SBIR-STTR Award

Radical prostatectomy (RP) is a commonly used treatment option for localized prostate cancer. Unfortunately, the procedure carries a risk of post-surgical complications including a high risk of erectile dysfunction (ED). The main pathophysiological mechanism behind this is neuropraxia in which surgery either directly damages the cavernous nerves (CN) or does so indirectly through activation of an inflammatory response. Given that phosphodiesterase inhibitors (PDE5i), the mechanism of FDA-approved oral treatments for ED, are dependent on the production of nitric oxide (NO) from CN endings, the majority of patients undergoing RP where CN function is perturbed or lost are refractory to this treatment. In prior publications from our group we have demonstrated that topically applied particles delivering NO or a PDE5i can generate an erectile response in animal models of aging or RP. However, there is a strong rationale for combining both NO and PDE5i to treat ED in patients with neuropraxia: NO will initiate an erection and the PDE5i will maintain cyclic guanosine monophosphate (cGMP) levels, which activates biochemical pathways resulting in a sustained erection. The goal of the present proposal is to develop a novel therapeutic for treating ED: a topically applied microparticle (MP) delivery system delivering NO (NO-MP) with the potential to act cooperatively with PDE5i to treat ED in men that are refractory to current FDA-approved therapies. The goal of this proposal will be achieved through two specific aims. In Specific Aim 1, NO-MP will be formulated and optimized for clinical translation. NO-MP will be generated and loaded with four different concentrations of NO and tested in an animal model of RP (bilateral CN transected) to assess the ability to elicit erections. In addition, these animals will be used to perform preliminary pathology studies to provide initial evidence of safety of the NO-MP. In Specific Aim 2 it will be determined if a greater response can be obtained with a combination of NO-MP and a PDE5i (sildenafil) in promoting erectile function. At the conclusion of this phase I study, a lead NO concentration will be determined to develop a novel, topical therapeutic for neurogenic ED.

Public Health Relevance Statement:
Radical prostatectomy (RP), a commonly used treatment option for localized prostate cancer, is unfortunately associated with a high risk of post-surgical erectile dysfunction (ED). The goal of the present proposal is to develop a novel therapeutic for treating ED: a topically applied microparticle (MP) delivering nitric oxide (NO) with the potential to enhance erectile function in combination with phosphodiesterase-5 inhibitors (PDE5i) in PDE5i-refractory patients. At the conclusion of this Phase I study, the optimal NO concentration in NO-MP will be identified to develop a novel, topical therapeutic for neurogenic ED.

Project Terms:
Aging; Animal Model; Animals; base; Bilateral; Biochemical Pathway; Cialis; Clinical; clinical translation; Combined Modality Therapy; Cyclic GMP; Development; Diabetes Mellitus; Dose; Elements; Erectile dysfunction; erection; FDA approved; Formulation; Generations; Goals; High Prevalence; high risk; improved outcome; Inflammatory Response; inhibitor/antagonist; Lead; Maintenance; Malignant neoplasm of prostate; Measures; men; Meta-Analysis; molecular pathology; Muscle relaxation phase; nanoparticle delivery; Nerve; Nerve Endings; Nitric Oxide; novel; novel therapeutics; Operative Surgical Procedures; Oral; particle; Pathology; Patients; phase 1 study; Phosphodiesterase Inhibitors; phosphodiesterase V; pressure; prevent; Procedures; Production; Publications; Publishing; Radical Prostatectomy; Refractory; response; Risk; Robotics; Safety; Signal Transduction; sildenafil; Smooth Muscle; Surgical complication; System; Systemic blood pressure; tadalafil; Techniques; Testing; Therapeutic; Time; Topical application; Viagra

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, orallyadministered phosphodiesterase 5 inhibitors (PDE5i), fail to elicit an erectile response for amajority of patients suffering from ED as a result of RP (ED-RP). Alternative treatments are highlyinvasive and/or have poor efficacy and are typically not even attempted. For a man whoexperiences ED following RP, the trauma of back-to-back diagnoses (cancer and ED) has aprofound impact on quality-of-life, relationships, and well-being. There is, therefore, an urgentneed 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 impairsneuronal 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 ofneuronal 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 transdermalmicroparticle delivery system for NO (NO-MP) was able to elicit an erectile response whenadministered 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 foronset of the first erectile response was observed, and the number of erections was greater thantreatment with NO-MP alone.In Specific Aim 1 of Phase II, we will determine if the cooperativity in eliciting an erectile responseseen 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 theportfolio of potential commercial partners. In Specific Aim 2 we will initiate a GMP start-up programat Zylö Therapeutics and confirm that a demonstration batch is as effective in eliciting an erectileresponse as the small batch prep used in Specific Aim 1. Specific Aim 3 will establish themaximum tolerated dose (MTD) in dose-range-finding studies conducted in rats and minipigs inorder to inform the design of later IND-enabling toxicology studies. In addition, a dermal sensitivitystudy in guinea pigs and a dermal irritation study in rabbits will be conducted as part of the suiteof safety studies required by the FDA for topical products. Finally, in Specific Aim 4, a pre-INDmeeting will be held with the FDA to finalize remaining studies required for an IND application andinitiation of a Phase I clinical study.At the conclusion of these phase II studies, we expect to have: (i) confirmed that NO-MP iscooperative across the PDE5i class; (ii) generated a demonstration batch of NO-MP withconfirmed efficacy; (iii) conducted dermal toxicity studies to provide sensitivity and irritation dataand to establish the MTD; and (iv) consulted with the FDA regarding future development workduring a pre-IND meeting. Overall, we will be ready to initiate further toxicity studies in preparationfor an IND filing and a Phase I clinical trial.

Public Health Relevance Statement:
Narrative Virtually all men experience erectile dysfunction (ED) following radical prostatectomy (RP), yet standard treatment with first-line, orally administered phosphodiesterase 5 inhibitors (PDE5i) is ineffective, as these treatments are dependent on the production of nitric oxide (NO) from cavernous nerve (CN) endings. In Phase I, a novel topical microparticle delivery system for nitric oxide (NO-MP) was shown to elicit an erectile response in an animal model of RP (CN transection), both as monotherapy and in combination with 1/10th the human-equivalent dose of the leading PDE5i, sildenafil. The goal for Phase II is to (i) confirm that NO-MP is cooperative across the PDE5i class; (ii) generate a demonstration batch of NO-MP with confirmed efficacy; (iii) conduct dermal toxicity studies to generate sensitivity and irritation data and to establish the maximum tolerated dose; and (iv) consult with the FDA during a pre-IND meeting regarding future development work required to initiate a Phase I clinical trial.

Project Terms: