High SVR4 Rates in Non-Cirrhotic HCV Genotype 2 Patients With Next-Gen Protease Inhibitor
Investigating the efficacy of the next-gen NS3/4A protease inhibitor ABT-493 and NS5A inhibitor ABT-530 in non-cirrhotic HCV genotype 2 patients, both treatment-naive and treatment-experienced. Study conducted by David Wyles, Mark Sulkowski, Stanley Wang, Michael Bennett, and Hugo E.
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SURVEYOR-II: High SVR4 Rates Achieved With the Next Generation NS3/4A Protease Inhibitor ABT-493 and NS5A Inhibitor ABT-530 in Non-Cirrhotic Treatment-Na ve and Treatment- Experienced Patients With HCV Genotype 2 Infection David Wyles,1Mark Sulkowski,2Stanley Wang,3Michael Bennett,4 Hugo E. Vargas,5J. Scott Overcash,6Benedict Maliakkal,7Asma Siddique,8 Bal Raj Bhandari,9Fred Poordad,10Sandra S. Lovell,3Chih-Wei Lin,3 Teresa I. Ng,3Federico J. Mensa,3Jens Kort3 1University of California San Diego, La Jolla, CA, USA; 2Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3AbbVie Inc., North Chicago, IL, USA; 4San Diego Digestive Disease Consultants, Inc., and Medical Associates Research Group, Inc., San Diego, CA, USA; 5Mayo Clinic, Phoenix, AZ, USA; 6eStudySite, San Diego, CA, USA; 7University of Rochester Medical Center, Rochester, NY, USA; 8Virginia Mason Hospital and Medical Center, Seattle, WA, USA; 9Gastroenterology & Nutritional Medical Services, Bastrop, LA, USA; 10Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA 66th Annual Meeting of the American Association for the Study of Liver Diseases San Francisco, CA 17 November 2015 1
Disclosures D Wyles: Grant/Research support: AbbVie, BMS, Gilead, Merck, Tacere Therapeutics; Consultant/Advisor: AbbVie, BMS, Gilead, Merck, Janssen. M Sulkowski: Research grants to Johns Hopkins University: AbbVie, BMS, Gilead, Janssen, Merck; Scientific advisory board: AbbVie, BMS, Cocrystal, Gilead, Janssen, Merck, Trek. M Bennett: Stockholder: AbbVie; Clinical trial investigator: AbbVie. HE Vargas: Grant/research support: AbbVie, BMS, Gilead, Merck. JS Overcash: No relevant conflicts to disclose. B Maliakkal: Speaker: AbbVie, Gilead, BMS. A Siddique: No relevant conflicts to disclose. B Bhandari: No relevant conflicts to disclose . F Poordad: Grant/Research support: Abbvie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ZymoGenetics. Speaker: Gilead, Kadmon, Merck, Onyx/Bayer, Genentech, GlaxoSmithKline, Salix, Vertex. Consultant/Advisor: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix, Merck, Novartis, Tibotec/Janssen, Theravance, Vertex. S Wang, SS Lovell, CW Lin, TI Ng, F Mensa, J Kort: AbbVie employees and may hold AbbVie stock or stock options. The design, study conduct, analysis, and financial support of the SURVEYOR-II (NCT02243293) study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the content. All authors had access to all relevant data and participated in writing, review, and approval of this presentation. Medical writing support was provided by Sharanya Ford, PhD, of AbbVie. This presentation contains information on the investigational products ABT-493 and ABT-530. SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 2
HCV Next Generation Direct-Acting Antivirals ABT-493: pangenotypic NS3/4A protease inhibitor* (GT2 EC50 2.7 nM) ABT-530: pangenotypic NS5A inhibitor (GT2 EC50 2 pM) In vitro characteristics:1,2 Higher barrier to resistance Additive/synergistic antiviral activity Clinical pharmacokinetics and metabolism: Once-daily oral dosing Minimal metabolism and primary biliary excretion No renal excretion (<1%) *ABT-493 identified by AbbVie and Enanta. 1. 2. Ng TI, et al. Abstract 636. 21st Conference on Retroviruses and Opportunistic Infections., Boston, 2014. Ng TI, et al. Abstract 639. 21st Conference on Retroviruses and Opportunistic Infections., Boston, 2014. SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 3
SURVEYOR-II Part 1 (GT2): Study Design SURVEYOR-II is an open-label, multicenter phase 2 trial evaluating the safety and efficacy of co-administered ABT-493 and ABT-530, at varying doses, ribavirin (RBV), in patients with HCV GT2 or GT3 infection Day 1 PT Week 24 Week 12 Post-treatment (PT) period Treatment period ABT-493 300 mg + ABT-530 120 mg n=25 ABT-493 200 mg + ABT-530 120 mg n=25 ABT-493 200 mg + ABT-530 120 mg + RBVa n=25 ClinicalTrials.gov: NCT02243293. N=75. aDaily dose of 1000 mg or 1200 mg RBV dosed BID based on patient body weight being <75 kg or 75 kg. SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 4
SURVEYOR-II Part 1 (GT2): Key Eligibility Criteria and Endpoints Key inclusion criteria 18 to 70 years of age, inclusive HCV GT2 infection, HCV RNA 10,000 IU/mL HCV treatment-na ve or failed previous PegIFN/RBV treatment Absence of cirrhosis Key exclusion criteria Previous use of any HCV DAAs CrCl <50 ml/min, platelet count <120 109/L Herbal supplements and potent P-gp inducers were prohibited *Commonly prescribed concomitant medications (e.g., PPIs) were allowed Endpoints Efficacy: SVR12 (primary) and virologic failure Safety: adverse events (AEs) and laboratory abnormalities SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 5
SURVEYOR-II Part 1 (GT2): Demographics and Patient Characteristics ABT-493 300 mg + ABT-530 120 mg (n = 25) ABT-493 200 mg + ABT-530 120 mg (n = 25)a ABT-493 200 mg + ABT-530 120 mg + RBV (n=25) Male, n (%) Race, n (%) White Black Hispanic or Latino ethnicity, n (%) Age, mean (range), years BMI, mean SD, kg/m2 IL28B non-CC genotype, n (%) HCV RNA, mean SD, log10 IU/mL HCV genotype 2b, n (%) Prior PegIFN/RBV experience, n (%) Baseline fibrosis stage, n (%) F0 F1 F2 F3 16 (64) 13 (52) 18 (72) 22 (88) 2 (8) 1 (4) 56 (27 69) 28 5.1 12 (48) 6.8 0.7 22 (88) 3 (12) 23 (92) 1 (4) 2 (8) 54 (23 69) 26 4.3 11 (44) 6.8 0.8 17 (68) 3 (12) 23 (92) 2 (8) 4 (16) 51 (20 68) 27 4.0 13 (52) 6.8 0.7 22 (88) 3 (12) 16 (64) 6 (24) 3 (12) 18 (72) 4 (16) 3 (12) 18 (72) 3 (12) 4 (16) aOne patient was found to have GT3 infection and was excluded from efficacy analyses but included in the safety analyses. SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 6
SURVEYOR-II Part 1 (GT2): ITT SVR12 Rates by Treatment 9 6 1 0 0 1 0 0 100 80 SV R 12, % Patients 60 40 20 a 2 4 2 4 2 5 2 5 2 4 2 5 0 200 mg + 120 mg + RBV ABT-493 + ABT-530 300 mg + 120 mg 200 mg + 120 mg aOne patient was lost to follow up after treatment week 2. SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 7
SURVEYOR-II Part 1 (GT2): ITT SVR12 Rates by Treatment 9 6 1 0 0 1 0 0 100 80 SV R 12, % Patients 60 40 20 a 2 4 2 4 2 5 2 5 2 4 2 5 0 200 mg + 120 mg + RBV ABT-493 + ABT-530 300 mg + 120 mg 200 mg + 120 mg aOne patient was lost to follow up after treatment week 2. SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 8
Amino Acid Variant Analysis by Population Sequencing Number of GT2-Infected Patients with Baseline Variantsa DAA Target NS3 only NS5A only 39b Patients (n= 74) 1 aVariants included are based on resistance-associated positions; they may not confer resistance to ABT-493 or ABT-530. bGT2-infected patients with NS5A 31M (alone or in a mixture) = 36. GT2 31M confers resistance to a number of NS5A inhibitors, but not to ABT-530 No virologic failures among patients with baseline variants Variant positions: NS3: 56, 80, 155, 156, and 168 NS5A: 24, 28, 29, 30, 31, 32, 58, 92, and 93 SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 9
SURVEYOR-II Part 1 (GT2): Summary of Adverse Events ABT-493 300 mg + ABT-530 120 mg (n = 25) 13 (52) ABT-493 200 mg + ABT-530 120 mg (n = 25) 15 (60) ABT-493 200 mg + ABT-530 120 mg + RBV (n=25) 22 (88) Event, n (%) Any AE AEs leading to study discontinuation Any severe AE Any serious AE Deaths AEs in >10% of patients Fatigue Nausea Diarrhea Headache AEs were graded per National Cancer Institute s Common Terminology Criteria for Adverse Events (CTCAE). aOne patient had the events of low potassium/hypokalemia and another patient had headaches. bOne patient had worsening headaches; another patient also had worsening headaches as well as insomnia. cOne patient had a serious AE of atrial fibrillation (not considered related to study drugs). 0 0 0 2 (8)a 0 0 2 (8)b 1 (4)c 0 0 0 0 2 (8) 3 (12) 4 (16) 1 (4) 3 (12) 1 (4) 1 (4) 3 (12) 10 (40) 8 (32) 6 (24) 6 (24) SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 10
SURVEYOR-II Part 1 (GT2): Laboratory Abnormalities ABT-493 300 mg + ABT-530 120 mg (n = 25) ABT-493 200 mg + ABT-530 120 mg (n = 25) ABT-493 200 mg + ABT-530 120 mg + RBV (n=25) Event, n (%) ALT Grade 3+ (>5 ULN) AST Grade 3+ (>5 ULN) Alkaline phosphatase Grade 3+ (>5 ULN) Total bilirubin Grade 3+(>3 ULN) Hemoglobin Grade 2 (<10-8 g/dL) Grade 3 (<8 g/dL) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (4) 0 In all patients with baseline ALT elevations, ALT levels normalized with DAA treatment; there were no on-treatment ALT elevations above baseline SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 11
SURVEYOR-II Part 1 (GT2): Summary In this 12-week dose-ranging study of once-daily ABT-493 and ABT-530: Efficacy was high regardless of ABT-493 and ABT-530 dose No virologic failures in 74 patients All patients with baseline NS3 or NS5A variants achieved SVR12 ABT-493 + ABT-530 demonstrated a favorable safety profile AEs were mostly mild in severity No increase in AE frequencies with increasing doses No premature discontinuations SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 12
SURVEYOR-II Part 1 (GT2): Conclusions Up to 100% SVR12 achieved with ABT-493 + ABT-530 The combination was well tolerated Based on these results and data in other genotypes, the selected doses moving forward are: ABT-493: 300 mg QD ABT-530: 120 mg QD Ongoing studies in patients with GT2 infection: Patients without cirrhosis (8-week treatment) Patients with compensated cirrhosis Sofosbuvir/RBV failures SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 13
Acknowledgments The authors would like to express their gratitude to the patients and their families who participated in this study. Additionally, we would like to acknowledge all members of the SURVEYOR-II study team and AbbVie s HCV Next Generation team who contributed to this study. SURVEYOR-II: ABT-493 and ABT-530 for HCV Genotype 2 Infection | AASLD | 17 November 2015 14
