An inhaled PDGF receptor inhibitor for the treatment of pulmonary arterial hypertension

 描述（由申请人提供）：Pulmokine正在开发一种新型吸入性PDGF受体（PDGFR）激酶抑制剂PK 10571，用于治疗肺动脉高压（PAH）。该IIB期小型市场桥梁奖的目的是通过1A期临床试验促进PK10571的安全性。PAH是一种罕见疾病，尽管目前有治疗方法，但发病率和死亡率较高。Pulmokine目前的II期SBIR资助旨在开发API吸入制剂，确定大鼠的药代动力学和最大耐受剂量。这些研究已经完成，并为IND使能研究奠定了基础。根据FDA的要求，IND启动研究将包括两个种属（大鼠和犬）的体内动物毒理学研究。这些研究目前通过NHLBI授予Pulmokine的B阶段VITA合同单独资助。IIB期小型市场奖将提供在健康志愿者中进行1A期首次人体暴露临床试验和进行长期毒理学研究的方法。在完成1A期临床试验后，将使用投资者资金在PAH患者中进行1B/2A期联合临床试验。1B/2A期试验的主要终点为安全性，疗效为次要终点。在完成1B/2A期试验后，Pulmokine将与一家大型制药公司结成战略联盟或合作伙伴关系（或进行收购）。这样的联盟将允许我们的药物产品作为PAH治疗的III期临床试验和商业化。该项目的部分将由IIB期资助，包括以下内容：1）在健康志愿者中进行干粉吸入PK 10571的1A期安全性研究。本项1A期临床试验将包括设盲单次给药剂量递增（SAD）安慰剂对照方案，随后是多次给药剂量递增（MAD）安慰剂对照方案。所有的关键组成部分都已到位，以进行首次人体临床试验：1）API的cGMP生产商（IRIX Pharmaceuticals）; 2）喷雾干燥粉末制剂的cGMP生产商（弯曲Research Inc.）; 3)性能临床研究中心：（Parexel I期单位）。2)在大鼠中进行6个月GLP毒理学研究。根据ICH M3（R2）指导原则，在启动较长的II期临床试验之前，有必要进行本研究。ICH指导原则建议进行毒理学研究， 与3-6个月临床试验相同。由于1B/2A期试验是 计划进行6个月，我们需要进行6个月大鼠GLP毒性研究。

 DESCRIPTION (provided by applicant): Pulmokine is developing a novel inhaled PDGF receptor (PDGFR) kinase inhibitor, PK10571 as a treatment for Pulmonary Arterial Hypertension (PAH). The purpose of this Phase IIB Small Market Bridge Award is to progress PK10571 through a phase 1A clinical trial for safety. PAH is an orphan disease with high morbidity and mortality despite currently available treatments. Pulmokine's current Phase II SBIR grant was designed to develop the formulation for inhalation of the API, determine pharmacokinetics, and maximum tolerated dose in the rat. These studies have been accomplished, and set the stage for IND enabling studies. The IND enabling studies will consist of in vivo animal toxicology studies in two species (rat and dog) as required by the FDA. These studies are currently funded separately through a Stage B VITA contract awarded to Pulmokine through the NHLBI. The phase IIB small market award will provide the means to perform a phase 1A first in human exposure clinical trial in healthy volunteers and to perform longer term toxicology studies. After completion of the Phase 1A clinical trial a combined phase 1B/2A clinical trial in patients with PAH will be performed with investor funds. The primary endpoint of the phase 1B/2A trial will be safety, with efficacy as a secondary endpoint. After completion of the phase 1B/2A trial, Pulmokine will form a strategic alliance or partnership with a larger pharmaceutical company (or undergo acquisition). Such an alliance will allow performance of a phase III clinical trial and commercialization of our drug product as a treatment for PAH. The part of the project that will be funded by this phase IIB award includes the following: 1) Performance of a phase 1A safety study of dry powder inhaled PK10571 in healthy human volunteers. This phase 1A clinical trial will consist of a blinded single ascending dose (SAD) placebo controlled protocol followed by a multiple dose ascending (MAD) placebo controlled protocol. All of the key components are in place to perform this first in human clinical trial: 1) cGMP manufacturer of of the API (IRIX Pharmaceuticals) ; 2) cGMP manufacture of spray dry powder formulation (BEND Research Inc.); 3) the Clinical site for Performance: (Parexel Phase 1 Unit). 2) Performance of a 6 month GLP toxicology study in the rat. This study is necessary per ICH M3(R2) guidelines before initiation of the longer phase 2 clinical trial. ICH guidelines recommend toxicology studies of the same length as the clinical trial for trials of 3-6 months duration. Since the Phase 1B/2A trial is planned for six months, we will need the 6 month rat GLP tox study.