Orphan Focused Patient Driven

Transcription

1 Orphan Focused Patient Driven June 21, Achillion Pharmaceuticals. All rights reserved. NASDAQ:ACHN

2 Cautionary Note Regarding Forward-Looking Statements This presentation includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements. Achillion may use words such as expect, anticipate, project target, intend, plan, aim, believe, seek, estimate, can, could, focus, will, look forward, continue, goal, strategy, may and similar expressions to identify such forward-looking statements. These forward-looking statements include statements about Achillion and its business and prospects, including, without limitation, statements regarding drug discovery, research, clinical development, timing of anticipated clinical trials and clinical data for our product candidates, our expectations regarding the potential safety, efficacy and clinical utility of our product candidates, regulatory approval processes, market opportunities, strategic goals, our previous collaboration with Janssen in HCV, intellectual property, competition, and financial results. To the extent that statements contained in this presentation are not descriptions of historical facts, they are forward-looking statements reflecting management s current beliefs and expectations. Various important factors may cause differences between our forward-looking statements and actual results, including without limitation, unexpected or unfavorable safety or efficacy data, lower than expected enrollment rates in clinical trials, changes in the competitive landscape for our product candidates, changes in the regulatory environment, changes in market conditions or future demand for our product candidates, the inability to protect our intellectual property, our freedom to operate under third party intellectual property, our need for future capital, the risk of litigation or other disputes, and general market and economic conditions. These and other risks and uncertainties are described in the reports filed by Achillion with the SEC, including its annual report on Form 10-K and quarterly reports on Form 10-Q, and subsequent filings with the SEC from time to time. You should read these reports, including the Risk Factors contained in these reports with the understanding that our actual future results may be materially different from what we currently expect. All forward-looking statements contained in this presentation speak only as of the date hereof, and Achillion undertakes no obligation to update any of these statements, except as required by law. 2

3 Complement Factor D Portfolio PROGRAM INDICATION DELIVERY PRECLINICAL CLINICAL MILESTONES Phase 1 Phase 2 Phase 3 ACH-4471 Factor D Inhibitor Oral C3G: 14-day proof-of-concept biomarker trial C3G: 12-month open-label therapeutic trial Interim 14-day data 3Q18 Interim ~3-month data 4Q18 C3G: 6-month randomized, double-blind trial Data in 2019 PNH: Monotherapy open-label untreated PNH Interim data 4Q18 PNH: Add-on to eculizumab sub-optimal PNH responders Interim data 4Q18 ACH-5228 Next-Generation Factor D Inhibitor AP-mediated diseases ACH-5548 Next-Generation Factor D Inhibitor AP-mediated diseases Oral Oral Interim data in 2H18 Initiate Ph 1 in 2Q18 3

4 Achillion: Factors for Success First-in-class pipeline for complement APmediated rare diseases Strong market opportunities for fd inhibitor portfolio Patient-focused and experienced management team $308M at 3/31/18 to support multiple value infection points 4

5 ACH-4471 Summary C3G Proof of Concept o Biomarkers o Proteinuria PNH Proof of Concept o LDH, hemoglobin, and FACIT scores o Two patients have been dosed for greater than one year o Well-tolerated to date Phase I Program o Multiple DDI, ADME, and support studies completed o >150 healthy volunteers dosed o Completing renal-impairment study Toxicology Program o 6 and 9 month studies completed and support continued development Regulatory o Support from regulatory agencies for Phase II program in C3G and PNH ACH-4471:Factor D Complex 0.8 A X-ray Structure 5

6 Intellectual Property Broad IP footprint IP filings support platform strategy to pursue distinct NCEs for specific drug delivery options and for disease groups Currently 9 issued U.S. patents owned solely by Achillion 18 additional COM patent applications published March 2017 o Represent the first three waves of patent applications filed by Achillion to cover new complement factor D inhibitors and uses. Aggressively protecting our complement factor D assets o Filed multiple additional non-provisional patent applications 6

7 Mechanism Matters: Factor D Inhibition Lectin Pathway Alternative Pathway C1q C1r-C1s C4 MBL MASP-1,2 C3 fh Ba fh C3 Classical Pathway C4a C2 C3b C3b C3(H 2 O) Bb C3(H 2 O) B C3(H 2 O) fb C2b C3 fd fb fd C4b2a C3a C3bBb Ba C3bB fb C3dg C3d C3c ic3b C3 protein Factor D C3 fd Fluid Phase C3b C5 C4b2a3b C5a C3bBb3b C6-9 FACTOR D A critical control point specifically within the AP TRIGGER POINT INHIBITOR Prevents amplification and modulates downstream complement cascade Terminal Pathway C5b 7

8 C3 Glomerulopathy (C3G) Rare Kidney Disease Associated with AP Hyperactivity

9 C3 Glomerulopathy A Rare Disease with No FDA-Approved Treatment ~4K ~4K ~1K Significant unmet medical need as nearly half of C3G patients progress to end-stage renal disease C3G caused by dysregulation of the complement system, leading to deposition of C3G fragments on the kidney 30 50% progress to ESRD within 10 years Significant disease burden at onset inflammation, profound fatigue and weakness Greater than 50% of patients experience disease recurrence post renal transplant, with a 50% chance of graft loss Sources: Servais et al (2013); Medjeral-Thomas et al (2014); Data on File. Achillion Pharmaceuticals

10 C3 Glomerulopathy Patients Need Effective Treatments that Address Root Cause Significant physical and emotional toll on patients including: o o o Hypertension and edema Susceptibility to infection Anxiety and depression from uncertainty regarding progression No approved therapies to treat disease and limited therapies to address edema and fatigue Urgent need for disease-modifying treatment to maintain kidney function in native or transplanted kidneys, not just address symptoms 10

11 Pillars of Achillion s Patient-Focused Support Moving beyond the Pill C3G Patient-focused Drug Development WeC3G patient support initiative Natural history study: Together, we are C3G First PFDD meeting focused on a renal disease led by the NKF with FDA participation Sponsored by Achillion Goal was to understand the patient experiences and perspective Unites voices of community impacted by disease Connects patients and caregivers to each other and to information, support and resources that can shine the light on C3G Raises awareness and understanding Ongoing study conducted by Imperial College of London in up to 400 patients globally Tracks natural course of disease over 4 years Achillion is a uniting force working to expand our awareness and understanding of C3G and patient needs

12 Normal Alternative Pathway and Kidney Histology C3 fh Ba fh C3 C3b C3(H 2 O) Bb C3(H 2 O) B C3(H 2 O) fb fd C3d ic3b C3 protein C3 C3dg C3c Factor D fd Fluid Phase C3dg C3d C3c ic3b C3d ic3b NORMAL GLOMERULAR FUNCTION No Proteinuria Normal GFR C3dg C3c 12 NORMAL KIDNEY HISTOLOGY

13 Overactive Alternative Pathway and C3G Kidney Histology fh fh C3 C3 NeF Ba C3 C3(H 2 O) Bb C3(H 2 O) B C3(H 2 O) fb C3 nephritic factor Mutated factor H C3b fd Increased C3d ic3b C3 protein C3 Decreased C3dg C3dg C3c Factor D fd Fluid Phase C3d ic3b C3d ic3b C3dg C3c C3dg C3c C3d ic3b C3dg C3c C3d ic3b C3dg C3c C3dg C3d C3d ic3b ic3b C3dg C3c C3d ic3b C3c C3dg C3c C3d ic3b C3d ic3b C3dg C3c C3dg C3c C3d ic3b C3d C3dg C3c g C3dg C3d C3G is a DISEASE of DEPOSITION Results in abnormal glomerular function Proteinuria Reduced GFR C3G DISEASE HISTOLOGY 13

14 ACH-4471 C3G: Phase 2 Clinical Development Program Interim Data and Next Steps

15 C3 Glomerulopathy Phase 2 14-Day Trial in Patients with C3G Clinical Trial Design Group 1: 2 patients received ACH mg TID x 14 days followed by 7-day taper Group 2: Up to 8 additional patients to receive ACH mg TID x 14 days followed by 7-day taper Criteria Must have confirmed diagnosis of C3G C3 must be <50% LLN with C4 >90% LLN Estimated glomerular filtration rate cannot be < 45 ml/min/1.73m 2 Outcome Measures Changes in biomarkers of alternative pathway activity (AP) including: - C3 fragments and intact C3 levels, Bb, and Ba Proteinuria Pharmacokinetic profiles Clinical Trial Status o Group 1: Complete Group 2: Ongoing 15

16 C3 GLOMERULOPATHY (C3G) Phase 2 14-day Trial in Patients with C3G or IC-MPGN DAY 1 DAY 49 OUTCOME MEASURES SCREENING TREATMENT 14 DAYS TAPER 7 DAYS FOLLOW UP 28 DAYS CRITERIA Must have diagnosis of C3G or IC-MPGN based on central review of historical biopsy Low C3 with normal/ near-normal C4 CLINICAL TRIAL DESIGN GROUP 1 2 patients received ACH mg TID x 14 days followed by 7-day taper GROUP 2 Up to 8 additional patients to receive ACH-4471 at doses up to 200mg TID x 14 days followed by 7-day taper Status: Data available for 4 patients; recruitment ongoing Ou Changes in AP biomarkers : - Intact C3 levels - C3 fragments - Bb/Ba Clinical manifestations of disease: albumin to creatinine ratio (ACR), BP, egfr Safety and tolerability Pharmacokinetic profile 16

17 Key Baseline Patient Characteristics Group Patient Age (Y) Sex Weight (kg) Urine dipstick for protein ACR (0-2.5 mg/mmol) Day 1 Pre-dose BP (mmhg) Renal Biopsy Diagnosis 1 A 30 M /72 C3GN B 19 M /80 IC-MPGN* 2 C 27 M 90 Trace /83 C3GN D 22 M /74 C3GN Concomitant medication doses were stable for at least one month prior to the first dose of study drug, and included mycophenolate mofetil (n=2), prednisone (n=2), ACE/ARB (n=4), atorvastatin (n=2), and spironolactone (n = 3) egfr > 60 ml/min/1.73m 2 in all patients * Final review by central pathologist confirmed that the historical biopsy met criteria for IC-MPGN Data presented May 26, 2018 at the 55 th ERA-EDTA Congress 17

18 Trends in AP Activity with 14-Day ACH-4471 Treatment Mean Serum C3 (g/l) Range: n=4 SCREENING DAY 1 DAY 15 FOLLOW-UP Pre-dose DAY 28 Mean Complement Bb (μg/ml) Range: n=4 SCREENING DAY 1 DAY 15 FOLLOW-UP Pre-dose DAY 28 FOLLOW-UP DAY 49 FOLLOW-UP DAY Mean Fragment C3 (% of total C3) Range: n=4 SCREENING DAY 1 DAY 15 FOLLOW-UP Pre-dose DAY 28 Mean Ba Production, ex vivo (ng/ml) n=4 FOLLOW-UP DAY 49 Day 1 predose Day 15 Day 28 Day 35 Ex vivo Ba production assay is non-glp Trends in AP biomarkers show reduction in AP hyperactivity with ACH-4471 treatment Data suggest that further improvements in AP hyperactivity may be observed with longer treatment durations Data presented May 26, 2018 at the 55 th ERA-EDTA Congress 18

19 Evidence of fd Inhibition and the AP Response PATIENT BIOMARKER BASELINE ON-TREATMENT POST-TREATMENT A B C D Serum C3 Low Increased Decreased to baseline Fragment C3 * (% of total) High Decreased Increased to baseline Bb Normal Slightly decreased Normal Serum C3 Low Slightly increased Decreased to baseline Fragment C3 * (% of total) High Decreased Remains decreased Bb High Decreased Increased to baseline Serum C3 Low Increased Decreased to baseline Fragment C3 * (% of total) Normal Normal Normal Bb Normal Decreased Normal Serum C3 Near lower limit of normal Increased Decreased to baseline Fragment C3 * (% of total) Fragment undetectable Fragment undetectable Fragment undetectable Bb Normal Decreased Normal Red, in the baseline and post-treatment columns, represents a value that is consistent with AP hyperactivity. Green in the on-treatment column indicates evidence for AP inhibition. * Fragment C3 (% of total) normal range is derived from normal ranges of components ON-TARGET EFFECT WITH REDUCED AP HYPERACTIVITY Data presented May 26, 2018 at the 55 th ERA-EDTA Congress 19

20 ACR (mg/mmol) ACR (mg/mmol) ACR (mg/mmol) ACR (mg/mmol) Reduction in ACR with 14-Day ACH-4471 Treatment Patient A: ACR (mg/mmol) Screening Treatment Taper Follow-up Patient C: ACR (mg/mmol) Patient B: ACR (mg/mmol) Screening Treatment Taper Follow-up Patient D: ACR (ng/mmol) and 24 hr protein excretion (g/day) Screening Treatment Taper Follow-up Screening Treatment Taper Follow-up Data presented May 26, 2018 at the 55 th ERA-EDTA Congress Stable egfr and blood pressure observed Patients A, B, & C had approximately 50% reduction in ACR Patient D had highly variable ACR values; as a result two 24 hr urinary proteins were collected on days 14 (0.7g/day) and 17 (2.44 g/day) 24hr UP (g/day) = Albumin:Creatinine Ratio (ACR) = 24 hr Urinary Protein (UP)

21 ACH-4471: A Potential Innovative Treatment for C3G C3G is a disease of AP hyperactivity with C3 fragment deposition in glomeruli ACH-4471 is an oral, potent, factor D inhibitor that reduces AP activity o o o Data presented today demonstrate ACH-4471 can mitigate the AP hyperactivity in C3G Short-term treatment with ACH-4471 was associated with approximately 50% reduction in ACR Acceptable safety profile in C3G to date (no treatment-emergent serious adverse events or discontinuations due to adverse events) Ongoing studies include o o o Proof-of-mechanism study (ACH ) recruiting 6-month, randomized, placebo-controlled, proof-of-concept study (ACH ) recruiting 12 month, open-label, proof-of-concept study (ACH ) recruiting 21

22 C3G Program Accomplishments ACH-4471 was safe and well-tolerated Established PoC Regulatory Status Ongoing Clinical Studies No SAEs or AEs of note. Well tolerated both on-treatment and post-cessation. POC established with 50% improvement in proteinuria AP inhibition confirmed based on changes in complement biomarkers Open U.S. FDA INDs for C3G and PNH Orphan drug designation for C3G Regulatory discussions for Ph 2 design and potential pivotal endpoints Phase 2: Evaluating 200 mg TID ACH-4471 for 14-days Data 3Q18 Phase 2:12-month Open Label Trial Data 4Q18 Phase 2: 6-month Randomized Double- Blind Trial Data

23 Paroxysmal Nocturnal Hemoglobinuria (PNH) Rare Disease Characterized by Destruction of Red Blood Cells by the AP

24 Achillion PNH Strategy Patient Perspective 25% to 40% of PNH patients still experience a sub-optimal response on standard of care Market research shows o o Strong desire for oral therapy 20% of patients currently decline therapy PNH Strategy Evaluate data from naïve and sub-optimal C5 responders in 4Q 2018 Determine go-forward development plan post data Sources: Achillion. Data of file. 24

25 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) Factor D and Potential Protection from Intra- & Extra-vascular Hemolysis Type III PNH erythrocytes No treatment Anti-C5 therapy C3 fragment deposition Intra-vascular hemolysis Breakthrough and Extra-vascular hemolysis C3 fragment opsonization via RES macrophages (liver, spleen) PNH RBCs treated with a fd inhibitor may be protected from both intra- and extra-vascular hemolysis Factor D inhibitor Protected Type III PNH erythrocytes Adapted from Luzzatto L, Risitano AM, Notaro R. Haematologica 2010;95(4): Harder M., et al. Blood. 2017; 129(8)

26 Study Status and Interim Results Phase 2 Trial of ACH-4471 in Untreated PNH Patients Three-month Dose Finding Long-term Extension Enrollment: 4 to 12 pts Day 1 Day 28 Day 84 KEY INCLUSION / EXCLUSION CRITERIA PNH clone size > 10% Anemia (Hgb < 12 g/dl) LDH > 1.5X ULN ANC > 1,000/ mm 3 Platelets > 50,000 μ/l Normal ALT Alk Phos 1.5X ULN Part 1 Investigator determines clinical response to guide entry into Part 2 Trial Summary to Date Part 2 Investigator assessment of benefit determines entry into extension trial Long-Term Extension Study Initial dose 100 mg TID. Protocol subsequently amended to allow: - Newly enrolled patients to start at 150 mg TID - Intra-patient dose escalation throughout both studies Objectives Reduction in LDH from baseline Improvements in Hgb, FACIT Increase PNH RBC clone size Two patients on therapy for greater than one year, one patient beyond eight months Well-tolerated to date Hgb: hemoglobin LDH: lactose dehydrogenase ANC : absolute neutrophil count ALT: alanine aminotransferase TID: three times daily 26 Continue to screen and enroll untreated PNH patients Patient status as of March 13, 2018

27 Clinical Efficacy & Safety Data for PNH Lactose dehydrogenase (LDH) Hemoglobin (Hgb) C3 fragment deposition Fatigue (FACIT scale) PNH RBC Clone Size Safety Clinically meaningful reduction in LDH Stabilize / increase hemoglobin Observe no C3 fragment deposition on PNH RBCs Improvement over time in objective measures of patient fatigue Increase percentage of PNH RBC clones from baseline Favorable tolerability profile Clinical data generated to date highlight the potential role of factor D inhibition in PNH 27

28 Phase 2 Trial of ACH-4471 with eculizumab in PNH Sub-optimal Responders Clinical Trial Design Open-label study of ACH-4471 with eculizumab Duration: Six-months of combination treatment Criteria Confirmed diagnosis of PNH and on stable dose of eculizumab Persistent anemia and continued transfusion requirements Outcome Measures Change in hemoglobin compared to baseline Number of units of RBCs during treatment period Change in LDH compared to baseline Clinical Trial Status o o Enrollment beginning 1H18 Interim data targeted 4Q18 28

29 Next-Generation fd Inhibitors An Expanding Portfolio of Candidates for Complement-mediated Diseases

30 FACTOR D INHIBITOR PORTFOLIO ACH-5228 and ACH-5548: Next-Generation Oral Factor D Inhibitors Advancing additional fd inhibitors in the clinic Creating strategic options for value creation Structural alterations designed to achieve significant improvements in potency and pharmacokinetic properties ACH-5228 Phase I single-ascending dose HV study initiated in December 2017 ACH-5548 Phase I single-ascending dose HV study targeted for initiation 2Q 2018 Leveraging our unique and deep understanding of the complement system to advance novel, next-generation therapies 30

31 Achillion: Research Realized First-in-class pipeline for complement APmediated rare diseases Strong market opportunities for fd inhibitor portfolio Patient-focused and experienced management team $308M at 3/31/18 to support multiple value infection points 31

32 2018 Goals and Milestones Near-term ACH-4471 Clinical Development Plan Compound Indication Anticipated Next steps ACH-4471 C3G 14-day Ph 2 Group 2 interim data 3Q18 12-month open label Ph 2: Interim data targeted 4Q18 6-month randomized double-blind C3G Ph 2: Full enrollment anticipated YE18 PNH Monotherapy Ph 2: Interim data targeted 4Q18 Add-on trial Ph 2: Interim data targeted by 4Q18 $308 million in cash, cash equivalents, and interest receivable at 3/31/18 to support execution on factor D inhibitor program Next-Gen Compounds ACH-5228 TBD Interim Ph 1 data targeted 2H18 ACH-5548 TBD Initiate Ph 1 in 2Q18 32

33 June 21, Achillion Pharmaceuticals. All rights reserved. NASDAQ:ACHN