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

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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.