Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies

Abstract

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI.

Trial registration: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390.

Fig 1. Patient disposition in DYNAMO 1.

BOC, boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin.

Fig 2. Patient disposition in DYNAMO 2.

MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin; TVR, telaprevir.

Fig 3. Study designs of DYNAMO 1 (a) and DYNAMO 2 (b).

BOC, boceprevir 800 mg TID (at recommended intervals of 7–9 hours); MCB, mericitabine 1000 mg BID; P/R, peginterferon alfa-2a 180 μg once/week + ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg); PBO, placebo; TVR, telaprevir 750 mg TID (at recommended intervals of 7–9 hours). Control Arms C in DYNAMO 1 and D in DYNAMO 2 were closed due to futility while the studies were ongoing (27 July 2012 in DYNAMO 1 and 10 July 2012 in DYNAMO 2), after which patients in these groups were given the option to receive mericitabine for a maximum duration of 24 weeks. MCB was added to the regimen for 5 patients in Arm C in DYNAMO 1 and to the regimen for 9 patients in Arm D in DYNAMO 2 at various time points and for various durations.

Fig 4. SVR12 rates by treatment arm in the overall populations and by HCV genotype and presence/absence of bridging fibrosis or cirrhosis in DYNAMO 1 (a) and DYNAMO 2 (b).

BOC, boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin; TVR, telaprevir.