Atyr Pharma, Inc. · NASDAQ:ATYR
Atyr Pharma — Technical Presentation (December 2016)
49 slides from Atyr Pharma's technical presentation, Dec 13, 2016
Slide 1: New Hope For Patients with Rare Myopathies Characterized by an Immune Component
New Hope For Patients with Rare Myopathies Characterized by an Immune Component John Mendlein, PhD, CEO of aTyr Pharma Sanjay Shukla, MD, MS, CMO of aTyr Pharma Sanuj Ravindran, MD, CBO of aTyr Pharma Guest: John Vissing, MD, Professor of Neurology at University of Copenhagen, Denmark Principal Inve
Slide 2: Forward-Looking Statements
Forward-Looking Statements The following slides and any accompanying oral presentation contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as “may,” “might,” “will,” “should,” “expect,”
Slide 3: Our Agenda
Our Agenda: 8:30am – 9:30am (EST) Resolaris: Derived from the Resokine Pathway John Mendlein, PhD Chief Executive Officer at aTyr Pharma Potential Therapeutic Approaches to Rare Myopathies with an Immune Component John Vissing, MD Professor of Neurology at the University of Copenhagen, Denmark Resol
Slide 4: Resolaris: Derived From the Resokine Pathway
Resolaris: Derived From the Resokine Pathway John Mendlein, PhD, CEO December 13, 2016
Slide 5: Rare Myopathies with an Immune Component
Rare Myopathies with an Immune Component Chronic damage, homeostasis disrupted RMICs Genetic Mutation Aberrant expression of multiple proteins in muscle Aberrant dysferlin proteins Aberrant dystrophin proteins Facioscapulohumeral Muscular Dystrophy (FSHD) Limb Girdle Muscular Dystrophy 2B (LGMD2B) D
Slide 6: Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy
Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and Glucocorticoid Treatment Effect Reference Flanigan et al, Human Gene Therapy, 2013
Slide 7: Connecting Genotype to Immune Cell Phenotype in DMD Patients
Connecting Genotype to Immune Cell Phenotype in Duchenne Muscular Dystrophy Patients Genetic Mutation Locations of Immune Response: Exons 1 – 9 Exons 17 – 26 Exons 42 – 50 Exons 50 – 59 Exons 59 – 69 Exons 70 - 79 DMD Patients: Splice exon 12 Del ex 45 Del ex 46 – 50 Del ex 49 – 54 Nonsense ex 59 No
Slide 8: Resokine Pathway Paradigm
Resokine Pathway Paradigm Directed at activated, local T cells in RMIC patient muscle 1st Physiocrine Based Product Candidate An extracellular homeostatic pathway that sets T cell responses as an agonist Arising from histidine aminoacyl tRNA synthetase (HARS) gene Pathway insufficiency leads to inap
Slide 9: IGF-1 Increases Resokine Release From Myoblasts
IGF-1 Increases Resokine Release From Myoblasts Differentiating to Myotubes Linking the Resokine pathway to muscle biology Antibodies sufficient to block 100pM Resokine block >50% of differentiation & growth (slower) IGF-1 Positive Impact Human Cells Human myoblasts were isolated from a healthy volu
Slide 10: Deflazacort Inhibits Muscle Growth and Resokine Release
Deflazacort Inhibits Muscle Growth and Resokine Release Steroid use to treat RMIC patients Myotube (myosin)/Nuclei (Hoechst), Images at 100× magnification; Differentiation Day 0-5 21-Desacetyl-Deflazacort (nM) Untreated Vehicle MeOH 1 10 0.1 100 Deflazacort Negative Impact Human cells *p<0.05, **p<0
Slide 11: Muscle Franchise Strategy: Looking Into The Future
Genetic Modifiers Resolaris: Naturally designed homeostatic protein Single agent, multiple diseases Potentially helpful with other MOAs Aberrant protein expression from aberrant genetics Phenotype dysfunction: Muscle degeneration/regeneration Immune dysregulation Fibrosis Muscle Franchise Strategy:
Slide 12: John Vissing, MD
John Vissing, MD Professional: Professor of Neurology at the University of Copenhagen, Denmark Director of the Neuromuscular Clinic & Research Unit at National Hospital, Rigshospitalet Disease Focus: Facioscapulohumeral muscular dystrophy, Kennedy disease, Becker muscular dystrophy, different forms
Slide 13: Potential Therapeutic Approaches to Rare Myopathies With an Immune Component
Potential Therapeutic Approaches to Rare Myopathies With an Immune Component John Vissing, MD, Professor of Neurology at University of Copenhagen, Denmark Principal Investigator for aTyr Pharma’s 004 Trial December 13, 2016
Slide 14: FSHD and LGMD2B
Facioscapulohumeral Muscular Dystrophy (FSHD) and Limb-Girdle Muscular Dystrophy 2B (LGMD2B) FSHD LGMD2B Genetics Immune Pathology Clinical Standard of Care Disease Progression Toxic gain of function (DUX4 region) Immune infiltration by activated T cells1 (primarily CD8+) Loss of function mutations
Slide 15: LGMD2B Disease Progression Case History
LGMD2B Disease Progression Case History Difficulty rising from a chair, raising hands above head Uses a cane and leg braces Walks normally, active childhood Abnormal gait Knees locked Difficulty climbing stairs and running Age <15 16 – 18 19 – 27 28 - 34 https://www.youtube.com/watch?v=JLqHis1yPUI h
Slide 16: T Cell Involvement in the Pathophysiology of RMICs
T Cell Involvement in the Pathophysiology of RMICs (For example: FSHD, LGMD2B, DMD) Gallardo et al. Inflammation in dysferlin myopathy: Immunohistochemical characterization of 13 patients. Neurol. 2001;57:2136–2138 Yin et al. CD4+ cells, macrophages, MHC-I and C5b-9 involve the pathogenesis of dysfe
Slide 17: Treatment of Dysferlinopathy with Deflazacort
Treatment of Dysferlinopathy with Deflazacort: A Double-Blind, Placebo-Controlled Clinical Trial Reference Walter et al, Orphanet Journal of Rare Diseases, 2013
Slide 18: LGMD Muscle Strength Declines Faster on Deflazacort vs Placebo
LGMD Patients Manual Muscle Strength* Decline at Double the Rate on Deflazacort vs Placebo *Manual muscle strength assessed bilaterally by the modified Medical Research Council Scales (MRC) CIDD (Clinical Investigation of Duchenne Dystrophy) score, graded from 0 (worst) to 10 (best) Treatment with D
Slide 19: Limitations of Steroids as Potential Treatment in RMICs
Limitations of Steroids as Potential Treatment in RMICs Muscle cell homeostasis disrupted by steroids The effects of glucocorticoids on postnatal skeletal muscle regeneration1 1Hanaoka, B. Y. et al. (2012) Implications of glucocorticoid therapy in idiopathic inflammatory myopathies Nat. Rev. Rheumat
Slide 20: Different Approaches to Treating Rare Myopathies
Different Approaches to Treating Rare Myopathies Genetic based modifiers: gene therapy & editing; oligo approaches Delivery of the agent Immune response to new protein Requires new molecules for many approaches Muscle modifiers: various pathways to promote muscle growth Such as myostatin blockade ag
Slide 21: Resolaris Clinical Program – Data Update
Resolaris Clinical Program – Data Update Sanjay Shukla, MD, MS, CMO December 13, 2016
Slide 22: Resolaris Clinical Program Summary
Resolaris Clinical Program Summary Trial Indication(s) Patients Highest Dose Design Data Timing 002 Adult FSHD 3 dose cohorts (n=20 Total) 3mg/kg weekly Placebo controlled, Double blinded; Interpatient Dose Escalation Announced 1Q 2016 003 Early onset FSHD Stage 1 (n=8) 3mg/kg weekly Open-label, Int
Slide 23: Adult LGMD2B and FSHD (004) Trial Study Design
1mg/kg (biw) 1mg/kg 0.3mg/kg Placebo Adult LGMD2B and FSHD (004) Trial Study Design Objective & Rationale Objective: Evaluate the safety/tolerability of total weekly exposure of 6.0mg/kg in LGMD2B and FSHD Assess drug activity more proximal to dosing Rationale: To evaluate different dosing regimens
Slide 24: Demographics and Baseline Characteristics
Demographics and Baseline Characteristics Characteristic Group A FSHD Group B FSHD Group B LBMD2B Enrolled 4 4 10 Age (Mean years) 45.0 34.0 37.2 Median (Range) 45.0 (39, 51) 33.5 (33, 36) 33.5 (22, 62) Male (number, %) 3, 75% 4, 100% 3, 30% White (number, %) 4, 100% 4, 100% 9, 90% BMI (kg/m2), mean
Slide 25: Global Manual Muscle Testing
Global Manual Muscle Testing Muscle function/strength was formally assessed by investigators using Manual Muscle Testing (MMT) 14 muscles evaluated at different time points in studies Muscles scored individually Composite score calculated Progression: lower scores Negative change from baseline Impro
Slide 26: MMT Scores FSHD and LGMD2B (004 Trial)
MMT Scores FSHD and LGMD2B (004 Trial) Individual Patient Changes from Baseline (%) *1-week follow-up is earlier than week 14 for 2 early discontinuations †One patient did not complete the MMT assessments due to being wheel chair bound Dosing up to 3 mg/Kg BIW Dosing up to 1 mg/Kg BIW FSHD/LGMD Clin
Slide 27: Global Patient Reported Outcomes: INQoL
Global Patient Reported Outcomes: INQoL Individualized neuromuscular quality of life assessment * Vincent KA et al: Construction and Validation of a Quality of Life Questionnaire for Neuromuscular Disease (INQoL). Neurology 2007, 68:1051-1057. FDA: “Generally, findings measured by a well-defined and
Slide 28: Overall INQoL Score (004 Trial)
Overall INQoL Score (004 Trial) Individual Change from Baseline FSHD/LGMD Clinical Activity Dosing up to 3 mg/Kg BIW Dosing up to 1 mg/Kg BIW Week 14 INQoL LGMD2B (n=10) Week 14 INQoL FSHD (n=8)
Slide 29: Summary Trial Clinical Activity Assessments
Summary 004 Trial Clinical Activity Assessments FSHD (up to 1.0 mg/kg biw) FSHD (up to 3.0 mg/kg biw) LGMD2B (up to 3.0 mg/kg biw) FSHD (up to 1.0 mg/kg biw) FSHD (up to 3.0 mg/kg biw) LGMD2B (up to 3.0 mg/kg biw) MMT INQoL
Slide 30: Biomarker Evaluation
Biomarker Evaluation 004 Trial 004 Trial included various exploratory biomarkers Exploratory biomarkers did not generally establish sufficiently high or consistent levels or robust signals across a sufficient number of patients to determine test article effects Including targeted muscle T2 and STIR
Slide 31: Early Onset FSHD (003) Trial
3mg/kg 1mg/kg 0.3mg/kg Placebo Early Onset FSHD (003) Trial Objective: Evaluate the safety/tolerability in a potentially different indication Early Onset FSHD Assess drug activity in new patient population and with additional endpoints Rationale: Investigate an often more severe form of disease, inv
Slide 32: Overall MMT Score (003 Trial)
Overall MMT Score (003 Trial) Individual Change from Baseline (%), Per Protocol Pop. Early Onset FSHD Week 14 MMT Early Onset FSHD (n=4)
Slide 33: Overall INQoL Score (003 Trial)
Overall INQoL Score (003 Trial) Individual Change from Baseline, Per Protocol Pop. Early Onset FSHD † One patient did not complete INQoL at baseline Week 14 INQoL Early Onset FSHD (n=3†)
Slide 34: Adult FSHD Long-Term Safety Extension (005) Trial
Adult FSHD Long-Term Safety Extension (005) Trial Evaluate Safety and Tolerability: Build safety dossier for Resolaris Evaluate Potential Activity Assessments: Manual Muscle Test (MMT) Individualized Neuromuscular Quality of Life (INQoL) Biomarker Assessments Patients receive weekly doses of 3.0 mg/
Slide 35: Safety & Tolerability Overview: 003, 004 & 005
As of December 1, 2016, 44 patients have received Resolaris, across all trials (including 002, 003, 004, and 005), for a total drug exposure of 149 patient months Resolaris demonstrated a favorable safety profile and was generally well-tolerated across all doses tested in: Adult FSHD, Early onset FS
Slide 36: Discontinuations and Potential Protocol Changes
Protocol related discontinuations: Discontinued with a single IRR*(4 FSHD/1 LGMD): all IRRs mild to moderate, transient If Jo-1 Ab unit levels reach cut-off (5 FSHD): without associated clinical symptoms One LGMD patient discontinued from the 004 Trial for non-drug related reasons After changing the
Slide 37: Overall MMT: FSHD, LGMD2B & Placebo
Overall MMT: FSHD, LGMD2B & Placebo Change from baseline at week 14 FSHD/LGMD Activity 004 FSHD 1mg/kg 004 FSHD 3 mg/kg 004 LGMD* 3 mg/kg 002 FSHD 3 mg/kg 002 Placebo 3 mg/kg *One patient in 004 Trial did not have an MMT measurement due to being wheelchair bound 003 E.O. FSHD 3 mg/kg 15/23 patients
Slide 38: Overall INQoL: FSHD, LGMD2B & Placebo
Overall INQoL: FSHD, LGMD2B & Placebo Change from baseline at week 14 FSHD/LGMD Activity 004 FSHD 1mg/kg 004 FSHD 3 mg/kg 004 LGMD 3 mg/kg 002 FSHD 3 mg/kg 002 Placebo 3 mg/kg 003 E.O. FSHD 3 mg/kg 14/23 patients improved or were stable with Resolaris of ≥ 3mg/kg for at least 6 weeks 3/4 patients im
Slide 39: Resolaris Discussion and Next Steps
Resolaris Discussion and Next Steps John Mendlein, PhD, Chief Executive Officer at aTyr Pharma December 13, 2016
Slide 40: 2017 Rationale and Plan
2017 Rationale and Plan Emphasis on Single RMIC Indication in 2017, dependent on: Leverage safety and activity data reviewed today Natural history & disease progression; favor homogeneous phenotype Ability to examine MOA with mechanistic assay in patients Peripheral cell and or biopsy samples Ideall
Slide 41: Next Steps: Potential Clinical Development Strategy
Next Steps: Potential Clinical Development Strategy* Adult FSHD 2016 2017 2018 Adult LGMD Early Onset FSHD iMod.Fc Program Legend: Resolaris iMod.Fc Research Physiocrine R&D Initiate First-in-Human Clinical Trial Mechanistic Assay Placebo-controlled, SOC RMIC Trial *Clinical advancement will be link
Slide 42: ic alyr Pharma
ic alyr Pharma
Slide 43: APPENDIX: Reference Papers
APPENDIX: Reference Papers
Slide 44: Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy
Anti-Dystrophin T Cell Responses in Duchenne Muscular Dystrophy: Prevalence and Glucocorticoid Treatment Effect Reference Flanigan et al, Human Gene Therapy, 2013
Slide 45: Connecting Genotype to Immune Cell Phenotype in DMD Patients
Connecting Genotype to Immune Cell Phenotype in Duchenne Muscular Dystrophy Patients Genetic Mutation Locations of Immune Response: Exons 1 – 9 Exons 17 – 26 Exons 42 – 50 Exons 50 – 59 Exons 59 – 69 Exons 70 - 79 DMD Patients: Splice exon 12 Del ex 45 Del ex 46 – 50 Del ex 49 – 54 Nonsense ex 59 No
Slide 46: Steroids Suppress Dystrophin Specific Peripheral T Cell Response in DMD
Steroids Suppress Dystrophin Specific Peripheral T Cell Response in Duchenne Muscular Dystrophy Flanigan et al, Human Gene Therapy, 2013 Percentage of Patients with Positive Immune Response
Slide 47: Treatment of Dysferlinopathy with Deflazacort
Treatment of Dysferlinopathy with Deflazacort: A Double-Blind, Placebo-Controlled Clinical Trial Reference Walter et al, Orphanet Journal of Rare Diseases, 2013
Slide 48: Manual Muscle Testing by CIDD
Manual Muscle Testing by CIDD Clinical Investigation of Duchenne Dystrophy (CIDD) Primary outcome measures were manual muscle strength assessed bilaterally by the modified Medical Research Council Scales (MRC) CIDD (Clinical Investigation of Duchenne Dystrophy) score, graded from 0 (worst) to 10 (be
Slide 49: LGMD Muscle Strength Declines Faster on Deflazacort vs Placebo
LGMD Patients Manual Muscle Strength* Decline at Double the Rate on Deflazacort vs Placebo *Manual muscle strength assessed bilaterally by the modified Medical Research Council Scales (MRC) CIDD (Clinical Investigation of Duchenne Dystrophy) score, graded from 0 (worst) to 10 (best) Treatment with D