i n e H T T p r o t e i n Vehicle Brain WBC 0 20 40 60 80 1
Slide 54: What are the Characteristics of PTC518?
What are the Characteristics of PTC518? 54 Orally bioavailable and penetrates blood brain barrier Reversible and titratable Reduces HTT mRNA and protein in the CNS and periphery Uniform lowering in key regions of the brain Highly selective Not effluxed
Slide 55: Agenda
PTC518 Huntington’s Disease Deep Dive Agenda 55 Preclinical Development of PTC518 Anu Bhattacharyya, Exec. Director, Biology PTC518 Huntington Deep Dive Splicing Platform and Huntington’s Disease Stuart Peltz, CEO PTC518 Phase 1 Study Matthew Klein, CDO
Slide 56: The Phase 1 Trial is a 4-Part Study
The Phase 1 Trial is a 4-Part Study 56 Phase 1 trial in healthy volunteers is ongoing Multiple ascending dose • Up to 5 cohorts of 8 healthy volunteers (6 active and 2 placebo) • Evaluate safety & tolerability; HTT mRNA splicing & protein lowering Food effect • Crossover design • Evaluate the effect
Slide 57: Phase 1 Objective: Establish Dose Dependent HTT Lowering
Phase 1 Objective: Establish Dose Dependent HTT Lowering Similar to the BACHD Mouse Data on file 57 120 100 80 60 40 20 0 Vehicle 1 3 7 21 63 HTT Protein Levels in Brain % of baseline H TT protein Dose (mg/kg)
Slide 58: SAD Study: Proof of Mechanism Demonstrated By Dose-Dependent HTT Splicing
58 SAD Study: Proof of Mechanism of PTC518 Demonstrated By Dose-Dependent HTT Splicing Placebo PTC518_45 m g PTC518_90 m g PTC518_135 m g 0 20 40 60 80 100 120 % o f b a s e l i n e H T T R N A ➢ Whole blood HTT splicing in humans ➢ Doses evaluated = 45 mg, 90 mg, and 135 mg ➢ Time – one day; single
Slide 59: SAD PK Demonstrates Dose Predictable Drug Exposure
SAD PK Demonstrates Dose Predictable Drug Exposure Data on file PTC518 -CNS- 001- HD 59 mg 135 90 45 15 5 PTC518 concentration (ng/mL) Time (hr)
Slide 60: Phase 1 SAD Interim Results Summary
Phase 1 SAD Interim Results Summary 60 Target splicing reduction achieved with single dose Well-tolerated with no safety-related findings Predictable pharmacology Dose-dependent splicing of HTT mRNA
Slide 61: MAD Study: Proof of Mechanism Confirmed By Dose-Dependent HTT Splicing
61 MAD Study: Proof of Mechanism of PTC518 Confirmed By Dose-Dependent HTT Splicing ➢ 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 Placebo PTC518_15 m g PTC518_30 m g 0 20 40 60 80 100 120 % o f b a
Slide 62: Durability of Response: Splicing Activity Persists Post Cessation
Durability of Response: Splicing Activity Persists 72 hrs Post Cessation 62 0 12 24 36 48 60 72 0 20 40 60 80 100 120 140 Time (hours following final dose) % o f b a s e l i n e H T T R N A Placebo PTC518_15 mg_QD14 PTC518_30 mg_QD14 HTT splicing monitored after the final dose at day 14 (calculated
Slide 63: Phase 1 MAD Interim Results Summary
Phase 1 MAD Interim Results Summary 63 Two cohorts completed; two to three additional planned Well-tolerated with no safety-related findings Dose dependent splicing of HTT mRNA Long-half life with maintenance of splicing up to 72 hours following last dose
Slide 64: Phase 1 Trial Next Steps
Phase 1 Trial Next Steps .. 64 1 Complete Additional MAD Cohorts 2 Complete CSF Cohort 3 Complete Food Effect Cohort 4 Finalize Clinical Development Plan
Slide 65: Defining Clinical Next Steps
Defining Clinical Next Steps 65 Natural History 1 Endpoints 2 Patient Population 3
Slide 66: Summary
Summary
Slide 67: Preclinical Studies Show PTC518 Has All the Characteristics of a Promising HD Therapeutic
Preclinical Studies Show PTC518 Has all the Characteristics Of a Promising HD Therapeutic .. 67 Orally bioavailable and penetrates blood brain barrier Reversible and titratable Reduces HTT mRNA and protein in the CNS and periphery Uniform lowering in key regions of the brain Highly selective Not eff
Slide 68: PTC518 Drug Development Objectives
PTC518 Drug Development Objectives 68 What is the Dose? 01 What is the Exposure? 02 What is the Level of HTT Reduction? 03 How to Demonstrate Clinical Benefit? 04
Slide 69: The Splicing Platform Has Proven to be a Robust Engine
Risdiplam PTC518 PTC-XXX 69 Molecules are designed to match a unique pre-mRNA/U1 interface and serve as molecular glue to help initiate splicing events Canonical duplex SMN2 HTT And the next one…. The Splicing Platform Has Proven to be a Robust Engine to Identify Development Candidates
Slide 70: Questions?
Questions? PTC)
PTC Therapeutics — Technical Presentation (April 2021) on 6ix