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

 描述(申请人提供)：Pulmokine正在开发一种新型的吸入型PDGFR(PDGFR)激酶抑制剂PK10571，用于治疗肺动脉高压(PAH)。这一IIB期小市场桥梁奖的目的是通过1A期临床试验来促进PK10571的安全性。尽管目前有治疗方法，但PAH是一种发病率和死亡率都很高的孤儿疾病。Pulmokine目前的第二阶段SBIR赠款旨在开发用于吸入原料药的配方，确定大鼠的药代动力学和最大耐受量。这些研究已经完成，并为IND支持研究奠定了基础。按照FDA的要求，IND支持研究将包括两个物种(大鼠和狗)的活体动物毒理学研究。这些研究目前是通过NHLBI授予Pulmokine的B阶段VITA合同单独提供资金的。第二阶段B小市场奖将提供在健康志愿者身上进行第一阶段人体暴露临床试验和进行长期毒理学研究的手段。在1A期临床试验完成后，将利用投资者资金进行针对PAH患者的1B/2A期联合临床试验。1B/2A阶段试验的主要终点将是安全性，疗效将作为次要终点。在完成1B/2A阶段试验后，Pulmokine将与一家更大的制药公司结成战略联盟或伙伴关系(或进行收购)。这样的联盟将允许进行第三阶段临床试验，并将我们的药物产品商业化，作为治疗PAH的方法。该项目将由IIB阶段奖资助的部分包括：1)在健康的人类志愿者身上进行了对吸入干粉的PK10571进行的1A阶段安全性研究。这项第1A期临床试验将由盲法单次递增剂量(SAD)安慰剂对照方案和随后的多剂量递增(MAD)安慰剂对照方案组成。所有关键组件都已就位，以在人体临床试验中首次实现这一目标：1)原料药(IRIX制药)的cGMP制造商；2)喷雾干粉配方的cGMP制造商(Bend Research Inc.)；3)临床性能现场：(PAREXEL阶段1单元)。2)对大鼠进行为期6个月的GLP毒理学研究。根据ICH M3(R2)指南，在启动较长的2期临床试验之前，这项研究是必要的。ICH指南建议进行毒理学研究 与为期3-6个月的临床试验的长度相同。由于1B/2A阶段试验是 计划了6个月，我们将需要6个月的大鼠GLP毒素研究。

 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.