Rene Verloes

Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial

BACKGROUND Antiviral activity of TMC435, an oral, once-daily, HCV NS3/4A protease inhibitor, was evaluated with pegylated interferon-α2a/ribavirin (P/R) in HCV genotype-1 patients. METHODS Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA-1; TMC435-C201; NCT00561353) is a Phase IIa, randomized, placebo-controlled study. Treatment-naive patients (n=74) received 25, 75 or 200 mg TMC435 once daily, or placebo for 7 days followed by 21 days of triple therapy with P/R, or triple therapy for 28 days. Treatment-experienced patients (n=37; 56.8% with cirrhosis) received 75, 150 or 200 mg TMC435 once daily, or placebo with P/R for 28 days. Patients continued P/R up to week 48. RESULTS Treatment-naive patients who received initial monotherapy had a rapid decline in HCV RNA by day 3. At day 7, HCV RNA reductions were greatest for the 75 and 200 mg doses (0.02, -2.63, -3.43 and -4.13 log(10) IU/ml for placebo, and TMC435 25, 75 and 200 mg, respectively). At day 28, all patients who received triple therapy with TMC435 75 or 200 mg had HCV RNA<25 IU/ml versus 4/9 for placebo. In total, 18/28 treatment-experienced patients (9/9 prior relapsers, 9/19 non-responders) who received TMC435 had HCV RNA<25 IU/ml at day 28 versus 0/9 for placebo; similar results were observed for the 150 and 200 mg doses. Most adverse events were grade 1/2. No relevant changes in laboratory parameters occurred, except mild and reversible bilirubin elevations, mostly at the 200 mg dose. CONCLUSIONS Once-daily TMC435 with P/R showed potent, dose-dependent antiviral activity over 28 days, and had a favourable tolerability profile.

Efficacy of Re-treatment With TMC435 as Combination Therapy in Hepatitis C Virus–Infected Patients Following TMC435 Monotherapy

In the TMC435-C101 study, 6 patients infected with hepatitis C virus genotype 1 were treated with the protease inhibitor TMC435 (200 mg once daily) as monotherapy for 5 days. Approximately 1.5 years later, 5 of these patients were re-treated with TMC435 (200 mg once daily) plus pegylated interferon alfa-2a and ribavirin (PegIFNα-2a and RBV) for 4 weeks, followed by PegIFNα-2a and RBV until week 48 (in the Optimal Protease inhibitor Enhancement of Response to therApy [OPERA-1] study). TMC435-resistant variants, which emerged in all 5 patients during the TMC435-C101 study, were no longer detected at the beginning of the OPERA-1 study based on virus population sequencing. During the OPERA-1 study, 3 patients had a sustained virologic response; deep sequencing indicated low-level persistence of resistant variants in the remaining 2 patients, which might have affected their response to re-treatment.

Antiviral Activity of TMC353121, a Respiratory Syncytial Virus (RSV) Fusion Inhibitor, in a Non-Human Primate Model.

Background The study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI). Methods African green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n=15; Group 1: prophylactic arm [Px50], 0.033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 24 hours pre-infection to 10 days; Group 2: therapeutic arm [Tx50], 0.033mg/mL TMC353121 from 24 hours postinfection to 8 days; Group 3: control [Vh1] vehicle, 24 hours post-infection to 8 days). Study 2 evaluated the prophylactic efficacy of TMC353121 at target plasma levels of 5 and 500 ng/mL (n=12; Group 1: prophylactic 5 arm [Px5], 0.0033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 72 hours pre-infection to 14 days; Group 2: prophylactic 500 arm [Px500], 0.33 mg/mL TMC353121; Group 3:control [Vh2] vehicle, 14 days). Bronchoalveolar lavage fluid and plasma were collected every 2 days from day 1 postinfection for pharmacokinetics and safety analysis. Findings TMC353121 showed a dose-dependent antiviral activity, varying from 1log10 reduction of peak viral load to complete inhibition of the RSV replication. Complete inhibition of RSV shedding was observed for a relatively low plasma exposure (0.39 μg/mL) and was associated with a dose-dependent reduction in INFγ, IL6 and MIP1α. TMC353121 administered as CI for 16 days was generally well-tolerated. Conclusion TMC353121 exerted dose-dependent antiviral effect ranging from full inhibition to absence of antiviral activity, in a preclinical model highly permissive for RSV replication. No new safety findings emerged from the study.

Antiviral activity, pharmacokinetics, and safety of the HIV-1 protease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1-infected patients.

Objectives:TMC310911 is a novel HIV type-1 (HIV-1) protease inhibitor with broad in vitro antiviral activity. In this phase 2a, open-label randomized study, the antiviral activity, pharmacokinetics, and safety and tolerability of ritonavir-boosted TMC310911 was assessed. Methods:In this study, treatment-naive HIV-1 patients (aged 18–60 years) received 1 of the 4 dosing regimens of TMC310911: 150 mg twice-daily (bid) (n = 8), 300 mg bid (n = 8), 75 mg bid (n = 9), or 300 mg once-daily (qd) (n = 8), for 14 days, all coadministered with 100 mg of ritonavir, as only antiretroviral therapy. Results:The mean change from baseline in HIV-1 RNA (log10 copies per milliliter; primary efficacy endpoint) was −1.30 (75 mg bid), −1.14 (150 mg bid), −1.07 (300 mg bid), and −1.06 (300 mg qd) on day 8 and −1.53 (75 mg bid), −1.79 (150 mg bid), −1.69 (300 mg bid), and −1.55 (300 mg qd) on day 15. At steady state (day 14), the mean maximum plasma concentration and mean area under the plasma concentration–time curve from 0 to 12 hours tended to increase dose proportionally for bid doses; TMC310911 daily exposures for the 300 mg qd treatment and 150 mg bid treatment were comparable. The most common (≥10%) treatment-emergent adverse events were fatigue (27.3%) and nausea (12.1%); no deaths or serious treatment-emergent adverse events were reported in this study. Conclusions:Combination treatment with TMC310911 and ritonavir showed potent antiviral activity (>1.5 log10 copies/mL decrease in plasma HIV-1 RNA) at all evaluated doses, and treatment was generally safe and well tolerated.

Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 phase 1 studies.

Objectives:To evaluate safety, tolerability, and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor. Methods:Healthy participants aged 18–55 years with body mass index 18–30 kg/m2 were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75–2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 [administered alone or with 100 mg ritonavir twice daily (bid)] in the subsequent open-label phase. The multiple-dose double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 [300 mg bid, 600 mg once daily or 150 mg bid (plus 100 mg ritonavir bid), 900 mg bid (alone) or 300 mg bid (plus ritonavir 50 mg bid)]; in all sessions, TMC310911 and ritonavir were administered for 6 and 9 days, respectively. Results:In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner after the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and area under plasma concentration–time curve values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system. Conclusions:TMC310911 exhibited a linear pharmacokinetic profile after the single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir.

Antiviral Activity of Oral JNJ-53718678 in Healthy Adult Volunteers Challenged With Respiratory Syncytial Virus: A Placebo-Controlled Study

Background Respiratory syncytial virus (RSV) disease has no effective treatment. JNJ-53718678 is a fusion inhibitor with selective activity against RSV. Methods After confirmation of RSV infection or 5 days after inoculation with RSV, participants (n = 69) were randomized to JNJ-53718678 75 mg (n = 15), 200 mg (n = 17), 500 mg (n = 18), or placebo (n = 17) orally once daily for 7 days. Antiviral effects were evaluated by assessing RSV RNA viral load (VL) area under the curve (AUC) from baseline (before the first dose) until discharge, time-to-peak VL, duration of viral shedding, clinical symptoms, and quantity of nasal secretions. Results Mean VL AUC was lower for individuals treated with different doses of JNJ-53718678 versus placebo (203.8-253.8 vs 432.8 log10 PFUe.hour/mL). Also, mean peak VL, time to peak VL, duration of viral shedding, mean overall symptom score, and nasal secretion weight were lower in each JNJ-53718678-treated group versus placebo. No clear exposure-response relationship was observed. Three participants discontinued due to treatment-emergent adverse events of grade 2 and 1 electrocardiogram change (JNJ-53718678 75 mg and 200 mg, respectively) and grade 2 urticaria (placebo). Conclusions JNJ-53718678 at all 3 doses substantially reduced VL and clinical disease severity, thus establishing clinical proof of concept and the compounds potential as a novel RSV treatment. Clinical trials registration ClinicalTrials.gov: NCT02387606; EudraCT number: 2014-005041-41.

PrEP-001 prophylactic effect against rhinovirus and influenza virus - RESULTS of 2 randomized trials

BACKGROUND PrEP‐001 Nasal Powder, a proprietary formulation of polyriboinosinic and polyribocytidylic acid effectively elicits a cellular innate immune response in nasal epithelium. The aim of these 2 studies was to investigate the safety and efficacy of PrEP‐001 prophylaxis against rhinovirus (HRV‐A16) and influenza‐A (H3N2‐IAV). METHODS Healthy subjects randomly received 2 doses of PrEP‐001 or placebo, 48 and 24 h pre‐challenge with 10 TCID50 of HRV‐A16 (Study 1) or H3N2‐IAV (Study 2). RESULTS In Study 1, PrEP‐001 reduced median total symptom score from 38.5 to 4.5 (p = 0.004), median symptom duration from 6.0 to 1.7 days and median mucus production from 15 g to 3 g. The percentage of subjects classified as ill was reduced 3‐fold (placebo 73%, PrEP‐001 23%, p = 0.002). In Study 2, PrEP‐001 reduced median total symptom score from 8.0 to 4.1 (p = 0.021), median symptom duration from 4.6 to 3.7 days and median mucus production from 3.6 g to 1.5 g. The percentage of subjects classified as ill was reduced 2‐fold (placebo 48%, PrEP‐001 24%, p = 0.064). PrEP‐001 reduced peak viral shedding in both studies, as assessed by qRT‐PCR of nasal lavage. Seroconversion rates were comparable between placebo and PrEP‐001 (Study 1: 77% [both arms]; Study 2: placebo 73%, PrEP‐001 80%). PrEP‐001 was well‐tolerated, with no clinically significant adverse events. CONCLUSIONS PrEP‐001 reduced the number of individuals with clinical illness and attenuated severity and duration of HRV‐A16 and H3N2‐IAV infections without compromising seroconversion, and was well‐tolerated. This supports further evaluation of PrEP‐001 as a potential pan‐viral prophylaxis for upper respiratory tract infections. CLINICAL TRIAL REGISTRATION Study 1, HRV‐A16 study: EudraCT Number 2012‐005579‐14 (study conducted before ClinicalTrials.gov registration required). Study 2, H3N2‐IAV study: EudraCT Number 2015‐002895‐26 and ClinicalTrials.gov: NCT03220048.

1076 EVALUATION OF METABOLIC INTERACTIONS FOR TMC435 VIA CYTOCHROME P450 (CYP) ENZYMES IN HEALTHY VOLUNTEERS

(cirrhosis vs. no cirrhosis) was significantly predicted only by the factor age (p < 0.001; OR=1.1), but not by other potential predictors such as nicotine and alcohol abuse. Conclusions: According to our findings, tobacco consumption seems to have at least some impact on the aggravation of inflammatory activity, while there was no influence on fibrosis progression. However, since nicotine abuse has been demonstrated to be a risk factor for the development of hepatocellular carcinoma, patients with HCV should be advised not to smoke.