I期试验表明，新型丙肝蛋白酶抑制剂的耐受性良好

The protease inhibitor TMC435 was found to be safe and well tolerated in healthy volunteers in a small phase I trial, according to Dr. Henk W. Reesink and colleagues writing in an online article in Gastroenterology.

Moreover, the drug exhibited potent antiviral activity in a subsequently enrolled open-label trial consisting of six chronic hepatitis C patients with genotype 1 who had failed previous interferon treatment.

“The protease inhibitor TMC435 is a promising addition to the growing arsenal of specifically targeted antivirals against HCV undergoing development,” wrote Dr. Reesink, an associate professor in the department of gastroenterology and hepatology at the Academic Medical Center in Amsterdam, and his colleagues (Gastroenterology 2009 Oct. 21 [doi:10.1053/j.gastro.2009.10.033]).

The investigators first looked at 49 healthy volunteers, divided into six panels of 6 to 9 subjects each, who received treatment for 5 days. In the first two panels, which included nine subjects each, “six subjects received active treatment and three received placebo after a standardized breakfast,” wrote the authors. “The doses of the test compound were consecutively escalated, following interim data reviews for safety, tolerability, and pharmacokinetics.”

The highest dose in either group was 600 mg once daily; it was found to be “generally safe and well tolerated,” without any serious adverse events.

Panel 3 received 100 mg once daily; panel 4 received 200 mg once daily; panel 5 received 200 mg twice daily; and panel 6 was given 400 mg once daily, all for 5 days. These subjects had no serious adverse events that were judged to be “very likely related to TMC435 by the investigator.” In panel 5, there was “mild and transient” photosensitivity in three out of the six healthy volunteers taking the drug. Other adverse events (AEs) included diarrhea, abdominal pain, and headache. None of the side effects resulted in patients discontinuing the drug.

Following this, the investigators enrolled a seventh panel of six hepatitis C patients. All of the patients were white males, and they had a median plasma hepatitis C RNA level of 6.75 log10 IU/mL (range 6.47-7.03 log10 IU/mL) at baseline.

Four patients were infected with genotype 1a; two had genotype 1b. Four were previous nonresponders to interferon therapy, and two were “relapsers.” The median age was 56.5 years, with a range from 32 years to 67 years. Two patients had hemophilia A.

“Given the safety profile of TMC435, both for the 200 mg and 400 mg [once daily] regimens in healthy volunteers and anticipating a higher exposure in patients as compared with healthy volunteers, a dose of 200 mg [once daily] was selected for hepatitis C patients” for 5 days, wrote the authors.

“No [significant adverse events] or AEs leading to treatment discontinuation were reported in hepatitis C patients, and no grade 3 or 4 AEs were reported,” the authors wrote.

There was, however, a reduction in hepatitis C RNA levels, with a median drop of 3.46 log 10 IU/ml at day 3 (range, 1.6 log10 to 3.8 log10 IU/mL). The median maximal reduction was 3.9 log10 IU/mL (range 2.9 log10 to 4.1 log10 IU/mL).

“Viral decline appeared similar in patients with genotype 1a and 1b virus, previous nonresponders or relapsers, or between patients presenting with or without hemophilia,” wrote the authors.

Viral RNA levels returned to baseline within 4 weeks after the final dose.

“The potency of TMC435 and in vitro work showing synergy with [pegylated interferon] and additivity with [ribavirin] are consistent with its use in combination with the current standard of care,” wrote the authors. “Additionally, it’s simple dosing schedule and low pill burden may become important attributes in future combination studies with other specifically targeted therapies for hepatitis C.”

The study was fully funded by Tibotec Pharmaceuticals Ltd., the maker of TMC435. Several authors (excluding Dr. Reesink) are employed by the company.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

而且，该药在随后开展的开放性试验中还表现出了强抗病毒活性，这项开放性试验共招募了6例之前经干扰素治疗失败的基因型1慢性丙肝患者。

荷兰阿姆斯特丹学术医学中心胃肠与肝病科的副教授Reesink博士及其同事写道：“目前抗丙肝病毒(HCV)的特异性靶向治疗药物正在不断涌现，尚处于研发阶段的蛋白酶抑制剂TMC435可谓是大有前途的一个新成员。” (Gastroenterology 2009 Oct. 21 [doi:10.1053/j.gastro.2009.10.033])。

研究者首先招募了49例健康志愿者，将其分成6组，每组6~9例受试者，共接受为期5天的治。在前两组中，每组各纳入了9例受试者，“进食标准早餐后，6例受试者接受阳性药物治疗，另外3例则服用安慰剂。”研究者写道：“针对药物安全性、耐受性和药动学的中期数据分析后，连续递增试验药物的剂量。”

这两组受试者服用的最大剂量是600 mg，每日1次；结果发现“安全性和耐受性普遍良好”，没有出现任何严重不良事件。

第3组受试者的服药剂量为100 mg，每日1次；第4组200 mg，每日1次；第5组200 mg，每日2次；第6组400 mg，每日1次；均治疗5天。所有受试者均未出现任何被研究者视为“非常可能与TMC435相关”的严重不良事件。在第5组中，服用试验药物的6例健康志愿者中有3例出现了“轻度的一过性”光敏反应。其他不良事件(AE)包括腹泻、腹痛和头痛。这些副反应均未导致受试者停止服药。

随后，研究者又招募了由6例丙肝患者组成的第7组。所有患者均为白种男性，且基线中位血浆丙肝RNA水平为6.75 log10 IU/ml (范围 6.47~7.03 log10 IU/ml)。

其中4例患者感染的是基因型1a；另外2例感染的是基因型1b。4例患者对之前的干扰素治疗无应答，另外2例则属于“治疗后复发”。患者的中位年龄是56.5岁，范围32~67岁。2例患者患有A型血友病。

研究者写道：“鉴于TMC435 200 mg和400 mg(每日1次)给药方案在健康志愿者中的安全性特征，同时估计到药物在丙肝患者中的暴露量可能会高于在健康志愿者中的暴露量，因此选择200 mg (每日1次)的剂量用于丙肝患者，共治疗5天。”

研究者报告称：“所有丙肝患者均未出现任何重大不良事件或导致停药的AE，无1例患者报告3级或4级AE。”

但丙肝RNA水平却降低了，治疗第3天中位下降值为3.46 log 10 IU/ml(范围1.6 log10 ~ 3.8 log10 IU/ml)。中位最大降幅为3.9 log10 IU/ml (范围2.9 log10 ~ 4.1 log10 IU/ml)。

研究者写道：“携带基因型1a和1b病毒的患者之间，无应答者与复发者之间，或血友病患者与非血友病患者之间，病毒滴度的降幅均相似。”

最后一次给药后4周内，病毒RNA水平恢复至基线水平。

研究者写道：“体外试验表明，TMC435与聚乙二醇化干扰素联用可发挥协同作用，与利巴韦林联用可发挥叠加作用，加之其强抗病毒活性，因此可以与目前的标准治疗联合使用。此外，TMC435给药方案简单且药丸负荷小，在即将开展的与其他特异性靶向丙肝治疗药物联用的试验中这些都可能成为其重要的特征。”

该试验完全由TMC435的生产商——Tibotec制药公司资助。除Reesink博士外的其他数名作者为该公司员工。

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