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 根治性前列腺切除术（RP）后，几乎所有男性都会出现勃起功能障碍（ED）， 主要是由于海绵体神经（CN）受损，但口服治疗是治疗 ED 的一线方法。 给予磷酸二酯酶 5 抑制剂 (PDE5i)，未能引起勃起反应 大多数因 RP (ED-RP) 而患 ED 的患者都采用替代疗法。 侵入性和/或效果不佳，并且通常不会被尝试。 在 RP 之后经历 ED，连续诊断（癌症和 ED）的创伤具有 对生活质量、人际关系和福祉产生深远影响，因此，迫切需要解决这一问题。 需要找到一种新的方法来治疗该患者群体的 ED。 ED-RP 发展的一个主要因素是 RP 期间对 CN 的损害 神经信号从 CN 末梢释放足够的 NO 来启动勃起。 增加局部 NO 水平的制剂可能会在缺乏 神经信号，还可能与 PDE5i 协同增强勃起反应。 这一假设在第一阶段得到了证实，该阶段证明了一种新型透皮药物 NO 微粒输送系统 (NO-MP) 能够在以下情况下引起勃起反应： 单独施用或与主要PDE5i的人体等效剂量的1/10组合施用， 当 NO-MP 和西地那非联合使用时，可缩短治疗时间。 观察到第一次勃起反应的开始，并且勃起次数大于 单独用NO-MP治疗。 在第二阶段的具体目标 1 中，我们将确定引发勃起反应的协同性是否 NO-MP 和西地那非之间存在与 FDA 批准的 PDE5i 类其他成员之间存在的差异。 这将确认第一阶段的观察是特定于类别的，并将扩展/定义 在具体目标 2 中，我们将启动 GMP 启动计划。 Zylö Therapeutics 并确认示范批次在引发勃起方面同样有效 响应作为特定目标 1 中使用的小批量制备。特定目标 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） 以便为后续 IND 毒理学研究的设计提供信息。此外，还包括皮肤敏感性。 作为套件的一部分，将进行豚鼠研究和兔子皮肤刺激研究 最后，在具体目标 4 中，进行 IND 前的研究。 将与 FDA 举行会议，以完成 IND 申请所需的剩余研究，并 启动 I 期临床研究。 在这些 II 期研究结束时，我们期望：(i) 确认 NO-MP 是 跨 PDE5i 类进行合作；(ii) 生成了一批 NO-MP 示范产品 确认功效；(iii) 进行皮肤毒性研究以提供敏感性和刺激性数据 并建立 MTD；以及 (iv) 就未来的开发工作向 FDA 进行咨询 总的来说，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。