Inhaled IRK inhibitors as a novel therapeutic for IPF

摘要 本项目的总体目标是开发吸入性重塑激酶抑制剂MPX-111 （IRKI）作为治疗特发性肺纤维化（IPF）的一流疾病缓解药物，具有上级 与目前的治疗方法相比，具有更好的医疗益处和更高的安全性和耐受性。本提案的主要目标 是在IPF动物模型中测试吸入MPX-111的功效，以及吸入毒理学研究。 IPF是一种慢性、进行性和致死性的纤维化肺病，治疗后的中位生存期为3-5年。 诊断.目前IPF的治疗选择有限，疗效极低，耐受性问题严重。 据估计，全世界约有500万人患有IPF。因此，IPF是一种严重的、常见的 这种疾病对能够改善发病率和死亡率的新药的医疗需求大量得不到满足。 Metera Pharmaceuticals（Metera）从Janssen获得专利IRKI项目的许可，该项目确定了 新型吸入小分子化合物，其有效抑制PDGFR、VEGFR和FGFR。 抑制这些受体酪氨酸激酶是口服尼达尼布的作用机制，尼达尼布已被批准用于 IPF的治疗。然而，尼达尼布存在显著的安全性和耐受性问题， 通过限制可以给予的剂量，可能影响其临床有效性。IRKI 该项目侧重于鉴别具有尼达尼布固有药理学特征的化合物，但 优化局部递送至肺部，以最大限度地减少全身暴露并减少副作用。梅泰拉 最近选择MPX-111作为临床开发化合物，基于其总体生物学，DMPK， 这些特征对于吸入药物非常有利，包括高的 局部给药后在啮齿类动物中的持续肺水平，口服生物利用度低（<1%）。另外还有按 已经鉴定了适合于大规模合成的MPX-111的稳定结晶、微粉化形式。 在具体目标1中，将比较MPX-111鼻内给药与尼达尼布口服给药的效果， 一种IPF的标准模型，博莱霉素诱导的大鼠肺纤维化，使用两种预防性药物（以评估 对细胞外基质标志物的影响）和治疗（评估对正在进行的、已开发的 疾病）治疗范例。将测量MPX-111和尼达尼布的血浆和肺水平， 可以确定它们的PK/PD关系对于特定目标2，关键吸入毒理学和毒代动力学 将进行MPX-111雾化研究：非GLP 7天剂量范围探索，然后GLP 28天 在大鼠和猴中进行的研究，这两种物种以前用于评价口服 尼达尼布。Metera将资助完成IND申请所需的其余IND使能研究。 该II期项目的结果将扩展小分子IRKI抑制剂的科学原理 作为一种用于IPF治疗的创新性疾病缓解吸入疗法，与 这将为MPX-111的IND申请和临床开发奠定基础。

ABSTRACT The overall objective of this project is to develop MPX-111, an inhaled remodeling kinase inhibitor (IRKI) as a 1st-in-class, disease-modifying medicine for idiopathic pulmonary fibrosis (IPF), with superior medical benefit and improved safety and tolerability than current treatments. The main goals of this proposal are the testing of the efficacy of inhaled MPX-111 in an animal model of IPF, and inhaled toxicology studies. IPF is a chronic, progressive and fatal fibrotic lung disease, with a median survival of 3-5 years after diagnosis. Current treatment options for IPF are limited with minimal efficacy and significant tolerability issues. It is estimated that about 5 million people worldwide suffer from IPF. Thus, IPF represents a serious, common disease with a massive unmet medical need for new medicines that will improve morbidity and mortality. Metera Pharmaceuticals (Metera) in-licensed the proprietary IRKI Program from Janssen, which identified novel classes of inhaled, small molecule compounds that potently inhibit PDGFR, VEGFR and FGFR. Inhibition of these receptor tyrosine kinases is the mechanism of action of oral nintedanib which is approved for the treatment of IPF. However, nintedanib has significant safety and tolerability issues which reduce compliance and likely impact its clinical effectiveness, by limiting the doses that can be given. The IRKI Program focused on identifying compounds with the inherent pharmacological profile of nintedanib, but are optimized for local delivery to the lung, to minimize systemic exposure and reduce side-effects. Metera recently selected MPX-111 as the clinical development compound, based upon its overall biological, DMPK, physicochemical and developability profiles which are very favorable for an inhaled medicine, including high sustained lung levels in rodents after local administration, and low oral bioavailability (<1%). In addition, a stable crystalline, micronized form of MPX-111 that is amenable to large-scale synthesis has been identified. In Specific Aim 1, the effects of intratracheal of MPX-111 will be compared with those of oral nintedanib in a standard model of IPF, bleomycin-induced pulmonary fibrosis in rat, using both prophylactic (to assess the impact on extracellular matrix markers) and therapeutic (to evaluate the effects on ongoing, developed disease) treatment paradigms. The plasma and lung levels of MPX-111 and nintedanib will be measured so that their PK/PD relationships can be determined. For Specific Aim 2, key inhaled toxicology and toxicokinetic studies with nebulized MPX-111 will be performed: non-GLP 7-day dose-range-finding and then GLP 28-day studies in rat and monkey, two of the species used previously to evaluate the toxicological profile of oral nintedanib. Metera will fund the rest of the IND-enabling studies required to complete an IND application. The results from this Phase II project will expand the scientific rationale for a small molecule IRKI inhibitor as an innovative, disease-modifying inhaled therapy for IPF treatment with improved safety profile compared to current oral medicines and will lay the foundation for an IND filing and the clinical development of MPX-111.