SAN DIEGO (EGMN) – Results of two phase III studies of pirfenidone, an oral antifibrotic and anti-inflammatory agent, have shown that the drug could slow the deterioration of lung capacity in patients with idiopathic pulmonary fibrosis.

The 72-week-long trials, known as CAPACITY 1 and CAPACITY 2, enrolled 779 patients at 110 sites in 11 countries.

“The findings of the CAPACITY trials, coupled with the results of the phase II and phase III studies in Japan and the urgent unmet medical need, suggest that pirfenidone may provide a meaningful clinical benefit in patients with IPF,” trial cochair. Paul Noble said during a late-breaker abstract session at an international conference of the American Thoracic Society.

Manufactured by InterMune Inc., pirfenidone is currently approved in Japan for the treatment of IPF. InterMune expects to submit a New Drug Application for the agent to the U.S. Food and Drug Administration in the summer of 2009.

Patients were eligible for the studies if they had a diagnosis of pulmonary fibrosis confirmed by CT scan or by biopsy and if they had a forced vital capacity (FVC) that was 50% of predicted value or greater and a diffusing capacity of the lung for carbon monoxide that was 35% of predicted value or greater.

The 344 patients in CAPACITY 1 were randomized to receive pirfenidone 2,403 mg/day or placebo for 72 weeks, while the 435 patients in CAPACITY 2 were randomized to receive either pirfenidone 2,403 mg/day, pirfenidone 1,197 mg/day, or placebo for 72 weeks. The primary end point was change in percent predicted FVC from baseline to week 72.

The mean age of patients in CAPACITY 1 was 68 years, while the mean age of CAPACITY 2 patients was 67 years, said Dr. Noble, professor of medicine and chief of pulmonary, allergy, and critical care medicine at Duke University, Durham, North Carolina.

In CAPACITY 2, patients in the treatment group achieved a significant reduction in change in percent predicted FVC at week 72, compared with placebo (–6.49% vs. –9.55%, respectively), and an increase in progression-free survival time (hazard ratio of 0.64). The treatment group also demonstrated a favorable effect on change in FVC category (P = .001).

In CAPACITY 1, there was no significant mean change in percent predicted FVC at week 72 between the treatment and placebo groups (–6.49% vs. –7.23%, respectively), but there was evidence of a treatment benefit at each assessment through week 48. “CAPACITY 1 did not achieve statistical significance on the primary end point,” Dr. Noble said. “However, results were generally consistent with and supportive of CAPACITY 2.”

According to a prepared statement from InterMune, a pooled analysis of categorical FVC change from the two studies “showed that 30% fewer patients experienced a 10% or greater decrease in FVC at week 72 in the pirfenidone group than in the placebo group. This magnitude of decline is considered clinically meaningful, as a 10% decline in percent predicted FVC has been shown in multiple studies to be an independent predictor of mortality in patients with IPF. In addition, 40% more patients in the pirfenidone group did not experience a decline in percent predicted FVC at week 72 versus baseline compared to those who received placebo.”

At the meeting, Dr. Noble reported that the pattern of adverse events in both trials was generally comparable to those observed in previous clinical studies of pirfenidone. The most common adverse events in the pirfenidone group compared with placebo were nausea (35% vs. 18% in CAPACITY 2, and 38% vs. 16% in CAPACITY 1), rash (31% vs. 10%, and 34% vs. 13%), fatigue (28% vs. 21%, and 33% vs. 20%), diarrhea (25% vs. 17%, and 33% vs. 21%), dyspepsia (17% vs. 9%, and 21% vs. 6%), and dizziness (19% vs. 10%, and 18% vs. 10%).

Rash was generally mild to moderate in both studies; only two patients (one in each CAPACITY study) who received pirfenidone had a severe rash.

The researchers also analyzed the incidence of patients who died during the treatment period, which was defined as the time between receiving the first dose of study treatment and 28 days after receiving the last dose. In CAPACITY 1, 5% of the pirfenidone group died during the treatment period, compared with 9% of the placebo group. In CAPACITY 2, 6% of pirfenidone patients died during the treatment period, compared with 8% of placebo patients.

“CAPACITY 2 demonstrated a statistically significant and a clinically meaningful effect on the primary end point of change in percent predicted FVC and the secondary end points of progression-free survival and categorical change in percent predicted FVC,” Dr. Noble concluded. “CAPACITY 1 did not, and it failed to achieve statistical significance on the primary end point.”

The studies were funded by InterMune.

Dr. Noble disclosed that he has served as a consultant, steering committee member, or cochair of a steering committee for InterMune, Actelion Pharmaceuticals Ltd., Boehringer Ingelheim GmbH, and Novartis.

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

圣地亚哥(EGMN)——吡非尼酮(pirfenidone)是一种口服抗纤维化和抗炎药物，对其进行的两项III期临床试验的结果显示，对患有特发性肺纤维化的患者，该药物能够减缓肺活量的下降。

这两项临床试验为CAPACITY 1和CAPACITY 2，为期72周，来自11个国家110个中心的779名患者入选研究。

“CAPACITY试验的结果结合日本进行的II期和III期研究的结果，再考虑到亟待满足的医疗需求，提示吡非尼酮可能对特发性肺纤维化患者的治疗有益，”担任临床试验联合主席的Paul Noble在美国胸科学会举办的一次国际会议中，在最新进展交流分会上报告。

InterMune公司生产的吡菲尼酮在日本已获准治疗特发性肺纤维化。InterMune公司预计会在2009年夏季向美国食物药物管理局(FDA)提交新药申请。

患者的入选标准为：CT或活检诊断结果为肺纤维化；用力肺活量不低于预期值的50%；肺一氧化碳弥散量不低于预期值的35%。

CAPACITY 1临床试验中的344名患者随机接受吡菲尼酮2,403 mg/d或安慰剂治疗72周，CAPACITY 2临床试验中的435名患者随机接受吡菲尼酮2,403 mg/d、吡菲尼酮1,197 mg/d或安慰剂治疗72周。主要研究终点为基线至72周时的用力肺活量占预期值的百分数变化。

CAPACITY 1临床试验中患者的平均年龄为68岁，CAPACITY 2试验中患者的平均年龄为67岁，美国北卡罗来纳州杜克大学内科学教授、呼吸病学、变态反应学和重症医学教授Noble博士说道。

在CAPACITY 2临床试验中，治疗组的患者在72周时用力肺活量占预期值的百分数变化(-6.49%)显著好于安慰剂组(-9.55%)，无进展生存期延长(危险比为0.64)。治疗组的用力肺活量分类变量的变化亦有更好的改善(P=0.001)。

在CAPACITY 1临床试验中，在72周时，治疗组和安慰剂组的用力肺活量占预期值的百分数的平均变化没有显著差异(分别为-6.49%和-7.23%)，但在48周时治疗组有更好的改善。Noble博士说：“虽然CAPACITY 1试验在主要研究终点方面没有获得统计学差异，但它的结果与CAPACITY 2试验一致，并支持CAPACITY 2的试验结果。”

按照InterMune公司的预先声明，将两项临床试验的用力肺活量的变化作为分类变量进行汇总分析，结果显示“在72周时，用力肺活量下降10%或以上的患者比例，在吡菲尼酮组比安慰剂组少30%。该减少量具有临床意义，因为多项研究显示，在患有特发性肺纤维化的患者用力肺活量占预期值的百分数下降10%是死亡率的独立预测因子。另外，用力肺活量占预期值的百分数没有下降的患者在吡菲尼酮组比安慰剂组多40%。”

在此次会议上，Noble博士报告，在两项临床试验中，吡菲尼酮的不良反应同以往临床试验中观察到的大致相同。吡菲尼酮组和安慰剂组最常见的不良反应为恶心(CAPACITY 2试验中分别为35%和18%；CAPACITY 1试验中分别为38%和16%)、皮疹(分别为31%和10%；34%和13%)，疲劳感(分别为28%和21%；33%和20%)、腹泻(分别为25%和17%；33%和21%)、消化不良(分别为17%和9%；21%和 6%)和眩晕(分别为19%和10%；18%和10%)。

在两项研究中，皮疹通常为轻微至中度；只有2名服用吡菲尼酮的患者(每项CAPACITY试验1名)出现重度皮疹。

研究者还分析了在治疗期间患者的死亡率，治疗期间指的是在临床试验中第一次用药的时间至接受最后一次用药后28天。在CAPACITY 1临床试验中，吡菲尼酮组5%的患者在治疗期间死亡，安慰剂组相应的患者比例为9%。在CAPACITY 2临床试验中，吡菲尼酮组6%的患者在治疗期间死亡，安慰剂组为8% 。

“在CAPACITY 2临床试验中，主要研究终点用力肺活量占预期值的百分数变化、次要研究终点无进展生存期以及用力肺活量占预期值的百分数的分类变量的变化均具有统计学意义和临床意义。”Noble博士总结道，“CAPACITY 1临床试验的情况不同，在主要研究终点方面未获得统计学意义。”

该研究由InterMune公司资助。

Noble透露说，他是Actelion制药有限公司、勃林格殷格翰制药公司和诺华制药公司的顾问、指导委员会成员和指导委员会的联合主席。