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20 th International AIDS Conference • Melbourne, Australia • 21 July 2014

TURQUOISE-I: SAFETY AND EFFICACY OF ABT-450/R/OMBITASVIR, DASABUVIR, AND RIBAVIRIN IN PATIENTS CO-INFECTED WITH HEPATITIS C AND HIV-1. Mark S. Sulkowski , Joseph J. Eron, David Wyles, Roger Trinh, Jay Lalezari, Jihad Slim, Joseph Gathe, Peter J. Ruane, Chia Wang, Richard Elion,

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20 th International AIDS Conference • Melbourne, Australia • 21 July 2014

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  1. TURQUOISE-I:SAFETY AND EFFICACY OF ABT-450/R/OMBITASVIR, DASABUVIR, AND RIBAVIRIN IN PATIENTS CO-INFECTED WITH HEPATITIS C AND HIV-1 • Mark S. Sulkowski, Joseph J. Eron, David Wyles, Roger Trinh, Jay Lalezari, Jihad Slim, Joseph Gathe, Peter J. Ruane, Chia Wang, Richard Elion, • Fritz Bredeek, Robert Brennan, Gary Blick, Amit Khatri, Krystal Gibbons, Yiran B. Hu, Linda Fredrick, Tami Pilot-Matias, Barbara Da Silva-Tillmann, Barbara McGovern, Andrew L. Campbell, Thomas Podsadecki 20th International AIDS Conference • Melbourne, Australia • 21 July 2014

  2. Disclosures • MS Sulkowski: Consultant/Advisory Board: AbbVie, BMS, Gilead, Idenix Pharmaceuticals, Janssen, Merck, Tobira Therapeutics; Data Safety Monitoring Board: Gilead (funds paid to Johns Hopkins University); Study Steering Committee: Pfizer; Grant/Research support: AbbVie, Boehringer Ingelheim, BMS, Gilead, Merck, Janssen, Vertex Pharmaceuticals (funds paid to Johns Hopkins University). • JJ Eron: Grant/Research support: AbbVie, Merck, BMS, GSK/ViiV; Consultant; AbbVie, Gilead, BMS, GSK/ViiV, Merck, Janssen. • D Wyles: Grant/Research support: AbbVie, BMS, Gilead, Merck, Vertex Pharmaceuticals; Consultant/Advisor: AbbVie, BMS, Gilead, Janssen. • J Lalezari:Research support: AbbVie. • J Slim: Speaker Bureau: AbbVie, BMS, Gilead, Merck, Janssen, Genentech. • J Gathe: Grant/Research support: AbbVie, Tobira, Boehringer Ingelheim, BMS, GSK, Parexel, Gilead, Huesped. • PJ Ruane:Grant/Research support: AbbVie, BMS, Gilead, Merck, Idenix, ViiV, Janssen; Consultant/Advisor: AbbVie, Merck, Gilead: Speaker: Gilead, ViiV, Merck. • C Wang: Nothing to disclose. • R Elion: Grant/Research support: AbbVie, Merck, BMS, GSK/ViiV, Gilead; Consultant: Gilead, BMS, GSK, ViiV; Speakers bureau: BMS, Merck, ViiV, Gilead, Janssen. • F Bredeek: Grant/Research support: AbbVie, BMS, Gilead, Merck, Sumagen, ViiV; Consultant/Advisor: AbbVie, Merck, ViiV. • R Brennan: Grant/Research support: AbbVie, Pfizer, Cubist Pharmaceuticals Inc, Achillion, Sanofi Pasteur, ViiV, GSK. • G Blick: Grant/Research support: AbbVie, Gilead Sciences, Pfizer, Sangamo Biosciences, ViiV; Consultant/Advisor: BMS, Merck, Serono, ViiV; Speaker: AbbVie, Auxilium, BMS, Merck, Serono, ViiV. • R Trinh, A Khatri, K Gibbons, YB Hu, L Fredrick, T Pilot-Matias, B Da Silva-Tillmann, B McGovern, AL Campbell, and T Podsadecki: Employees of AbbVie and may hold stock or options. • The design, study conduct, analysis, and financial support of the clinical trials were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the presentation. All authors had access to all relevant data. • This presentation contains information on the investigational products ABT-450/r, ombitasvir (ABT-267), and dasabuvir (ABT-333) and investigational use of ribavirin.

  3. Background • Coinfection with HCV occurs in 20 – 40% of persons living with HIV • HCV/HIV coinfection is associated with more rapid liver disease progression2 • Liver-related disease is a leading cause of morbidity and mortality in HCV/HIV coinfected patients in the era of ART1 • The addition of direct-acting antivirals to pegIFN/ribavirin (RBV) has improved sustained virologic response (SVR) rates, but these regimens are associated with the well-known treatment-limiting toxicities of IFN-based therapy3-5 • IFN-free regimens have shown promise with higher SVR rates and an improved safety profile 1Kitahata MM, et al. N Engl J Med. 2009;360:1815-26.2Martin-Carbonero L, et al. Clin Infect Dis. 2004;38:128-33. 3Sulkowski MS, et al. Lancet Infect Dis. 2013;13:597-605. 4Sulkowski MS, et al. Ann Intern Med. 2013;159:86-96. 5Rodriguez-TorresM, et al. IDWeek 2013.

  4. 3 Direct-Acting Antiviral Regimen (3D) • The multi-targeted 3D regimen includes: • ABT-450, a potent NS3/4A protease inhibitor (identified by AbbVie and Enanta) co-dosed with low-dose ritonavir* (ABT-450/r) to increase the peak, trough, and overall drug exposures of ABT-450, enabling once daily dosing6 • Ombitasvir(ABT-267), a potent NS5A inhibitor • Dasabuvir(ABT-333), a non-nucleoside NS5B RNA polymerase inhibitor • ABT-450, ritonavir, and ombitasvir are co-formulated as a single tablet • Extensive phase 1 drug-drug interaction studies in healthy volunteers with tenofovir, emtricitabine, atazanavir, and raltegravirindicated no clinically meaningful alterations in HCV or HIV drug exposures *Ritonavir does not have antiviral activity against HCV. 6Menon R, et al. HepDART 2009.

  5. 3 Direct-Acting Antiviral Regimen (3D) • The 3D regimen, with and without RBV, has been studied in >2700 patients to date • High SVR12 rates were achieved with 3D + RBV in genotype (GT) 1-infected patients within a phase 3 program • ≥96% SVR12 in treatment-naïve and -experienced patients after 12 weeks of treatment7-10 • 92 – 96% SVR12 in treatment-naïve and -experienced patients with cirrhosis treated for 12 or 24 weeks11 • TURQUOISE-Iis a 2-part, multicenter, phase 2/3 study assessing the safety and efficacy of 3D + RBV in HCV GT1/HIV-1 coinfected patients, including those with cirrhosis 7Feld JJ, et al. N Engl J Med. 2014;370:1594-603. 8Ferenci P, Bernstein D, et al. N Engl J Med. 2014;370:1983-92. 9Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614. 10Andreone P, et al. Gastroenterology. 2014;doi:10.1053/j.gastro.2014.04.045. 11Poordad F, et al. N Engl J Med. 014;370:1973-82.

  6. TURQUOISE-I: Part 1 Study Design (N = 63) All patients will be followed for 48 weeks after HCV treatment end • 3D: coformulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID • RBV: 1000 or 1200 mg daily according to body weight in 2 divided doses(<75 kg and ≥75 kg, respectively) Open-label Treatment SVR12 3D + RBV (N = 31) SVR4 3D + RBV (N = 32) Week 24 Week 36 Day 1 Week 12

  7. TURQUOISE-I: Study Analyses • Efficacy analyses • Rapid virologic response (RVR; week 4 of treatment) • End-of-treatment response (EOTR; week 12 or 24 of treatment) • Sustained virologic response (SVR4 and SVR12; post-treatment week 4 and 12, respectively) • On-treatment HCV virologic failure • Post-treatment HCV viral relapse • Safety analyses • Maintenance of plasma HIV-1 RNA suppression • Treatment-emergent adverse events • On-treatment lab abnormalities Virologic response is defined as HCV RNA <LLOQ (25 IU/mL)

  8. TURQUOISE-I: Key Eligibility Criteria • 18 to 70 years of age • BMI ≥18 and <38 kg/m2 • HCV GT1 infection (plasma HCV RNA >10,000 IU/mL) • HCV treatment-naïve or pegIFN/RBV-experienced • For pegIFN/RBV-experienced, prior: Relapse*, Partial response†, or Null response‡ • Child-Pugh A Cirrhosis • HIV-1 infected • Plasma HIV-1 RNA <40 copies/mL • CD4+ count ≥200 cells/mm3 or CD4+% ≥14% • Stable atazanavir or raltegravir-inclusive ART regimen *Relapse: HCV RNA undetectable at or after the end of treatment, but with a detectable level within 52 weeks thereafter † Partial response: >2 log10 IU/mL HCV RNA reduction at treatment week 12 but detectable at end of treatment ‡ Null response: <2 log10 IU/mL or <1 log10IU/mL HCV RNA reduction at treatment week 12 or 4, respectively

  9. TURQUOISE-I:Baseline Demographics and Disease Characteristics

  10. TURQUOISE-I Results:ITT Virologic Response Rates 3D + RBV Regimen 12-Week Arm 24-Week Arm 30 31 31 31 32 32 31 32

  11. TURQUOISE-I Results:ITT Virologic Response Rates 3D + RBV Regimen 12-Week Arm 24-Week Arm 31 32 29 31 29 31 31 31 32 32 31 32 30 31

  12. TURQUOISE-I: Reasons for Non-Response • Virologic failure occurred in 2 patients; both were prior null responders with HCV genotype 1a infection and had compensated cirrhosis • Each had resistance-associated variants in at least 2 targets at the time of virologic failure not present at baseline • 1 patient (12-week Arm) withdrew consent but had an undetectable HCV RNA at last study visit (week 10) • No patient discontinued due to adverse events Variants at Time of Failure

  13. TURQUOISE-I: Treatment-Emergent Adverse Events ≥ 10% • The majority of adverse events were mild or moderate in severity • 5 severe adverse events were reported: insomnia, hypophosphatemia, disseminated herpes zoster, tooth abscess, and vertigo • No treatment-emergent serious adverse events were reported

  14. TURQUOISE-I: On-Treatment Laboratory Abnormalities • 6 patients reduced RBV dose due to hemoglobin declines; all achieved SVR • Indirect hyperbilirubinemia was the most common laboratory abnormality • 15/17 (88.2%) patients experiencing grade 3 total bilirubin elevations were receiving atazanavir-inclusive ART • 5 patients (2 in the 12-week Arm, and 3 in the 24-week Arm) had a confirmed HIV-1 RNA ≥40 copies/mL (but <200 copies/mL) during the treatment period • All 5 patients achieved plasma HIV-1 RNA re-suppression while maintaining the same HIV-1 ART regimen without 3D + RBV interruption

  15. TURQUOISE-I: Summary • This study evaluated the IFN-free 3D + RBV regimen in HCV treatment-naïve and –experienced patients coinfected with HIV-1, including those with cirrhosis: • SVR12 rate of 93.5% was achieved with 12 weeks of 3D + RBV • SVR4 rate of 96.9% was achieved with 24 weeks of 3D + RBV • 3D + RBV coadministered with atazanavir or raltegravir ART was well-tolerated with no treatment-emergent serious adverse events and no patient discontinuations due to adverse events • These results are consistent with those in HCV GT1-monoinfected populations receiving the 3D + RBV regimen

  16. TURQUOISE-I: Next Steps • A cohort of patients on a stable darunavir-inclusive ART regimen who will receive treatment with the 3D + RBV regimen for 12 weeks (Part 1b) will be evaluated • TURQUOISE-I, Part 2 will be conducted globally and will initiate later this year

  17. Acknowledgements The authors would like to express their gratitude to the patients and their families, investigators, and coordinators who made these studies possible. The authors thank AbbVie employees Christine Collins, Sandra Lovell, Rakesh Tripathi, Martin King, KarminRobinson-Morgan, GretjaSchnell, Jill Beyer, and Thomas Reisch for contributions to the study. Medical writing support was provided by Douglas E. Dylla, an employee of AbbVie.

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