Ptc Therapeutics, Inc. · NASDAQ:PTCT
Ptc Therapeutics — Investor Day (December 2025)
113 slides from Ptc Therapeutics's investor day presentation, Dec 2, 2025
Slide 1: PTC R&D Day
PTC R&D Day December 2, 2025
Slide 2: R&D Day 2025 Agenda
R&D Day 2025 Agenda Welcome and Introduction Matthew Klein, MD Oral Small Molecule Splicing Platform: Overview & Programs Christopher Trotta, PhD Anu Bhattacharyya, PhD Splicing Q&A Inflammation & Ferroptosis Platform: Overview & Programs Jeff Trimmer, PhD Mayzie Johnston, PharmD Inflammation & Ferr
Slide 3: 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 presentation, other than statements of historic fact, are forward-looking statements, including statements reg
Slide 4: Oral Small Molecule Splicing Program Overview
Oral Small Molecule Splicing Program Overview 4 PTC Therapeutics
Slide 5: Central Dogma of Life: DNA to RNA to Protein
Central Dogma of Life: DNA to RNA to Protein DNA replication DNA DNA DNA Transcription DNA RNA RNA Translation RNA Protein protein 5 PTC Therapeutics
Slide 6: Splicing Enables Diversity of Protein Production from Limited Number of Genes
Splicing Enables Diversity of Protein Production from Limited Number of Genes 20,000 genes Richard Phillip Roberts Sharp 1993 1,000,000 proteins 6 PTC Therapeutics
Slide 7: Pre-mRNA Splicing is a Complex Process Rich in Potential Targets
Pre-mRNA Splicing is a Complex Process Rich in Potential Targets Splicing is a multi-step process using many RNA-enzyme interactions 7 PTC Therapeutics
Slide 8: Why Small Molecule (Oral) Splicing Molecules?
Why Small Molecule (Oral) Splicing Molecules? • Antisense oligonucleotides have historically been used to correct splicing abnormalities • Lack of oral bioavailability • Do not cross the blood-brain barrier • Require repeat intrathecal or intraparenchymal delivery yet incomplete brain distribution •
Slide 9: PTC Pioneered Small Molecule Splicing Therapies
PTC Pioneered Small Molecule Splicing Therapies votoplam (PTC518) Global leading spinal muscular atrophy Leading oral disease-modifying (SMA) therapy approved in therapy in development for > 100 countries Huntington’s disease Our two flagship splicing programs remain at the forefront of innovation f
Slide 10: Small Molecules Target U1-RNA Interaction to Affect mRNA Composition and Protein Expression
Small Molecules Target U1-RNA Interaction to Affect mRNA Composition and Protein Expression Strong Strong U1 U1 U1 U2 U2 U2 Spliceosome subunits that define U1 U2 splice sites in pre-mRNA 10 PTC Therapeutics
Slide 11: Small Molecule Enhancement of U1 Interaction Leads to Increased Inclusion of Exons
Small Molecule Enhancement of U1 Interaction Leads to Increased Inclusion of Exons Strong Strong U1 U1 U1 U2 U2 U2 Targeting must be highly SM specific for RNA sequence and binding site morphology Spliceosome subunits that define U1 U2 splice sites in pre-mRNA 11 PTC Therapeutics
Slide 12: Small Molecule Enhancement of U1 Interaction Leads to Increased Inclusion of Exons
Small Molecule Enhancement of U1 Interaction Leads to Increased Inclusion of Exons Strong Strong Strong U1 U1 U1 U2 U2 U2 SM Distinct mRNA transcripts are generated Exon inclusion leading to increase of functional SMN protein deficient in SMA votoplam Exon inclusion leading to decrease of mutant U1
Slide 13: Targeting Alternative Splicing of SMN2 Gene to Address SMA Pathology
Targeting Alternative Splicing of SMN2 Gene to Address SMA Pathology SMN1 SMN2 U1 6 7 8 6 7 8 C GA T GA mRNA 6 7 8 6 7 8 6 8 FL mRNA FL mRNA Δ7 mRNA Functional Functional Truncated unstable SMN protein SMN protein SMN protein Singh et al. Crit rev euk gene expr (2004) 13 PTC Therapeutics Cho and Dre
Slide 14: Targeting Alternative Splicing of SMN2 Gene to Address SMA Pathology
Targeting Alternative Splicing of SMN2 Gene to Address SMA Pathology SMN1 SMN2 U1 U1 6 7 8 6 7 8 C GA T GA Small molecule splicing modifiers increase production of SMN protein mRNA 6 7 8 6 7 8 6 8 FL mRNA FL mRNA Δ7 mRNA Functional Functional Truncated unstable SMN protein SMN protein SMN protein Si
Slide 15: Splicing Modulator Increases SMN Protein in Multiple Tissues
Splicing Modulator Increases SMN Protein in Multiple Tissues to Near or Above Heterozygous Levels Oral dosing for 10 days in mild SMA mouse model Brain Peripheral Blood Mononuclear Cells SEM SEM increase (±) SEM increase (±) SEM protein SMN protein protein SMN protein % increase %increase SMN SMN %
Slide 16: Novel Splicing Mechanism Leading to Degradation of Mutant HTT mRNA
Novel Splicing Mechanism Leading to Degradation of Mutant HTT mRNA to Decrease Toxic Protein Levels No compound Pseudoexon is not spliced in; full length HTT protein is produced With votoplam Pseudoexon is spliced in; Nonsense mutation leads to mRNA degradation 16 PTC Therapeutics
Slide 17: HD Splicing Small Molecules Demonstrate Broad Tissue Distribution in BACHD Mice
HD Splicing Small Molecules Demonstrate Broad Tissue Distribution in BACHD Mice Dose dependent HTT lowering in the Measurements demonstrate uniform HTT lowering across brain brain in BACHD mice regions with ~1:1 brain and blood concentrations Striatum Cortex 120 120 Brain % HTT Remaining % HTT Remai
Slide 18: PTC Leveraged SMA and HD Learnings to Build a Robust Discovery Platform
PTC has Leveraged the Learnings from SMA and HD Programs to Build a Robust Discovery Platform Including PTSeek Screening Technology Splicing Foundation Splicing Platform Splicing Future Database Screening tools 2005 2020 2025 and beyond SMA Huntington’s disease Library Neurodegenerative Diseases Onc
Slide 19: Oral Small Molecule Splicing Platform
Oral Small Molecule Splicing Platform Christopher Trotta, PhD Anu Bhattacharyya, PhD 19 PTC Therapeutics
Slide 20: Targeting RNA Significantly Increases Druggable Target Space
Targeting RNA Significantly Increases Druggable Target Space DNA PROTEIN Traditional small Pre-mRNA molecule targets • GPCRs • Enzymes Targeting RNA Splicing with small molecules has • Ion Channels significantly expanded the pool of therapeutic targets • Nuclear Receptors 10 - 15% are druggable with
Slide 21: PTC Has Pioneered Targeting RNA Splicing
PTC Has Pioneered Targeting RNA Splicing Huntingtin pre-mRNA 180,000 nucleotides, 67 exons, 66 introns pre-mRNA Splicing Huntingtin mRNA 13,000 nucleotides, 67 exons intron exon 21 PTC Therapeutics
Slide 22: Deep Understanding of Splicing Identified the Key Targetable Step
Deep Understanding of Splicing has Enabled Identification of the Key Targetable Step in Pre-mRNA Splicing Spliceosome 5’ Splice Site Recognition pre-mRNA (substrate) mRNA U1 (product) 5’SS 3’SS Recognition of a 5’ splice site by U1 snRNP is key step in The Spliceosome is a pre-mRNA engagement comple
Slide 23: U1 Binding to the 5' Splice Site is Mediated by a Stable RNA Duplex
U1 Binding to the 5’ Splice Site is Mediated by Formation of a Stable RNA duplex Canonical 5’ splice site 5’ Splice Site Recognition U1 U1 snRNA pre-mRNA 3’ U1 GUCCAΨΨCA 5’ intron 5’ exon 3’ CAGGUAAGU 5’ pre-mRNA intron exon Interaction between U1snRNA and the pre-mRNA at the 5’ splice site is media
Slide 24: U1 Binding to a Noncanonical 5' Splice Site Forms an Unstable Duplex
U1 Binding to the 5’ Splice Site of a Noncanonical 5’ Splice Site Forms an Unstable RNA Duplex Noncanonical 5’ splice site 5’ Splice Site Recognition U1 U1 snRNA pre-mRNA 3’ U1 C A Ψ Ψ C A 5’ intron 5’ exon 3’ G U A A G U 5’ pre-mRNA intron exon U1-pre-mRNA interactions that are non-complementary ar
Slide 25: Protein Enhancers Stabilize Structures at Noncanonical 5' Splice Sites
Protein Enhancers Stabilize the Structures Found at Noncanonical 5’ Splice Sites Noncanonical 5’ splice site 5’ Splice Site Recognition U1 pre-mRNA enhancers U1 G U C C A Ψ Ψ C A 5’ intron ENHANCER 5’ exon 3’ G G AG U A A G U 5’ pre-mRNA intron exon Enhancers strengthen the U1 interaction with non-c
Slide 26: SMA is Caused by a Noncanonical 5' Splice Site in SMN2 Pre-mRNA
Spinal Muscular Atrophy is Caused by a Noncanonical 5’ Splice Site in the SMN2 Pre-mRNA SMN1 Activation SMN2 ESE pre-mRNA 6 7 8 6 7 8 C GA U GA FL mRNA FL mRNA Δ7 mRNA mRNA 6 7 8 6 7 8 6 8 SMA patients lack SMN1 Functional SMN Functional SMN Truncated unstable protein protein SMN protein 26 PTC Ther
Slide 27: PTC's Discovery of a Small Molecule 5' Splice Site Enhancer
PTC’s Discovery of a Small Molecule 5’ Splice Site Enhancer Established a New Small Molecule Therapeutic Modality SMN1 Activation SMN2 Small molecule splicing enhancer ESE pre-mRNA 6 7 8 6 7 8 C GA U GA FL mRNA FL mRNA Δ7 mRNA mRNA 6 7 8 6 7 8 6 8 SMA patients lack SMN1 Functional SMN Functional SMN
Slide 28: Evrysdi is the First Small Molecule Splicing Modulator for SMA
Evrysdi is the First Small Molecule Splicing Modulator for the Treatment of SMA Evrysdi functions as a sequence specific splicing enhancer U1 3’ G G U C C A Ψ Ψ C A 5’ 3’ A G G A G U A A G 5’ 28 PTC Therapeutics
Slide 29: PTC's Discovery of Votoplam for Huntington's Disease
PTC’s Discovery of Votoplam, the Second Small Molecule Splicing Modulator, which is Being Advanced to Treat Huntington’s Disease HTT pre-mRNA 1 49 50 67 CAGCAGCAG Normal Splicing HTT mRNA CAGCAGCAG Translation Toxic HTT protein QQQQQQQQQ 29 PTC Therapeutics
Slide 30: PTC's Discovery of Votoplam for Huntington's Disease
PTC’s Discovery of Votoplam, the Second Small Molecule Splicing Modulator, which is Being Advanced to Treat Huntington’s Disease Votoplam (PTC518) HTT pre-mRNA 1 49 49a 50 67 CAGCAGCAG Normal Splicing STOP Votoplam successfully HTT mRNA demonstrated HTT reduction in HD patients CAGCAGCAG CAGCAGCAG i
Slide 31: PTC's Splicing Enhancers are Sequence Specific and Target Selective
PTC’s Small Molecule Splicing Enhancers are Sequence Specific and Target Selective U1 Sequence splicing enhancer 3’ G G U C C A Ψ Ψ C A 5’ 3’ Exon 7 A G G A G U A A G U Functional SMN protein 5’ Sequence splicing U1 enhancer 3’ G G U C C A Ψ Ψ C A Votoplam 5’ (PTC518) 3’ Exon 49a QQQQQQQQQ C A G A G
Slide 32: PTC has Discovered the Next Generation of Novel Splicing Therapies
PTC has Discovered the Next Generation of Novel Splicing Therapies 5′ Exon NNNNGU 3′ SMN 256 potential HTT targetable sequences • How many and in what genes do iExons exist? • Can we systematically discover distinct small molecule splicing enhancers for each of the sequence found at the 5’ splice si
Slide 33: PTC Discovered iExons Throughout the Entire Transcriptome
PTC Discovered iExons Throughout the Entire Transcriptome U1 3’ Genome-wide evaluation C A ΨΨ C A U1 variant induced 5′ 3’ 5’ iExon GUAAGN iExons exist for all 256 sequences covering a majority of genes 33 PTC Therapeutics
Slide 34: Targeting the Splicing of iExons to Identify Novel Small Molecule Enhancers
Targeting the Splicing of iExons to Identify Novel Small Molecule Enhancers 3’ G G U C C A Ψ Ψ C 5’ Risdiplam induced 3’ 5’ Exon 7 A G G A G U A A G Can we leverage our knowledge of small molecule splicing modulation of risdiplam and votoplam to systematically 3’ G G U C C A Ψ Ψ C target iExons to r
Slide 35: PTC Leveraged Insights from SMA and HD to Develop PTSeek
PTC has Leveraged Insights from the SMA and HD Programs to Develop PTSeek 2005 2020 2022 2025 Splicing Foundation Splicing Platform Targeted High Throughput Transcriptome-wide Direct Screening Splicing Interrogation SMA Huntington’s Disease Screening Tools PTC’s proprietary splicing library Informat
Slide 36: PTSeek Led to Discovery of Novel Sequence Selective Splice Site Enhancers
PTSeek has Led to Discovery of Novel Sequence Selective 5’ Splice Site Enhancers for iExons Distinct from the SMA and HD Space PTSeekTM platform has identified: SMN HTT • Numerous novel chemical scaffolds with distinct Structure-Sequence-Relationship (SSR) 36 PTC Therapeutics
Slide 37: PTSeek Discovered Molecules that Induce iExon Inclusion
PTSeek Discovered Molecules that Induce iExon Inclusion in Targets Associated with a Broad Range of Therapeutic Indications PTSeekTM platform has identified: SMN HTT • Numerous novel chemical scaffolds with distinct Structure-Sequence-Relationship (SSR) • Numerous targetable iExons within therapeuti
Slide 38: PTSeek Enables Rapid Identification of High-Quality Hits
PTSeek Enables Rapid Identification of High-Quality Hits Leading to Accelerated Preclinical Development Timelines SMA Hit Early Lead Lead Op EC50 >1 μM EC50 = 44 nM EC50 = 29 nM Time Historical timeline Hit ID/validation Lead optimization DC timeline DC Target A Hit Early Lead Lead Op EC50 >1 μM EC5
Slide 39: PTC's Innovative Advantage in Splicing Modulation
PTC’s Innovative Advantage in Splicing Modulation is Delivering on the Promise of Targeting Splicing to Develop Novel Therapeutics 2005 2020 2022 2025 and beyond Splicing Foundation Splicing Platform Targeted High Throughput Transcriptome-wide Direct Novel molecules for targets in multiple Screening
Slide 40: Oral Small Molecule Splicing Programs
Oral Small Molecule Splicing Programs Anu Bhattacharyya, PhD 40 PTC Therapeutics
Slide 41: Select Splicing Platform Programs
Select Splicing Platform Programs TARGET INDICATION(S) Late Stage MSH3 Huntington’s Disease, Myotonic Dystrophy I ATXN3 Spinocerebellar Ataxia 3 Undisclosed Brain Tumors & Metastases Early Stage Undisclosed Sickle Cell Disease, -Thalassemia Undisclosed Neurodegenerative Diseases 41 PTC Therapeutics
Slide 42: MSH3 Program: Targeting Nucleotide Repeat Disorders
MSH3 Program: Targeting Nucleotide Repeat Disorders Patient living with HD 42 PTC Therapeutics
Slide 43: Nucleotide Repeat Disorders – Disease Onset and Progression and Somatic Expansion
Nucleotide Repeat Disorders (NRDs) – Disease Onset and Progression Associated with Rate of Somatic Expansion No Evidence Disease Inherited Repeats of Disease Onset/Progression Huntington’s Disease Gene Myotonic Dystrophy 1 Repeats expand over time 43 PTC Therapeutics
Slide 44: PTC's Splicing Technology Targets Key Proteins Driving Somatic Expansion
PTC’s Splicing Technology Targets Key Proteins Driving Somatic Expansion Disease Inherited Repeats Onset/Progression Gene Somatic Expansion The more rapid the expansion rate, the earlier disease onset and faster disease progression The rate of somatic expansion is primarily driven by a family of pro
Slide 45: PTC's Splicing Technology Targets Key Proteins Driving Somatic Expansion
PTC’s Splicing Technology Targets Key Proteins Driving Somatic Expansion Disease Inherited Repeats Onset/Progression Gene Somatic Expansion PTC MMR Protein Lowering Delayed disease onset & slower progression 45 PTC Therapeutics
Slide 46: MSH3 has Emerged as a Promising Therapeutic Target
MSH3 has Emerged as a Promising Therapeutic Target 46 PTC Therapeutics
Slide 47: Linear Correlation Between MSH3 Reduction and HD Progression
Clear Linear Correlation Between Magnitude of MSH3 Reduction and HD Progression in Patients 60 VARIATION IN DELAY IN AGE Reduction in MSH3 Expression (%) MSH3 MSH3 GENE AT MOTOR PROTEIN E233 IY461-462 (HD PATIENTS)* ONSET (YEARS) 50 3a -17% 1.05 40 30 5AM2 5AM2 -30% 6.1 3a 20 E233 IY461-462 -50% 10.
Slide 48: Novel Splicing Modulators that Lower MSH3 mRNA and Protein
PTC Identified a Novel Class of Splicing Modulators that Lower MSH3 mRNA and Protein Levels MSH3 lowering by oral splicing modulators Novel splicing modulators selectively induce Exon Exon Exon MSH3 mRNA decay Novel Splicing molecules STOP SMN HTT NMD MSH3 mRNA decay Reduction of MSH3 protein leve
Slide 49: PTC Compounds Optimized for Activity, Selectivity, and Drug-like Properties
PTC Compounds Optimized for Activity, Selectivity, and Drug-like Properties In vitro In vivo Expansion model % repeat expansion 119 HTT Exon1 CAG Human somatic expansion model MSH3 lowering • Highly potent and selective • Dose-dependent lowering of MSH3 mRNA and protein levels • Uniform distribution
Slide 50: MSH3 Program Status
MSH3 Program Status • Novel class of small molecule splicing modulators identified and optimized • In vitro and in vivo proof of concept MSH3 lowering validated • Plan to select clinical candidate in early 2026 • Phase 1 ready expected late 2026 50 PTC Therapeutics
Slide 51: Spinocerebellar Ataxia (SCA3) Program
Spinocerebellar Ataxia 3 (SCA3) Program 51 PTC Therapeutics
Slide 52: Spinocerebellar Ataxia – a Progressive and Devastating Neurodegenerative Disease
Spinocerebellar Ataxia 3 – a Progressive and Devastating Neurodegenerative Disease Most common autosomal dominant ataxia • Spinocerebellar Ataxia 3 (SCA3) is an inherited ~3.5K Patients (US) monogenic disorder • Neurodegenerative disease – cerebellum, brainstem, and ~2K Patients (Japan) spinal cord
Slide 53: Therapeutic Strategy Directed Towards Lowering Disease-Causing Protein
Therapeutic Strategy Directed Towards Lowering Production of Disease-Causing Protein • Mutant ATXN3 is the primary toxicity driver of SCA3 Mutant ATXN3 3 4 5 6 noncanonical Pre-mRNA Splicing 3 4 5 6 mRNA Translation Toxic mutant ATXN3 protein 53 PTC Therapeutics
Slide 54: Therapeutic Strategy Directed Towards Lowering Disease-Causing Protein
Therapeutic Strategy Directed Towards Lowering Production of Disease-Causing Protein • Mutant ATXN3 is the primary toxicity driver of SCA3 • Splicing modulators lower mutant ATXN3 protein by inducing a skipping event Mutant ATXN3 Mutant ATXN3 3 4 5 6 3 4 5 6 noncanonical Pre-mRNA noncanonical Pre-mR
Slide 55: Lead Compound Optimized for Activity, Selectivity, and Drug-like Properties
Lead Compound Optimized for Activity, Selectivity, and Drug-like Properties In vitro In vivo • Highly potent and dose-dependent lowering of ATXN3 levels • Uniform distribution in both the central nervous system and peripheral organs 55 PTC Therapeutics
Slide 56: SCA3 Program Status
SCA3 Program Status • Lead selected from a novel class of small molecule splicing modulators • Demonstrated lowering of ATXN3 mRNA and protein levels in vitro and in vivo • Plan to select clinical candidate in early 2026 • Phase 1 ready expected late 2026 56 PTC Therapeutics
Slide 57: Brain Tumors and Metastases
Brain Tumors and Metastases 57 PTC Therapeutics
Slide 58: Targeted Enhancing of T-cell Function and Anti-tumor Immunity in Solid Tumors
Targeted Enhancing of T-cell Function and Anti-tumor Immunity in Solid Tumors Synergistically • Target for cancer immunotherapy PD-1/PD-L1 Target protein lowering blockade • Works synergistically with immune Immunity Apoptosis checkpoint inhibitors to target Induction activation solid tumors and add
Slide 59: Therapeutic Strategy Targets Production of Key Protein in Cancer Biology
Therapeutic Strategy Targets Production of Key Protein in Cancer Biology Target lowering by oral splicing modulators Novel splicing modulators selectively induce Exon Exon Exon mRNA decay Novel Splicing molecules STOP SMN ONCOLOGY HTT TARGET NMD mRNA decay Reduction of protein levels 59 PTC Therap
Slide 60: PTC Compounds Lower mRNA and Protein Levels and Activate T-Cell Function
PTC Compounds Lower mRNA and Protein Levels and Activate T-Cell Function In vitro In vivo • Highly potent and dose-dependent lowering of target levels • Robust functional validation – activates T-cells • Molecules optimized for brain penetration 60 PTC Therapeutics
Slide 61: Oncology Program Status
Oncology Program Status • Novel class of small molecule splicing modulators identified • Lead molecules reduce levels of targeted protein and activate T-cell function • Assessment of synergy with anti-checkpoint inhibitors in progress • Clinical candidate selection planned for early 2026 61 PTC Ther
Slide 62: Hemoglobinopathies Program
Hemoglobinopathies Program 62 PTC Therapeutics
Slide 63: Therapeutic Strategy: Induction of Fetal Hemoglobin (HbF)
Therapeutic Strategy to Target -Hemoglobinopathies – Induction of Fetal Hemoglobin (HbF) Sickle Cell Disease (SCD) -thalassemia • Well-validated therapeutic strategy • Severity is ameliorated by increase in fetal hemoglobin (HbF) levels • Leverage PTSeek to find molecules that target regulators of
Slide 64: Therapeutic Strategy Directed Towards Lowering Key Inhibitor of HbF
Therapeutic Strategy Directed Towards Lowering Key Inhibitor of HbF Protein Production Target lowering by oral splicing modulators Novel splicing modulators selectively induce Exon Exon Exon mRNA decay Novel Splicing molecules STOP SMN HTT NMD mRNA decay Reduction of target protein levels increase
Slide 65: Lowering Key Inhibitor of HbF Protein Production
Therapeutic Strategy Directed Towards Lowering Key Inhibitor of HbF Protein Production Target Knockdown HbF Induction % Baseline of Target Clinical effect threshold • Novel splicing modulators lowered a validated target of HbF induction • Lowering of target resulted in HbF induction in the therapeut
Slide 66: Undisclosed Target: Neurodegenerative Disease Pathology
Undisclosed Target: Targeting a Key and Common Aspect of Neurodegenerative Disease Pathology 66 PTC Therapeutics
Slide 67: Targeting a Common Pathway in Neurodegenerative Diseases
Therapeutic Strategy Directed Towards Targeting a Common Pathway in Neurodegenerative Diseases • Accumulation of protein aggregates is a common feature of many neurodegenerative diseases including PD, AD, and ALS • Leveraging PTSeek to identify novel splicing modulators that can mitigate the neurona
Slide 68: PTC Compounds Target a Key Protein in Neurodegenerative Diseases
PTC Compounds Target a Key Protein in Neurodegenerative Diseases 100% RNA Splicing Change Protein Change % Change Target Modulation 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Compound (μM) Compound (μM) 0% • Novel splicing modulators with good activity and selectivity identified • Target modulation observe
Slide 69: Summary: PTC Well Positioned to Lead Small Molecule Splicing
Summary: PTC Well Positioned to Continue to Lead the Field of Small Molecule Splicing Our innovative splicing platform is unlocking a previously unknown RNA target space cementing Votoplam PTC as the industry leader (PTC518) in delivering novel RNA small molecule therapies Groundbreaking work to dev
Slide 70: Splicing Q&A
Splicing Q&A 70 PTC Therapeutics
Slide 71: Inflammation and Ferroptosis
Inflammation and Ferroptosis Jeff Trimmer, PhD Mayzie Johnston, PharmD 71 PTC Therapeutics
Slide 72: Inflammation & Ferroptosis Platform Overview
Inflammation & Ferroptosis Platform Overview • Targeting specialized enzyme hubs that act as essential regulators of biological functions, such as inflammation, energy production and oxidative stress • Leverage PTC’s unique small molecule library to deliver differentiated or first-in- class therapie
Slide 73: Summary of Inflammation Platform Programs
Summary of Inflammation Platform Programs TARGET INDICATION(S) Pre-Clinical 15-LO Parkinson’s Disease NRF2 CNS, non-CNS IND Enabling/Clinical NLRP3 Inflammatory Lung Diseases DHODH T-Cell Mediated Autoimmune Diseases 73 PTC Therapeutics
Slide 74: Parkinson's Disease Program
Parkinson’s Disease Program 74 PTC Therapeutics
Slide 75: Ferroptosis is Key Pathway in Parkinson's Disease
Ferroptosis is Key Pathway in Parkinson’s Disease • Ferroptosis is a newly identified form of programmed cell death characterized by oxidative stress, iron accumulation, and formation of highly reactive lipid peroxides • Together these processes elicit oxidative damage, cell membrane disruption, act
Slide 76: Growing Body of Evidence Linking Ferroptosis and Parkinson's Disease
Growing Body of Evidence Linking Ferroptosis and Parkinson’s Disease 76 PTC Therapeutics
Slide 77: Ferroptosis Linked to Several Key Aspects of Parkinson's Disease
Ferroptosis Linked to Several Key Aspects of Parkinson’s Disease 77 PTC Therapeutics Zhou et al., Int J Mol Sci. 2024 Dec 4;25(23):13042. PMID: 39684753, PMCID: PMC11641825
Slide 78: Targeting 15-LO & Ferroptosis Addresses Four Fundamental Parkinson's Processes
Targeting 15-LO & Ferroptosis Addresses Four Fundamental Parkinson’s Disease Processes Neuronal Cell Microglial Cell Activation: Prevent activation of Death 4 1 proinflammatory astrocytes and glial cells to mitigate neuroinflammation 2 Lewy Body Formation: Block α-synuclein Microglial Cell 3 Glutath
Slide 79: PTC Compounds Prevent Activation of Proinflammatory Cells (in vitro)
PTC Compounds Prevent Activation of Proinflammatory Cells to Mitigate Neuroinflammation (in vitro) Astrocytes 2.0 * • Astrocytes and glial cells activated by Control Astrocyte Activation# introducing a ferroptosis challenge 1.5 • Addition of PTC compound inhibits 1.0 ferroptosis-induced activation o
Slide 80: PTC Compounds Block α-Synuclein Phosphorylation and Aggregation (in vitro)
PTC Compounds Block α-Synuclein Phosphorylation and Aggregation (in vitro) Neuronal cells expressing α- * synuclein -Synuclein Aggregation# • α-Synuclein phosphorylation and Control aggregation occurs following ferroptosis challenge and activation of astrocytes and glial cells Vehicle • Addition of
Slide 81: PTC Compounds Prevent Protein Degradation in Critical Neuronal Pathways (in vivo)
PTC Compounds Prevent Protein Degradation in Critical Neuronal Pathways (in vivo) • Human α-synuclein expressing Parkinson’s Disease mouse model (Line 61 mouse) • PTC compounds dose-dependently restore structural and functional brain proteins in critical pathways Neuronal Structure Synaptic Plastici
Slide 82: PTC Compound Protects Locomotor Function in 6-OHDA Parkinson's Model
PTC Compound Protects Locomotor Function in 6-OHDA Parkinson’s Disease Model Vehicle Treated 82 PTC Therapeutics
Slide 83: PTC Compound Protects Locomotor Function in 6-OHDA Parkinson's Model
PTC Compound Protects Locomotor Function in 6-OHDA Parkinson’s Disease Model Vehicle Treated 83 PTC Therapeutics
Slide 84: Parkinson's Disease Program Status
Parkinson’s Disease Program Status • In vitro & in vivo POC established across several Parkinson’s disease models • Plan to select Development Candidate in Q1 2026 • Phase 1 initiation planned for H2 2026 • Translational biomarker program initiated to facilitate and accelerate clinical program 84 PT
Slide 85: NRF2 Activation Program
NRF2 Activation Program 85 PTC Therapeutics
Slide 86: NRF2 Program Leverages a Novel Mechanism for Greater Anti-inflammatory Effects
NRF2 Program Leverages a Novel Mechanism to Provide Greater Anti-inflammatory Effects • NRF2 is an intrinsic transcription factor that regulates cellular inflammation and stress response • Program features differentiated mechanism of activation with enhanced selectivity and comprehensive NRF2 activa
Slide 87: PTC Compounds Distinctly Modulate Inflammation Pathways Across Cell Types
PTC Compounds Distinctly Modulate Inflammation Pathways Across a Range of Cell Types (in vitro) Cell Type Cytokine PTC-XXX Omav* Cell Type Cytokine PTC-XXX Omav* IFNy + – ALS TNF + – Human IL4 + – PBMCs MCP1 + – Human Human IL10 + – Microglia MHCII + – Astrocytes Human T- IL-6 + – cells IL2 + – C3 +
Slide 88: PTC Compounds Uniquely Modulate Inflammation Pathways Compared to Omaveloxolone
PTC Compounds Uniquely Modulate Inflammation Pathways Compared to Omaveloxolone (in vitro) NRF2 Pathway Anti-Inflammatory Pro-Inflammatory (10 proteins) (12 proteins) (12 proteins) * 0.5 0.6 0.4 Fold Change Fold Change Fold Change 0.4 0.3 0.2 0.2 0.1 0.0 0.0 * XX XX av av XX av m m m -X -X -X O O O
Slide 89: PTC Compounds Protect in Relapsing Remitting MS Mouse Model
PTC Compounds Provide Significant Protection in Relapsing Remitting MS Mouse Model Prophylactic Dosing Vehicle 2 Omaveloxelone (30 mg/kg) Clinical Score PTC-XXX NfL pg/mL 1 0 5 10 15 20 Days of Treatment • PTC-compound administration protects when given before or after onset of disease presentation
Slide 90: PTC Compounds Protect in Relapsing Remitting MS Mouse Model
PTC Compounds Provide Significant Protection in Relapsing Remitting MS Mouse Model Prophylactic Dosing Therapeutic Dosing Vehicle 2 Omaveloxelone (30 mg/kg) Clinical Score Clinical Score PTC-XXX NfL pg/mL PTC-compound 1 dosing initiated 0 5 10 15 20 Days of Treatment • PTC-compound administration pr
Slide 91: PTC Compounds Protect in Mouse Kidney Injury Model
PTC Compounds Provide Significant Protection in Mouse Kidney Injury Model * * • Renal inflammation model induces 240 * structural damage and fibrosis Body Weight Change (%) 160 BUN/CRE • PTC compounds preserve kidney function and reverse weight loss 80 • Bardoxolone (a non-selective 0 l XX e ne XX l
Slide 92: PTC Compounds Protect in Pulmonary Fibrosis Mouse Model
PTC Compounds Provide Significant Protection in Pulmonary Fibrosis Mouse Model * * * * • Pulmonary fibrosis model induces 2.4 1250 structural damage and fibrosis 2.0 1000 Relative Lung Weight • PTC compounds preserve lung Hydroxyproline 1.6 750 morphology and prevent fibrosis 1.2 500 • Supports NRF2
Slide 93: NRF2 Program Status
NRF2 Program Status • Novel class of NRF2 activator small molecules identified and optimized • Demonstrated competitive differentiation compared to existing NRF2 activators • Expect Development Candidate nomination in 2026 • Indication selection work ongoing 93 PTC Therapeutics
Slide 94: PTC612 NLRP3 Inhibition Program
PTC612 NLRP3 Inhibition Program Mayzie Johnston, PharmD 94 PTC Therapeutics
Slide 95: NLRP3 - A Key Signaling Protein in the Innate Immune System
NLRP3 - A Key Signaling Protein in the Innate Immune System • NLRP3 is an Intracellular sensor protein in macrophages and other immune cells • Detects infection, stress or tissue damage • Upon detection, NLRP3 is activated triggering the assembly and activation of the NLRP3 inflammasome leading to e
Slide 96: PTC612 is a Highly Potent & Selective NLRP3 Inhibitor
PTC612 is a Highly Potent & Selective NLRP3 Inhibitor • Novel chemistry and favorable drug properties compared to other NLRP3 inhibitors leading to potential better safety and tolerability profile • Demonstrates greater potency and selectivity for NLRP3 than many other NLRP3 inhibitors in developmen
Slide 97: PTC612 Inhibits IL-1 Secretion in Multiple Cellular Models
PTC612 Inhibits IL-1 Secretion in Multiple Cellular Models (in vitro) THP-1 hMDM Human Whole Blood IC50 0.99nM IC50 1.799nM IC50 9.7nM PTC612 (nM) PTC612 (nM) PTC612 (nM) THP-1: Myeloid tumor cell line hMDM: Human monocyte derived macrophages 97 PTC Therapeutics
Slide 98: PTC612 Has Greater Potency Compared to Other NLRP3 Inhibitors
PTC612 Has Greater Potency Compared to Other NLRP3 Inhibitors Compound PTC612 Selnoflast1 DFV8902 Usnoflast3 AZD41444 THP-1 0.99 220 13 13 23-82 IL1β IC50 (nM) Compound PTC612 Vent-015 DFV8902 VTX-32326 VTX-27356 hWB 9.7 124 180 13 80 IL1β IC50 (nM) 1. In house data; 2. JMC 2025; 3. Brain Res 2024;
Slide 99: PTC612 Dose-Dependent Effect on Fibrosis in Murine IPF Model
PTC612 Demonstrates Dose-Dependent Effect on Fibrosis in Murine IPF Model (in vivo) Prophylactic Model Therapeutic Model ****p < 0.0001 ****p < 0.0001 Treatment initiated on Day -1 Treatment initiated on Day 7 99 PTC Therapeutics
Slide 100: PTC612 Summary and Program Status
PTC612 Summary and Program Status • PTC612 is a highly selective NLRP3 inhibitor demonstrating significant reduction in inflammatory cytokines and pathology across multiple preclinical models • PTC612 IND enabling studies ongoing • Phase 1 study initiation planned for H1 2026 • Finalizing pulmonary
Slide 101: PTC844 DHODH Inhibition Program
PTC844 DHODH Inhibition Program Mayzie Johnston, PharmD 101 PTC Therapeutics
Slide 102: DHODH is a Key Regulator of T Cell Mediated Inflammation
DHODH is a Key Regulator of T Cell Mediated Inflammation • DHODH plays critical role in inflammation by regulating the proliferation of immune cells and modulating cytokine production • Inhibition starves activated T cells by depleting pyrimidine nucleotides • Marketed DHODH inhibitors have limitati
Slide 103: PTC844 Suppresses Proliferation of Activated T Cells
PTC844 Suppresses Proliferation of Activated T Cells Cytokine T Cell Activation Clonal Expansion Differentiation Production T Cells Th1 DHODH Inhibition PTC844 Th17 103 PTC Therapeutics
Slide 104: PTC844 Demonstrates Superior Potency Compared to Other DHODH Inhibitors
PTC844 Demonstrates Superior Potency Compared to Other DHODH Inhibitors PTC844 Vidofludimus Teriflunomide IC50=1nM IC50~5000nM IC50>10,000nM 104 PTC Therapeutics
Slide 105: PTC844 Demonstrates Superior Selectivity Compared to Other DHODH Inhibitors
PTC844 Demonstrates Superior Selectivity Compared to Other DHODH Inhibitors PTC844 Vidofludimus Teriflunomide IC50=1nM IC50~5000nM IC50>10,000nM 105 PTC Therapeutics
Slide 106: PTC844 Potently Inhibits Proinflammatory Cytokine IL-17 in Human Cells
PTC844 Potently Inhibits the Proinflammatory Cytokine IL-17 in Human Cells (in vitro) Human PBMCs IL-17A (CD3/CD28+ IL-2) Human PBMCs IL-17F (CD3/CD28+ IL-2) 106 PTC Therapeutics
Slide 107: PTC844 Efficacy in Murine Multiple Sclerosis Model
PTC844 Demonstrates Significant Efficacy in Murine Multiple Sclerosis Model (in vivo) Myelin Oligodendrocyte Glycoprotein (MOG) Proteolipid Protein (PLP) 107 PTC Therapeutics *PTC844 analog for murine model
Slide 108: PTC844 Efficacy in Antigen Induced Model of Rheumatoid Arthritis
PTC844 Demonstrates Efficacy in an Antigen Induced Model of Rheumatoid Arthritis (in vivo) Knee, Change in Diameter Knee, % Change in Diameter, Day 40 PTC844 was comparable to methotrexate in reducing knee inflammation after antigen challenge 108 PTC Therapeutics
Slide 109: Phase 1 Study Demonstrates Consistent Pharmacology and Favorable Safety
Phase 1 Study Demonstrates Consistent Pharmacology, Favorable Safety Profile and Proof of Mechanism of Action Single Ascending Dose (SAD) Multiple Ascending Dose (MAD) DHO* AUC SAD PK AUC (Day 1) DHO* AUC (Day1) PK AUC (Day 14) Dose (Day 14) Doses (hr*ng/ml) (hr*ng/ml) (hr*ng/ml) (hr*ng/ml) 1.5 mg 1
Slide 110: PTC844 Program Status
PTC844 Program Status • PTC844 demonstrated safety in GLP toxicology studies • SAD/MAD completed • Food Effect study ongoing • Finalizing indication selection • Expect to initiate Phase 2A PK/PD study in mid-2026 110 PTC Therapeutics
Slide 111: Summary of Inflammation Platform Programs
Summary of Inflammation Platform Programs • 15-Lipoxygenase inhibition: Prevention of ferroptosis-mediated cell death and alpha-synuclein aggregation to deliver a disease modifying treatment for Parkinson’s disease • NRF2 activation: Activate NRF2 to mitigate oxidative stress and inflammation for CN
Slide 112: Inflammation and Ferroptosis Q&A
Inflammation and Ferroptosis Q&A 112 PTC Therapeutics
Slide 113: Questions and Closing Remarks
Questions and Closing Remarks 113 PTC Therapeutics