Combination Therapy in IPF

描述(由申请人提供)： 特发性肺纤维化(IPF)是一种致命的疾病，目前的治疗方法已经失败。在远端呼吸道预防肺泡上皮细胞(AEC)损伤和肌成纤维细胞(MF)激活/存活可能会减缓纤维化的进展并提高存活率。来自体外研究、肺纤维化体内模型和先前临床试验的最新证据表明，阻断生长因子产生或成纤维细胞存活的药物可以减轻纤维化。吡非尼酮和干扰素-γ(IFN-？)HMGCoA还原酶抑制剂(洛伐他汀)下调成纤维细胞的存活，5-脂氧合酶激活蛋白(FLAP)抑制剂(MK-0591)下调成纤维细胞产生的细胞外基质的产生。我们假设这些药物有可能改善IPF患者的存活率并减缓疾病进展。为了解决这一问题，我们提出了以下具体目标： 具体目标1：通过吡非尼酮和干扰素-β-1b的联合治疗，确定下调远端呼吸道生长因子的产生是否能提高IPF患者两年以上的存活率。我们假设，与单独使用吡非尼酮相比，这两种药物的联合使用将在更大程度上降低死亡率和减缓疾病进展。为了验证这一点，我们将进行一项多中心、随机、双盲、安慰剂对照、分层、平行分组的为期两年的研究，将吡非尼酮和干扰素-1b与单独使用吡非尼酮或安慰剂在一大批IPF患者中的临床效果进行比较。 具体目标2：确定洛伐他汀和MK-0591联合应用下调成纤维细胞存活和基质蛋白产生是否能提高IPF患者两年以上的存活率。我们假设，这两种药物的组合将比单独使用任何一种药物更大程度地降低死亡率和减缓疾病进展。为了验证这一点，我们将在一大批IPF患者中进行一项多中心、随机、双盲、安慰剂对照、分层、平行分组为期两年的临床疗效研究，比较洛伐他汀和MK-0591与单独用药或安慰剂的临床效果。这些临床试验将确定调节血管内皮细胞和成纤维细胞之间的相互作用，从而减少远端呼吸道的纤维化和相继损伤的药物是否可以降低死亡率和减缓IPF的疾病进展。(摘要结束)

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a fatal disease for which current therapies have failed. Preventing alveolar epithelial cell (AEC) injury and myofibroblast (MF) activation/survival in distal airways may slow progression of fibrosis and enhance survival. Recent evidence from in vitro studies, in vivo models of pulmonary fibrosis, and previous clinical trials indicate that agents that block either growth factor production or fibroblast survival may attenuate fibrosis. Pirfenidone and interferon-gamma (IFN-?) may down-regulate both AEC apoptosis and fibroblast survival, HMGCoA reductase inhibitors (lovastatin) down-regulate fibroblast survival and 5-lipoxygenase activating protein (FLAP) inhibitors (MK-0591) down-regulate fibroblast-generated extracellular matrix production. We hypothesize that these agents have the potential to improve survival and slow disease progression in patients with IPF. To address this, we propose the following specific aims: Specific Aim 1: Determine if down-regulating growth factor production in distal airways via treatment with the combination of pirfenidone and IFN-?-lb improves survival over two years in patients with IPF. We hypothesize that the combination of these two agents will decrease mortality and slow disease progression to a greater extent than pirfenidone agent alone. To test this, we will conduct a multi-center, randomized, double-blind, placebo-controlled, stratified, parallel group two-year study of clinical effect of pirfenidone and IFN?-1b compared with pirfenidone alone or placebo in a large cohort of patients with IPF. Specific Aim 2: Determine if down-regulating fibroblast survival and matrix protein production with the combination of lovastatin and MK-0591 improves survival over two years in patients with IPF. We hypothesize that the combination of these two agents will decrease mortality and slow disease progression to a greater extent than either agent alone. To test this, we will conduct a multi-center, randomized, double-blind, placebo-controlled, stratified, parallel group two-year study of clinical effect of lovastatin and MK-0591 compared with either agent alone or placebo in a large cohort of patients with IPF. These clinical trials will establish whether agents that modulate interactions between AECs and fibroblasts, and thus reduce fibrosis and sequential damage in distal airways, can reduce mortality and slow disease progression in IPF. (End of Abstract)