Results from Investigational Studies of Boceprevir Presented at the Conference on Retroviruses and Opportunistic Infections to Understand Potential Use in Patients Coinfected with Chronic Hepatitis C and HIV-1

SEATTLE, March 6, 2012 /CNW/ - Merck today announced results from two different investigational studies conducted to better understand the potential role of boceprevir (known commercially as VICTRELIS™), the company's oral HCV protease inhibitor, in treating patients coinfected with chronic HCV and HIV-1.  These data are being presented for the first time today at the 19^th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Results were presented from a 12-week post treatment interim analysis of a Phase IIb clinical study evaluating the investigational use of boceprevir in combination with peginterferon alfa-2b and ribavirin for the treatment of chronic HCV genotype 1 infection in adult patients coinfected with HIV-1 (n=100). In the study, a higher percentage of patients receiving boceprevir in combination with peginterferon alfa-2b and ribavirin had undetectable hepatitis C virus (HCV-RNA) 12 weeks after treatment ended (sustained virologic response 12¹ - or SVR-12) than patients receiving peginterferon alfa-2b and ribavirin alone.

Additionally, Merck announced results as part of a late-breaker poster session [Poster #771] from a pharmacokinetic study evaluating drug interactions between boceprevir and ritonavir-boosted HIV protease inhibitors in 39 healthy volunteers. In this study, concomitant administration of boceprevir with ritonavir in combination with atazanavir or darunavir, or with lopinavir/ritonavir, resulted in reduced exposures of the HIV medicines and boceprevir. These drug interactions may be clinically significant for patients infected with both chronic HCV and HIV by potentially reducing the effectiveness of these medicines when co-administered. Merck does not recommend the co-administration of boceprevir and ritonavir-boosted HIV protease inhibitors.

"In light of the differing results in these data sets, Merck recognizes it is important to continue to study boceprevir in combination therapy in this difficult-to-treat patient population," said Eliav Barr, M.D., vice president, Project Leadership and Management, Infectious Diseases, Merck Research Laboratories. "Our collaborative studies with the French National Agency for Research on AIDS and Viral Hepatitis² (ANRS) and the AIDS Clinical Trials Group (ACTG), which is funded by the U.S. National Institute of Allergy and Infectious Diseases, will provide greater insight into the potential role of boceprevir in treating patients with chronic HCV genotype 1 infection who are coinfected with HIV-1."

Boceprevir in Canada

Boceprevir was approved for use in Canada in July 2011 for the treatment of chronic hepatitis C genotype 1 infection, in combination with peginterferon alpha and ribavirin, in adult patients (18 years of age and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy.³

Common side effects of combination treatment include fatigue, anemia, nausea, headache and bad taste (dysgeusia).⁴

The safety and efficacy of boceprevir alone or in combination with peginterferon alpha and ribavirin has not been established in patients coinfected with HIV and HCV.

Interim SVR-12 Results from Phase IIb HCV-HIV Coinfection Study

One hundred (100) adult patients with previously untreated HCV genotype 1 infection, on an optimized antiretroviral regimen and with stable HIV-1 disease (HIV-RNA less than 50 copies/mL; CD4 cell counts equal to or greater than 200 cells/mm3) were randomized into the study. Two patients randomized to the treatment arm receiving boceprevir in combination with peginterferon alfa-2b (P) and ribavirin (R) did not receive boceprevir. Thus, the interim analysis was based on 98 patients who received at least one dose of study drug: 64 patients in the arm receiving boceprevir plus PR, and 34 patients in the control arm receiving PR alone.

All patients treated in the study received a 4-week lead-in with PR alone followed by boceprevir plus PR or placebo plus PR for 44 weeks, for total treatment duration of 48 weeks. Preliminary 24-week on-treatment data from this study were presented at the Infectious Diseases Society of America annual meeting in October 2011. Final study completion will be at week 72, or 24 weeks after the end of all treatment.

The interim analysis showed that 60.7 per cent (n=37/61) of patients receiving boceprevir in combination with PR achieved SVR-12 compared to 26.5 per cent (n=9/34) of patients receiving PR alone, a treatment difference of 34.2 per cent. Three (3) patients in the boceprevir plus PR arm had not reached 12 weeks post treatment and were excluded.

Three (3) patients in treatment arms receiving boceprevir plus PR and four (4) patients in the PR control arm experienced HIV breakthrough (HIV viral load greater than 50 copies/mL at two consecutive visits). Preliminary safety data for boceprevir in combination therapy in HCV/HIV-1 coinfected patients demonstrated a profile similar to that previously observed in patients with HCV mono-infection.

The most common clinical adverse events with a difference of equal to or greater than 10 per cent for the treatment arm receiving boceprevir plus PR compared to the PR control arm, respectively, were: anemia (41 vs. 26 per cent), pyrexia (fever) (36 vs. 21 per cent), asthenia (weakness) (34 v. 24 per cent), decreased appetite (34 vs.18 per cent), diarrhea (28 vs. 18 per cent), dysgeusia (bad taste) (28 vs. 15 per cent), vomiting (28 vs. 15 per cent), flu-like illness (25 vs. 38 per cent) and neutropenia (19 vs. 6 per cent). Serious clinical adverse events occurred in 17 per cent and 21 per cent of patients in the two treatment arms, respectively. Dose modification for any study drug due to a clinical adverse event occurred in 28 per cent and 24 per cent of patients, respectively, and study discontinuation due to a clinical adverse event occurred in 20 per cent and 9 per cent of patients, respectively.

About the Phase IIb coinfection study

The primary objective of this ongoing randomized, multicenter, double-blinded Phase IIb study is to compare the efficacy of 800 mg of boceprevir three times daily in combination with peginterferon alfa-2b (P) 1.5 mcg/kg weekly plus ribavirin (R) 600 to 1,400 mg/daily to therapy with PR alone in adult patients coinfected with chronic HCV genotype 1 and HIV-1. Patients were randomized in a 2:1 ratio to the treatment arm with boceprevir plus PR or the PR control arm, respectively. Patients were stratified by cirrhosis (yes/no) and baseline HCV-RNA (less than 800,000 IU/mL vs. equal to or greater than 800,000 IU/mL).

The majority of patients were non-cirrhotic (95 per cent), white (82 per cent) and male (69 per cent), with a median age of about 43 years. Most patients had high HCV-RNA (88 per cent) at baseline and HCV genotype 1a infection (65 per cent).

Antiretroviral regimens for HIV-1 that included non-nucleoside reverse transcriptase inhibitors (NNRTIs), or zidovudine, stavudine or didanosine were not permitted. Patients with detectable HCV-RNA and less than a 2 log HCV-RNA decline at treatment week 12 or detectable HCV-RNA at treatment week 24 were considered treatment failures and discontinued all HCV treatment.

Primary pharmacokinetic drug interaction study results

The study was a single-center, three-arm, open-label, drug-interaction study in 39 healthy adults. Patients received 800 mg of boceprevir three times daily on Days 1-6. Following a 4-day "washout" period, patients received either 300 mg of atazanavir/100 mg of ritonavir once daily, 400 mg of lopinavir/100mg of ritonavir twice daily, or 600 mg of darunavir/100 mg of ritonavir twice daily on Days 10-31. From Days 25-31, patients also received 800 mg of boceprevir three times daily. Blood samples were collected for the pharmacokinetic assessment of the HIV medicines and boceprevir.

In the study, co-administration of boceprevir reduced mean trough concentrations of ritonavir-boosted atazanavir, lopinavir and darunavir by 49, 43 and 59 per cent, respectively. Mean reductions of 34 to 44 per cent and 25 to 36 per cent were observed in AUC and Cmax of atazanavir, lopinavir and darunavir. Co-administration of ritonavir-boosted atazanavir with boceprevir did not alter the exposure of boceprevir, but co-administration of boceprevir with lopinavir/ritonavir or ritonavir-boosted darunavir decreased the exposure of boceprevir by 45 and 32 per cent, respectively.

Merck's global commitment to advancing hepatitis therapy

Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis.  In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with boceprevir, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck

Today's Merck is a global healthcare leader working to help the world be well.  Merck is known as MSD outside the United States and Canada. Through our medicines, vaccines, biologic therapies, and consumer and animal products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information about our operations in Canada, visit www.merck.ca.

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^TM Trademark of Schering Corporation, a subsidiary of Merck & Co., Inc. Used under license.

¹SVR, the protocol-specified primary efficacy endpoint of the study, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication.

References:

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¹SVR-12, the primary endpoint of the interim analysis, is defined as achievement of undetectable HCV-  RNA at the 12 week post-treatment visit.

² ANRS HC27 BOCEPREVIR pilot study; clinicaltrials.gov identifier: NCT01335529.

³ VICTRELIS^TM, Product Monograph, July 27, 2011, p. 3.

⁴ VICTRELIS^TM, Product Monograph, July 27, 2011, p. 8.

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