Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS: Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS: Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS: Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.

Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial.

BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.

Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.

BACKGROUND: The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection. METHODS: We provided open-label treatment to eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus ribavirin for 12 weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24 weeks after therapy. RESULTS: Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response at 24 weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks had a sustained virologic response at 24 weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia. CONCLUSIONS: Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection. (Funded by Pharmasset and Gilead Sciences; ClinicalTrials.gov number, NCT01260350.).

Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor-in patients with chronic HCV infection. METHODS: Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255. FINDINGS: 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3·7 to -5·2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5·1 log(10) IU/mL (IQR -5·6 to -4·7) in treatment-naive patients and -4·9 log(10) IU/mL in previous standard of care null responders (-5·2 to -4·5) compared with an increase of 0·1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations. INTERPRETATION: This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV. FUNDING: Roche Palo Alto.

The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects.

AIMS: This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects. METHODS: In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg + LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2. RESULTS: In Part 1, a single RTV dose increased the APL AUC(0-infinity) by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, C(max), and C(min), respectively. No change in LPV AUC or C(max) and a small increase in RTV AUC and C(max) (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported. CONCLUSIONS: Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.

Evaluation of the drug interaction potential of aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail.

Aplaviroc is a novel CCR5 antagonist, a class of compounds under investigation as viral entry inhibitors for the treatment of human immunodeficiency virus infection. A modified Cooperstown 5+1 cocktail was used to assess the drug interaction potential of aplaviroc. Fifteen healthy subjects were administered single oral doses of caffeine (CYP1A2), warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) alone (reference treatment) and during steady-state administration of aplaviroc (400 mg every 12 hours, test treatment). Metabolite-to-parent area under the plasma concentration versus time curve (AUC) ratios (paraxanthine/caffeine and 5-hydroxyomeprazole/omeprazole), oral clearance (S-warfarin), AUC (midazolam), and metabolite-to-parent urinary excretion ratio (dextrorphan/dextromethorphan) were determined. The test-to-reference treatment ratios (geometric mean ratio and 90% confidence interval) were caffeine, 1.06 (0.97-1.17); S-warfarin, 0.93 (0.76-1.15); omeprazole, 1.07 (0.98-1.16); dextromethorphan, 1.17 (0.97-1.42); midazolam, 1.30 (1.04-1.63). No significant inhibition of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 enzyme activity was observed. Mild inhibition of CYP3A isozymes should not preclude the use of concomitant CYP3A substrates in future clinical studies with aplaviroc.

Ritonavir increases plasma amprenavir (APV) exposure to a similar extent when coadministered with either fosamprenavir or APV.

To compare the effect of ritonavir on plasma amprenavir pharmacokinetics, healthy adults received either fosamprenavir (700 mg twice a day [BID]) or amprenavir (600 mg BID) alone and in combination with ritonavir (100 mg BID). Ritonavir increased plasma amprenavir pharmacokinetic parameters to a similar extent when coadministered with either fosamprenavir or amprenavir.

Pharmacokinetics and short-term safety of 873140, a novel CCR5 antagonist, in healthy adult subjects.

873140 is a novel CCR5 antagonist with potent in vitro anti-human immunodeficiency virus (HIV) activity. This study was a double-blind, randomized, placebo-controlled, single- and repeat-dose escalation investigation of the safety, pharmacokinetics, and food effect of 873140 in 70 adult subjects. During single-dose escalation, three cohorts (each composed of 10 subjects, with 8 subjects receiving the active drug and 2 subjects receiving the placebo [8 active and 2 placebo]) received doses of 50, 200, 400, 800, and 1,200 mg after an overnight fast, or 400 mg plus a standard high-fat breakfast in an alternating panel design. During repeat-dose escalation, four cohorts (each with 8 active and 2 placebo) received doses of 200, 400, 600, or 800 mg every 12 h (BID) for 8 days. Laboratory safety tests, vital signs, and electrocardiograms (ECGs) were performed at regular intervals, and blood samples were obtained for pharmacokinetics. Single and repeat doses of 50 mg to 800 mg were well tolerated, with no serious adverse events and no grade 3 or 4 adverse events. The mild-to-moderate side effects were primarily gastrointestinal and included abdominal cramping, nausea, and diarrhea. No specific trends in laboratory parameters or clinically significant ECG changes were noted. Plasma 873140 concentrations increased rapidly; the median time to maximum concentration of drug in serum was 1.75 to 5 h. The median area under the plasma concentration-time profile (AUC) and the maximum concentration of drug in serum (C(max)) ranged from 127 ng.h/ml and 24 ng/ml at 200 mg BID to 329 ng.h/ml and 100 ng/ml at 800 mg BID, respectively. Food consumption increased the AUC and C(max) by a mean of 1.7- and 2.2-fold, respectively. The pharmacokinetic and safety profile supports the continued investigation of 873140 with HIV-infected subjects.

Concordance between HIV source partner identification and molecular confirmation in acute retroviral syndrome.

Most HIV-1 transmission studies use self-reported history to define the source contact. To evaluate the reliability of epidemiologic source partner reporting, heteroduplex mobility assays (HMAs) were performed comparing the different viral strains present in the partners. Partners were typed for human leukocyte antigen (HLA) to evaluate the degree of shared alleles. Of 11 couples evaluated, HMA analysis confirmed nine transmissions (including 1 oral-genital transmission), indicated probable transmission in 1 couple, and suggested an alternative source partner in another. Nine source partners transmitted a major variant. Four source partners knew their HIV status. Previous HIV monitoring was reported by 5 of the 6 confirmed source partners who were unaware of their HIV status at the time of transmission. We also evaluated potential "sharing of HLA alleles" as a risk factor for HIV-1 acquisition; partners were not found to have a higher degree of shared HLA alleles. Lack of awareness about infection status as a consequence of infrequent testing plays a major role in the secondary transmission of HIV. These findings re-emphasize the importance of using safe sex practices at all times.