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Building a New Class of Medicines Physiocrine Based Therapeutics 1st Rare Disease Trial Completed New Hope For Muscular Dystrophy Patients May 2016
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,” “plan,” “anticipate,” “believe,” “estimate,” “project,” “intend,” “future,” “potential,” “opportunity,” or “continue,” and other similar expressions are intended to identify forward-looking statements. For example, all statements we make regarding the potential therapeutic benefits of Physiocrines and our product candidates, including Resolaris™ and iMod. Fc, the ability to successfully advance our pipeline or product candidates, the timing within which we expect to initiate, receive and report data from, and complete our planned clinical trials, and our ability to receive regulatory approvals for, and commercialize, our product candidates, our ability to identify and discover additional product candidates, and the ability of our intellectual property portfolio to provide protection are forward-looking statements. All forward-looking statements are based on estimates and assumptions by our management that, although we believe to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that we expected. These risks, uncertainties and other factors are more fully described in our filings with the U.S. Securities and Exchange Commission, including our most recent Annual Report on Form 10-K and in our subsequent filings. The forward-looking statements in this presentation speak only as of the date of this presentation and neither we nor any other person assume responsibility for the accuracy and completeness of any forward-looking statement. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law. We own various U.S. federal trademark applications and unregistered trademarks, including our company name and Resolaris™. All other trademarks or trade names referred to in this presentation are the property of their respective owners. Solely for convenience, the trademarks and trade names in this presentation are referred to without the symbols ® and ™, but such references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto.
Augmenting Natural Homeostatic Pathways In patients with rare diseases of muscle & lung Autonomous Pipeline & Unique Business Model Physiocrine* Disruptive Opportunity Resokine: One Pathway Many Rare Diseases Resolaris: Clinical Development Program Pioneering new biology, yielding new therapeutic intervention points Focusing on natural modulators of immune & fibrotic pathways Connecting immune/fibrotic nexus to rare muscle & lung diseases Therapeutically dose above normal levels to promote tissue homeostasis 3 ongoing trials in muscular dystrophies 1st muscular dystrophy trial completed 1st potential activity signal in FSHD 1st safety & tolerability data in patients 1st in class biologics pipeline 2nd molecule for lung disease Build franchises in muscle, lung & liver based on new biology aTyr Highlights *Proteins for life (physio) specific activity (crine)
Harnessing the Power of Physiocrines for Patients 1 Facioscapulohumeral Muscular Dystrophy 2Limb-girdle Muscular Dystrophy 2B 3RPIC: Rare pulmonopathies with an immune component, including Interstitial Lung Disease (“ILD”) Therapeutic Focus Preclinical Phase 1 Phase 1b/2 Discovery aTyr Pipeline Liver Muscle Lung Resokine Pathway Rights Worldwide iMod.Fc RPIC (2nd IND Candidate)3 Liver Worldwide Worldwide Worldwide Resolaris Adult FSHD1 (002); completed cohorts 1-3 Worldwide Resolaris Adult FSHD (004) Worldwide Resolaris Adult LGMD2B2 (004) Resolaris Early Onset FSHD (003) Patient Phenotype Focus Severe impact from disease with the potential for large treatment effect Subject to poor standard of care 1st in class candidates for rare diseases with an immune or fibrotic component Resolaris Adult FSHD Long-term safety extension study (005)
Potential of Physiocrine Proteins Discovery of a New Class of Proteins from Alternative Splicing of Ancient Genes Humira® WW sales over $14B in 2015 (TNF inhibitor) Insulins used by over 3 million Americans to treat diabetes in 2012 Complement inhibitors being studied in a dozen ongoing clinical trials Soliris® net product sales over $2.6B in 2015 (complement inhibitor)
Nature 2015 aTyr Pioneering the New Biology of Physiocrines Physiocrine Proteins Science 2014 Nature 2013 Nature 2010 Science 1999 ~300 proteins involved in physiological pathways, >70 issued or allowed patents Focus on natural modulators of immune & fibrotic pathways in vivo Indication selection: preclinical & clinical phenotype overlap Resolaris focused on rare myopathies with an immune component iMod.Fc focused on rare lung diseases with an immune & fibrotic component
At least 14/23 tRNA Synthetases in family w/ known disease connections Clinical phenotypes present tissue-by-tissue homeostasis Genetic disease paradigm: Genetic aberration à protein absence or abnormality à abnormal function/structure à immune system engagement Soliris® ($2.6B in 2015): example of therapeutic altering the immune component in diseases with genetic aberration Potential for Novel Physiological Modulation in Disease Muscle Heart Liver Brain/CNS Lung Physiocrine Proteins HARS* genetic syndrome (“HGS”) and anti-synthetase syndrome (Jo-1 Ab to HARS) Disease phenotype: effects skeletal muscles and lung Potentially deficient pathway *histidyl-tRNA synthetase
Harnessing the Resokine* Pathway Natural Pathway From Skeletal Muscle to Treat Multiple Rare Muscle Diseases *Resokine: for resolution of activated immune & fibrotic pathways
Genetic mutation Structural protein Transcription factors Mitochondrial proteins Auto-Immune Immune system dysregulation Agent Induced Statins Model of Resokine Pathway In skeletal muscle health and disease Resokine Pathway + = IGF induced growth Muscle progenitor cell ResokineA release Resokine release Free ResokineA circulating levels ~100 pM Anti-synthetase syndrome free ResokineA <10 pM (lung/muscle phenotype) HARS genetic syndrome (lung/muscle phenotype) Normal damage Immune cells Immune cell invasion/residence FSHD1, LGMD2, DMD3 >30 different muscular dystrophies Our Hypothesis: Severe damage (myopathies) 10-100x’s normal levels Therapeutic Resolaris Normal resting muscle Potentially healthier muscle = + Skeletal muscle 1 Facioscapulohumeral Muscular Dystrophy 2Limb-girdle Muscular Dystrophy 3Duchenne Muscular Dystrophy AaTyr Pharma discovery
ê Cytokines, ê T-cells and ê Monocytes with Resolaris administration aTyr unpublished data Treating Immune Cell Invasion in Skeletal Muscle Two weeks of therapeutic treatment in Statin myopathy model 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 Resokine Pathway Resolaris
1st Physiocrine based therapeutics to promote homeostasis Establish & explore: Safety, tolerability Activity/end-point potential Focus on Rare Myopathies with an Immune Component (RMIC) Multiple opportunities for advancement for patients with few or no treatment options Staging rare muscle disease indications Clinical Path for Resolaris in Skeletal Muscle Resokine Pathway Resolaris Phase 1b/2 Trial (002) – Completed 1 Facioscapulohumeral Muscular Dystrophy 2Limb-girdle Muscular Dystrophy 2B Clinical Trials Phase 1b/2 Trial (004) – Ongoing Phase 1b/2 ext. (005) – Ongoing Phase 1b/2 Trial (003) – Ongoing Phase 1b/2 Trial (004) - Ongoing Adult FSHD1 Early Onset FSHD Adult LGMD2B2 Preclinical Phase 1 Phase 1b/2 RMIC
Clinical Development of Resolaris Potential New Therapies for Patients with Rare Muscle Diseases
Muscle-by-muscle disease progression FSHD: A Severe Skeletal Muscle Disease Pathology Dominant/spontaneous toxic gain of function (↑Dux4) Immune component (e.g. ↑ T cells) Asymmetric muscle loss, fat infiltration Standard of care No therapeutic treatments Only supportive care provided Clinical Debilitating muscle weakness Often diagnosed before adulthood May have visual or auditory impairment (early onset) “Unaffected muscle” in an FSHD Patient Transition to immune activity Infiltration of fat/atrophy Muscle destruction Clinical Development
*One reversible Infusion Related Reaction (IRR) patient in 002 & two reversible IRR patients in 005 trial Adult FSHD 002 Design & Trial Objectives Objectives Build dossier for Resolaris & new class Safety Tolerability Immunogenicity PK Explore FSHD pertinent readouts Circulating markers of disease Targeted MRI of disease muscle Strength Patient reported outcomes Across 3 dose cohorts over 1 or 3 months of dosing Results Completed 1st multiple dose trial Safety Tolerability* Immunogenicity PK Completed 1st FSHD only trial Only 2/20 patients with elevated levels Targeted MRI may be too narrow Muscle testing may hold promise Potential signal to confirm Potential active dose: 3.0 mg/kg (weekly) @ 3 months Design Double-blinded, 4 sites, 4 countries, n=20 Multiple Ascending Dose, 3:1 Randomization (Resolaris:placebo) Clinical Development
Clinical Development 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 ADA*’s were of low titer and no demonstrated effect on pharmacokinetics of Resolaris Procedures in effect to minimize IRRs/ADAs moving forward 001/002 trials collectively yield safety data from 39 subjects First Physiocrine therapeutic assessed in patients Establishing the Safety Profile: 1st FSHD Trial *ADA: Anti-drug antibody
Clinical Development 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 I) Activities II) Independence III) Social Relationships IV) Emotions V) Body Image Symptoms, Treatment Effects Overall INQoL score; derived from 5 Life Domains Improvement = decreased scores In individual Life Domains & Overall INQoL (negative change from baseline) Individualized neuromuscular quality of life assessment Global Patient Reported Outcomes: INQoL * 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 reliable PRO instrument in appropriately designed investigations can be used to support a claim in medical product labeling if the claim is consistent with the instrument’s documented measurement capability.”** ** FDA Guidance for industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims; 2009.
Potential dose response and duration response 17 Proportion of Patients with Improved INQoL Overall Scores Clinical Development 1 Month % Response 2/5 1/3 2/4 4/6 5/6 Dose: Placebo Placebo 0/2 3 Months Placebo Resolaris
Multiple Dimensions Improve on INQoL 18 (n=6) (n=5) (n=3) (n=6) (n=4) (n=2) 1 Month 3 Months* Clinical Development INQoL Overall Scores Change from Baseline (%); ITT Population (n=20) Trial not powered to show statistical significance. Data suggest potential improvement in this relatively small clinical trial of FSHD patients. Increasing Disease Burden Decreasing Disease Burden Placebo Resolaris *Relative improvement placebo v. 3.0 mg/kg cohort at 3 months: 25.5% (p=0.03) Placebo
Overall INQoL Score Placebo v. 3.0 mg/kg Patients Suggestive of patient improvement in 3 months Clinical Development 19
Testing muscle function/strength 15 muscles evaluated at 4 time points in study Muscles scored individually Composite score calculated Common endpoints for particular muscles Global Manual Muscle Testing Clinical Development Data suggest small trends of slower progression or potential improvement
A severe muscle disease with a genetic loss of function Clinical Development 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 provided Clinical Debilitating muscle weakness Challenges moving limbs May have respiratory insufficiency
Adult LGMD2B and FSHD (Trial-004) Purpose 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 test whether a total weekly exposure of 6.0mg/kg demonstrates different outcomes than a total weekly exposure of 3.0mg/kg Design & Study Sites Open-label, intra-patient dose escalation; multiple sites in US & Europe Study Population / Entry Criteria 16 patients, 8 each with LGMD2B and FSHD, 18-75 years of age MRI positive or Circulatory markers (in LGMD2B patients only) Clinical Development Weeks Weeks Total Weekly dosage (mg/kg) Total Weekly dosage (mg/kg) Resolaris placebo Resolaris Already completed enrollment
Early Onset FSHD Case History Weakness in 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 Early speech impediment Difficulty forming facial expressions Lower limb muscle weakness/walker or chair Development of severe speech impediment Foot drop and loss of ability to stand/multiple falls Diagnosed age 8 with FSHD Part time wheelchair-bound Age First symptoms Full dependency due to severe physical disability <6 6 – 12 12 – 18 18 - 24 http://www.theguardian.com/lifeandstyle/2009/may/28/muscular-dystrophy-disability-fshd Climbing Mountains; Sarabjit Parmar, 2014 Full time wheelchair-bound Clinical Development Early progression, devastating disease impact
Early Onset FSHD (Trial-003) Clinical Development Weeks Total weekly dosage (mg/kg) Purpose 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 often more severe form of disease, involves additional organ systems Design & Study Sites Open-label, intra-patient dose escalation; multiple sites in US & Europe Study Population / Entry Criteria 16 patients, Stage 1: 8 patients 16-25 years of age, Stage 2: 8 patients 12-15 years of age, Genetically confirmed diagnosis of FSHD and onset of symptoms prior to age 10 Enrollment ongoing in Stage 1 Resolaris
Promise for severely afflicted myopathy patients Resolaris: One Product, Multiple Rare Diseases Clinical Development 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 based on recent census data equals approximately 19,000. LGMD: 16,000 cases estimated in US population. 1/20,000 Wickland and Kissel, Neural. Clin. 2014. Relative Prevalence of Limb Girdle Muscular Dystrophies in the United States Population. Wicklund et al., Neurology 2013. DMD: Prevalence of approximately 5/100,000. Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014 - Number 1 Leadership position in FSHD clinical trials Leverage registries, sites and advocacy Common physician base
Readouts in 3 More Resolaris Trials in 2016 Next trial(s) based on results of 002, 003, 004 & 005 trials Establishing data dossier on safety Exploring activity assessments & optimal dose Directionality on endpoints for approval Clinical Development Adult FSHD (002) N = 20 Early Onset FSHD (003) N = 8 Adult LGMD2B (004) N = 8 Adult FSHD ext. (005) N = 8 Status: 002 complete 004 enrollment complete 003 enrolling 005 ongoing long-term Additional data expected in 4Q from ongoing trials Adult FSHD (004) N = 8
iMod.Fc the First Engineered Physiocrine Augmenting a Natural Pathway to Treat Multiple Lung Diseases
An Engineered Physiocrine for Lung Disease: iMod.Fc New TPP and new molecule to open up lung indications Rationale for iMod.Fc* Resolaris TPP: Weekly dosing; limits lung applications Develop new molecule with new TPP: potentially once-monthly dosing Product Concept Two iMod domains per Fc of an antibody Extend exposure to hit TPP Modulating the immune and fibrotic pathways Preclinical Status and Goals Successful E. coli production for low COGs Activity in industry proven model of IPF (approved drugs: Pirfenidone & Nintedanib) Immuno- & fibro- modulatory activity Rat/non-human primate safety and PK data supportive advancement to IND Expect to initiate clinical trial with iMod.Fc in 2017 Potential Therapeutic applications Rare pulmonopathies with an immune component (RPICs) Broader reach into RPICs and interstitial lung disease (ILD) indications iMod.Fc Program *iMod.Fc refers to immunomodulatory domain of HARS fused to an Fc region of an antibody TPP = Target Product Profile
iMod.Fc Program 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 fibrosis is the analysis of stained histological samples by visual assessment Improvement in Ashcroft Score (%)* Vehicle IPF Model Activity TGF β Ab 3mg/kg IP QOD D 0-D 21 Pirfenidone 100 mg/kg PO BID D8-D 21 iMod.Fc 0.4 mg/kg IV mg/kg D8, D15
Building a New Class of Therapeutics Foundation for the Future
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, Enterprise Talent and Organization Sanuj Ravindran, M.D. Chief Business Officer Ashraf Amanullah, Ph.D. VP, Manufacturing Grove Matsuoka SVP, Product Programs and Planning
Resolaris for LGMD2B/Adult FSHD Resolaris for Early Onset FSHD Resolaris for Adult FSHD Resolaris for Adult FSHD Focused Execution with Strong Cash Position Balance sheet well-aligned to achieve near-term catalysts Phase 1b/2 Trial (002) Phase 1b/2 Trial (004) Phase 1b/2 Trial (005) Long-term extension Phase 1b/2 Trial (003) Stage 1 2015 2016 2017 Program 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q iMod.Fc to enter clinical trials in 2017 Cash Balance as of 3/31/16: $111.6M Well-positioned to achieve all aforementioned clinical milestones iMod.Fc for RPICs
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 2007 History and Future of Biotech
Appendix
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 Muscle Heart Liver Brain/CNS Lung Physiocrine Proteins Work via GPCRs, TLRs, cytokine receptors & other proteins Not glycosylated & non-canonical leader sequences Size range 40-500AA
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 Skeletal Muscle Result Immune Cell Invasion Disease Status Normal Silent Normal No Normal FSHD Activatible ↑DUX 4 ↑“Non-muscle” proteins Yes Moderate to Severe Most Severe Typically Highly Activatible ↑DUX 4 ↑“Non-muscle” proteins Yes Severe Full Epigenetic Control ~100 repeats Partial Epigenetic Control Greatest Loss of Epigenetic Control Genetics = D4Z4 Repeat (containing DUX4)
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 Analysis based on data available through early March 2016 Exploratory Study of Resolaris in Adult FSHD Baseline Study Characteristics * One patient discontinued dosing at week 11 of the 12 weeks of treatment, but completed all study visits.
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 circulating markers did not record a difference between placebo and 3.0 mg/kg group Only 2 subjects started with elevated levels of immune markers of interest To be monitored in additional studies and extension phase Targeted MRI & Circulating Markers Clinical Development
* Targeted MRI only if qualified with Stir+ muscle at baseline. ** Only for Cohort 3 subjects Resolaris Phase 1b/2 Program Summary 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 3.0 ü Yes ü ü ü ü ü 003 EO FSHD 8 3.0 No Yes No Yes Yes Yes 4Q16 004 Adult FSHD 8 3.0 (2x) Yes Yes Yes Yes Yes Yes 4Q16 004 Adult LGMD 8 3.0 (2x) Serum marker or MRI Yes Yes* Yes Yes Yes 4Q16 005 Adult FSHD (002 ext. study) 8 3.0 No Yes Yes** Yes Yes Yes 4Q16 Next trial(s) based on results of 002, 003, 004 & 005 trials Establishing data dossier on safety Exploring activity assessments & optimal dose Directionality on endpoints for approval Clinical Development
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 Fibrosis Induced with Bleomycin Promising therapeutic activity* Compared favorably to Pirfenidone Promising Therapeutic Activity Resolaris
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 Non-GLP double dose 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 >1nM for at least 500 hours at 1mg/kg iMod.Fc Preclinical
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 breath and cough Specific chest radiographic abnormalities Decreased lung volume noticed in pulmonary function tests Standard of care O2 , pulmonary rehabilitation; lung transplant Immunosuppressive (cyclophosphamide with low dose prednisone) For IPF, Pirfenidone & Nintedanib iMod.Fc for Multiple Lung Indications Expect to initiate clinical trial with iMod.Fc in 2017 Evaluating appropriate forms of RPICs, including ILD Goal is to explore safety, tolerability, biological and clinical activity Upcoming Trials
