Next Generation Therapeutics for Disorders of Complement Regulation

Transcription

1 Next Generation Therapeutics for Disorders of Complement Regulation January 2018

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. Data from the Company s global Phase 2 clinical program evaluating RA for the treatment of PNH in this presentation is as of November 30, 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 Phase 2 program in paroxysmal nocturnal hemoglobinuria (PNH) ongoing Safe and well-tolerated with >300 patient weeks of exposure Primary endpoint met for LDH reduction in eculizumab naïve patients (p=0.002) Successful switching demonstrated in transfusion-independent patients Encouraging early data from first patient in inadequate responder cohort Phase 3 Ready: dose, population, and device all tested and validated in Phase 2 Phase 2 study in generalized myasthenia gravis (gmg) ongoing Phase 1b PK study in renally impaired patients initiating in January 2018 to support development in atypical hemolytic uremic syndrome (ahus) and lupus nephritis (LN) 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 gmg: 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 Our Extreme Diversity Platform 6

7 mrna Display Platform: A New Approach to Building Drug-like Peptide Libraries Large and diverse library of macrocycle peptide-cdna fusions Affinity selection to immobilized target P 3 P 4 Cyclize to create macrocyclic peptides, convert mrna to cdna 2 P P 5 Large and diverse library of peptide-mrna fusions 1 Ribosome Translation of mrna to peptides to create peptidemrna fusion mrna library with 3 Puromycin (P) Copy DNA into mrna and attach puromycin Translation with natural and non-natural amino acids and cyclization to increase stability, potency, cell permeability, and bioavailability Rapid lead generation capabilities Utility Filling unmet needs associated with current monoclonal antibody, biologic, and peptide therapies Ability to distinguish between closely related targets Modulators of the undruggable proteome: Disrupt intracellular protein-protein interactions Macrocyclic peptide-cdna fusions bound to immobilized target PCR amplify cdna to produce large quantities of corresponding DNA DNA corresponding to selected peptides 6 Sequence DNA and synthesize peptide candidates Candidate Peptides 7 Optimize Hits Drug Lead 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, atypical hemolytic uremic syndrome (ahus), and generalized myasthenia gravis (gmg) 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 Phase 2 PNH Program 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 (29 patients, 18 sites, 9 countries) Eculizumab Naïve 10 patients enrolled; dosing completed Eculizumab Switch 16 patients enrolled; dosing ongoing; recruitment closed Eculizumab Inadequate Responders (US only) 3 patients enrolled; dosing ongoing; recruitment closed 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 Phase 2 Interim Data from the Eculizumab Naïve Cohort 11

12 Eculizumab Naïve Cohort Complete Baseline Characteristics Study population is consistent with real-world eculizumab naïve population Parameter Patients (n=10) Age in years, median (range) 56 (32, 81) Females, n (%) 6 (60) Disease duration in years, median (range) 0.8 (0.01, 12) LDH (U/L), mean, (range); ULN = (462, 2435) % Granulocyte clone size, median (range) 87.7 (42.8, 99.7) % RBC clone size, median (range) 41.3 (8.3, 63.3) Transfusion dependent within prior 6 months (%) 6/10 (60%) 12

13 % H e m o ly s is L D H (U /L ) Eculizumab Naïve Cohort Complete Primary Endpoint Met Rapid, near complete, and sustained inhibition of complement activity observed in srbc assay Rapid, robust, and sustained LDH reduction: primary endpoint p= x U L N B a s e lin e Week Week R A R A R A R A ( W e e k ) ( W e e k ) ( W e e k ) ( W e e k ) Load, 0.1mg/kg, Majority of patients at 0.3mg/kg and 1 titration hr) 0, N= Week Baseline* Patients, n *Baseline is the average of the screening and week 0 data per patient 13

14 Eculizumab Naïve Cohort Complete Overlay*: RA SC (Naïve) and Eculizumab Phase 3 Data 1,2 Transfusion avoidance rates (50%), and QOL improvements also similar to observations from published eculizumab Phase 3 data **Relative overdosing of eculizumab during weekly loading period coincides with relative underdosing of RA during dose-titration ** RA N= Hillmen et al. N Engl J Med U.S. FDA/CDER. (2007) BLA Pharmacometrics Review Eculizumab/Soliris *Not a head-to-head comparison. No head-to-head comparison study has been conducted comparing RA SC and eculizumab. Differences exist between trial designs and subject characteristics. 14

15 L D H (U /L ) L D H (U /L ) Eculizumab Naïve Cohort Complete Notable Case Studies Maximum activity was observed in the patient with the highest baseline LDH No recurrence of breakthrough hemolysis observed at week 6 in association with viral infection % reduction from baseline LDH remains well-controlled through 6 months of follow-up x U L N x U L N 0 B a s e lin e W e e k Week Case Study 1: 32 yr. old M Caucasian Patient with the highest baseline LDH (2435U/L) 0 B a s e lin e R A ( W e e k ) Week R A ( W e e k ) Case Study 2: 65 yr. old F Caucasian Patient 2 from initial data release (June 2017) 15

16 Eculizumab Naïve Cohort Complete Improvements in Transfusion Dependence Observed Subject ID Transfused during 6 months prior to Week 0 visit Transfused anytime after Week 0 visit* No No Yes Yes No No Yes Yes Yes Yes No No Yes No No No Yes No Yes No 50% of treatment naïve, transfusion-dependent patients have been transfusion-free on RA SC *All patients have completed a minimum of 12 weeks dosing 16

17 Eculizumab Naïve Cohort Complete QOL and Treatment Satisfaction QOL Assessment Mean FACIT Fatigue Scores (SE), n=10 Treatment Satisfaction Score Mean (SE), n=10 Very Satisfied 5 Satisfied 4 Neutral 3 Dissatisfied 2 Very Dissatisfied 1 Increase of 5.9 points from baseline to Week 12 QOL = quality of life FACIT = functional assessment of chronic illness therapy At the final study visit (W12) patients were asked: How satisfied are you with the overall method of study medication administration (subcutaneous self-injection; 5-point scale, 1= very dissatisfied, 5= very satisfied)? 17

18 Phase 2 Interim Data from the Eculizumab Switch Cohort 18

19 Eculizumab Switch Cohort Ongoing Switch Population: Response to Long-Term Eculizumab Therapy Two distinct populations after 3 years of eculizumab treatment 80% 20% Hillmen et al. Br J Hematol

20 Eculizumab Switch Cohort Ongoing Baseline Characteristics Study population is overrepresented by poor responders to eculizumab who remain transfusion-dependent on long-term therapy (69% in study vs 20% real-world 1 ) Parameter Patients (n=16) Age in years, median (range) 53 (22, 72) Females, n (%) 7 (44) Disease duration in years, median (range) 5.1 (1.8, 36) LDH (U/L), mean, (range; ULN = 234) 287 (222, 542) % Granulocyte clone size, median (range) 97.0 (21.2, 99.8) % RBC clone size, median (range) 66.0 (5.4, 99.0) Eculizumab dose > 900mg, n (%) 4 (25%) Duration of eculizumab treatment in years, median (range) 3.8 (1.0, 12) Transfusion dependent within prior 6 months 11/16 (69%) 1 Hillmen et al. Br J Hematol

21 % H e m o ly s is E c u liz u m a b ( g /m L ) Eculizumab Switch Cohort Ongoing Near Complete Complement Inhibition Observed Near complete, sustained, and uninterrupted inhibition of complement activity has been observed in srbc assay during and after eculizumab washout, which exceeded the level of inhibition present at eculizumab trough (Week 0) % H e m o ly s is E c u liz u m a b ( g /m l) Week R A ( W e e k ) 21

22 L D H (U /L ) Eculizumab Switch Cohort Ongoing Robust LDH Control in Transfusion-Independent Patients - In transfusion-independent eculizumab patients (~80% of real-world population on long-term treatment), switching to RA SC has resulted in stable LDH levels and no episodes of breakthrough hemolysis - In transfusion-dependent eculizumab patients (~20% of real-world population on long-term treatment), breakthrough hemolysis was observed in 7, all of whom reverted to eculizumab therapy between Week 4 and Week 10 without complications T ra n s fu s io n D e p e n d e n t T ra n s fu s io n In d e p e n d e n t x U L N 0 B a s e lin e Week N= R10 A R1 A (7 early withdrawals) ( W e e k ) ( W e e k ) N= (No early withdrawals) 16 Transfusion-dependent switch patients will be excluded from planned Phase 3 22

23 L D H (U /L ) Eculizumab Switch Cohort Ongoing Case Study: Successful Switching from Eculizumab to RA SC Example of successful switching from eculizumab to RA SC with no LDH excursions Last dose of eculizumab was two weeks prior to baseline visit x U L N 0 B a s e lin e W e e k 28 yr. old transfusion-independent M Caucasian on eculizumab for 7 years 23

24 Phase 2 Interim Data from the Eculizumab Inadequate Responder Cohort 24

25 L D H (U /L ) Inadequate Responder Cohort Ongoing Case Study: First Inadequate Responder (USA) - 53 yr. old M Caucasian with elevated LDH and documented intolerance to eculizumab (fatigue and pain post-infusions) receiving 450mg every 2 weeks - Since switching to RA SC, LDH has been well-controlled and pain medications have been down-titrated x U L N 0 S c r e e n in g Week R A

26 RA SC Phase 2 PNH Program Safety and Tolerability Cumulative RA SC exposure: Over 300 patient-weeks 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 7 mild (grade 1) ISRs among 3 subjects out of >2,000 self-administered injections 26

27 Opportunity to Expand Patient Access with a More Convenient and Cost Effective C5 Inhibitor Naïve patients: PNH: Majority of patients with PNH have yet to initiate treatment (Alexion 3Q17 Earnings Presentation, Oct. 26, 2017) Transfusion dependent eculizumab patients (18%) ~16,000 PNH patients WW PNH Registry data (2017 ASH Abstracts) Nearly 2,500 patients in PNH safety database were not receiving eculizumab (July 2016) 1 Significant disease burden even among patients with clone size <10% 2 Transfusion independent eculizumab patients (72%) Naïve patients (new starts) (10%) ~$1.5B eculizumab PNH market (2017) Current accessible RA SC market Switch patients: Addressable population 80% of long-term eculizumab patients are transfusion independent 3 5/5 transfusion-independent patients switching to RA SC have had stable LDH levels and no episodes of breakthrough hemolysis A more convenient and cost-effective C5 inhibitor may expand access for PNH patients WW untreated naïve patients Potential for market growth and increased/earlier use in naïve patients based on patient access and convenience Data as of November 30,

28 RA SC Phase 2 PNH Program Future Plans for Approval & Expanding Patient Access Our goal is to seek the most rapid path to approval combined with highly competitive pricing to expand patient access around the world and establish RA SC as first-line therapy in PNH End-of-Phase 2 meetings with regulators are planned 1H2018 Start of PNH Phase 3 program planned 2H2018 Follow-up programs in preclinical development Extended Release RA SC to support weekly dosing Oral Small Molecule C5 program BD UltraSafe Plus (with pre-filled syringe) Used in more than 50 commercial products 28

29 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) 1-2x daily Every 8-weeks Biweekly Unknown Daily 3x daily Stage Ph2 Ph2 Ph3 (fully enrolled) Ph3 Ph1/2 Ph1b Ph2 R885H/C Mutations Comments 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 Immunogenicity and generalized pruritis seen in Phase 1 Not adequate for monotherapy Increased risk of infection Very high doses, Large volumes via infusion pump Significant LFT liability in Ph1 Increased risk of infection and breakthrough hemolysis Additional PNH programs: Novartis (Ph2), Regeneron (Ph1) 29

30 RA SC Phase 2 PNH Program Summary Primary endpoint met in naïve cohort (p=0.002) In treatment-naïve patients, LDH reductions, transfusion avoidance, and QOL improvements are similar to observations from published eculizumab Phase 3 data Successful switching observed for transfusion-independent eculizumab patients, which constitutes the vast majority (80%) of patients on long-term eculizumab therapy Encouraging early data from first patient in inadequate responder cohort PK and PD data support 0.3 mg/kg as the preferred dose for Phase 3 No meaningful safety, tolerability, or compliance concerns observed 30

31 % H e m o ly s is Alternative Pathway RA SC: Inhibition of Complement Activity in Phase 2 Provides Read-Through Across Multiple C5-Mediated Diseases Activated by non-self cells Activated by antibody-antigen complexes Activated by pathogen su Factor D, Factor B C3 Classical Pathway Classical C5Pathway Factor targeted by Ra Pharma product candidates R A Week R A Factor targeted ( W eby e k Ra ) Pharma product ( Wcandidates e e k ) C1q C1r C1s C2, C3, C4 Near Complete Inhibition of Complement Alternative Pathway C5-Mediated Diseases Activated by non-self cells C5a Activated by antibody-antigen complexes C5b Activated by pathogen surfaces Proinflammatory C3 C1q C1r C1s cytokine C6 Factor D, Factor B C2, C3, C4 PNH: rupture of RBC eculizumab RA C5b6 C5 Binds C5 Binds C5 & C5b C7, C8, C9 C5a Proinflammatory 5cytokine eculizumab Binds C RA Binds C5 & C5b 16 C5b C5b6 MAC C6 MAC C7, C8, C9 Lectin Pathway Lectin Pathway PNH: rupture of RBCs gmg: destruction of neuromuscular junction gmg: destruction of neuromuscul junction PNH: rupture of RBC ahus: thrombotic micro-angiopathy LN: inflammation of kidney glome gmg: destruction of neuromuscular junction LN: inflammation of kidney glomerulus LN: inflammation of kidney glomerulus 1 31

32 RA SC in Generalized Myasthenia Gravis (gmg) 32

33 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 33

34 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 34

35 RA SC in Renal Diseases 35

36 Renal Indications for RA SC Phase 1b PK study in renally impaired patients initiating in 1Q 2018, 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 36

37 RA SC Large Market Opportunity Across Multiple C5 Indications Undertreated, segmented populations, rare vs. ultra rare pricing, and convenience offer the opportunity to capture and expand multiple market segments across initial target indications PNH Worldwide population ~16,000 Treated population (est.) 4,000-5,000 ahus Worldwide population ~5,500 Treated population (est.) 2,000-3,000 gmg Worldwide population ~94,000 Treatable population ~47,000 XR formulation and oral small molecules provide lifecycle management opportunities Source: data on file 37

38 Small Molecule C5 Inhibitors and Broader Pipeline 38

39 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 39

40 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 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 Reduce C3 fragment coating on PNH RBCs and subsequent spleen phagocytosis (extravascular hemolysis, EVH) 1. Klein, R., et al, Science,

41 Corporate Summary 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 Phase 2 program in paroxysmal nocturnal hemoglobinuria (PNH) ongoing Safe and well-tolerated with >300 patient weeks of exposure Primary endpoint met for LDH reduction in eculizumab naïve patients (p=0.002) Successful switching demonstrated in transfusion-independent patients Encouraging early data from first patient in inadequate responder cohort Phase 3 Ready: dose, population, and device all tested and validated in Phase 2 Phase 2 study in generalized myasthenia gravis (gmg) ongoing Phase 1b PK study in renally impaired patients initiating in January 2018 to support development in atypical hemolytic uremic syndrome (ahus) and lupus nephritis (LN) 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 41