Next Generation Therapeutics for Disorders of Complement Regulation

Transcription

1 Next Generation Therapeutics for Disorders of Complement Regulation November 2017

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 and regulatory and clinical progress of our product candidates, including RA 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 RA101495, will not successfully be developed or commercialized; the risk that initial data from the Company s global Phase 2 clinical program evaluating RA for the treatment of PNH may not be indicative of final study results; the risk that initial data from a limited number of patients may not be indicative of results from the fully patient enrollment planned for such study; 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. All information in this presentation is as of November 10, 2017, and Ra Pharma undertakes no duty to update this information unless required by law. 2

3 Overview Focused on complement-mediated diseases Rare hematologic, renal, and neurologic indications, as well as ocular and autoimmune diseases Lead clinical program: RA SC Potent, synthetic, macrocyclic peptide inhibitor of complement C5 Convenient, self-administered, subcutaneous (SC) dosing Completed Phase 1 safety, PK, and PD study in healthy volunteers Rapid, sustained, near-complete suppression of complement activity Phase 2 program in paroxysmal nocturnal hemoglobinuria (PNH) ongoing Phase 2 study recruiting in generalized myasthenia gravis (gmg) Phase 1b study to support development in atypical hemolytic uremic syndrome (ahus) and lupus nephritis (LN), initiating in 4Q17 Portfolio of C5 inhibitors in pre-clinical development Extended release formulation of RA SC Oral small molecule C5 inhibitor Powerful proprietary drug discovery engine Trillion member, highly diverse, synthetic macrocyclic peptide libraries Combines the diversity and specificity of mabs with pharmacologic advantages of small molecules Collaboration with Merck for an oral peptide targeting a large CV market opportunity 3

4 Pipeline C5 Inhibition Franchise RA SC (PNH) DISCOVERY PRECLINICAL PHASE 1 PHASE 2 RA SC (gmg) RA SC (ahus/ln) RA Extended Release (XR) Factor D Inhibition Partnered Program Oral Small Molecule Inhibitor Orphan Renal Diseases (SC) Other Complement Inhibitors Ocular/Autoimmune/CNS diseases (Non-Complement target) Oral Macrocyclic Peptide (Cardiovascular target with a large market opportunity) 4

5 The Complement Pathway A Target-Rich Alternative Opportunity Pathway Supporting Classical Pathwaya Multi-Indication Franchise Alternative Pathway Activated by non-self cells Activated by antibody-antigen complexes Activated by pathogen surfaces Classical Pathway Lectin Pathway Lectin Pathway C3 C1q C1r C1s Alternative Pathway Classical Pathway Lectin Pathway Activated by non-self Factor D, Factor cells B Activated by antibody-antigen C2, C3, C4complexes Activated by pathogen surfaces Activated by non-self cells Activated by antibody-antigen complexes Activated by pathogen surfaces C3 C5 C1q C1r C1s C3 C1q C1r C1s Alternative Factor D, Factor Pathway B Classical Pathway Lectin Pathway Factor D, Factor B C5a C2, C3, C4 C5b Activated by non-self Proinflammatory cells Activated C5 by antibody-antigen complexes Activated by pathogen surfaces cytokine C5 C6 PNH: rupture of RBC C3 C1q C1r C1s PNH: rupture of RBC C5b6 Factor D, Factor C5a B eculizumab RA C5a C2, C3, C4 C5b Binds C5 Binds C5 & C5b C5b Proinflammatory Proinflammatory C7, C8, C9 cytokine C6 rmg: destruction of neuromuscular cytokine C5 C6 MAC junction gmg: destruction of neuromuscular PNH: rupture junction of RBC eculizumab eculizumab RA RA C5b6 C5b6 C5a C5b Binds C5 Binds C5 Binds C5 Binds & C5b & C5b Proinflammatory C7, C8, C7, C9 C8, C9 cytokine C6 ahus: hemolytic anemia, MAC MAC gmg: destruction of neuromuscular PNH: rupture thrombocytopenia, of RBC LN: inflammation and renal of failure kidney glomerulus junction eculizumab RA C5b6 Binds C5 Factor targeted Binds by C5 Ra & Pharma C5b product C7, candidates C8, C9 MAC Factor targeted by Ra Pharma product candidates gmg: destruction LN: LN: inflammation of neuromuscular of of kidney kidney glomerulus junction 1 LN: inflammation of kidney glomerulus 1 Factor targeted by Ra Pharma product candidates 5

6 About RA SC Potent inhibitor of complement C5, designed for convenient, subcutaneous selfadministration (vs. IV) Improved quality of life (inconvenience and lack of freedom associated with IV infusion) Reduced complications of IV infusion (infection, venous access, thrombosis, discomfort of ports) Reduced treatment costs and reduced time/economic losses associated with home/clinic infusion Single and repeat SC doses of RA were safe and well tolerated in healthy volunteers Highly predictable PK profile with minimal peak/trough variability Robust complement inhibition demonstrated Phase 2 program ongoing in PNH Orphan drug designation from U.S. FDA and European Medicines Authority (EMA) As of November 9, 2017, 28 patients enrolled with 27 patients dosed (10 patients in eculizumab naïve cohort; 16 patients in eculizumab switch cohort; 1 patient in inadequate responder cohort) Anticipated interim data read-out around year-end 2017 Phase 2 study in gmg recruiting Anticipated initial data read-out 1H19 Phase 1b PK study in renally impaired patients initiating in 4Q 2017 Supports development in ahus and LN 6

7 RA SC: Pharmacodynamics Robust Suppression of Hemolytic Activity in Phase 1 Multiple-Dose Cohort Suppression of hemolysis and complement activity was rapid, near-complete and sustained across the dosing period in all subjects Inhibition of hemolysis activity at D8 (24h after receiving the last dose) was observed to be 97% in all subjects Hemolysis activity returned to pre-dose levels within two weeks following the last dose ] n=2 (placebo) or 4 (0.2 mg/kg RA101495) dosed daily per group 7

8 RA SC in Paroxysmal Nocturnal Hemoglobinuria (PNH) 8

9 RA SC: Paroxysmal Nocturnal Hemoglobinuria (PNH) Rare, chronic, acquired hematologic syndrome where red blood cells (RBCs) are destroyed by the complement system ~16,000 patients worldwide Results in death of 35% of patients within 5 years and 50% within 10 years of diagnosis Most common cause of mortality is thrombosis Only 1 approved therapy: anti-complement C5 monoclonal antibody [eculizumab (Soliris ); Alexion] Biweekly IV infusion Approved for PNH and atypical hemolytic uremic syndrome (ahus) 2016 revenues: ~$2.8B Straightforward clinical endpoints Markers of hemolysis, hemoglobin levels, transfusion requirements Strong correlation between level of hemolysis suppression and clinical benefit 9

10 RA SC: PNH Phase 2 Design Goal: Dose-finding study to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics, and pharmacodynamics of RA SC in patients with PNH Design: Open-label (12 weeks) with long-term extension Global program addressing 3 PNH populations Eculizumab Naïve (Cohort A): n= 8 12 Eculizumab Switch (Cohort B): n= 6 8 Eculizumab Inadequate Responders: n = 6 8 Dose-finding regimen Loading dose: 0.3mg/kg SC on Day 1 Starting dose: 0.1mg/kg SC once daily for the first 2 weeks Up-titration: from the week 2 visit onwards, if LDH is 1.5xULN, the dose is increased to 0.3mg/kg SC once daily Primary efficacy endpoint: Change in lactate dehydrogenase (LDH) from baseline to the mean level from Week 6 to Week 12 10

11 RA SC: PNH Phase 2 Initial Data: Executive Summary As of November 9, 2017, 28 patients enrolled with 27 patients dosed 10 eculizumab naïve patients 16 eculizumab switch patients 1 inadequate responder As of June 27, 2017, two naïve patients had completed 7 weeks of follow-up No safety or tolerability concerns identified; no injection site reactions Near-complete inhibition of hemolytic activity achieved Rapid declines in LDH observed; mean LDH at Week 7 = 1.6 x ULN As seen with other C5 inhibitors, one transient episode of breakthrough hemolysis associated with inter-current illness 100% compliance with once-daily subcutaneous self-administration First two patients in the naïve cohort elected to continue treatment with RA SC in a long-term extension study Eculizumab switch cohort opened following review of the initial data reported in the naïve cohort 11

12 R A (n g /m L ) H e m o g lo b in (g /d L ) % H e m o ly s is H e m o g lo b in (g /d L ) L D H (U /L ) RA SC: PNH Individual Data: Patients 001 and Direct Hemolysis Assay (sheep RBC) * H o u r Log Drug Levels * W e e k * * * * D o s e In8 c0 re 0 a s e to * 0.3 m g /k g * W e e k D o s e In c re a s e to 0.3 m g */k g LDH T T * T P a tie n t P a tie n t D o s e In c re a s e to 0.3 m g /k g T ra n s fu s io n Hemoglobin * W e e k * * T T 1.5 x U L N * T * D o D o s e T ra n s H o u r W e e k Scheduled visits W0,1,2,3,4,6. Other visits unscheduled; Data as reported on June 27, 2017 W e e k 12

13 RA SC: A Well-Differentiated Profile For Treating PNH RA Coversin ALXN1210 ABP959 RO (SKY59) APL-2 ACH-4471 Chemistry Cyclic peptide Tick saliva protein mab mab mab Cyclic peptide Small molecule Target C5 C5 C5 C5 C5 C3 Factor D Administration SC SC IV, SC IV IV, SC SC Oral Frequency Daily, (Weekly) 2x daily Every 8-weeks Biweekly Unknown Daily 3x daily Stage Ph2 Ph2 R885H/C Mutations Comments Ph3 (fully enrolled) Ph3 Ph1/2 Ph1b Ph2 Rapidly and potently inhibits hemolysis Small volume, Convenient dosing Favorable PK Short half-life Immunogenicity No safety margin for missed doses Extremely high doses FcRn recycling technology Potential saturation of FcRn Biosimilar to Soliris, Initiating Phase 3 FcRn and C5 sweeping technology Potential saturation of FcRn Not adequate for monotherapy Increased risk of infection Very high doses, Large volumes Significant LFT liability in Ph1 Increased risk of infection and breakthrough hemolysis Additional PNH programs: Novartis (Ph2), Regeneron (Ph1) 13

14 RA SC in Generalized Myasthenia Gravis (gmg) 14

15 RA SC: Generalized Myasthenia Gravis (gmg) Rare, complement-mediated, autoimmune disease that causes weakness in the skeletal muscles ~30,000 to 50,000 patients in the United States Caused by auto-antibodies to neuromuscular junction (NMJ) proteins critical for the normal transmission of signals from nerves to muscles Acetylcholine Receptor (AChR) is common target (80%) Leads to MAC deposition and tissue damage at NMJ Image from: Engel et al., Neurology 1977 Ultrastructural localization of acetylcholine receptor (AChR) at the muscle end-plate in a control subject (A) and in a patient with generalized myasthenia gravis (B). Typical treatments include: cholinesterase inhibitors, chronic corticosteroids and other non-specific immunosuppressants, intravenous immunoglobulin, plasma exchange, and thymectomy Inhibition of complement component C5 is a validated target in myasthenia gravis Eculizumab recently approved as a treatment for adult patients with gmg who are AChR antibody-positive 15

16 RA SC: gmg Phase 2 Design Goal: To evaluate the safety, tolerability, and efficacy of 2 doses of RA SC in patients with gmg Design: Randomized, double-blind placebo-controlled multicenter study, 12- week treatment period followed by a long term extension (LTE) study Patient population: Generalized MG (Myasthenia Gravis Foundation of America class II-IVa) AChR-antibody positive Quantitative Myasthenia Gravis (QMG) score of 12 No requirement to have failed multiple prior therapies Stable doses of corticosteroids and/or immunosuppressants Patients will be randomized in a 1:1:1 ratio to receive daily doses of: 0.1 mg/kg SC (n=12) 0.3 mg/kg SC (n=12) Placebo (n=12) Primary Efficacy Endpoint: Change in QMG score from baseline to week 12 Secondary Endpoints include: Myasthenia gravis activities of daily living (MG-ADL) Placebo patients will switch to active drug in LTE study Phase 2 study in gmg recruiting Anticipated initial data read-out 1H19 16

17 RA SC in Renal Diseases 17

18 Renal Indications for RA SC Phase 1b PK study in renally impaired patients initiating in 4Q 2017, supporting development in: Atypical hemolytic uremic syndrome (ahus): ~1,000 patients in the US ~33-40% of patients die or progress to end-stage renal disease with the first clinical manifestation of ahus despite plasma exchange/plasma infusion ~79% of all patients with ahus have died, required kidney dialysis, or had permanent kidney damage within three years of diagnosis despite plasma exchange/plasma infusion Eculizumab only approved therapy (inhibits complement-mediated thrombotic microangiopathy) Lupus nephritis (LN): ~63,000 patients in the US ~10-15% develop end-stage renal disease requiring kidney transplant or initiation of dialysis Inhibiting C5 activation may prevent progression of kidney disease by blocking complement-mediated damage to kidney cells 18

19 Small Molecule C5 Inhibitors and Broader Pipeline 19

20 Next Generation C5 Inhibitors: Orally Bioavailable Small Molecules Series of orally bioavailable (%F=50) small molecules that bind C5, inhibit its cleavage/activation (IC nm in sheep RBC lysis assay), and prevent hemolysis of PNH erythrocytes in a dose dependent manner Serum* Serum + HCl Serum + HCl + Eculizumab Serum + HCl + RAX-4110 Type III Type I+II RAX-4110 concentration High resolution co-crystal structures of SM inhibitors bound to C5 available Complete understanding of mechanism of action Enables structure-guided optimization *18h incubation of PNH RBCs with 50% acidified serum. PNH RBCs provided by Dr. Jaroslaw Maciejewski 20

21 Therapeutic Use Of Factor D Inhibitors Factor D (FD) is a critical mediator of alternative pathway activation Cleaves Factor B bound to C3b, generating C3 convertase (C3bBb) FD Potential indications: Dense deposit disease/membranoproliferative Glomerulonephritis type II/C3 Glomerulopathy (High priority) Uncontrolled activation of alternative pathway results in glomerular C3 deposition Mutations/polymorphisms in complement genes associated with increased risk Extravascular hemolysis in PNH patients treated with C5 inhibitor (Lower priority) Reduce C3 fragment coating on PNH RBCs and subsequent spleen phagocytosis (extravascular hemolysis, EVH) 1. Klein, R., et al, Science,

22 Clinical Milestones Commence dosing for Phase 2 PNH program Initial interim data read-out for Phase 2 PNH program Phase 2 study in gmg recruiting Initiate Phase 1b study to support ahus and LN 2Q17 Mid-17 4Q17 4Q17 Interim data readout for Phase 2 PNH program Around YE 17 22

23 Investment Highlights Focused on complement-mediated diseases Rare hematologic, renal, and neurologic indications, as well as ocular and autoimmune diseases Lead clinical program: RA SC Potent, synthetic, macrocyclic peptide inhibitor of complement C5 Convenient, self-administered, subcutaneous (SC) dosing Completed Phase 1 safety, PK, and PD study in healthy volunteers Rapid, sustained, near-complete suppression of complement activity Phase 2 program in paroxysmal nocturnal hemoglobinuria (PNH) ongoing Phase 2 study recruiting in generalized myasthenia gravis (gmg) Phase 1b study to support development in atypical hemolytic uremic syndrome (ahus) and lupus nephritis (LN), initiating in 4Q17 Portfolio of C5 inhibitors in pre-clinical development Extended release formulation of RA SC Oral small molecule C5 inhibitor Powerful proprietary drug discovery engine Trillion member, highly diverse, synthetic macrocyclic peptide libraries Combines the diversity and specificity of mabs with pharmacologic advantages of small molecules Collaboration with Merck for an oral peptide targeting a large CV market opportunity $84.1 million in cash and cash equivalents as of September 30,

24 Contact: Jen Robinson Senior Director, Investor Relations & Corporate Communications 24