An estimated 347 million people worldwide have diabetes, including over 29.1 million Americans. A major cause of morbidity and hospitalization in patients with diabetes is diabetic foot ulceration (DFU), which can result in infection, amputation, prolonged hospitalization, and costly treatments. Diabetes treatments cost the American healthcare system ~$245 billion annually, representing 20% of the total healthcare expenditure; and DFU treatment consumes ~50% of these costs. Chronic diabetic wounds remain stalled in the initial inflammatory phase of wound healing and remain unresponsive to conventional treatments. Current treatment approaches tend to have limited to marginal efficacy and high cost. A large unmet need exists for safe, cost- effective therapeutics that are easily applied in the home care or clinical setting and conform to practice of medicine in DFU care without reducing efficacy. FirstString Research, Inc., a clinical stage biopharmaceutical company, is advancing the development of novel bioengineered peptides based on the C-terminus of connexin proteins; a protein with important roles in the wound healing process. Our lead peptide, aCT1 (25 amino acids) based on connexin43, has demonstrated a unique capability of switching the body's healing response from excessive inflammation and scarring to a healthy regenerative stage. With the assistance of SBIR/STTR grants and significant private funding, FirstString has developed aCT1 in a topical product called Granexin gel (Granexin); obtained IND approval; and demonstrated its mechanism of action, safety, and efficacy in a Phase 1 (N=48) and three Phase 2 clinical trials (N=276). Tissue injuries treated with Granexin show clinically and statistically significant faster healing, reduced inflammation, and improved mechanical properties without treatment related adverse events. FirstString has received Phase IIb SBIR funding to continue clinical development and evaluate the efficacy and safety of Granexin in a larger clinical trial currently underway. During the End of Phase 2 meeting, the FDA requested a 9-month repeat dose pig study as an integral part of Granexin's NDA (New Drug Approval) review process, in line with FDA's Guidance for Industry in the development and approval for chronic wound therapeutics.
The Specific Aim of this CRP SB1 project is to conduct a standard 39-week repeat dose GLP dermal toxicity study of Granexin gel in the Gttingen mini-pig followed by a 14-day recovery.
Sub aim 1 involves the assessment of the safety of repeat topical dosing of Granexin at low (100 ?M), medium (200 ?M), and high (500 ?M) concentrations, with appropriate controls, on skin wounds that will be rewounded every 15 days.
Sub aim 2 will involve the toxicokinetic analysis of aCT1 peptide and assessment of systemic exposure. This study is similar to our previously conducted 92-day repeat dose toxicity study in pigs. Successful completion of this aim will fill in a necessary gap in obtaining NDA approval for Granexin from the FDA and support the eventual market launch of Granexin for the treatment of DFUs.
Patients with diabetes have an underlying refractory wound healing phenotype. A major cause of morbidity and hospitalization is diabetic foot ulceration (DFU), which can significantly impair a patient's quality of life, result in infection, gangrene, amputations, and costly treatments that require prolonged hospitalization. FirstString Research has made significant clinical progress toward approval of its novel connexin-based peptide for DFUs with the help of SBIRs and private funding. In our effort to complete all FDA mandated studies to support Granexin approval, we need to conduct a 39-week GLP dermal toxicity study of Granexin gel in the Gttingen mini-pig followed by a 14-day recovery to satisfy FDA's recommendation consistent with the published FDA Guidance for Industry in the development and approval for chronic wound therapeutics. Successful completion of this aim will fill in a necessary gap in obtaining New Drug Approval for Granexin from the FDA and support the eventual market launch of Granexin for the treatment of DFUs.