ZIRCON: Pharmacokinetics, Safety, and Efficacy of Ombitasvir/Paritaprevir/Ritonavir ± THU-251 Dasabuvir ± Ribavirin in Adolescents With Genotype 1 or 4 Hepatitis C Virus Infection

Leung, Daniel;Yao, Betty;Gonzalez-Peralta, Regino;Jonas, Maureen;Rosenthal, Philip;et.al.
(2017) The International Liver Congress (EASL) — Location: Amsterdam, the Netherlands (19.April.2017)

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Authors
  • Leung, DanielTexas Children Hospital
    Author
  • Yao, BettyAbbvie
    Author
  • Gonzalez-Peralta, ReginoUniversity of Florida College
    Author
  • Jonas, MaureenBoston Children's Hospital
    Author
  • Sokal, EtienneUCLouvain
    Author
  • Larsen, LoiseUCLouvain
    Author
  • Liu, LiUCLouvain
    Author
  • Shuster, DianaUCLouvain
    Author
  • Cohen, DanielUCLouvain
    Author
  • Rosenthal, PhilipUniversity of California
    Author
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Abstract
BACKGROUND In adults, treatment of hepatitis C virus (HCV) genotype 1 (GT1) and GT4 with ombitasvir, paritaprevir, ritonavir ± dasabuvir (OBV/PTV/r ± DSV) ± ribavirin (RBV) results in high rates of sustained virologic response (SVR)1–6. However, these direct-acting anti virals (DAAs) have not been studied in children or adolescents. ZIRCON is an ongoing, global, open-label, 3-part study to evaluate the pharmacokinetics (PK), safety, and efficacy of OBV/PTV/r ± DSV ± RBV for pediatric and adolescent patients infected with HCV GT1 or GT4 (NCT02486406) Data for patients aged ≥12–17 years enrolled in Parts 1 and 2 are presented here OBJECTIVES To asess the PK of OBV/PTV/r + DSV ± RBV in HCV GT1-infected adolescents in Part 1 • To assess the efficacy and safety of OBV/PTV/r ± DSV ± RBV for 12 or 24 weeks in HCV GT1- or GT4-infected adolescents in Parts 1 and 2 METHODS STUDY DESIGN • Part 1 is a Phase 2 study enrolling treatment-naïve, non-cirrhotic, HCV GT1-infected patients who received treatment for 12 weeks • Part 2 is a Phase 3 study enrolling treatment-naïve or -experienced HCV GT1- or GT4-infected patients with or without compensated cirrhosis who received treatment for 12 or 24 weeks depending on their GT subtype and cirrhosis status. Enrollment in Part 2 began as soon as dosing recommendations for the study drugs were available based on PK and clinical data from Part 1 • Treatment was OBV/PTV/r 25 mg/150 mg/100 mg once daily ± DSV 250 mg twice daily ± weight-based RBV 1000 mg or 1200 mg divided twice daily • Blood samples were collected for intensive PK sampling in Part 1 at treatment Week 2 (at 2, 4, 8, 12, and 24 hours post dose) • Blood samples were collected for measurement of HCV RNA in Parts 1 and 2 at treatment Day 1 and at Weeks 2, 4, 8, and 12 for patients who received the 12-week regimen, as well as Weeks 16, 20, and 24 for patients who received the 24-week regimen • SVR was assessed at post-treatment Week 12 (SVR12) PATIENT SELECTION Key Inclusion Criteria • Patients aged ≥12–17 years with a body weight of ≥45 kg • HCV infection (GT1 in Parts 1 and 2; GT4 in Part 2), defined as positive anti –HCV anti body and HCV RNA level >1000 IU/mL at screening • Previous HCV therapy – Part 1: Treatment naïve – Part 2: Treatment naïve or interferon (IFN) experienced; IFN-based therapy must have been completed ≥6 months before enrollment Key Exclusion Criteria • Coinfection with hepatitis B virus or human immunodefi ciency virus • Current or past clinical evidence of Child-Pugh B or C (Child-Pugh score ≥7) or clinical history of liver decompensation • Radiographically confirmed hepatocellular carcinoma • Previous or current use of any investi gati onal or commercially available anti -HCV drug other than IFN, pegylated IFN, or RBV • History of solid organ transplantation • Albumin <2.8 g/dL, hemoglobin <10 g/dL, platelets <25 000 cells/mm3, or total bilirubin >3.0 mg/dL ENDPOINTS • In Part 1 of the study, PK endpoints for each study drug were: – Maximum plasma concentration (Cmax) aft er dosing at Week 2 – Area under the plasma concentration–ti me curve (AUC) at 0–12 hours (for DSV and RBV) or 0–24 hours (for OBV, PTV, and ritonavir) aft er dosing at Week 2 – Trough concentrati on (Ctrough) aft er dosing at Week 2 • In Parts 1 and 2, the primary effi cacy endpoint was the percentage of patients who achieved SVR12 (HCV RNA <15 IU/mL at post-treatment Week 12) • Results of the interim analysis performed at post-treatment Week 12 are reported here • Adverse events (AEs) were recorded throughout the study STATISTICAL ANALYSES The percentages of pati ents who achieved SVR12 in Parts 1 and 2 were calculated for the intention-to-treat (ITT) population, which comprised all patients who received at least 1 dose of the study drugs CONCLUSIONS In adolescent patients with HCV GT1 or GT4 infection, treatment with OBV/PTV/r ± DSV ± RBV resulted in 100% SVR12 OBV/PTV/r ± DSV ± RBV was well tolerated in this population, and no Grade 3 or 4 laboratory abnormalities or treatment emergent SAEs were reported The exposures in adolescent patients were comparable to those observed in adults, suggesting that this regimen is suitable for treating adolescents without dosage adjustment Dosing in ≥9–11 and ≥3–8 year old pediatric patients is ongoing Long-term follow-up (approximately 3.5 years) of OBV/PTV/r ± DSV ± RBV in these patients will be investigated in Part 3 or Zircon
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Leung, D., Yao, B., Gonzalez-Peralta, R., Jonas, M., Lobritto, S., Narkewicz, M., Sokal, E., Fortuny, C., Hsu, E., Wirth, S., Del Valle-Segarra, A., Zha, J., Larsen, L., Liu, L., Shuster, D., Cohen, D., & Rosenthal, P. (2017). ZIRCON: Pharmacokinetics, Safety, and Efficacy of Ombitasvir/Paritaprevir/Ritonavir ± THU-251 Dasabuvir ± Ribavirin in Adolescents With Genotype 1 or 4 Hepatitis C Virus Infection. The International Liver Congress (EASL), Amsterdam, the Netherlands. https://hdl.handle.net/2078.5/40317