A combination of two oral drugs for reducing viral load in hepatitis C patients had good safety and tolerability in a small, phase I study.
The finding, published online Oct. 15 in the Lancet, points the way toward an alternative to the current standard of care – subcutaneous pegylated interferon-alfa plus oral ribavirin – which has limited tolerability and efficacy.
The novel therapies that were tested in this study are RG7128, a nucleoside polymerase inhibitor, and danoprevir, a protease inhibitor, wrote Dr. Edward J. Gane of Auckland (New Zealand) Clinical Studies Ltd., an early-phase clinical pharmacology unit, and his colleagues.
Both compounds have potent in vitro and in vivo activity against HCV, and at the time of this study, each was in phase I development, wrote the authors. Both agents are made by Roche, which funded the study and employed several of the researchers.
The study, known as INFORM-1 (Interferon-Free Regimen for the Management of HCV) was a randomized, double-blind, placebo-controlled, dose-escalation trial. Eligible patients were aged 18-65 years and had been chronically infected with HCV genotype 1, with a minimum HCV RNA of 105 IU/mL.
Patients with cirrhosis, other hepatic or renal failure, and comorbid HIV were not included in this study – a potential limitation, the authors wrote (Lancet 2010 Oct. 14 [doi:10.1016/S0140-6736(10)61384-0]).
In all, 88 patients from six centers in New Zealand and Australia were randomized into seven groups, to receive either placebo or various doses of the novel treatment. Most were white (90%), male (80%), and infected with genotype 1a (79%). The mean age was roughly 47 years.
Overall, 73 patients were ultimately given at least one dose of the assigned treatment, and 14 received placebo.
The investigators found that among patients who received the highest doses of treatment (1,000 mg RG7128 twice daily plus 900 mg of danoprevir twice daily), “five of eight treatment-naive patients and two of eight [previous] null responders [to standard HCV therapy] had HCV RNA concentrations below the limit of detection (less than 15 IU/mL),” according to the authors.
Additionally, “seven of eight treatment-naive patients and four of eight null responders had HCV RNA concentrations below the limit of quantification (43 IU/mL).”
The median reduction in HCV RNA concentrations among the treatment-naive patients was 5.1 log10 IU/mL, and among the previous null responders it was 4.9 log10 IU/mL. In comparison, the mean baseline log10 plasma HCV RNA concentration was 6.4 IU/mL.
The treatment group who received the lowest dose (500 mg RG7128 twice daily, plus 100 mg danoprevir every 8 hours) also saw a median reduction in viral load of 3.7 log10 IU/mL. Of the eight patients in this low-dose cohort, one patient achieved viral levels below the level of detection at 14 days.
“No evidence of treatment-emergent resistance to either compound was identified during the study, and 72 of 73 patients in the treatment groups had a continuous decline in viral load, which was maintained throughout dosing,” wrote the investigators.
The authors noted that they did not find many serious adverse events during treatment. There was one case of severe back pain, and one instance of severe influenzalike illness. However, many patients experienced headache, lethargy, rash, gastrointestinal disorder, and nausea.
At 14 days – the study’s completion – patients continued therapy by switching to standard of care treatment with pegylated interferon alfa-2a and ribavirin.
“The INFORM-1 study provides proof of concept for an oral approach to the treatment of HCV, in which a combination of direct-acting antiviral drugs is safely coadministered without pegylated interferon,” wrote the investigators.
The study treatment “marks a major shift in the future management of HCV infection and the biggest development in treatment of the disease” for the past 2 decades, they added.
In an editorial accompanying the article, Dr. David L. Thomas wrote that “we are on the eve of a new era in hepatitis C virus treatment” (Lancet 2010 Oct. 15 [doi:10.1016/50140-6736(10)61497-3]).
Indeed, he added, for the first 2 decades after the virus was discovered, “only ribavirin and interferon-alfa–related compounds were approved for HCV treatment, and nearly a decade has passed since the last substantive upgrade.”
“The long wait for new HCV treatments is about to end,” wrote Dr. Thomas of Johns Hopkins University in Baltimore.
However, he pointed out some “important limitations” to early-phase trials such as this. For example, although the study met its safety objectives, “the goal of HCV treatment is to eradicate infection,” an end point that is achieved when HCV RNA cannot be detected in blood at the end of treatment and 6 months later.
Because patients in Dr. Gane and colleagues’ study rolled over to pegylated interferon-alfa and ribavirin after completion of study drug treatment, “the study will never tell us about the ultimate efficacy of the combined use of the two direct-acting agents.”
Moreover, “long-term risk of viral resistance with a two-drug direct-acting regimen cannot be confidently assessed, because drug use was directly observed in a clinical trial unit, and only limited resistance testing was presented.”
In any case, Dr. Thomas argued, there is an even bigger problem with HCV treatment: “Most HCV-infected individuals are not patients. Only a small fraction of the estimated 170 million individuals with chronic hepatitis C infection know they are infected; far fewer ever start treatment.”
Even if a treatment with 100% efficacy is ultimately developed, “what is unclear at this stage is whether HCV testing and treatment will penetrate to the prisons, drug-treatment centres, and other venues where many HCV infected individuals are found and unknowingly harbour the virus,” Dr. Thomas wrote.
“It will take both safe, effective drugs and a coordinated, well-resourced response to achieve major global impact.”
The study was funded by Roche, which developed RG7128 and recently bought the worldwide development and commercialization rights to danoprevir from InterMune Inc. Several investigators, including Dr. Gane, have received grants, travel fees, advisory board fees, and other support from Roche and other drug makers; several are employees of Roche or InterMune and have stock options in Roche. Dr. Thomas disclosed that he has been supplied with drugs for phase IV studies with Merck & Co. and Gilead Sciences Inc., and has received an honorarium from Merck, and payment for development of educational materials from companies who in turn receive support from drug companies.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
10月5日在线发表于《柳叶刀》(Lancet)的INFORM-1研究显示，在丙型肝炎病毒(HCV)感染患者中，联用核苷聚合酶抑制剂RG7128和蛋白酶抑制剂danoprevir可降低病毒载量，其安全性和耐受性良好。
这项随机、双盲、安慰剂对照、剂量递增、小规模Ⅰ期研究在新西兰和澳大利亚的6家研究中心选取88例HCV RNA≥105 U/ml的HCV基因型1慢性感染患者，排除肝硬化、肝功能或肾功能衰竭以及合并HIV感染的患者。多数为感染基因型1a (79%)的男性(80%)白人(90%)患者，平均年龄为47岁(18~65岁)。患者被随机分成7组，接受安慰剂或不同剂量的联合治疗。73例至少接受1个剂量的联合治疗，14例接受安慰剂处置(Lancet 2010 Oct. 14 [doi:10.1016/S0140-6736(10)61384-0])。
结果显示，在联合治疗最大剂量组(1,000 mg RG7128，2次/天+ 900 mg danoprevir，2次/天)中，8例首次治疗者中的5例和8例此前经标准HCV治疗无效者中的2例实现HCV RNA低于检出限(15 U/ml)。此外，8例首次治疗者中的7例和8例此前治疗无效者中的4例实现HCV RNA低于定量限(43 U/ml)。基线血浆HCV RNA平均为6.4 log10 U/ml。首次治疗者和此前治疗无效者的HCV RNA较基线的中位降幅分别为5.1 log10 U/ml和4.9 log10 U/ml。在联合治疗最低剂量组(500 mg RG7128，2次/天+100 mg danoprevir，1次/ 8 h)中，病毒载量的中位降幅为3.7 log10 U/ml。在最低剂量组8例中，1例病毒载量在14天时低于检出限。在研究期间，未发现有患者对任一治疗药物产生耐药，联合治疗组73例中有72例的病毒载量在给药期间持续降低。严重不良事件包括1例严重背痛和1例严重流感样疾病。但有许多患者出现头痛、嗜睡、皮疹、胃肠道不适和恶心。14天(研究结束)时，改用聚乙二醇化干扰素α- 2a+利巴韦林的标准疗法对患者继续进行治疗。
本研究为通过口服方式治疗HCV的理念提供了依据。不过，有专家认为，由于本研究的患者在研究结束时改用聚乙二醇化干扰素α- 2a和利巴韦林进行治疗，因此无法知道RG7128和danoprevir这两种直接作用的口服药物联合治疗的最终效果。
本研究获罗氏公司资助。部分研究者声明获多家医药公司经济资助。
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