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

摘要 在根治性前列腺切除术(RP)后，几乎所有男性都会经历勃起功能障碍(ED)， 主要是由于海绵体神经(CN)受损。然而，一线治疗ED，口服 给予磷酸二酯酶5抑制剂(PDE5i)，未能引起勃起反应 大多数患者因RP(ED-RP)而罹患ED。替代疗法在很大程度上 侵入性和/或疗效较差，通常甚至不尝试。对于一个 经历ED在RP之后，背靠背诊断的创伤(癌症和ED)有 对生活质量、人际关系和幸福感产生深远影响。因此，有一个紧急的 需要找到一种新的方法来治疗这一组患者的ED。 ED-RP发展的一个主要因素是在RP过程中对CN的损害 从CN末端释放足够的NO以启动勃起的神经元信号。因此， 在缺乏勃起的情况下，增加局部NO水平的配方可能会引起勃起反应 神经元信号，也可能使与PDE5i的协同作用，以增强勃起反应。 这一假说在第一阶段得到了证实，在这一阶段，一种新型的透皮贴剂被证明 NO微粒递送系统(NO-MP)在以下条件下可引起勃起反应 单独给药或与领先的PDE5i人体等量剂量的1/10联合使用， 西地那非。当NO-MP和西地那非联合使用时， 观察到首次勃起反应，勃起次数大于 单用无甲氧西林治疗。 在第二阶段的具体目标1中，我们将确定在引发勃起反应方面的协同性 与FDA批准的PDE5i类别的其他成员一起存在的无MP和西地那非之间。 这将确认第一阶段中的观察是特定于类的，并将扩展/定义 潜在商业合作伙伴的组合。在具体目标2中，我们将启动GMP启动计划 在ZylöTreateutics，并确认示范批次在诱导勃起方面同样有效 响应作为特定目标1中使用的小批量准备。特定目标3将建立 年在大鼠和小型猪身上进行的剂量范围发现研究中的最大耐受剂量(MTD) 以便为以后的IND毒理学研究的设计提供信息。此外，皮肤敏感性 对豚鼠的研究和对兔的皮肤刺激性研究将作为该套装的一部分进行。 FDA要求对外用产品进行的安全性研究。最后，在具体目标4中，前IND 将与FDA举行会议，以最终确定IND申请所需的剩余研究 启动I期临床研究。 在这些第二阶段研究结束时，我们预计将：(I)证实无MP是 跨PDE5i类合作；(Ii)生成了一批无MP的演示批次 确认疗效；(3)进行皮肤毒性研究，以提供敏感性和刺激性数据 和建立MTD；以及(Iv)就未来的开发工作咨询FDA 在一次IND前会议上。总体而言，我们将准备启动进一步的毒性研究 用于IND申请和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.