一个bstract
Efficient IPF drug development is needed to ensure unmet medical need isn't overshadowed by scientific/financial riskhttp://ow.ly/k0aev
尽管Nintedanib和Pirfenidone计划最近取得了成功[1,,,,2], idiopathic pulmonary fibrosis (IPF) remains a high-risk disease area for drug development. There are no adequate preclinical models in which to test potential compounds, and no established early clinical development pathway on which to make quick decisions regarding potential efficacy [3]。The historical approach in IPF of moving compounds directly from phase 1 safety and tolerability studies into large phase 2 studies with clinical end-points required major commitments from sponsors and research subjects. Now, with effective therapies reducing the frequency and responsiveness of clinical end-points, sponsors may decide that IPF is too costly a disease to invest in.
IPF需要更有效和信息丰富的早期临床开发途径。W的创新研究ilkes等。[[4],发表在本期European Respiratory Journal,描述口头immunothe的第一阶段的结果rapy with type V collagen in patients with IPF illustrates one such approach. This study is worth careful consideration, both for the novelty of its potential therapy and for the approach it takes to three core study design issues.
问题1:针对哪种机制
most therapies under clinical development for the treatment of IPF target collagen production, the most salient (but also the most terminal) event in IPF pathobiology [5]。less attention has been given to upstream events, and for good reason as the aetiology of IPF appears complex and heterogeneous, and knowing where to focus one's efforts has been a major challenge.
越来越多的共识是,IPF代表肺泡上皮细胞功能障碍的疾病,并且这种功能障碍导致肺部的纤维化微环境[6]。There are many ways in which alveolar epithelial cell dysfunction may occur, including age-related senescence, genetic predisposition, inhalational exposure and autoimmunity. All of these areas represent potential upstream targets for novel therapeutics. Wilkes等。[[4] demonstrate that clinical research using cohorts of carefully phenotyped patients with accompanying biological samples can identify a plausible target, in this case autoimmunity against collagen V, with a potential therapeutic intervention. We need more of these types of programmes that use clinical and biological data from patients with IPF to identify potential aetiological pathways and test compounds that may modify them.
Issue 2: which patients to enrol
队列富集一直是IPF临床试验设计的热门话题。大多数讨论都是关于“预后”的同伴富集,或者对患者的识别更有可能经历感兴趣的结果(e.g.decline in forced vital capacity (FVC)). Little attention has been given to “predictive” cohort enrichment, or the identification of patients more likely to respond to a specific therapy [7]。预测富集是精确(或分层)医学概念的核心,这种方法有望针对IPF等条件更具针对性和有效的治疗方法,该疾病可能包含多个不同的病原体亚组[8]。
wilkes等。[[4] use a precision medicine approach to identify a sizable subgroup of IPF patients with elevated autoantibody levels to collagen V and hypothesise that therapy directed at modulating the immune response to collagen V will preferentially benefit these patients. Importantly, this early stage study provides no proof of this hypothesis, and there is a danger of false dichotomisation in precision medicine that deserves careful consideration. Nonetheless, predictive cohort enrichment has been transformative in developing therapies for other pulmonary diseases like lung cancer and cystic fibrosis, and it is worth further study in IPF. It may be particularly relevant when developing compounds focused on upstream targets, like autoimmunity against type V collagen, where heterogeneity in pathobiological pathways may be more clinically relevant.
Issue 3: which end-points to measure
虽然已广泛讨论了IPF晚期疗效试验的适当终点[9,,,,10],对临床药物开发的更为核心挑战是为早期临床试验发现有效的,信息丰富的终点。默认的终点是FVC的变化,但这是一个相对无反应的终点,需要数百名患者在数百个月内进行足够的供电[11]。分子生物标志物通过提供更快的响应终点,但不可用的IPF疾病活动和/或进展的分子生物标志物通过提供更快的响应终点来承诺较小,更快,更便宜的早期试验。12]。
wilkes等。[[4] incorporate molecular biomarkers into their study, including matrix metalloproteinase 7, serum albumin, and anti-collagen V antibody-bound C1q, a mechanistic biomarker. The more effective oral immunotherapy with type V collagen is in reducing anti-collagen V antibody activity, the less C1q should be bound by anti-collagen V antibodies in the serum. Mechanism specific molecular biomarkers may prove most useful for early phase clinical drug development, as they directly reflect the impact of a compound on the biological process of interest. Indeed, it was the mechanistic marker anti-collagen V antibody-bound C1q that showed the most consistent results. Although not statistically significant, C1q binding appeared to be reduced by oral immunotherapy in a dose-dependent manner, and 24-week change in C1q binding appeared correlated with 24-week change in FVC [4]。
molecular biomarkers (in particular mechanistic molecular biomarkers) add an important dimension to the early clinical assessment of potential compounds and warrant consideration as primary end-points in phase 2 trials given their efficiency and responsiveness. Ultimately, sponsors will need to decide if early phase clinical trials designed around molecular biomarker end-points provide sufficient evidence of efficacy to justify investing in definitive phase 3 trials using clinical end-points.
我们所有人前进的挑战是使IPF临床药物开发足够高效,因此仍然没有受到科学和财务风险的掩盖,但仍未满足的医疗需求并不掩盖。IPF社区可以通过多种方式与赞助商合作以提高临床试验效率,其核心将涉及对本社论中提出的三个研究设计问题的核心解决。如果药物开发人员针对的是相关的途径和设计试验,围绕同类和终点的终点,以增强检测小样本量中可靠信号的可能性,则可以更迅速,便宜地研究潜在的化合物,并且可以做出更多的“ go/no go”决策。明智地。wilkes等。[[4]通过进行一项试验,该试验使用前瞻性的研究设计来确定有希望的新疗法,并希望IPF中未来的临床药物开发计划将本研究视为模型。
Footnotes
Conflict of interest: Disclosures can be found alongside the online version of this article atwww.qdcxjkg.com
- Receiveddecember 28, 2014.
- 公认january 6, 2015.
- Copyright ©ERS 2015