Ph2.Study of PAT-001 for Treatment of Congenital Ichthyosis IND122058(7/27/2016)
PAT-001治疗先天性鱼鳞病二期研究IND122058(7/27/2016)
基本信息
- 批准号:10496801
- 负责人:
- 金额:$ 12.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-15 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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.
项目摘要
先天性鱼鳞病是一组异质性遗传性皮肤病,其特征是
皮肤异常生长和角质化,可导致结垢和皮肤增厚。患有中度疾病的个人
严重的CI可能会出现终生症状,包括积垢、皮肤发痒和/或破裂,令人疼痛
还会流血。与CI相关的瘙痒、裂伤和皮肤屏障功能异常可进一步导致
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
建议在美国大约有13万人患有CI,这使其成为一种孤儿疾病。
目前还没有FDA批准的治疗CI的方法。消火栓和润滑剂可以促进水合,但
不处理潜在的疾病异常。标签外使用口服维甲酸可以改善症状和
已被用于治疗某些类型的脑梗塞。然而,当治疗停止时,症状很快就会复发。在……里面
此外,口服维甲酸有严重的副作用,使其无法长期使用。其中包括致畸
风险、皮肤脆弱、甘油三酯和肝酶浓度升高,以及弥漫性骨骼
骨质增生。异维A酸在美国境外被批准用于治疗严重的痤疮,是一种更好的治疗方法
是长期脑梗塞治疗的候选药物,因为与其他维甲酸相比,它的半衰期更短,致畸风险更低。
然而,局部使用的异维A酸制剂将活性物质输送到表皮和真皮的效果很差。
并且需要高浓度的乙醇作为渗透性增强剂,在以下情况下会导致严重的红斑
适用于大面积的身体表面积。与口服维甲酸类似,外用异维甲酸是长期禁忌。
CI的术语用法。开发一种安全有效的脑梗塞治疗适应证一直是困难的,尽管
对这种治疗的公认的迫切需要。
巴塔哥尼亚公司率先推出了一种用于CI:PAT-001的创新外用异维A酸软膏。这项正在申请专利的
配方不含乙醇,全身吸收极少。此外,与目前的配方不同,
异维甲酸选择性地作用于表皮和真皮。PAT-001被授予孤儿药物称号
2014年,巴塔哥尼亚已经完成了临床前的普洛斯药代动力学和毒理学研究,包括90-
小型猪每日重复给药的皮肤毒性研究,豚鼠的致敏研究,牛角膜混浊和
通透性研究,以及对兔的光毒性。巴塔哥尼亚还完成了一项真皮测距研究
小型猪,这不需要符合GLP标准。这些研究表明,治疗浓度
以最小的系统吸收选择性地到达靶组织,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似乎不会比口服更有效
维甲酸和其他外用异维A酸制剂副作用显著减少。
在这项申请中,巴塔哥尼亚公司将进行2期临床试验(有效IND 122,058,收到日期
2016年7月27日)在12岁及以上患有板层状和隐性X连锁鱼鳞病的受试者中。2a期是一个
多点、随机、双盲、载体对照、双侧对照研究(8周)
治疗随访(4周)。它将提供PAT-001的概念验证安全性和有效性。阶段性目标
2a)评估PAT-001的安全性和耐受性;2)评估PAT-001的潜在疗效
3)通过测定血浆中异维A酸和维甲酸的水平进行试验性的探索性PK研究
外用PAT-001前后背景维甲酸水平的比较
治疗。阶段2b将侧重于剂量发现、安全性和有效性;议定书将根据
2a阶段的结果,并在2a阶段会议结束时与FDA进行沟通。这一第二阶段试验将
促进进入第三阶段,并最终提交保密协议并获得机构批准,将PAT-001作为第一个也是唯一一个
FDA批准的脑梗塞治疗方法。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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