Ph2.Study of PAT-001 for Treatment of Congenital Ichthyosis IND122058(7/27/2016)

项目摘要 先天性鱼鳞病（CI）是一组异质性遗传性皮肤病，其特征在于： 皮肤异常生长和角质化，可导致鳞屑和皮肤增厚。中度感染者 严重的CI可能会有终身的症状，包括积累鳞片，瘙痒和/或皮肤破裂，这是痛苦的 流血与CI相关的瘙痒、龟裂和异常皮肤屏障功能可引起进一步的 并发症，包括感染，并可显著影响生活质量。保守的流行率估计 这表明在美国大约有13万人患有CI，使其成为孤儿疾病。 目前还没有FDA批准的CI治疗方法。水合物和润滑剂可以促进水合作用， 不能解决潜在的疾病异常。口服类维生素A的标签外使用可以改善症状， 已被用于治疗某些类型的CI。然而，当治疗停止时，症状很快复发。在 此外，口服类维生素A具有严重的副作用，这妨碍了它们的长期使用。其中包括致畸 风险，皮肤脆性，甘油三酯和肝酶的血液浓度升高，以及弥漫性骨骼肌损伤。 骨质增生局部异维甲酸，这是批准在美国以外，用于治疗严重的痤疮，是一个更好的 长期CI治疗的候选者，因为它具有比其他类维生素A更短的半衰期和更低的致畸风险。 然而，局部异维A酸制剂将活性物质递送至表皮和真皮的能力较差 并且需要高浓度的乙醇作为渗透剂增强剂，当 适用于较大的体表面积。与口服类维生素A类似，局部使用异维A酸是禁忌的， 用于CI术语。开发一种安全有效的治疗CI的方法一直很困难，尽管 对这种治疗的迫切需要。 Patagonia是CI：PAT-001的创新外用异维A酸软膏的先驱。这个正在申请专利的 制剂不含乙醇，全身吸收最小。此外，与目前的配方不同， 异维甲酸选择性地靶向表皮和真皮。PAT-001获得孤儿药认定 2014年，Patagonia完成了临床前GLP药代动力学和毒理学研究，包括90- 在小型猪中进行的24天重复给药皮肤毒性研究、在豚鼠中进行的致敏研究、牛角膜混浊和 渗透性研究和兔的光毒性。Patagonia还完成了一项皮肤范围探索研究， 小型猪，不要求符合GLP。这些研究表明， 的PAT-001选择性地到达靶组织，全身吸收最小，并且没有证据表明新的 或独特的毒性。基于这些研究，我们预计PAT-001的有效性不会超过口服 类维生素A和其他局部异维甲酸制剂，副作用显著较少。 在本申请中，Patagonia将进行2期临床试验（活性IND 122，058，接收日期 2016年7月27日）在12岁及以上的层状和隐性X连锁鱼鳞病受试者中进行。第2a阶段是a 多中心、随机化、双盲、溶剂对照、双侧比较研究（8周），仅含活性药物 治疗随访（4周）。它将提供PAT-001的概念验证安全性和有效性。阶段的目的 2a是为了1）评估PAT-001的安全性和耐受性; 2）评估PAT-001的潜在疗效， 3）通过测定异维甲酸的血浆水平进行初步探索性PK研究， 局部应用PAT-001的维甲酸与治疗前和治疗后背景全身类维生素A水平的比较 治疗2b期将侧重于剂量探索、安全性和有效性;方案将根据 2a期的结果以及在2a期会议结束时与FDA的沟通。第二阶段试验将 促进PAT-001作为第一个也是唯一一个进入第3阶段和最终NDA备案和机构批准 FDA批准的CI治疗。

Project Summary Congenital Ichthyosis (CI) is a heterogeneous group of inherited dermatological diseases characterized by abnormal skin growth and keratinization that can lead to scaling and skin thickening. Individuals with moderate to severe CI can have life-long symptoms including accumulating scales, itchy and/or cracked skin that is painful and bleeds. The itching, fissuring, and abnormal skin barrier function associated with CI can cause further complications, including infection, and can significantly impact quality of life. Conservative prevalence estimates suggest there are around 130,000 individuals in the United States with CI, making this an Orphan Disorder. Currently there are no FDA-approved therapies for CI. Hydrants and lubricants can facilitate hydration but do not address the underlying disease abnormalities. Off-label use of oral retinoids can improve symptoms and has been used to treat certain types of CI. However, symptoms quickly recur when treatment is stopped. In addition, oral retinoids have serious side effects that preclude their long-term use. These include teratogenic risk, skin fragility, elevated blood concentrations of triglycerides and liver enzymes, and diffuse skeletal hyperostosis. Topical isotretinoin, which is approved outside of the US and used to treat severe acne, is a better candidate for long-term CI treatment as it has a shorter half-life and less teratogenic risk than other retinoids. However, topical isotretinoin formulations have poor delivery of the active article to the epidermis and dermis and require high concentrations of ethanol as a penetrant enhance, which can cause significant erythema when applied over large body surface areas. Similar to oral retinoids, topical isotretinoin is contraindicated for long- term use for CI. Development of a safe and effective therapeutic indicated for CI has been difficult, despite the well-recognized critical need for such a treatment. Patagonia is pioneering an innovative topical isotretinoin ointment for CI: PAT-001. This patent-pending formulation has no ethanol and has minimal systemic absorption. In addition, unlike current formulations, isotretinoin is selectively targeted to the epidermis and dermis. PAT-001 was granted Orphan Drug Designation in 2014, and Patagonia has completed pre-clinical GLP pharmacokinetics and toxicology studies, including 90- day repeat-dose dermal toxicity study in minipigs, sensitization study in guinea pigs, bovine corneal opacity and permeability study, and phototoxicity in rabbits. Patagonia has also completed a dermal range-finding study in minipigs, which was not required to be GLP-compliant. These studies indicated that therapeutic concentrations of PAT-001 selectively reached targeted tissues with minimal systemic absorption and had no evidence of new or unique toxicity. Based on these studies, we expect that PAT-001 will be as if not more effective than oral retinoids and other topical isotretinoin formulations with significantly fewer side effects. In this application, Patagonia will conduct a Phase 2 clinical trial (active IND 122,058, date of receipt 07/27/2016) in subjects aged 12 and older with Lamellar and Recessive X-linked Ichthyosis. Phase 2a is a multisite, randomized, double-blind, vehicle controlled, bilateral comparison study (8 weeks) with active only treatment follow-up (4 weeks). It will provide proof-of-concept safety and efficacy of PAT-001. The Aims of Phase 2a are to 1) Assess the safety and tolerability of PAT-001; 2) Assess the potential efficacy of PAT-001 compared to a vehicle; and 3) Conduct a pilot, exploratory PK study by determining plasma levels of isotretinoin and tretinoin from topically applied PAT-001 with comparison to background systemic retinoid levels pre-and post- treatment. Phase 2b will focus on dose-finding, safety, and efficacy; the protocol will be finalized based on the results of the Phase 2a and communication with the FDA at the end of Phase 2a meeting. This Phase 2 trial will facilitate advancement to Phase 3 and eventual NDA filing and agency approval of PAT-001 as the first and only FDA-approved therapy for CI.