This Small Business Innovation Research (SBIR) Phase II project aims to develop the process and engineering controls necessary to scale up the manufacturing of a nitric-oxide-releasing active pharmaceutical ingredient (API). One of the applications is a wound-healing product for diabetic foot ulcers. This project will focus on 1) optimizing the process parameters required to scale production of a nitric-oxide-releasing API to reproducible 1 kg batches, and 2) implementing the analytical methodologies to meet the requirements of the Chemistry, Manufacturing and Control (CMC) sections of an Investigational New Drug (IND) application. The expected outcome is a manufacturing process capable of producing large batches of the API that are suitable for an IND submission of a wound-healing product for diabetic foot ulcers or other nitric-oxide-releasing drug.
The broader/commercial impacts of this project will be the potential to provide a new standard of care for the treatment of diabetic foot ulcers. Currently, there are no products that address both wound healing and infection in diabetic foot ulcers. Infection is particularly problematic in diabetic foot ulcers due to the lack of normal skin barrier function, long duration of wound exposure to the external environment (months to years), poor blood circulation to the extremities that limits the migration of inflammatory cells to the site of infection, and the recent understanding of biofilm formation which protects bacteria from topically applied antimicrobials and systemically administered antibiotics. Nitric-oxide-releasing wound-healing therapeutics have the potential of addressing both infection and healing in diabetic foot ulcers.
Description of Project The goal of this NSF-funded, SBIR Phase II and IIB project was to develop the process and engineering controls necessary to scale up the manufacture of the nitric oxide-releasing particle technology, Nitricil™, and to conduct the nonclinical toxicology work necessary to submit an Investigational New Drug (IND) application to the Food and Drug Administration (FDA). During the Phase I research period Novan overcame the main challenge of controlling the manufacturing process while moving toward reproducible, production scale quantities of its lead drug NVN1000. The research effort optimized critical process parameters, increased production capacity, improved cost efficiency, and implemented more environmental friendly manufacturing techniques by reducing waste output. The efforts of Phase II research were designed to increase knowledge on the process variables and provide new insights in controlling the quality of the final product. Following the manufacturing of pharmaceutical quantities of product in accordance with current Good Manufacturing Practices (cGMP), Novan proposed Phase IIB research to assess the safety and tolerability of NVN1000. Nitric oxide, a free radical gas naturally produced by the human body to help fight infections, has broad spectrum antimicrobial activity including the ability to combat drug resistant bacteria without the potential for breeding resistance. The scale up production of Novan’s nitric oxide-releasing drug candidate has the potential to provide a number of therapies for healthcare infections. Specifically for this project, Novan’s goal is to use its Nitricil platform technology to develop a topical treatment for diabetic foot ulcers (DFU) that is safe and effective. DFUs are particularly difficult chronic wounds to treat as the patient may have co-morbidities, and the long duration of the wounds may result in infections or osteomyelitis. It is estimated that 15% (2.82 million) of patients in the United States with diabetes develop foot ulcers, and 12-24% (338,000 to 677,000) of the patients with foot ulcers eventually require amputation. The average cost to heal a DFU in 2010 was $8,000, to heal an infected ulcer was $17,000, and to amputate a lower extremity was $45,000. The total cost for such amputations performed in the United States is estimated to be over $3.6 billion annually imparting a major burden on society and the healthcare system. A nitric oxide-releasing ointment encompassing the Nitricil™ technology developed under this program may be used to decrease the rate of infection and the need for systemic antibiotic use in patients with DFUs. The product has other key differentiators as a topical wound therapy including a low propensity for breeding microbial resistance and the ability to simultaneously promote wound healing from a single active agent. Future commercialization of this innovative wound healing product for the treatment of diabetic foot ulcers requires large-scale pharmaceutical production capabilities and clinical efficacy of Novan’s topical therapy that is superior to currently available bioactive and antimicrobial wound healing therapies. Significant Outcomes The Phase II and IIB project was highly successful. The Novan team expanded its understanding of key process parameters which led to optimization of the pilot scale production of the Company’s proprietary Nitricil technology. An innovative production process resulted in greater control over the quantity of nitric oxide storage on the active pharmaceutical ingredient, NVN1000. Novan successfully scaled up production of NVN1000 to larger scale pharmaceutical grade quantities (6.5 kg per batch) for clinical trials and implemented quality-by-design principles for manufacturing under cGMP conditions. Advanced development activities related to the supplement included a seminal nonclinical study – a 28-day, repeat-dose, GLP toxicology study in miniature swine with the NVN1000 Ointment formulation – required to submit an IND application to the FDA with the ointment formulation and treat wounds. The objective of the study was to evaluate the local tolerance and toxicokinetics of NVN1000 Ointment at multiple doses with and without Hydrogel following once daily topical administration over 10% TBSA in Göttingen miniature swine. Additionally, Novan used in-house bioanalytical methods to determine systemic exposure levels to NVN1000 by measuring systemic levels of methemoglobin, nitrate, and elemental silicon. Under the conditions of these studies, doses were identified for further clinical development that had no adverse macroscopic or microscopic findings and no, or very limited, systemic exposures to NVN1000. The successful completion of Phase II and Phase IIB research aims has positioned Novan to execute its regulatory strategy and transition a Nitricil™-based product into human trials.
