Surveyor-II, Part 3: Efficacy and Safety of Glecaprevir/Pibrentasvir (Abt-493/Abt-53) in Patients with Hepatitis C Virus Genotype 3 Infection with Prior Treatment Experience and/or Cirrhosis David L. Wyles, Fred Poordad, Stanley Wang, Laurent Alric, Franco Felizarta, Paul Y. Kwo, Benedict Maliakkal, Kosh Agar- wal, Tarek I. Hassanein, Frank Weilert, Samuel S. Lee, Ran Liu, Chih-Wei Lin, Teresa Ng, Federico Mensa Abstract 3 Next Generation Direct-Acting Antivirals Glecaprevir (formerly ABT-493) PIB pangenotypic NS3/4A protease inhibitor Pibrentasvir (formerly ABT-53) pangenotypic NS5A inhibitor Collectively: In vitro:, Clinical PK & metabolism: High barrier to resistance Potent against common NS3 polymorphisms (eg, positions 8, 55, and 68) and NS5A polymorphisms (eg, positions 8, 3, 3 and 93) Additive/synergistic antiviral activity Once-daily oral dosing Minimal metabolism and primary biliary excretion Negligible renal excretion (<%) is coformulated and dosed once daily as three mg/4 mg pills for a total dose of 3 mg/ mg Glecaprevir was identified by AbbVie and Enanta. Ng TI, et al. Abstract 636. CROI, 4.. Ng TI, et al. Abstract 639. CROI, 4.. Wyles D, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. 3.
SURVEYOR-II Part 3: Study Design and Patient Population : Randomized Treatment Period TE without cirrhosis TE without cirrhosis N = 4 TN with cirrhosis N = 47 TE with cirrhosis Post-Treatment Period SVR SVR SVR SVR 6 4 8 36 4 Weeks Included GT3 Patients without cirrhosis or with compensated cirrhosis Excluded prior treatment with HCV DAA other than SOF Excluded HBV or HIV coinfection Wyles D, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. 3. Baseline Demographics and Clinical Characteristics Characteristic : Randomized Treatment Experienced Treatment Experienced Cirrhosis Cirrhosis Weeks 6 Weeks Treatment Naïve Cirrhosis Weeks N = 4 Treatment Experienced Cirrhosis 6 Weeks N = 47 Male, n (%) 4 (64) 4 (64) 4 (6) 36 (77) White race, n (%) 7 (77) (9) 37 (93) 4 (89) Age, median years (range) 56 (35 68) 59 (9 66) 56 (36 7) 59 (47 7) BMI, median kg/m (range) 6 (9 4) 8 ( 48) 9 ( 5) 7 ( 4) IL8B non-cc genotype, n (%) 5 (68) 9 (86) (5) 34 (7) HCV RNA, median log IU/mL (range) 6.6 (5. 7.5) 6. (4.7 7.3) 6. (4. 7.) 6.5 (4.6 7.) HCV RNA 6,, IU/mL, n (%) 9 (4) 7 (3) 4 () () Prior treatment history, n (%) Naïve 4 () IFN/pegIFN ± RBV 4 (64) 3 (59) (47) SOF RBV ± pegifn 8 (36) 9 (4) 5 (53) Baseline Fibrosis Stage*, n (%) F-F (5) 5 (68) F 4 (8) (9) F3 7 (3) 5 (3) F4 4 () 47 () BMI, body mass index;, coformulated glecaprevir and pibrentasvir; HCV, hepatitis C virus; IFN, interferon; IL8B, interleukin 8; NS, non-structural protein; pegifn, pegylated interferon; SOF, sofosbuvir *Data missing for patient in Arm A (column ) and patient in Arm B (column 3) Wyles D, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. 3.
Baseline Polymorphisms Baseline Polymorphism, n (%) Treatment Experienced Cirrhosis Weeks Treatment Experienced Cirrhosis 6 Weeks N = Treatment Naïve Cirrhosis Weeks N = 39 Treatment Experienced Cirrhosis 6 Weeks N = 47 6 (73) 8 (86) 9 (74) 4 (85) NS3 only (3) () NS5A only 6 (7) 3 (4) 9 (3) 6 (3) Both NS3 and NS5A *Baseline polymorphisms detected at 5% next-generation sequencing threshold only within samples that had sequences available for both targets at key amino acid positions: NS3: 55, 56, 68 NS5A: 4, 8, 3, 3, 58, 9, 93 Wyles D, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. 3. SURVEYOR-II, Part 3: SVR 9 8 7 6 5 4 3 Weeks Cirrhosis T-Experience Breakthrough LTFU SVR, % Patients 9 - : Randomized 96 98 39 4 GT GT4 GT5 GT6 6 6 - - 96 45 47 98% of patients had HCV RNA <LLOQ by treatment week 4 Wyles D, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. 3.
Virologic Failure: Patient Details Characteristic SURVEYOR-II Treatment Virologic Failure Compensated Cirrhosis Prior Treatment Experience Fibrosis Stage Baseline HCV RNA, IU/mL Treatment Compliance Patient A weeks No F-F 8,4, Patient B weeks No F 9,4, Patient C 6 weeks No F-F 8,9, Patient D 6 weeks F4,84, Patient E 6 weeks BT F4 7,4, NA* Sequence Analysis Baseline NS3 Failure Patient A Patient B Patient C Patient D Patient E A66S Y56H, Q68R A56G, A66S Baseline Y93H A3K A3K Failure Y93H A3K, Y93H A3K, Y93H L3F, Y93H A3K, Y93H NS5A BT, breakthrough NA, not available; *Patient E had drug exposures 85% lower than average at week 4 Substitutions detected by next-generation sequencing at 5% detection threshold NS3: 36, 43, 54, 55, 56, 8, 55, 56, 66, and 68 NS5A: 4, 8, 9, 3, 3, 3, 58, 9, and 93 Wyles D, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. 3. SURVEYOR-II, Part 4: Glecaprevir/Pibrentasvir Demonstrates High SVR Rates in Patients with HCV Genotype, 4, 5, or 6 Infection without Cirrhosis Following an 8-Week Treatment Duration T.I. Hassanein, D.L. Wyles, S. Wang, R. Liu, T. Ng, C. Lin, F.J. Mensa, P.Y. Kwo, M.L. Shiffman, Z. Younes, S. Greenbloom, C.A. Stedman, J. Sasadeusz, H.I. Aguilar, J. Heo, Abstract LB-5
SURVEYOR-II, Part 4: Study Design SVR Assessment GT, 4, 5, 6 N =3 3 mg/ mg * Day Wk 8 Wk Wk 4 Open-label Treatment *Three mg/4 mg pills taken once daily. Hassanein T, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. LB-5. SURVEYOR-II, Part 4: Results - SVR, ITT Population % Patients with SVR 8 6 4 Breakthrough Discontinuation Missing SVR Data 97 98 93 9 96 3 : : : 3: 4 45 * 43 46 Overall GT GT4 GT5 GT6 9 Dotted line (yellow) represents the non-inferiority threshold (89%) *Patient discontinued on Day 5 due to loss to follow-up. Patient discontinued on Day 36 due to non-compliance. Hassanein T, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. LB-5.
SURVEYOR-II, Part 4: Characteristics of Patients with Virologic Failure Time of Failure Patient A* Patient B post-treatment Day 9, post-treatment Day 55 Age/Race/Gender 56-year-old white female 55-year-old white male Genotype/Subtype GTa GTa C/C C/T IL8B Genotype Fibrosis Stage F F F3 5 IU/mL 7 IU/mL Experienced Experienced Treatment Compliant Compliantƚ NS3 NS5A Baseline Viral Load Prior Treatment Exposure Treatment Treatment-emergent substitutions at time of failure *Patient had a medical history of gastric bypass. Exposure of GLE on Day and Week 4 was >75% lower than the men in patients in the same treatment arm; exposure of PIB was comparable to the other patients in the cohort. ƚ Measured as the percentage of tables taken relative to the total tablets expected to be taken during the treatment period; compliance achieved if percentage was 8%. Hassanein T, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. LB-5. EXPEDITION-IV: Safety and Efficacy of GLE/PIB in Adults with Renal Impairment and Chronic Hepatitis C Virus Genotype 6 Infection D. Pugatch, Y. Lei, M.P. Kosloski, F.J. Mensa, E. Lawitz, E.J. Gane, G.V. Papatheodoridis, N. Bräu, James J. Peters, A.S. Brown, S. Pol, V. Leroy, M. Persico, C. Moreno, M. Colombo, E.M. Yoshida, D.R. Nelson, G.V. Papatheodoridis, N. Bräu Abstract LB-
EXPEDITION-IV: Safety and Efficacy of GLE/PIB in Adults with Renal Impairment and Chronic Hepatitis C Virus Genotype 6 Infection EXPEDITION-4: Objective and Study Design GT 6 Stage 4/5 CKD /- cirrhosis TN or TE Treatment Period N = 4 Post-Treatment Period SVR 6 4 8 36 Weeks Objective Determine the efficacy and safety of pangenotypic for weeks in patients with HCV GT-6 and stage 4 or 5 chronic kidney disease (CKD) Endpoints Efficacy: SVR defined as HCV RNA below the lower limit of quantification (LLOQ; 5 IU/mL) Safety: Adverse events (AEs) and laboratory abnormalities is coformulated and dosed once daily as three mg/4 mg pills for a total dose of 3 mg/ mg Gane E, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. LB-. EXPEDITION-IV: Baseline Characteristics Characteristic N = 4 Male, n (%) 79 (76) Black race, n (%) 6 (5) Age, median years (range) 57 (8 83) BMI, median kg/m (range) 6 (8 45) IL8B non-cc genotype, n (%) 8 (77) HCV RNA, median log IU/mL (range) 5.9 (3.4 7.5) Concomitant PPI use, n (%) 43 (4) Patients were enrolled across 9 countries: Australia, Belgium, Canada, France, Greece, Italy, New Zealand, the United Kingdom, and United States BMI, body mass index; CrCl, creatinine clearance; egfr, estimated glomerular filtration rate;, coformulated glecaprevir/pibrentasvir; HCV, hepatitis C virus; IL8B, interleukin 88; PPI, proton pump inhibitor Gane E, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. LB-.
EXPEDITION-IV: Baseline Demographics and Clinical Characteristics Characteristic N = 4 Male, n (%) 79 (76) Black race, n (%) 6 (5) Age, median years (range) 57 (8 83) BMI, median kg/m (range) 6 (8 45) IL8B non-cc genotype, n (%) 8 (77) HCV RNA, median log IU/mL (range) 5.9 (3.4 7.5) Concomitant PPI use (%) 43 (4) Characteristic, (n%) N = 4 HCV genotype a / b / other 3 () / 9 (8) / () 7 (6) 3 () 4 / 5 / 6 (9) / () / () Prior treatment history Naïve 6 (58) IFN/pegIFN ± RBV 4 (4) SOF RBV ± pegifn () Compensated cirrhosis (9) No 84 (8) CKD stage Stage 4 3 () Stage 5 9 (88) Hemodialysis 85 (8) Patients were enrolled across 9 countries: Australia, Belgium, Canada, France, Greece, Italy, New Zealand, the United Kingdom, and United States Gane E, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. LB-. EXPEDITION-IV: Results SVR by Intent-To-Treat (ITT) Analysis % Patients with SVR 8 6 4 Breakthrough Discontinuation LTFU 98 GT ITT mitt = --% SVR 4 AEs leading to study drug discontinuation One death weeks post-treatment due to cerebral hemorrhage non study drug related Gane E, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. LB-.
EXPEDITION-IV: Post-Baseline Laboratory Abnormalities N = 4 Event, n (%) Hemoglobin Grade 3 (<8. 6.5 g/dl) 5 (5) AST Grade (>3 x ULN) ALT Grade (>3 x ULN) Total bilirubin Grade 3 (>3 x ULN) () Grade 3 or higher laboratory abnormalities were rare Gane E, et al. 67th AASLD; Boston, MA; November -5, 6; Abst. LB-.