Transforming Complement Therapeutics. April 2019

Transcription

1 Transforming Complement Therapeutics April 2019

2 Forward-Looking Statements This presentation contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the safety, efficacy, regulatory and clinical progress, and therapeutic potential of our product candidates, including zilucoplan, plans and timing for the presentation of clinical data, expectations surrounding the initiation of a Phase 3 clinical trial evaluating zilucoplan for the treatment of gmg and timing thereof, expectations surrounding the nomination of a new neurology indication for zilucoplan and timing thereof, our market opportunities, the anticipated pricing of our product candidates, if approved, including zilucoplan, and management s estimates about the potential size and characteristics for the patient populations that our product candidates are targeting. All such forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include the risks that Ra Pharma s product candidates, including zilucoplan, will not successfully be developed or commercialized, as well as the other factors discussed in the Risk Factors section in Ra Pharma s most recently filed Annual Report on Form 10-K, as well as other risks detailed in Ra Pharma s subsequent filings with the Securities and Exchange Commission. There can be no assurance that the actual results or developments anticipated by Ra Pharma will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, Ra Pharma. Except as noted, all information in this presentation is as of April 9, 2019, and Ra Pharma undertakes no duty to update this information unless required by law. 2

3 Transforming Complement Therapeutics Focused on delivering innovative and accessible therapies to patients with rare neurologic, hematologic, and renal indications Zilucoplan: A convenient, self-administered, subcutaneous C5 inhibitor gmg: Successful Phase 2 study in a broad spectrum of patients with gmg Met clinically meaningful, statistically significant reductions in pre-specified primary and key secondary endpoints Phase 3 clinical trial planned for 2H19 PNH: Positive Phase 2 study in naïve and majority of switch patients Ethno-bridging study: Completed dosing in Phase 1 study designed to support development in Japan Renal: Positive Phase 1b PK study in renally impaired patients; No dose adjustment required Building a pipeline within a product, leveraging gmg for a 3 rd indication (neurology), TBA 1H19 Advancing a portfolio of C5 inhibitors in pre-clinical development XR: Zilucoplan XR achieved greater than one week of target dose concentrations following a single subcutaneous injection in non-human primates, supporting once weekly or less frequent dosing SMi: First-in-class oral small molecule C5 inhibitor Proprietary drug discovery engine Trillion member, highly diverse, synthetic macrocyclic peptide libraries; Diversity and specificity of mabs with the pharmacologic advantages of small molecules Merck Collaboration: Oral peptide targeting a large CV market opportunity Announced receipt of 3 rd development milestone in December

4 Pipeline Programs C5 Inhibition Franchise DISCOVERY/ PRE-CLINICAL PHASE 1 PHASE 2 PHASE 3 Factor D Inhibition Partnered Program Zilucoplan (gmg) Zilucoplan (PNH) Zilucoplan (renal disorders) Zilucoplan (3 rd indication, neurology, TBA 1H19) Zilucoplan Extended Release (XR) Oral Small Molecule Inhibitor Orphan Renal Diseases (SC) Other Complement Inhibitors Renal/Autoimmune/CNS Diseases (Non-Complement Target) Oral Macrocyclic Peptide Cardiovascular target with a large market opportunity 4

5 Zilucoplan: A Subcutaneously Self-Administered, Macrocyclic Peptide Inhibitor of Complement C5 Multiple validated indications, pipeline-in-a-product potential Alternative Pathway Classical Pathway Lectin Pathway Multiple Indications Activated by non-self cells Activated by antibody-antigen complexes Activated by pathogen surfaces gmg: Phase 2 positive C3 C1q C1r C1s Factor D, Factor B C5 PNH: Phase 2 positive C5a Proinflammatory cytokine C5b C6 Renal Disorders: Phase 1b positive Eculizumab (IV) Binds C5, blocks cleavage Zilucoplan SC Binds C5, blocks cleavage; Blocks MAC assembly C5b6 C7, C8, C9 Membrane attack complex (MAC) Neuropathies and Myopathies: TBA 15 amino-acid cyclic peptide inhibitor of C5 gmg generalized myasthenia gravis; PNH paroxysmal nocturnal hemoglobinuria 5

6 Zilucoplan Positioned for Success Large mab (140 kda) Small Peptide (3 kda) Last Line Long Infusion (~1 hr) High Volume IV ( ml) Rising Expectations for Complement Inhibition Earlier Use Brief Injection (5-8 sec.) Convenient SC (~0.5 ml) Exclusive Accessible Today Zilucoplan 6

7 Generalized Myasthenia Gravis (gmg) Is a Rare, Debilitating, C5-Mediated Disease 1 FREQUENCY /Million, ~60,000 (US), ~100,000 (EU), ~24,000 (JP) 2 Autoantibodies and complement-mediated destruction of the neuromuscular junction cause pathology in gmg 1,2 CAUSE DIAGNOSIS Autoantibodies block signals from nerves to muscles and complement activation destroys the neuromuscular junction 3 Acetylcholine receptor antibody positive 2 Normal Acetylcholine (ACh) Acetylcholine receptor (AChR) Signal proceeds CONSEQUENCES Serious and progressive Significantly impacts quality of life 1,2 ~80% progress to generalized muscle weakness 4 Muscle cell Muscle contracts ~20% experience crisis 5 TREATMENT Sporadic, expensive, and often non-specific Cholinesterase inhibitors, corticosteroids, ISTs, thymectomy Myasthenia Gravis Signal blocked IVIG, PLEX total maintenance costs ~$150,000 6,7 per year Eculizumab (Soliris ; Alexion), bi-weekly IV therapy approved in ; ~$700,000 9 Autoantibody that binds to AChR Complement-mediated MAC assembly Destruction of membrane References: 1. Howard JF. Lancet Neurol. 2017;16(12): Gilhus N, N Engl J Med 2016;375: Conti-Fine BM. J Clin Invest. 2006; 116(11): Wang et al. BMC Neurology. 2017;17: Renton AE, et al. JAMA Neurol Apr;72(4): Heatwole C, et al. J Clin Neuromuscul Dis. 2011; 13(2): MG Cost Calculator, Data on File. 8. Soliris [package insert]. Alexion Pharmaceuticals Inc; revised 1/ Prime Therapeutics. AMCP 2018, April 23-26, Boston. 7

8 Market Opportunity: Extend Complement Inhibition to More Patients MG Diagnosis Acetylcholinesterase Inhibitor Steroids Immunosuppressive Therapies IVIG/PLEX (Crises or Chronic) >20K pts ~ 35% <10K pts ~ 15% REGAIN Population (Eculizumab) Zilucoplan Phase 2 Population Target Complement-Mediated Damage Earlier (~50% of MG patients are Uncontrolled) US Prevalence: ~200 per million (~60K pts) Opportunity to Treat ~30K Patients (U.S. Only) with AChR+ gmg Data source: IQVIA market projections (93% retail, 1.5B LRx & Dx claims, CDM ~350 hospitals, PharMetrics health plan 150M pts) Jan 2016 Dec 2017 selection period (patients with at least 1 MG diagnosis claim ICD-10 G70.00 or G70.01); 5 years history for treatment and procedures (starting Jan 2013) Applied best practice eligibility controls and apply appropriate pre-screener/end-treater rules Used Rx/Dx intersection to project Rx and office-based treatments, and projected hospital utilization of relevant therapies (ie. IVIG, PLEX) using CDM Segment size projected with Pharmetrics Plus data, therapy usage does not use Pharmetrics Plus; therapy analysis on steroid dosage used to allocate patients on high dose steroid to Uncontrolled 8

9 Phase 2 Study Targets Broad gmg Patient Population Broad Patient Population: Generalized MG (Myasthenia Gravis Foundation of America class II-IVa) AChR-antibody positive Quantitative Myasthenia Gravis (QMG) score of 12 Stable doses of corticosteroids and/or immunosuppressants No requirement to be refractory or have failed multiple prior therapies Endpoints: Primary: Change in QMG score from baseline to week 12 Key Secondary: Change in MG-ADL score from baseline to week 12 Pre-specified significance testing at 1-sided alpha of 0.1 Enrollment: 44 patients (vs. target of 36) 0.3 mg/kg SC + Standard of Care Screening 1:1:1 Randomization 0.1 mg/kg SC + Standard of Care Long-term Extension (Active Drug) Placebo + Standard of Care Main Study Period (12 Weeks) Long Term Extension Randomized, double-blind, placebo-controlled, multi-center study followed by an open-label, long-term extension (LTE) 9

10 Baseline Characteristics Confirm Breadth of gmg Study Population Variable Placebo (n=15) Zilucoplan 0.1 mg/kg (n=15) Zilucoplan 0.3 mg/kg (n=14) Age, mean years (± SD) 48 (15.7) 46 (15.7) 55 (15.5) Male, n(%) 4 (27%) 7 (47%) 10 (71%) Race, n(%) White Asian Black or African American 12 (80%) 1 (7%) 2 (13%) 13 (87%) 0 2 (13%) 11 (79%) 1 (7%) 2 (14%) MGFA Class at Screening II III IVa 7 (47%) 8 (53%) 0 5 (33%) 10 (67%) 0 5 (36%) 5 (36%) 4 (29%) Duration of Disease, mean years (min, max) 8.0 (0.1, 20.9) 8.7 (1.6, 24.1) 8.3 (0.5, 26.0) Baseline QMG Score, mean (± SD) 18.7 (4.0) 18.7 (4.0) 19.1 (5.1) High Unmet Medical Need Baseline MG-ADL Score, mean (± SD) 8.8 (3.6) 6.9 (3.3) 7.6 (2.6) Baseline MG Composite Score, mean (± SD) 18.7 (5.7) 14.5 (6.3) 14.6 (6.3) Baseline MGQoL15r Score, mean (± SD) 15.9 (7.4) 19.1 (5.0) 16.5 (7.3) Prior MG Therapies (Standard of Care) Pyridostigmine, n(%) Corticosteroids, n(%) Immunosuppressants, n(%) 14 (93%) 13 (87%) 12 (80%) 15 (100%) 13 (87%) 12 (80%) 14 (100%) 14 (100%) 9 (64%) Prior IVIG, n(%) 9 (60%) 8 (53%) 10 (71%) Prior Plasma Exchange, n(%) 7 (47%) 9 (60%) 7 (50%) Non-Refractory Patients Included 9% no prior steroids 25% no prior ISTs 39% no prior IVIG 48% no prior PLEX Prior Thymectomy, n(%) 5 (33%) 8 (53%) 7 (50%) Prior MG Crisis Requiring Intubation, n(%) 3 (20%) 4 (27%) 2 (14%) 10

11 Primary and Key Secondary Endpoints Met with 0.3 mg/kg Zilucoplan Dose: Rapid, Clinically Meaningful, and Statistically Significant Reductions in QMG and MG-ADL Change from Baseline in QMG Placebo 0.3 mg/kg Zilucoplan Change from Baseline in MG-ADL p= p= Study Week Study Week Pre-specified significance testing at 1-sided alpha of 0.1 with LOCF ANCOVA p values shown; error bars denote standard errors of least squares mean; mitt 11

12 Primary and Key Secondary Endpoints Also Met with 0.1 mg/kg Zilucoplan Dose Change from Baseline in QMG Placebo 0.1 mg/kg Zilucoplan Change from Baseline in MG-ADL p= p= Study Week Study Week Pre-specified significance testing at 1-sided alpha of 0.1 with LOCF ANCOVA p values shown; error bars denote standard errors of least squares mean; mitt 12

13 Pre-Specified Pooled Analysis of Approval Endpoint (MG-ADL) Satisfies 2-Sided p<0.05 Change from Baseline in MG-ADL p= Zilucoplan in Phase 2 met approvable endpoint (MG-ADL) at 12 weeks with similar magnitude and statistical significance as eculizumab in Phase 3 REGAIN study at 26 weeks* Placebo Study Week Zilucoplan Pooled LOCF ANCOVA 2-sided p value shown; error bars denote standard errors of least squares mean; mitt * Placebo-corrected change in MG-ADL at 26 weeks in REGAIN study: -1.9 LOCF ANCOVA p=0.039; ref. Howard et al AANEM

14 Responder Analysis: Robust and Meaningful Improvements over Placebo QMG Zilucoplan arm favored overall and in patients exhibiting largest point improvements MG-ADL 14

15 Patients Can Achieve Minimal Symptom Expression by Week 12 Minimal symptom expression (MSE) = Achieving MG-ADL score of 0 or 1 25 Percent of Patients (%) m g/kg 1200 m g 0.3 m g/kg 23% of patients (placebo-corrected) achieved MSE in 12 weeks in 0.3 mg/kg zilucoplan arm Zilucopla p n Eculizum a b Zilucopla p n W eek 12 W eek 26 W eek 12 Placebo-Corrected Rates *Vissing J, Jacob S, Fujita K, et al. Minimal Symptom Expression with Eculizumab in Myasthenia Gravis. AANEM

16 Safety and Tolerability Profile Supports Continued Development Placebo (n=15) Zilucoplan 0.1 mg/kg (n=15) Zilucoplan 0.3 mg/kg (n=14) Patients Requiring Rescue with IVIG or PLEX 3 (20%) 1 (7%) 0 (0%) Patients with adverse events (AEs) Patients with related AEs Patients with serious AEs Patients with related serious AEs Patients with most common related AEs: No patients required rescue in 0.3 mg/kg zilucoplan arm Nausea Injection site bruising Injection site scab Contusion Headache Patients with injection site reactions No meningococcal infections Profile consistent with Ph1 and Ph2 PNH studies All 44 subjects completed 12-week study; No early withdrawals 42/44 subjects (95%) entered long-term extension MedDRA Version 20.0 Adverse Event Preferred Terms; injection site reactions defined as pain, tenderness, erythema, or induration 16

17 Zilucoplan in gmg: Phase 2 Top-Line Data Summary Positive Phase 2 study in broad gmg population (not restricted to refractory ) Primary and key secondary endpoints met with clinically meaningful and statistically significant reductions in QMG and MG-ADL in both 0.3 mg/kg and 0.1 mg/kg dose groups Magnitude and speed of effect, no rescue therapy required, and higher rate of minimal symptom expression all favor 0.3 mg/kg dose over 0.1 mg/kg dose for Phase 3 Favorable safety and tolerability profile with no early withdrawals in the study; Safety and PK/PD profile consistent with Phase 1 healthy volunteer and Phase 2 PNH studies Alignment with FDA on single, pivotal, 12-week, placebo-controlled, Phase 3 clinical trial to initiate in 2H19 Expanded dataset, including pharmacodynamics and extension data, planned for 1H19 17

18 Zilucoplan: A Convenient Complement Inhibitor for a Broad gmg Population Administration Tx Time Population Mechanism QMG, ADL Mean δ vs Placebo 1 % Improvement 12wks Zilucoplan ~0.5 ml (3 kda) SC daily self-admin 5-8 sec. Uncontrolled MG (~30k) C5 Cyclic Peptide QMG -2.8 ADL % 6 26wks Eculizumab ml (140 kda) Intravenous infusion every 14 days 45 min. Refractory MG (~3-5k) C5 mab QMG ADL ~-2.5 (-3*) ~ % 6 39% (-1.9*) *At 26wks 1 Soliris QMG, ADL at 12wk estimated (Ref. Howard et al. Lancet 2017) 2 Soliris QMG, ADL improvement at 26wks (Ref. Howard et al. Lancet 2017) 3 Soliris Highlights of Prescribing Information; 18

19 Zilucoplan: Designed for Everyday Complement Control Efficacious: Rapid and meaningful reductions in QMG & MG-ADL with high proportion of patients achieving MSE; Favorable safety and tolerability Convenient: 5-8 sec push, ~0.5 ml, room temperature; Experience comparable to daily insulin injection Easy to Use: BD UltraSafe Plus PFS with >13,000 doses administered in zilucoplan clinical trials; 91% of gmg patients interested in daily self-administered SC complement inhibitor 1 Accessible: Pricing expected to enable broader access; Non-refractory and refractory patients Positioned for Earlier Use: Targets complement-mediated damage at all stages of treatment paradigm 1 Data on file: market research with MGFA (n=372) 19

20 Paroxysmal Nocturnal Hemoglobinuria (PNH) Rare, Life-Threatening, C5-Mediated Disease 1 Frequency ~8,000 to 10,000 people in North America and Europe ~1,000 to 2,000 in Japan 2 Cause Spontaneous mutations in the PIG-A gene in red blood cells (RBCs) cause PNH 1 Natural History Early diagnosis and intervention is critical Variability of PNH delays diagnosis, often up to 10 years 3 35% of PNH patients die within 5 years of diagnosis 1,3 Median survival after diagnosis is 10 years 1,3 Complement-mediated hemolysis underlies progressive morbidities and mortality in PNH 1 PIG-A mutation results in surface complement deposition and activation due to loss of complement regulators (CD59, CD55) C3b, a fragment of complement C3, is deposited on RBC surface Convertases containing C3b activate C5 leading to MAC formation Treatment Expensive and exclusive Anti-complement C5 monoclonal antibody Eculizumab (Soliris ); Alexion 3 : Bi-weekly IV infusion 3 ; Approximate annual cost $600,000 4 Ravulizumab-cwvz (Ultomiris TM ); Alexion: Q8W IV infusion; Approximate annual cost $500,000 C3b MAC C5 activation and assembly of the membrane attack complex (MAC) Consequences Serious and progressive Life-threatening complications in PNH include thromboses, renal insufficiency, and other organ damage Estimated 1.3 per million per year newly diagnosed patients 2 RBC Lysis Destruction of RBC 1. Kanakura Y. Int J Hematol. 2013; 98: Hill A. Blood. 2006; 108: Soliris [package insert]. Alexion Pharmaceuticals Inc; revised 1/ Houlton S. Prescriber Jan;

21 Zilucoplan Phase 2 Study in Treatment Naïve PNH Patients Rapid, Robust, Sustained Reduction of LDH Dose Dependence of Complement Inhibition Comparable LDH Reduction to Eculizumab 1,2 100 Phase 1 HV Phase 2 PNH; 0.1 mg/kg **Relative overdosing of eculizumab during weekly loading period coincides with relative underdosing of zilucoplan during dose-titration % Hemolysis 50 Phase 2 PNH; 0.3 mg/kg LDH (U/L) Eculizumab (N=41) Zilucoplan X ULN ** Zilucoplan Plasm a concentration (ng/m L) Weeks Zilucoplan N = *Not a head-to-head comparison. **Weekly eculizumab loading period 21

22 Zilucoplan Phase 2 PNH Program Safety and Tolerability Profile Long-term zilucoplan exposure: > 60 weeks of dosing No dosing interruptions, down-titrations, or discontinuations due to tolerability No meningococcal infections observed No thromboembolic events observed ~100% compliance with once-daily subcutaneous self-administration at home observed (monitored remotely by smartphone) Majority of adverse events observed deemed unrelated to study drug Most common related adverse event observed has been headache Well tolerated, with very low incidence of ISRs 22

23 Zilucoplan Phase 1b PK Study in Patients with Renal Impairment Multi-Center, Open-Label Trial 8 patients with severe renal impairment 8 healthy control subjects with normal renal function Each patient received a single, SC dose of 0.3 mg/kg of zilucoplan PK profile in patients with renal impairment with subjects with normal renal function Zilucoplan can be used in patients with renal impairment without any need for dose adjustment. 23

24 Zilucoplan Phase 1b PK Study in Renally Impaired Patients Plasma Concentration-Time Profile After Single Dose Zilucoplan (ng/ml) Healthy Volunteers (n=8) Renally Impaired (n=8) No difference in PK characteristics No dose adjustment required for renal indications No dose adjustment for gmg/pnh patients with reduced GFR No adverse events reported Hours 24

25 Humanized Liver Mouse Model Inhibition of Complement C5 Following Oral Dosing Small molecule C5 inhibitors (SMi) do not bind to mouse complement C5 Immunodeficient mice transplanted with human hepatocytes provide circulating human complement + Zymosan Inhibition C5 SMi Oral dosing of SMi results in full blockade of ex vivo zymosan-mediated C5 activation (incubation in whole blood) 25

26 Array of C5 Inhibitor Assets Provides an Opportunity to Build a Transformative Franchise in Neurology Neurology Disease Targets Systemic & Local C5 Neurodegenerative C5 Lifecycle Oral Small Molecule C5 Inhibitor Highly potent, orally available Neuropathies/Myopathies Zilucoplan XR Added convenience of SC once weekly Neuromuscular Zilucoplan QD SC once daily, small peptide inhibitor, designed to inhibit C5 systemically and locally Potential of a Peptide Inhibitor in Tissue-Based C5 Diseases and a First-in-Class Oral Small Molecule 26

27 Transforming Complement Therapeutics Focused on delivering innovative and accessible therapies to patients with rare neurologic, hematologic, and renal indications Zilucoplan: A convenient, self-administered, subcutaneous C5 inhibitor gmg: Successful Phase 2 study in a broad spectrum of patients with gmg Met clinically meaningful, statistically significant reductions in pre-specified primary and key secondary endpoints Phase 3 clinical trial planned for 2H19 PNH: Positive Phase 2 study in naïve and majority of switch patients Ethno-bridging study: Completed dosing in Phase 1 study designed to support development in Japan Renal: Positive Phase 1b PK study in renally impaired patients; No dose adjustment required Building a pipeline within a product, leveraging gmg for a 3 rd indication (neurology), TBA 1H19 Advancing a portfolio of C5 inhibitors in pre-clinical development XR: Zilucoplan XR achieved greater than one week of target dose concentrations following a single subcutaneous injection in non-human primates, supporting once weekly or less frequent dosing SMi: First-in-class oral small molecule C5 inhibitor Proprietary drug discovery engine Trillion member, highly diverse, synthetic macrocyclic peptide libraries; Diversity and specificity of mabs with the pharmacologic advantages of small molecules Merck Collaboration: Oral peptide targeting a large CV market opportunity Announced receipt of 3 rd development milestone in December