Development of microparticle-based topical treatments for treating erectile dysfunction in patients refractory to oral PDE5 inhibitors

摘要 根治性阴茎切除术（RP）后，几乎所有男性都会出现勃起功能障碍（艾德）， 主要是由于海绵体神经（CN）的损伤。然而，艾德的一线治疗，口服 给予磷酸二酯酶5抑制剂（PDE5i），不能引起勃起反应， 大多数患者因RP而患有艾德（ED-RP）。替代治疗是高度 侵入性和/或具有差的功效，并且通常甚至不尝试。的男人 经历RP后的艾德，背靠背诊断（癌症和艾德）的创伤具有 对生活质量、人际关系和幸福感产生深远影响。因此，迫切需要 需要找到一种新的方法来治疗这一患者群体的艾德。 在ED-RP的发展中的一个主要因素是在RP受损期间CN的损伤 从CN末梢释放足够的NO以启动勃起的神经元信号。因此，在本发明中， 增加局部NO水平的制剂可以在缺乏刺激的情况下引起勃起反应。 神经元信号，并且还可以使能与PDE5i的协同性以增强勃起反应。 这一假设在第一阶段得到了证实，其中证明了一种新的透皮吸收剂， NO微粒递送系统（NO-MP）能够引起勃起反应， 单独给药或与1/10人等效剂量的前导PDE 5i组合给药， 西地那非当NO-MP和西地那非联合使用时， 观察到第一次勃起反应的发作，勃起次数大于 单独用NO-MP治疗。 在第二阶段的具体目标1中，我们将确定在引起勃起反应中的协同性是否 NO-MP和西地那非之间的差异存在于FDA批准的PDE 5i类别的其他成员中。 这将确认第一阶段的观察结果是特定于类别的，并将扩展/定义 潜在的商业合作伙伴。在具体目标2中，我们将启动GMP启动计划 在Zylö Therapeutics，并确认一个示范批次是有效的诱导勃起 响应与特定目标1中使用的小批量制备相同。具体目标3将建立 在大鼠和小型猪中进行的剂量范围探索研究中的最大耐受剂量（MTD） 以便为后期IND启用毒理学研究的设计提供信息。此外，皮肤敏感性 将进行豚鼠研究和家兔皮肤刺激研究，作为套件的一部分 FDA要求的外用产品的安全性研究。最后，在具体目标4中， 将与FDA举行会议，以完成IND申请所需的剩余研究， 启动I期临床研究。 在这些II期研究结束时，我们预计：（i）证实NO-MP是 合作的PDE5i类;（ii）产生了一个示范批次的NO-MP与 已证实的疗效;（iii）进行了皮肤毒性研究，以提供敏感性和刺激性数据 并确定MTD;以及（iv）就未来的开发工作与FDA进行磋商 在一次IND前会议上总的来说，我们将准备启动进一步的毒性研究， 申请IND和I期临床试验

Abstract Following radical prostatectomy (RP), virtually all men experience erectile dysfunction (ED), primarily due to damage to the cavernous nerve (CN). Yet, first-line treatments for ED, orally administered phosphodiesterase 5 inhibitors (PDE5i), fail to elicit an erectile response for a majority of patients suffering from ED as a result of RP (ED-RP). Alternative treatments are highly invasive and/or have poor efficacy and are typically not even attempted. For a man who experiences ED following RP, the trauma of back-to-back diagnoses (cancer and ED) has a profound impact on quality-of-life, relationships, and well-being. There is, therefore, an urgent need to find a novel approach to the treatment of ED in this patient group. A primary factor in the development of ED-RP is that damage to the CN during RP impairs neuronal signals that release sufficient NO from CN endings to initiate an erection. Thus, formulations that increase local levels of NO may elicit an erectile response in the absence of neuronal signals and may also enable cooperativity with PDE5i to enhance the erectile response. This hypothesis was proven in Phase I where it was demonstrated that a novel transdermal microparticle delivery system for NO (NO-MP) was able to elicit an erectile response when administered alone or in combination with 1/10 the human equivalent dose of the leading PDE5i, sildenafil. When NO-MP and sildenafil were used in combination, an improvement in the time for onset of the first erectile response was observed, and the number of erections was greater than treatment with NO-MP alone. In Specific Aim 1 of Phase II, we will determine if the cooperativity in eliciting an erectile response seen between NO-MP and sildenafil exists with other members of the FDA-approved PDE5i class. This will confirm that the observation in Phase I is class-specific and will expand/define the portfolio of potential commercial partners. In Specific Aim 2 we will initiate a GMP start-up program at Zylö Therapeutics and confirm that a demonstration batch is as effective in eliciting an erectile response as the small batch prep used in Specific Aim 1. Specific Aim 3 will establish the maximum tolerated dose (MTD) in dose-range-finding studies conducted in rats and minipigs in order to inform the design of later IND-enabling toxicology studies. In addition, a dermal sensitivity study in guinea pigs and a dermal irritation study in rabbits will be conducted as part of the suite of safety studies required by the FDA for topical products. Finally, in Specific Aim 4, a pre-IND meeting will be held with the FDA to finalize remaining studies required for an IND application and initiation of a Phase I clinical study. At the conclusion of these phase II studies, we expect to have: (i) confirmed that NO-MP is cooperative across the PDE5i class; (ii) generated a demonstration batch of NO-MP with confirmed efficacy; (iii) conducted dermal toxicity studies to provide sensitivity and irritation data and to establish the MTD; and (iv) consulted with the FDA regarding future development work during a pre-IND meeting. Overall, we will be ready to initiate further toxicity studies in preparation for an IND filing and a Phase I clinical trial.