Slide 1: Building a New Class of Medicines - Physiocrine Based Therapeutics
Building a New Class of Medicines - Physiocrine Based Therapeutics 1st Rare Disease Trial Completed - New Hope for Muscular Dystrophy Patients April 2016
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: aTyr Highlights
Augmenting Natural Homeostatic Pathways in Patients with Rare Diseases of Muscle & Lung Autonomous Pipeline & Business Model Physiocrine* Disruptive Opportunity Resokine: One Pathway Many Rare Diseases Resolaris Encouraging Phase 1b/2 Data Pioneering new biology, yielding new therapeutic interventio
Slide 4: Discovery of Physiocrine Proteins: New Class of Proteins from Alternative Splicing
Discovery of Physiocrine Proteins: New Class of Proteins from Alternative Splicing of Ancient Genes
Slide 5: Pioneering the New Biology of Physiocrines
Nature 2015 aTyr Pioneering the New Biology of Physiocrines Therapeutically Tapping Novel Pathways ~300 proteins involved in physiological pathways, >70 issued patents Focus on natural modulators of immune & fibrotic pathways in vivo Indication selection: preclinical & clinical phenotype overlap Res
Slide 6: Extracellular functions of tRNA Synthetases; Properties of Physiocrines
Extracellular functions of 4 billion year old gene family, tRNA Synthetases Genes yield ~300 proteins (e.g. alternative splicing, etc.) of new function Potential new class of modulators of tissue homeostasis Properties of Physiocrines Potential for novel physiological modulation in disease At least
Slide 7: Leadership Team
Leadership Team Experienced Industry Veterans Kelly Blackburn VP, Clinical Operations Andrew Cubitt, Ph.D. VP, Product Protection and Interim Head of Research John Mendlein, Ph.D. Chief Executive Officer John Blake, CPA VP, Finance Sanjay Shukla, M.D. Chief Medical Officer Holly D. Chrzanowski VP, E
Slide 8: Immuno/Fibrosis Modulation Pipeline
Immuno/Fibrosis Modulation Pipeline 1 Facioscapulohumeral Muscular Dystrophy 2Limb-girdle Muscular Dystrophy 3RPIC: Rare pulmonopathies with an immune component, including Interstitial Lung Disease Therapeutic Focus Preclinical Phase 1 Phase 1b/2 Discovery Paradigm Shift in Treatments Liver Muscle L
Slide 9: Harnessing the Resokine Pathway
Harnessing the Resokine* Pathway: Potential New Therapies for Patients with Rare Muscle & Lung Diseases *Resokine: for resolution of activated immune & fibrotic pathways
Slide 10: Resokine Released From Human Primary Skeletal Muscle Cells
Resokine Released From Human Primary Skeletal Muscle Cells IGF1 Facilitated Differentiation Human Skeletal Muscle Resokine Released from Human Skeletal Muscle
Slide 11: Molecules of the Resokine Pathway
Naturally occurring Physiocrines Resolaris™ iMod (slightly truncated from wildtype) (splice variant) ** Molecules of the Resokine Pathway New hope for rare muscle & lung disease patients Engineered Physiocrine iMod.Fc Resokine Franchise Resokine* Pathway Discovery: Clinical correlates: myopathies &
Slide 12: Resolaris Improves Muscle & Lung Immune/Fibrotic Components
Two weeks of therapeutic treatment in Statin myopathy & Bleomycin IPF* models Resolaris Improves Muscle & Lung Immune/Fibrotic Components Augmenting The Resokine Pathway Resolaris *Idiopathic Pulmonary Fibrosis (“IPF”), a subset of Interstitial Lung Disease (“ILD”)
Slide 13: Clinical Path for Resolaris & iMod.Fc
1st Physiocrine based therapeutics to promote homeostasis Exploratory stage trials in rare diseases Establish & explore: Safety, tolerability Activity/end-point potential Multiple opportunities for advancement For patients with few or no treatment options Staging Rare Muscle & Lung Disease Indicatio
Slide 14: Clinical Development of Resolaris
Clinical Development of Resolaris: Harnessing a Natural Pathway to Treat Multiple Rare Muscle Diseases
Slide 15: FSHD: A Severe Skeletal Muscle Disease
With dominant/spontaneous genetic toxic gain of function Disease Presentation FSHD: A Severe Skeletal Muscle Disease Facioscapulohumeral Muscular Dystrophy (FSHD) Pathology Dominant/spontaneous toxic gain of function (Dux4) Immune component (e.g. T cells) Muscle loss, fat infiltration Standard of ca
Slide 16: Slow Muscle-by-Muscle Disease Progression
Slow Muscle-by-Muscle Disease Progression Therapeutically promoting homeostasis in FSHD Muscle throughout the body Intervening Early “Unaffected muscle” in an FSHD Patient Transition to Immune activity Conversion to fat/atrophy Muscle destruction Potential areas of therapeutic intervention by Resola
Slide 17: First Physiocrine Patient Trial Data
Important advancement for hard to treat diseases (FSHD/RMICs) Establishing data dossier on safety Exploring activity assessments & optimal dose Directionality on endpoints for approval Significant step forward to advancing Physiocrine based therapeutics 1st FSHD Trial Highlights Foundation to build
Slide 18: Adult FSHD 002 Design & Trial Objectives
* 1 reversible Infusion Related Reaction (IRR) patient in 002 & 2 reversible IRR patients in 005 trial Adult FSHD 002 Design & Trial Objectives Build dossier for Resolaris & class: Safety Tolerability Immunogenicity PK Explore FSHD pertinent readouts Circulating markers of disease Targeted MRI of di
Slide 19: Study Demographics
Study Demographics Resolaris Placebo Patients 15 5 Age (years), Median 46 52 Male/Female (%) 53/47 80/20 Patients with 3 D4Z4 repeats or less 2 0 Completed Study 100%* 100% Elevated cytokines of interest 1/15 1/5 Baseline FSHD Clinical Severity Score, Mean (SD) 3.2 (0.8) 2.7 (0.7) Resolaris Clinical
Slide 20: Establishing the Safety Profile of Resolaris
Generally safe and well-tolerated over the dose range/duration studied No SAEs reported by study investigators One generalized infusion related reaction (IRR) reclassified by aTyr to serious adverse event ADAs confirmed in approximately 40% of patients dosed with Resolaris No demonstrated effect of
Slide 21: INQoL: Patient Reported Outcome
Validated neuromuscular assessment tool* Global systemic assessment used in clinical studies and trials Not frequently used in clinical practice Self-administered questionnaire consisting of 45 queries/4 dimensions Life Domains 1) Activities 2) Independence 3) Social Relationships 4) Emotions 5) Bod
Slide 22: Multiple Dimensions Improve on INQoL
Improvement reflected by negative change from baseline Multiple Dimensions Improve on INQoL NA is not applicable; only 1 month of dosing Relative improvement placebo v. 3.0 mg/kg cohort at 3 months: 25.5% (p=0.03) 1st FSHD Trial Results Activity INQoL Overall Scores Change from Baseline (%) ITT Popu
Slide 23: Overall INQoL Score: Placebo v 3.0 mg/kg
Placebo v 3.0 mg/kg Patients Overall INQoL Score Suggestive of patient improvement in 3 months 1st FSHD Trial Results Activity
Slide 24: MMT Measurement
Muscle function/strength was formally assessed by investigators using Manual Muscle Testing (MMT) 15 muscles evaluated at 4 time points in study Muscles scored individually Composite score calculated Progression: lower scores; negative change from baseline Improvement: higher scores; positive change
Slide 25: Targeted MRI & Circulating Markers
MRI used to evaluate immune components in a targeted muscle did not record a difference between placebo and 3.0 mg/kg group To be followed through extension study No evidence of immune suppression was observed with exploratory circulating cytokines, as well as immune cells Assessment of selected cir
Slide 26: LGMD: A Severe Muscle Disease
With a genetic loss of function Disease Presentation LGMD: A Severe Muscle Disease Limb-girdle Muscular Dystrophy 2B (LGMD2B) Pathology Immune component (e.g. T-cells) Toxic loss of function mutation (dysferlin) Muscle group progression Standard of care No therapeutic treatments Only supportive care
Slide 27: Adult LGMD2B and FSHD (Trial-004)
Adult LGMD2B and FSHD (Trial-004) Purpose – 1) to evaluate the safety/tolerability of biweekly infusions in patients with LGMD2B and FSHD; 2) to assess drug activity more proximal to dosing Rationale – More frequent dosing may demonstrate better outcomes Design & study sites – Open-label, intra-pati
Slide 28: Early Onset FSHD Case History
Early Onset FSHD Case History Weakness in the lower back/curvature of the spine Leg muscle weakness/walking with a limp Normal early childhood Requires full-time use of wheelchair and assisted living Diagnosed with scoliosis Muscle weakness and early speech impediment Difficulty forming facial expre
Slide 29: Early Onset FSHD (Trial-003)
Early Onset FSHD (Trial-003) Purpose – 1) to evaluate the safety/tolerability of weekly infusions in patients with Early Onset FSHD; 2) to assess drug activity in new patient population & with additional endpoints Rationale – Investigate often more severe form of disease, involves additional organ s
Slide 30: Resolaris Trial Summary 2016
* Targeted MRI only if qualified with Stir+ muscle at baseline. ** Only for Cohort 3 subjects Resolaris Trial Summary 2016 Trial Patient Populations N Highest Ending Dose Weekly (mg/kg) MRI (+) Entrance MRI Broad Readout MRI Targeted Readout INQoL MMT Immune Markers Readout Timing 002 Adult FSHD 20
Slide 31: Resolaris: One Product, Multiple Rare Diseases
Promise for severely afflicted myopathy patients Resolaris: One Product, Multiple Rare Diseases Commercial Rationale 19,000 US FSHD 16,000 US LGMD 16,000 US DMD 51 45 53 44 52 50 Other exons FSHD: Average prevalence rates of FSHD are approximately 1/17,000. Applying this rate to the US population ba
Slide 32: iMod.Fc the First Engineered Physiocrine
iMod.Fc the First Engineered Physiocrine: Augmenting a Natural Pathway to Treat Multiple Lung Diseases
Slide 33: An Engineered Physiocrine for Lung Disease: iMod.Fc
An Engineered Physiocrine for Lung Disease: iMod.Fc New TPP to open more lung indications Rationale for iMod.Fc*: Resolaris TPP: Weekly dosing; limits lung applications Develop molecule for new TPP: potentially once-monthly dosing Product Concept: Two iMod domains per Fc of an antibody Extend exposu
Slide 34: Attractive ILD Candidate iMod.Fc
Attractive ILD Candidate iMod.Fc 1/250th of Pirfenidone dose Better than 10 TGFβ Ab doses Established IPF rodent model Improves inflammation & fibrosis Differentiated mechanism Two iMod.Fc Doses Outperform 28 Pirfenidone Doses * *The Ashcroft scale for the evaluation of bleomycin-induced lung fibros
Slide 35: Non-Human Primate and Rodent PK and Safety
Non-Human Primate and Rodent PK and Safety Supports potential for monthly dosing in patients Non-Human Primates Rodents Non-GLP toxicology 1-month study at dose level 25x efficacious dose No pro-inflammatory cytokine signal No clinical observations No changes in body or tissue weights Attractive PK
Slide 36: iMod.Fc for Multiple Lung Indications
Severe, rare disorders with high unmet medical need iMod.Fc Clinical > 80 RPIC Forms Including Interstitial Lung Diseases Pathogenesis Lung damage leading to alveolar inflammation or fibrosis Worst prognosis: lower DLCO and rapid decline of DLCO over three years Clinical manifestations Shortness of
Slide 37: Building a New Class of Therapeutics: Foundation for the Future
Building a New Class of Therapeutics: Foundation for the Future
Slide 38: Strong Cash Position and Focused Execution
Strong Cash Position and Focused Execution Balance sheet well-aligned to achieve near-term catalysts Cash as of 12/31/15: $125.3M Shares Outstanding: 23.7M Financials Milestones 2016/2017 Early Onset FSHD 003 Data (4Q16) Adult LGMD/Adult FSHD 004 Data (4Q16) Adult FSHD Long Term Extension 005 Data (
Slide 39: Opportunity to own a new class of meaningful medicines
Opportunity to own a new class of meaningful medicines Revolutionary Drugs Leveraging New Biology Pioneer New biology Insulin First product 1923 1968 1989 Coagulation factors Erythropoietin Enzyme replacement therapy TNF pathway VEGF pathway Complement pathway Physiocrine pathways 1990 1998 2004 200
Slide 40: Appendix
Appendix
Slide 41: Ability to Treat Immune Cell Invasion in Muscle
aTyr unpublished data Ability to Treat Immune Cell Invasion in Muscle Control Statin days 1-14 (toxic dose) 0.3 mg/kg Resolaris days 7-14 Statin days 1-14 1.0 mg/kg Resolaris days 7-14 Statin days 1-14 3.0 mg/kg Resolaris days 7-14 Statin days 1-14 Resolaris Preclinical ê Cytokines, ê T-cells and ê
Slide 42: Resolaris: Active In Lung Inflammation & Fibrosis Model
Three week rodent model, two weeks of therapeutic treatment Resolaris: Active In Lung Inflammation & Fibrosis Model Experimental data provided by Stelic CRO CT scans taken at day 14, lung histology taken at day 21 * Activity of mouse Resolaris (3mg/kg) vs vehicle control Pulmonary Inflammation and F
Slide 43: FSHD Molecular Pathology Links Loss of Epigenetic Control to Immune Status
FSHD Molecular Pathology Links Loss of Epigenetic Control to Immune Status with Disease Statland, J., C. M. Donlin-Smith, et al. Journal of Neuromuscular Diseases, 2014. Lemmers, E. et al, Gene Reviews 2014 FSHD Muscle Phenotype 4th Chromosome Terminal Repeats DUX 4 Non-Germline Gene Expression Skel