A Single and Multiple Ascending Dose Study of Toll-Like Receptor 7 Agonist (RO7020531) in Chinese Healthy Volunteers.

Toll-like receptor 7 (TLR7) agonists modulate broad spectrum immune activity and are evaluated in the treatment of human diseases, including cancer and chronic viral infection. RO7020531, an oral prodrug of a TLR7 agonist, is in clinical development as part of a curative regimen against chronic hepatitis B. We report the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO7020531 in healthy Chinese volunteers following single and multiple ascending doses (SAD and MAD). PK and PD samples were evaluated from four SAD cohorts and 3 MAD cohorts with 10 subjects each (8 active and 2 placebo). Safety and tolerability were monitored throughout the study. A total of 155 adverse events (AEs) were reported in 49 subjects. Fifty-one AEs in 18 subjects were assessed as treatment-related. Most of the AEs were mild; nine subjects experienced moderate AEs; there were no severe AEs. In two 150 mg MAD cohorts given every other day (q.o.d.), 7 of 20 subjects experienced pyrexia and were discontinued due to transient asymptomatic lymphopenia, which resolved 24-48 hours postdose. The PK of the active metabolite, RO7011785, increased linearly with dose from 40 mg to 170 mg. There was no PK accumulation following q.o.d. dosing. The PK profile is consistent with observations in white subjects in the global first-in-human study. SADs and MADs of RO7020531 resulted in dose-dependent increases in TLR7 response markers at 100 mg or above. Flu-like symptoms were associated with higher interferon-α levels. RO7020531 was safe and acceptably tolerated in healthy Chinese volunteers with a multiple 150 mg q.o.d. dose regimen.

The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: Randomized controlled phase II trial with 2.5 years of follow-up.

BACKGROUND: While prophylactic human papillomavirus (HPV) vaccination exists, women are still developing cervical intraepithelial neoplasia (CIN) grade 2 or 3 for which an immunotherapeutic, non-surgical, approach may be effective. The primary aim was to assess the efficacy of tipapkinogen sovacivec (TS) vaccine in achieving histologic resolution of CIN2/3 associated with high risk (HR) HPV types. METHODS: Women 18 years and older who had confirmed CIN2/3 were enrolled in a randomized, double blind, placebo-controlled phase II trial and assigned to drug in a 2:1 ratio (vaccine:placebo). The primary endpoint occurred at month 6 when the excisional therapy was performed; cytology and HR HPV typing were performed at months 3, 6 and every six months through month 30. The safety population included all patients who received at least one dose of study drug. RESULTS: Of the 129 women randomized to vaccine and 63 to placebo, complete resolution was significantly higher in the vaccine group than placebo for CIN 2/3 regardless of the 13 HR HPV types assayed (24% vs. 10%, p < 0.05); as well as for only CIN 3 also regardless of HR HPV type (21% vs. 0%, p < 0.01). Irrespective of baseline HPV infection, viral DNA clearance was higher in the vaccine group compared to placebo (p < 0.01). The vaccine was well tolerated with the most common adverse events being injection site reactions. CONCLUSIONS: The TS vaccine provides histologic clearance of CIN 2/3 irrespective of HR HPV type in one third of subjects and is generally safe through 30 months.

Interferon-free regimens containing setrobuvir for patients with genotype 1 chronic hepatitis C: a randomized, multicenter study.

BACKGROUND & AIMS: Setrobuvir is a direct-acting antiviral (DAA) non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study examined interferon-free combinations containing setrobuvir, a ritonavir-boosted protease inhibitor (danoprevir/r) and ribavirin, with/without the nucleoside inhibitor mericitabine in HCV genotype (G)1 patients. METHODS: Non-cirrhotic treatment-naïve patients (N = 110) were randomized to five groups. Three groups received a 14-day mericitabine/ribavirin lead-in followed by treatment with 3 DAAs (setrobuvir, danoprevir/r, mericitabine) plus ribavirin for 12 weeks (Group A: G1a; D: G1b) or 24 weeks (B: G1a), and two groups received 2 DAAs (setrobuvir, danoprevir/r) plus ribavirin for 12 weeks (E: G1b) or 24 weeks (C: G1a). Efficacy was defined as sustained virological response (HCV RNA <25 IU/ml after 12 weeks' follow-up, SVR12). RESULTS: Two groups met predefined futility criteria for breakthrough (C) or relapse (A) and were discontinued. SVR12 rates were 42.9% (3/7) and 74.1% (20/27) in G1a patients in Groups A and B, respectively, and 95.7% (22/23) and 68.2% (15/22) in G1b patients in Groups D and E respectively. All G1a patients assigned to 24 weeks of treatment who experienced a decrease in HCV RNA of ≥2.3 log10 IU by the end of the lead-in period (n = 28) achieved SVR12. Overall, treatment was well tolerated and most adverse events were mild to moderate. No major safety signals were identified. CONCLUSIONS: An interferon-free setrobuvir-based regimen (3 DAAs plus ribavirin) is safe and effective in treatment-naïve G1 patients.