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

开发基于微粒的局部治疗方法，用于治疗口服 PDE5 抑制剂难治性患者的勃起功能障碍

• 批准号: 10258888
• 负责人: Andrew R Draganski
• 金额: $ 69.72万
• 依托单位: ZYLO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258888
• 关键词: Alprostadil; Animal Model; Animals; Back; Back Trauma; Binding; Cavia; Clinical Research; Clinical Trials; Consult; Data; Dermal; Development; Diagnosis; Dose; Erectile dysfunction; FDA approved; Feedback; Formulation; Future; Goals; Grant; Human; Impairment; Injections; Malignant Neoplasms; Maximum Tolerated Dose; Miniature Swine; Nerve; Nerve Endings; Nitric Oxide; Operative Surgical Procedures; Oral; Oryctolagus cuniculus; Patients; Penile Prosthesis; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Positioning Attribute; Preparation; Production; Quality of life; Radical Prostatectomy; Rattus; Refractory; Research Design; Suppositories; System; Systemic blood pressure; Therapeutic; Time; Topical application; Toxic effect; Toxicology; Vacuum Pumps; Work; alternative treatment; analytical method; base; compliance behavior; design; erection; experience; first-in-human; in vivo; inhibitor/antagonist; irritation; man; meetings; member; men; nerve damage; nerve transection; neurotransmission; novel; novel strategies; patient tolerability; penis; phase 2 study; phosphodiesterase V; programs; response; safety study; sildenafil; standard care; virtual

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.

抽象的 遵循根治性的前列腺切除术（RP），几乎所有男性都有勃起功能障碍（ED）， ED，口服的一线治疗 施用的磷酸二酯酶5抑制剂（PDE5I）未能引起勃起反应 大多数因RP（ED-RP）而患有ED的患者。替代治疗高度高度 侵入性和/或效率较差，通常甚至没有尝试。对于一个男人 RP之后的经验ED，背靠背诊断（Cancer and Ed）的创伤具有 对生活质量，人际关系和福祉的深远影响。因此，有一个紧急的 需要在该患者组中找到一种新颖的方法来治疗ED。 ED-RP发展的主要因素是RP损害期间CN的损害 神经元信号从CN末端释放足够的NO以启动勃起。那， 增加局部水平的公式可能会在没有的情况下引起勃起反应 神经元信号，还可以与PDE5I协调以增强勃起反应。 该假设在第一阶段证明了一种新型的透皮 NO（NO-MP）的微粒输送系统能够引起勃起响应 单独给药或与1/10结合使用的人类等效剂量。 西地那非。当使用NO-MP和Sildenafil结合使用时， 观察到第一个勃起反应的发作，勃起的数量大于 单独使用NO-MP治疗。 在第二阶段的特定目标1中，我们将确定是否在引发勃起响应中的协调 与FDA批准的PDE5I类的其他成员一起，在NO-MP和Sildenafil之间看到。 这将确认第一阶段的观察是特定于班级的，并且会扩展/定义 潜在商业合作伙伴的投资组合。在特定目标2中，我们将启动GMP启动计划 在Zylötherapeictics，确认示范批次在引发勃起的情况下同样有效 响应是特定目标1中使用的小批次准备。特定目标3将建立 在大鼠和小型剂量的剂量范围调查研究中的最大耐受剂量（MTD） 为了告知以后的毒理学研究的设计。另外，真皮敏感性 豚鼠的研究和兔子的皮肤刺激研究将作为套件的一部分进行 FDA需要用于局部产品的安全研究。最后，在特定目标4中 会议将与FDA举行，以最终确定IND申请所需的剩余研究，并 I期临床研究的启动。 在这些第二阶段研究的结论中，我们希望有：（i）确认没有MP是 整个PDE5I班级合作； （ii）与 确认效率； （iii）进行了皮肤毒性研究以提供灵敏度和刺激性数据 并建立MTD； （iv）就未来的开发工作咨询了FDA 在一次预定会议上。总体而言，我们将准备开始进行进一步的毒性研究 用于IND提交和I期临床试验。