R1626与Peginterferon alfa-2a (40KD)联合使用的强烈协同抗病毒效应，含有或不含利巴韦林-2a阶段研究的中间分析结果

P. J. Pockros¹; D. Nelson²; E. Godofsky³; M. Rodriguez-Torres⁴; G. Everson⁵; M. W. Fried⁶; R. H. Ghalib⁷; S. A. Harrison⁸; L. M. Nyberg⁹; M. L. Shiffman¹⁰; G. Z. Hill¹¹; A. Chan¹²

1. Scripps Clinic, La Jolla, CA, USA.
2. University of Florida, Gainsville, FL, USA.
3. University Hepatitis Center, Bradenton, FL, USA.
4. Fundacion de Investigacion de Diego, Santurce, PR, USA.
5. University of Colorado Health Sciences Center, Denver, CO, USA.
6. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
7. The Liver Institute at Dallas Methodist Hospital, Dallas, TX, USA.
8. Brooke Army Medical Center, Houston, TX, USA.
9. Kaiser Permanente Medical Center, San Diego, CA, USA.
10. McGuire VA Medical Center, Richmond, VA, USA.
11. Roche, Palo Alto, CA, USA. 12. Roche, Nutley, NJ, USA.
 
The novel nucleoside, R1626, is a potent inhibitor of the HCV RNA polymerase. When administered as monotherapy to patients with chronic hepatitis C, R1626 demonstrates dose-dependent decreases in HCV RNA blood levels.

This Phase 2a study evaluated the safety and efficacy of R1626 administered for 4 weeks in combination with 180 µg peginterferon alfa-2a (PEG-IFNα-2a) ± 1000–1200 mg ribavirin (RBV) in HCV genotype 1 treatment-naive patients. 104 patients were randomized to: Dual Low: 1500 mg bid + PEG-IFNα-2a (n=21); Dual High: 3000 mg bid + PEG-IFNα-2a (n=32); Triple Low: 1500 mg bid + PEG-IFNα-2a + RBV (n=31); SOC: PEG-IFNα-2a + RBV (n=20). Virological response was measured by Roche COBAS TaqMan (undetectable <15 IU/mL).

At 4 weeks HCV RNA was undetectable in 81% of patients treated with Triple Low (mean reduction of 5.2 log10 IU/mL), 69% treated with Dual High (mean reduction of 4.5 log10 IU/mL), and 33% treated with Dual Low (mean reduction of 3.6 log10 IU/mL), compared to only 5% of patients treated with SOC (mean reduction of 2.4 log10 IU/mL). Synergy was observed between R1626 and SOC (additional 2.8 log10 IU/mL, Triple Low vs. SOC), and between R1626 and RBV (additional 1.6 log10 IU/mL, Triple Low vs. Dual Low) (Figure). ALT normalized in approximately 50% of patients in R1626 treatment groups.

Most adverse events (AEs) were mild or moderate. Six patients had 8 serious AEs during the 4-week period: 4 in Dual High, 1 in Triple Low and 1 in SOC. The incidence of Grade 4 neutropenia was 48%, 78%, 39% and 10% in Dual Low, Dual High, Triple Low and SOC, respectively and was the main reason for dose reductions.

In conclusion, a robust synergistic antiviral effect was observed when R1626 is combined with PEG-IFNα-2a ± RBV, with up to 81% of patients undetectable by week 4. Dosing of R1626 may be limited mainly by neutropenia; additional studies of different dosages of R1626 in combination with PEG-IFNα-2a and RBV are underway. 

    新的核苷R1626是HCV RNA聚合酶有力的抑制工具。当作为慢性丙型肝炎病毒感染的单一疗法给药时，在HCV RNA血液水平R1626表现出剂量依赖性的减少。

    2a阶段的研究用于评价R1626与180 µg peginterferon alfa-2a (PEG-IFNα-2a) ± 1000–1200 mg 利巴韦林 (RBV)联合使用4周后，对HCV1型治疗阴性病人的安全性和有效性。104名患者被随即分组：双低：1500 mg bid + PEG-IFNα-2a (n=21)；双高：3000 mg bid + PEG-IFNα-2a (n=32)；三低：1500 mg bid + PEG-IFNα-2a + RBV (n=31)；SOC：PEG-IFNα-2a + RBV (n=20)。使用Roche COBAS TaqMan (undetectable <15 IU/mL)测量病毒学反应。在4周中，使用三低疗法 (平均减少5.2 log10 IU/mL)的患者81%检测不到HCV RNA，使用双高治疗(平均减少4.5 log10 IU/mL)的为69%，使用双低治疗(平均减少 3.6 log10 IU/mL) 的为33%，SOC(平均减少 2.4 log10 IU/mL)与其它相比仅为5%。在R1626和ROC之间 (额外的 2.8 log10 IU/mL, 三低与SOC相比)，及R1626和RBV之间(额外的1.6 log10 IU/mL,三低与双低相比) (图表) 可以观察到协同效应。在R1626治疗组大约50%的病人ALT正常。

    大多数的不良反应(AEs)是轻度的或适度的。在4周治疗过程中，6位患者有严重的不良反应：4位在双高治疗中、1位在3低、另一位在SOC治疗中。在双低、双高、三低和SOC治疗中，4级中性粒细胞减少症的发生率分别为48%, 78%, 39%及10%，并且是剂量减少的主要原因。

   总之，当R1626与PEG-IFNα-2a ± RBV联合使用时，可以观察到强烈的协同抗病毒效应，在4周治疗后有81%的患者血中检测不到HCV RNA。R1626的剂量主要被中性粒细胞减少症限制；附加的不同剂量R1626 与PEG-IFNα-2a 及 RBV联合使用的研究正在进行中。