Topical sirolimus Phase 1b trial for pachyonychia congenita (IND number 117347)

摘要 致衰弱的先天性厚甲皮肤病(PC)影响不到10,000名患者 由可诱导角蛋白(KRT)的显性突变引起，包括KRT6a，6b， 16和17。我们发现KRT6a和6b的5‘非翻译区含有一个 对西罗莫司和其他mTOR抑制剂具有敏感性的调控基序。MTOR抑制剂也 有效抑制核糖体蛋白S6(RpS6)等mTOR途径成分的磷酸化。 我们推测KRT6a/b基因的表达是mTOR途径的下游靶点，我们 西罗莫司对KRT6a基因转录水平的抑制作用 人角质形成细胞培养。此外，我们还发现mTOR信号通路被激活 在PC病变与邻近未受影响的皮肤患者的活检组织中进行比较。基于这些临床前数据， 我们在三名PC患者中启动了一项口服Rapamune®(辉瑞)的小型标签外研究， 这导致了PC症状的显着改善，包括足底疼痛。不幸的是，所有的 参与试验的患者遭受与全身性口服西罗莫司相关的众所周知的副作用 曝光。为了避免口服西罗莫司相关的不良事件，我们建议 用局部制剂直接治疗前列腺癌病变，以在需要的部位达到高药物水平， 将系统性风险降至最低。为此，我们建议在PC患者中进行一项1b期临床试验。 Transderm公司开发的专有外用西罗莫斯制剂(TD201)。这个提法很容易 如rpS6所示，可穿透人皮肤并向小鼠皮肤输送功能性抑制物 磷酸化抑制。这项TD201研究是一项前瞻性、随机、双盲、分裂的研究， 安慰剂对照1b期安全性研究，具有二次疗效目标，已获批准 FDA和斯坦福大学机构审查委员会。因此，这条明确的监管路径，再加上 从制造商辉瑞公司获得临床雷帕明，并同意允许 交叉参考他们的CMC和毒性包，表明TD201的临床评估是 高度可行，没有重大障碍向前推进。重要的是，FDA批准了Transderm 用西罗莫司治疗PC患者的孤儿药物指定，与给药途径无关。 证明外用西罗莫司是有效和安全的，在以下情况下副作用较少 与全身应用西罗莫司相比，应该为批准外用西罗莫司铺平道路 治疗由激活的mTOR通路引起的一系列其他疾病，包括瘢痕形成 激光治疗结节性硬化症合并鲜红斑点胎记、血管纤维瘤 复杂的，可能是牛皮癣和鳞状细胞癌。

ABSTRACT The debilitating ultrarare skin disorder pachyonychia congenita (PC) affects less than 10,000 patients worldwide and is caused by dominant mutations in the inducible keratins (KRT) including KRT6a, 6b, 16 and 17. We discovered that the 5' untranslated regions of KRT6a and 6b transcripts contain a regulatory motif that confers sensitivity to sirolimus and other mTOR inhibitors. mTOR inhibitors also potently inhibit phosphorylation of mTOR pathway components such as ribosomal protein S6 (rpS6). We postulate that KRT6a/b gene expression is a downstream target of the mTOR pathway and we demonstrated KRT6a gene inhibition at the level of mRNA translation following sirolimus treatment in human keratinocyte cultures. Furthermore, we identified that the mTOR signaling pathway is activated in PC lesions compared to adjacent unaffected skin in patient biopsies. Based on these preclinical data, we initiated a small off-label study of orally administered Rapamune® (Pfizer) in three PC patients, which resulted in marked improvement of PC symptoms including plantar pain. Unfortunately, all of the participating patients suffered from the well-known side effects associated with systemic oral sirolimus exposure. To avoid the adverse events associated with oral sirolimus administration, we propose to treat PC lesions directly with a topical formulation to achieve high drug levels at the site where needed, minimizing systemic exposure. To this end, we propose a Phase 1b clinical trial in PC patients with a proprietary topical sirolimus formulation (TD201) developed at TransDerm. This formulation readily penetrates human skin and delivers functional inhibitor to mouse skin as exhibited by rpS6 phosphorylation inhibition. This TD201 study is a prospective, randomized, double-blinded, split-body, placebo-controlled Phase 1b safety study with secondary efficacy objectives that has been approved by the FDA and by the Stanford Institutional Review Board. Therefore, this clear regulatory path, coupled with the availability of clinical Rapamune from the manufacturer Pfizer and their agreement to allow cross-referencing of their CMC and toxicity packages, suggests that clinical evaluation of TD201 is highly feasible with no major obstacles to move forward. Importantly, the FDA granted TransDerm orphan drug designation to treat PC patients with sirolimus, independent of the route of drug delivery. The demonstration that topical sirolimus is effective and safe, and has fewer side effects when compared to systemic sirolimus administration, should pave the way for approval for topical sirolimus treatment of a host of other disorders resulting from an activated mTOR pathway including scarring associated with laser treatment of port wine stain birthmarks, angiofibromas in tuberous sclerosis complex and possibly psoriasis and squamous cell carcinoma.