Complement Focused. Patient Driven.

Transcription

1 ACH-4471: Factor D Complex Complement Focused. Patient Driven. Interim Data and Strategic Update December 17, 2018 NASDAQ:ACHN All rights reserved.

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, objective, 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, 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, our ability to replicate in later clinical trials data seen in earlier trials, 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 Strategic Update & Key Interim Data AGENDA Introduction & Overview Joe Truitt, CEO ACH-4471: Achillion s First Generation Oral Factor D Inhibitor Dr. Steven Zelenkofske, CMO ACH-4471 PNH naïve monotherapy interim clinical data update (enrollment completed at n=10) ACH-4471 PNH add-on to eculizumab in sub-optimal responders (interim data on first 4 patients) ACH-4471 C3G 14-day biomarker Proof of Mechanism (PoM) trial (enrollment completed at n=6) ACH-4471 C3G 12-month Open-label Proof of Concept (PoC) trial (interim data on first 3 patients) ACH-4471 C3G 6-month Randomized, Double-blind PoC trial (currently dosing 6 patients) ACH-5228: Achillion s Next Generation Oral Factor D Inhibitor Dr. Steven Zelenkofske, CMO ACH-5228 & ACH-5548 Single Ascending Dose (SAD) PK and PD comparisons ACH-5228 Development Plans Upcoming Milestones & Portfolio Strategy Joe Truitt, CEO Q&A 3

4 Development Overview ACH-4471: Moving into Late Stage Development ACH-4471: Key Milestones PNH PoC as Monotherapy - data demonstrate: Increased hemoglobin Lower reticulocyte count Fewer transfusions Improved FACIT fatigue scores Reductions in LDH Levels PoC in Combination w/eculizumab Increased hemoglobin Lower reticulocyte count Zero on treatment transfusions Combination therapy may address ongoing unmet medical needs in PNH patients C3G PoM 14-day Biomarker & Dose Ranging Study Data support target engagement on C3G biomarkers (C3, Bb and C3 fragments) Initial reductions in proteinuria observed PoC 6- & 12- month trials recruiting Agreement from FDA to include adolescents ( 12 yrs) in ongoing 6- and 12-month trials 18 trial sites open Continuing to expand clinical sites to accelerate patient recruitment in

5 Development Overview ACH-5228 & ACH-5548 Next Generation Factor D Inhibitors % Inhibition % of of AP AP Further Gains in Potency and Half-Life ACH-4471/5228/5548 Single Ascending Dose: PK vs APH (AP Hemolysis) (Fit with Sigmoid Model) ACH-447/5228/5548 SAD APH (Fit with Sigmoid Model) 90% inhibition (IC90) ACH x higher potency Projected BID dosing with half-life of 12 hrs MAD study planned to begin in January 2019 ex- US ACH-5548 ACH-5228 ACH-4471 ACH-5548 Projected half-life of 16 hrs Potential for QD dosing Drug Plasma Conc. (ng/ml) Drug Plasma Conc. (ng/ml) Phase 1 SAD results with steady state modeling, before tablet form Ex-vivo APH (AP Hemolysis) assays for inhibition curve 5

6 Potent and Selective AP Inhibition Oral Factor D Inhibitors Differentiators of Achillion s Factor D Platform Small molecule with oral bioavailability and broad systemic distribution targeting the Alternative Pathway (AP) Factor D is a ratelimiting enzyme of the AP with a relatively low plasma concentration (~2 µg/ml) Selective inhibition of AP vs. C5 or C3 inhibition allows the Classical and Lectin pathways to remain intact to fight infections 1 1 Achillion Poster 55 th ERA-EDTA Congress May 2018 Abstract FP082; Granoff & Konar Blood

7 ACH-4471 First Generation Oral Factor D Inhibitor Dr. Steven Zelenkofske, CMO

8 First Generation Oral Factor D Inhibitor ACH-4471 Moving into Late Phase Development Treatment Experience Summary Safety Experience Summary >200 healthy volunteers and patients dosed to-date Multiple DDI, ADME, and support studies Completed 6- and 9-month chronic toxicology studies Completed renal impairment study & hepatic impairment study Completed DART (Development & Reproductive Toxicology) studies 2 year carcinogenicity studies - ongoing ACH-4471: Factor D Complex 0.8 A X-ray Structure >25 C3G & PNH patients dosed (with 250mg TID) >10 patient years of dosing 2 patients dosed >18 months SAE in one patient in PNH monotherapy study: - LFT elevations coincident with break-through hemolysis - Resolved with drug taper and discontinuation with no residual liver effect 8 of 10 PNH monotherapy patients have entered the extension study Recent agreement from FDA to include adolescents ( 12 yrs) in ongoing 6- and 12- month trials for C3G 8

9 Development Overview ACH-4471: Key Interim Data PNH Naïve Monotherapy PNH in Combination w/eculizumab C3G 14-day Biomarker PoM Trial C3G 12-month PoC Trial (Enrollment Completed n=10) (n=4 with Interim Data) (Enrollment Completed n=6) (n=3 with Interim Data) Established PoC Patients achieved gains in hemoglobin and FACIT-fatigue scores and reductions in LDH and transfusion requirements 8 of 10 patients continuing treatment in extension study 1 SAE to-date Established PoC Improvements across all key parameters, gains in hemoglobin, while transfusions reduced to zero on ACH week data expected 2H: 2019 Well-tolerated to-date Established PoM Serum C3, Bb and C3 fragment biomarkers demonstrated evidence of inhibition on AP Well-tolerated to-date Early changes in biomarkers and reductions in proteinuria Trial size will be data dependent and determined in 2019 Well-tolerated to-date 9

10 ACH-4471 Monotherapy in PNH Naïve Patients Dr. Steven Zelenkofske, CMO

11 Paroxysmal Nocturnal Hemoglobinuria (PNH) Driven by Overactivation of the Complement System Rare, acquired, blood disorder with remaining unmet medical need Reported prevalence approximately 16 per million people 1 Up to ~75% of patients treated with C5 inhibitor (eculizumab) remain anemic 2 Red blood cells lacking complement regulatory proteins, leads to intra- and extra-vascular hemolysis 3 Our Approach Target Factor D A critical control point within the alternative pathway that targets both intra-vascular and extra-vascular hemolysis 1. Szer and Hill et al, Clin Hemtol Oncol McKinley et al, ASH Abst Brodsky et al, Blood

12 ACH-4471 in Untreated PNH Patients Baseline Characteristics RBC transfusions in last 52 wks* Patient Age/ Sex BMI # of Transfusions Total # of Units Hemoglobin (g/dl) M: F: LDH M/F: Reticulocytes M: F: Bilirubin M/F: Notes 1 40/M 26 16x Previously diagnosed with aplastic anemia 2 36/M 25 None /M 26 None /M 34 None Voluntarily withdrew at week /F 18 None /F 25 5x Viral respiratory infection week /F 24 1x SAE for LFT elevation in week 8 with treatment discontinuation 8 27/F 24 None /M 29 None /F 20 1x Male: n=5; Female: n=5 *Transfusion history provided for reference (52 weeks) 12

13 LDH x ULN ACH-4471 in Untreated PNH Patients Reductions in LDH L D H ( M E A N + / - S D ) Primary Endpoint All 10 patients had meaningful reductions in LDH levels from baseline demonstrating an effect on intravascular hemolysis 5 patients achieved <1.5x upper limit of normal (ULN) by week x Upper Limit of Normal (ULN) xuln N N=10 N=10 N=10 N=10 N=10 N=10 N=10 N=9 N=8 N=8 N=8 N=8 N=8 Visit D1 W1 W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12 Change In week 7 driven by Patient #6 experiencing breakthrough hemolysis with acquired viral respiratory infection, subsequently recovered and remained on treatment Individual subject s missing data points were imputed by taking the arithmetic mean of the two adjacent time points. 13

14 Hemoglobin (g/dl) ACH-4471 in Untreated PNH Patients Mean Hgb Near Normal Range H E M O G L O B I N ( M E A N + / - S D ) Secondary Endpoint Normal Hgb* 6 patients achieved >12 g/dl by Week 9 Mean increase of >2g/dL in Hgb 23 transfusions 52-weeks prior to treatment reduced to 4 transfusions during 12-week study Four On Treatment Transfusions Patient 1 aplastic anemia 3 transfusions Patient 6 viral infection 1 transfusion *Normal (female): g/dl; Normal (male): g/dl Individual subject s missing data points were imputed by taking the arithmetic mean of the two adjacent time points. 14

15 ACH-4471 in Untreated PNH Patients Clinically Meaningful Improvements in Quality of Life (QoL) Measures FA C I T FAT I G U E S C O R E S ( M E A N + / - S D ) Exploratory Endpoint QoL improvements as demonstrated by a mean change of 13 points from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores over 12-week study Severe fatigue The patient with breakthrough hemolysis in week 7 had a FACIT-Fatigue score of 18 in week 8, subsequently recovered to a normal range score of 52 in week 12 Derived scores are based on the FACIT Fatigue Scale V4. Score range A score of less than 30 indicates severe fatigue. The higher the score, the better the quality of life. 15

16 ACH-4471 in Untreated PNH Patients Approaching Normalization of Reticulocyte Count R E T I C U L O C Y T E S ( M E A N + / - S D ) Exploratory Endpoint Achieved mean normal range by week 2 Reticulocyte (10^9/L) Normal reticulocyte count* In Phase 3 studies of Eculizumab in PNH, reticulocyte count in patients remained elevated and did not change significantly from baseline values throughout the treatment period (1) ^9/L at 26 weeks (TRIUMPH) ^9/L at 52 weeks (SHEPHERD) 1) Schubert et al, British Journ Hematol 2008 *Normal (female): x 10 9 /L; Normal (male): x 10 9 /L Individual subject s missing data points were imputed by taking the arithmetic mean of the two adjacent time points. 16

17 ACH-4471 in Untreated PNH Patients Data Support PoC for Factor D Inhibition Improvements across several measures with gains in Hgb Clinically differentiated results (Hgb, reticulocyte, reduced transfusions) from those reported with C5 inhibition Improvement in fatigue as demonstrated by mean change of 13 points from baseline as measured by FACIT-Fatigue Scale Patient LDH response correlated with ACH-4471 exposure 8 of 10 patients continuing treatment in long-term extension study PNH Monotherapy Development Plan Data compelling, but decision not to move forward with ACH-4471 as monotherapy and advance ACH-5228 in PNH monotherapy (projected improved, potency, lower Cmax and projected 2x daily dosing 8 of 10 patients continuing treatment in long-term extension study Convert extension patients to ACH-5228 subject to regulatory review 17

18 ACH Eculizumab In Treatment-experienced Suboptimal Responders Dr. Steven Zelenkofske, CMO

19 PNH Patients Treated with Eculizumab ~75% Remain Anemic Hgb for Eculizumab-Treated Patients (ACHN Market Research) 1 Studies of Eculizumab-Treated Patients ~75% with residual anemia Severely Anemic Anemic 141 PNH patients treated with eculizumab for >13 months 2 72% had a mean hemoglobin <12.0 g/dl Mean Hgb was 10.9 g/dl 36% had at least one transfusion in the last 12 months Reticulocyte count correlated with indicators of extravascular hemolysis, including C3 loading of PNH cells 195 PNH patients >66 months on eculizumab 3 Mean Hgb was 10.5 g/dl at 24 and 36 months 123 PNH patients treated with eculizumab after a median follow-up of 4.5 years 4 72% were anemic 1 Achillion Internal Market Research. 2 McKinley et al, ASH Dec Abst Hillmen et al. Br J Haematol Loschi et al. Am J Hematol

20 ACH-4471 in PNH Patients Treated with Eculizumab Baseline Characteristics Patient Age/Sex BMI ECU Dose Dose (mg) Freq # of Tx RBC transfusions in last 52 weeks* Total # of Units Initial ACH-4471 (mg TID) Hemoglobin (g/dl) M: F: LDH (U/L) M/F: Reticulocyte Count (10^9/L) M/F: Bilirubin (mg/dl) M: F: Notes 1 41/F Q2W None mg TID at W12 Religious objection to transfusions Concomitant hereditary elliptocytosis Lower retics with depressed Hgb may indicate bone marrow dysfunction 2 51/F Q2W Patient s insurance company dropped ECU dose from 1200 to 900 mg W /M Q2W Lower retics with depressed Hgb may indicate bone marrow dysfunction 4 29/F Q2W Hgb 9.9 g/dl at screening *Transfusion history provided for reference (52 weeks). Study inclusion requires patients to have had a RBC transfusion within the last 12 weeks (exception made for Patient 1). 20

21 ACH-4471 Increased Hemoglobin Change in Addition to Eculizumab HEMOGLOBIN (MEAN +/ SD) Primary Endpoint Normal Hgb* Patient 1 Patient 2 Patient 3 Patient 4 Eliminated need for transfusions to-date Early data indicates potential for ~3 g/dl rise in Hgb and potential to treat unmet medical need in patients with ongoing extravascular hemolysis in ECU-treated patients *Normal (female): g/dl; Normal (male): g/dl Individual subject s missing data points were imputed by taking the arithmetic mean of the two adjacent time points. 21 Data date 30 Nov2018

22 LDH (U/L) ACH-4471 Further Reduced LDH Change in Addition to Eculizumab LDH Patient 1 Patient 2 Patient 3 Patient 4 Secondary Endpoint Further reductions of LDH in sub-optimal responders demonstrated ongoing intravascular hemolysis and room for improvement on top of C5 inhibition Normal range* *Normal range: U/L Individual subject s missing data points were imputed by taking the arithmetic mean of the two adjacent time points. 22 Data date 30 Nov2018

23 Reticulocyte (10^9/L) ACH-4471 Reduced Reticulocytes Change in Addition to Eculizumab RETICULOCYTES Patient 1 Patient 2 Patient 3 Patient 4 Exploratory Endpoint Significant reduction of reticulocytes indicates positive bone marrow response to anemia whether caused by intra-vascular and/or extravascular hemolysis in patients currently on eculizumab Normal range* *Normal (female): x 10 9 /L; Normal (male): x 10 9 /L Individual subject s missing data points were imputed by taking the arithmetic mean of the two adjacent time points. 23 Data date 30 Nov2018

24 Improvement in Fatigue Measures in PNH Patients Change in Addition to Eculizumab FACIT FATIGUE SCORES Exploratory Endpoint Greatest improvements in FACIT fatigue scores in patients with severe fatigue Zero on treatment transfusions vs 14 in last 52 weeks Severe fatigue Patient 1 Patient 2 Patient 3 Patient 4 Derived scores are based on the FACIT Fatigue Scale V4. Score range A score of less than 30 indicates severe fatigue. The higher the score, the better the quality of life. 24 Data date 30 Nov2018

25 ACH-4471 in PNH Patients Treated with Eculizumab Data Support PoC for Factor D in Combination with a C5 Inhibitor Early clinical data demonstrated additional benefit of AP inhibition to C5-only treatment Increased hemoglobin levels Reduced reticulocyte count Improved FACIT fatigue scores Further LDH reductions observed Patients required zero transfusions after beginning ACH-4471 treatment No safety or tolerability issues observed with ACH-4471 in combination with C5 PNH Combination with C5 Development Plan ACH-4471 in combination with a C5 inhibitor targets an unmet medical need for PNH patients and supports potential Phase 3 studies PNH Phase 2 combination therapy top-line data expected 2H: 2019 Further exploration into QoL benefits in late stage development 25

26 ACH-4471 Complement 3 Glomerulopathy (C3G) Dr. Steven Zelenkofske, CMO

27 C3 Glomerulopathy (C3G) C3 Glomerulopathy Overactive alternative pathway leads to deposition of C3 fragments in the kidney glomeruli, causing decline in kidney function over time Rare, potentially lethal disorder with no approved treatments Estimated to affect between 8-12 per million people in major markets ~1-2 per million people diagnosed per year Up to ½ of C3G patients progress to end-stage renal disease within 10 years Sources: Gulbis B et al (2010); Medjeral-Thomas et al (2014); Servais et al (2013); 27

28 Importance of Complement Biomarkers in C3G Complement Activation Complement biomarkers in Serum/Plasma are valuable for assessing systemic AP activation Complement Deposits and Kidney Damage Inappropriate and excessive consumption of C3 leads to an excess production of C3 fragments Measures of Kidney Function Estimated Glomerular Filtration Rate (egfr) egfr is considered to be the an important measurement for assessing kidney function Serum/Plasma Complement C3/C4, C3 Fragments, Ba/Bb, etc. DECREASING egfr MILD MODERATE SEVERE Urine Complement Ba, Bb, sc5b-9, etc. INCREASING PROTEIN IN URINE (can be measured with ACR & Protein/24hrs) Urine complement levels may provide additional information about AP activation in the kidney C3 fragments are deposited in kidney and may contribute to kidney damage Albumin to Creatinine Ratio (ACR) In glomerular disease, increased ACR & proteinuria may indicate early signals of glomerular damage and potentially serve as a risk factor for progression 28

29 ACH-4471 Phase 2 Trials in C3G Accelerating Patient Enrollment 2 C3G Clinical Trials Ongoing Current Phase 2 Programs 14- D A Y B I O M A R K E R P o M T R I A L 12- M O N T H P o C T R I A L 6 - M O N T H B L I N D P o C T R I A L Enrollment Summary Enrollment completed at 6 patients Recruiting Recruiting Expanding investigational sites for increased enrollment PoM validated Initial response was dose dependent Directing enrollment to long term PoC trials Interim data on N=3 presented today Trial size will be data dependent Next data update expected in H including proteinuria and egfr data N=6 patients enrolled and dosing Trial size will be data dependent Data may be used to support Phase 3 registration program Opened 10 trial sites in Q Currently 18 active global trial sites recruiting Recent agreement with FDA to include adolescents ( 12 yrs) in ongoing 6- and 12-month studies T A R G E T E N D O F P H A S E 2 M E E T I N G S I N 4 Q : Combine data from both the 6- and the 12-month studies, up to 20 patients Efficacy, including available biopsy, data will be submitted for End of Phase 2 meeting with FDA 29

30 ACH-4471 in C3G 14-Day Biomarker Response Dose Dependent Positive signals for reduction of AP hyperactivity in all biomarkers Biomarker % Change from Baseline Day 1 to Day 14 Patient # M/31 egfr = 91 M/27 egfr = 143 M/19 egfr = 73 M/22 egfr = 207 F/48 egfr = 67 M/ 20 egfr = 79 Biomarkers (units) Targeted Outcome 100mg TID 200mg TID 100mg TID 150mg TID 200mg TID 200mg TID Serum C3 (g/l) + 14 % + 35 % 0 % + 16 % + 32 % - 8 % Bb (ug/ml) - 13 % > - 67 % - 29 % - 38 % - 44 % - 31 % C3 Fragments (ug/ml) - 70 % - 12 % - 41 % not detectable - 45 % in process Urinary Ba (1) - 75 % (2) - 71 % - 70 % - 71 % - 84 % - 87 % Urinary C5b-9 (1) - 30 % (2) > - 59 % - 24 % - 57 % - 88 % - 82% uacr(mg/g) - 32 % - 47 % - 41 % + 27 % (3) - 38 % - 37 % 1) Measurement by Achillion 2) Day 15 (Day 14 not performed) 3) Patient is 86 lbs. in weight 30

31 ACH-4471 in C3G 14-Day Biomarker Study PoM Validated at N=6 Serum and urine complement biomarkers demonstrated evidence of inhibition of AP hyperactivity Dose ranging indicates better biomarker response at higher doses Two-week treatment associated with early proteinuria reduction in 5 of 6 patients Well-tolerated to-date. No treatment-related SAEs C3G Development Plan Validated factor D Proof of Mechanism in C3G Supports C3G patient enrollment in long-term 6- and 12-month trials Results support 200mg TID dose for greater inhibition 31

32 ACH-4471 in C3G 12-Month Open Label Study Design and Summary of Results Outcome Measures DAY 1 DAY 400 S C R E E N I N G T R E A T M E N T 12 MONTHS INCLUDING INITIAL DOSE TITRATION O P E N L A B E L E X T E N S I O N INCLUSION CRITERIA Adult and adolescent patients, not on dialysis or post kidney transplant, with C3G or IC-MPGN On stable background medications 4 weeks Estimated glomerular filtration rate (egfr) cannot be < 30 ml/min/1.73m 2 CLINICAL TRIAL DESIGN TREATMENT (N = 20) All patients will receive oral ACH-4471 three times a day for a total of 12 months of treatment Kidney biopsy performed at beginning and end of study (except in adolescents) Trial Summary to-date: RECRUITING PoC trial: interim data on N=3 today with 1, 2 and 3 months of data respectively Interim 3- and 6-month proteinuria and egfr data expected 2H:2019 Changes in disease markers: Amount of protein in the urine Kidney function (egfr) Safety Factors Changes in markers of AP activity 32 Patient status as of Dec 12, 2018

33 ACH-4471 in 12-Month PoC Study in C3G Early Data Promising Improvement in AP biomarkers & early reduction in proteinuria Patient 1 Male/31 (Dose=100 mg TID) Normal Range Targeted Outcome Day 1 Week 2 Week 4 Week 6 Week 8 % Change from Baseline* Serum C3 (g/l) % Complement Bb (ug/ml) % uacr (ug/mg) < % egfr (ml/min/1.73 m^2) > 90 Stable N/A 1) Previously subject # 1 in 14-day study (100mg TID) with uacr of 2295 ug/mg at Day 1 of 14-Day Trial 2) Existing Disease Related Medications: MMF, Prednisone, ACE Inhibitor, Diuretic 3) 24 hour Total screening: 4700 mg * % Change from Day 1 of 14-Day Trial uacr to week 8 of 12-month trial = - 40% 33

34 ACH-4471 in 12-Month PoC Study in C3G Early Data Promising Improvement in AP biomarkers & early reduction in proteinuria Patient 2 Male/20 (Dose=200 mg TID) Normal Range Targeted Outcome Day 1 Week 2 Week 4 Week 6 Week 8 Week 12 Week 16 % Change from Baseline Serum C3 (g/l) % Complement Bb (ug/ml) % uacr (ug/mg) < * 3922** % egfr (ml/min/1.73 m^2) > 90 Stable N/A 1) Previously subject # 3 in 14-day study (100mg TID) with uacr of 5136 ug/mg on Day 1 of 14-Day Trial 2) Existing Disease Related Medications: MMF, ARB, Diuretic 3) Diagnosed with IC-MPGN 4) Biopsy: 40% Interstitial Fibrosis and Tubular Atrophy 5) 24Hr Total Protein at screening: 6330 mg * Week 5; ** Week 7 34 % Change from Day 1 of 14-Day Trial uacr to Week 16 of 12-month trial = - 56%

35 ACH-4471 in 12-Month PoC Study in C3G Improvement in AP Biomarkers Better than normal kidney function at baseline among C3G patients Patient 3 Female/24 (Dose=100 mg TID) Normal Range Targeted Outcome Day 1 Week 2 Week 4 Week 6 Week 8 % Change from Baseline Serum C3 (g/l) % Complement Bb (ug/ml) In process - 70% uacr (ug/mg) < % egfr (ml/min/1.73 m^2) >90 Stable NA 1) 24Hr Total Protein at screening: 1554 mg 35

36 ACH-4471 in C3G 12-month PoC Study Early PoC Supports Continuation of Study and Expansion of Trial Sites Serum and urine complement biomarkers showed evidence of inhibition of alternative pathway hyperactivity and early reduction in proteinuria Looking forward to 6- and 12- month data to evaluate longer term effect on kidney function Well-tolerated to-date, no treatment-related SAEs Agreement with FDA to enroll adolescents (aged years) C3G Development Plan Up-dosing patients to 200mg TID 18 global sites now open for increased patient enrollment Combine 6- & 12-month study data with up to 20 patients for End of Phase 2 Targeting End of Phase 2 FDA meeting Q4:

37 ACH-5228 & ACH-5548 Next Generation Oral Factor D Inhibitors Dr. Steven Zelenkofske, CMO

38 Development Overview ACH-5228 & ACH-5548 Next Generation Factor D Inhibitors % Inhibition % of of AP AP Further Gains in Potency and Half-Life ACH-4471/5228/5548 Single Ascending Dose: PK vs APH (AP Hemolysis) (Fit with Sigmoid Model) ACH-447/5228/5548 SAD APH (Fit with Sigmoid Model) 90% inhibition (IC90) ACH x higher potency Projected BID dosing with half-life of 12 hrs MAD study planned to begin in January 2019 ex- U.S ACH-5548 ACH-5228 ACH-4471 ACH-5548 Projected half-life of 16 hrs Potential for QD dosing Drug Plasma Conc. (ng/ml) Drug Plasma Conc. (ng/ml) Phase 1 SAD results with steady state modeling, before tablet form Ex-vivo APH (AP Hemolysis) assays for inhibition curve 38

39 Alternative Pathway Inhibition ACH-5228 Increased Potency Projects >90% Inhibition with Lower Dose PK Profiles of ACH mg TID (Liquid Filled Capsule) vs Projected Steady-State ACH mg BID (Powder In Capsule) ACH: % Inhibition with ACH % Inhibition with ACH-5228 Lower dosing with higher potency Lower trough concentrations required Half-life (10-14 hrs) vs ACH-4471 (5-8 hrs) Significantly lower Cmax Provides dosing flexibility *Phase 1 SAD results with steady state modeling, before tablet formulation. Ex-vivo APH assays for inhibition curve 39

40 Our Path Forward Strategic Update & Upcoming Milestones Joe Truitt, CEO

41 Achillion Portfolio Development Plan Summary ACH-4471: First Generation Factor D Inhibitor PNH monotherapy PoC established - transition to ACH-5228 with higher potency and dosing flexibility PNH combination w/c5 PoC established - top-line data 2H:2019 C3G, PoC ongoing - combine 6- and 12-month data up to 20 patients, targeting End of Phase 2 4Q: 2019 ACH-5228: Next Generation Factor D Inhibitor ACH-5228 Phase I Multiple-Ascending Dose (MAD) study planned to begin Q1: 2019 Submit IND 4Q: 2019 PNH monotherapy - switch 8 extension patients to ACH-5228 targeting early 2020 USPTO has issued a composition of matter patent for ACH This is the first in a series of filings expected to protect ACH-5228 through 2035 Evaluate additional indications for development ACH-5548: Next Generation Factor D Inhibitor Initiate IND enabling work in 2019 and anticipate Phase 1 MAD in YE Cash of $270MM & Projected Cash Burn for 2019 of $80-85MM 41

42 Q&A Discussion

43

44 Appendix Study Designs

45 ACH-4471 in Untreated PNH Patients Study Design and Summary of Results Enrollment: 10 pts Three-month Dose Finding Long-term Extension KEY INCLUSION CRITERIA Anemia (Hgb <12 g/dl) Day 1 Day 28 Day 84 LDH >1.5X ULN PNH clone size > 10% (Type III RBCs and/or granulocytes) Initial dose 100 mg TID. Protocol subsequently amended to allow newly enrolled patients to start at 150 mg TID P A R T 1 Investigator determines clinical response to guide entry into Part 2 P A R T 2 Investigator assessment of benefit determines entry into extension trial L O N G - T E R M E X T E N S I O N S T U D Y Intra-patient dose escalation throughout both studies OBJECTIVES Reduction in LDH from baseline Improvements in Hgb and FACIT fatigue scores Hgb: hemoglobin LDH: lactose dehydrogenase ALT: alanine aminotransferase RBC : red blood cell TID: three times daily 45 Trial Summary to Date n=10 Patients achieved gains in hemoglobin and FACIT fatigue scores combined with reductions in LDH & RBC transfusions Reductions in transfusion requirements on treatment 8 of 10 patients continuing treatment in extension study 1 SAE from LFT elevations in week 8, self-resolving with ACH-4471 taper and discontinuation Patient status as of Nov 30, 2018

46 ACH-4471 in PNH Patients treated with Eculizumab Study Design and Summary of Results Enrollment: 4 to 12 pts Six-month Dose Finding Long-term Extension KEY INCLUSION CRITERIA RBC transfusion within the last 12 weeks Anemia (Hgb <12 g/dl) with adequate reticulocytosis On a stable regimen of eculizumab Day 1 Investigator determines clinical response and adjusts dose accordingly ACH-4471 doses: 100 mg TID, 150 mg TID and 200 mg TID Optimal dose will be determined from Groups 1-3 Week 24 E X T E N S I O N S T U D Y OBJECTIVES Increase Hgb Reduce Transfusions Maintenance/Improvements in LDH Improvements in FACIT Hgb: hemoglobin LDH: lactose dehydrogenase RBC : red blood cell TID: three times daily Trial Summary to-date (n=4) Improvements across key parameters seen as low as 100mg TID Zero transfusions post treatment vs 14 transfusions in last 52 weeks Well-tolerated to-date Continue to screen and enroll up to 12 total sub-optimal responder PNH patients on eculizumab Patient status as of Nov 30,

47 ACH-4471 in C3G 14-Day Biomarker Study Design and Summary of Results Outcome Measures DAY 1 DAY 49 S C R E E N I N G T R E A T M E N T T A P E R F O L L O W - UP 14 DAYS 7 DAYS 28 DAYS KEY INCLUSION 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 (Dose Ranging) 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 Trial Summary to Date n=6 Biomarker Data for 6 patients indicate Proof of Mechanism Completed enrollment Dec 2018 Focused on patient enrollment for 6-month and 12-month PoC trials Changes in biomarkers: C3 levels C3 fragments Bb/Ba Clinical manifestations of disease: albumin to creatinine ratio (ACR), BP, egfr Safety and tolerability Pharmacokinetic profile Patient status as of Dec 12,

48 ACH-4471 in C3G 12-Month Open Label Study Design and Summary of Results Outcome Measures DAY 1 DAY 400 S C R E E N I N G T R E A T M E N T 12 MONTHS INCLUDING INITIAL DOSE TITRATION O P E N L A B E L E X T E N S I O N INCLUSION CRITERIA Adult and adolescent patients, not on dialysis or post kidney transplant, with C3G or IC-MPGN On stable background medications 4 weeks Estimated glomerular filtration rate (egfr) cannot be < 30 ml/min/1.73m 2 CLINICAL TRIAL DESIGN TREATMENT (N = 20) All patients will receive oral ACH-4471 three times a day for a total of 12 months of treatment Kidney biopsy performed at beginning and end of study (except in adolescents) Trial Summary to-date: RECRUITING PoC trial: interim data on N=3 today with 1, 2 and 3 months of data respectively Interim 3- and 6-month proteinuria and egfr data expected 2H:2019 Changes in disease markers: Amount of protein in the urine Kidney function (egfr) Safety Factors Changes in markers of AP activity 48 Patient status as of Dec 12, 2018

49 ACH-4471 in C3G 6-Month Randomized, Blinded Study Design and Summary of Results Outcome Measures DAY 1 DAY 205 S C R E E N I N G & R A N D O M I Z A T I O N ACH-4471 three times daily for six months Placebo three times daily for six months O P E N L A B E L E X T E N T I O N KEY INCLUSION CRITERIA Adult & Adolescent patients, not on dialysis or post kidney transplant, with C3G On stable background medications 4 weeks Estimated glomerular filtration rate (egfr) cannot be < 30 ml/min/1.73m 2 CLINICAL TRIAL DESIGN TREATMENT (N = 20) Patients will be randomized to receive either oral ACH-4471 three times daily or a matched placebo for six months Kidney biopsy conducted before start of treatment, and after the end of treatment (except in adolescents) Trial Status: RECRUITING 6 patients enrolled and dosing as of Trial size will be data dependent Change in C3 fragments observed from kidney biopsy Changes in disease markers: Amount of protein in the urine Kidney function Safety Factors 49