Phase II year
2015
(last award dollars: 2019)
Phase II Amount
$4,160,460
Cleft lip and palate (CLP) is the most common craniofacial congenital anomaly in the US. Since CLP can cause severe developmental, functional, aesthetic, and psychological difficulties if not corrected, it is the most frequently reported birth defect requiring surgery. Unfortunately, hypertrophic scar (HS) formation is a common complication of cleft lip repair surgery (8%-47% according to various studies) and often requires multiple surgical revisions. HS management in CLP repair is significantly more challenging than other scars due to: 1) lack of tissue (cleft); 2) excessive tension in the repaire cleft due to missing tissue, action of the perioral muscles, and head growth; and 3) higher expectations for aesthetics. Current treatments such as corticosteroids have undesirable side effects such as reduced wound strength and skin atrophy while radiation carries a risk of future malignancy. Therefore, there is a pressing need for alternative therapies to reduce HS formation especially in CLP repair. We previously identified fibromodulin (FMOD) as being critical for fetal scarless skin repair. Remarkably, FMOD protein application to adult wounds can decrease scarring without reducing wound tensile strength in multiple mammalian species including mouse, rat, and pig. In a technological innovation, we have developed a synthetic 40 amino acid FMOD peptide sequence, F06-C40, that exhibits similar efficacy as the 376 amino acid FMOD whole protein. F06-C40 can be produced much more rapidly, inexpensively, and with higher purity than FMOD protein. Like FMOD, F06-C40 significantly reduced scar without compromising wound strength in two separate pig models (Yorkshire pigs simulating normal human scar and red Duroc Pigs more closely simulating human HS). Importantly, at our recent pre- Investigational New Drug (IND) meeting, the Food and Drug Administration (FDA) clearly outlined the required safety studies before first-in-man F06-C40 clinical trials. The goal of this Fast-Track SBIR proposal is to perform these critical IND-enabling studies to accelerate bench to bedside translation of FMOD peptide-based therapy to minimize HS formation in CLP patients. The Phase I Milestone will be to establish an optimized F06-C40 dose ("testable product formulation") demonstrating significant efficacy (compared with control) in improved gross visual appearance, scar size reduction, and wound tensile strength maintenance. With the "testable product formulation" in hand, the Phase II Milestones will be to complete F06- C40 mode of action and FDA-required safety studies, establish quality control assays for F06-C40, and submit a well-supported IND application that is accepted by the FDA to initiate Clinical Phase I studies. Overall, this proposal will accomplish key regulatory, Chemistry, Manufacturing, Controls (CMC), and business objectives to expedite F06-C40 product commercialization. If successful, F06-C40-based therapy can significantly improve the quality of life of CLP patients suffering from HS and patients with HS from burns, surgery, or other trauma.
Public Health Relevance Statement: Public Health Relevance: Cleft lip and palate is the most common birth defect of the head, occurring at a rate of 79.1 per 100,000 live births in the US. Cleft lips are typically repaired during infancy, but hypertrophic or excessive scar formation is a common complication surgery. This excessive scarring often tethers or retards the growth of bone and soft tissues in the upper jaw/lip and leads to the need for extensive surgeries to correct both the bone and soft tissue deformities. This project seeks to develop an effective, novel peptide-based treatment to reduce scarring and improve the quality of life of cleft lip and palate patients suffering from excessive scar formation.
NIH Spending Category: Congenital Structural Anomalies; Dental/Oral and Craniofacial Disease; Pediatric; Pediatric Research Initiative
Project Terms: Adrenal Cortex Hormones; Adult; Adverse effects; Alternative Therapies; Amino Acid Sequence; Amino Acids; Animals; Apoptosis; Appearance; Atrophic condition of skin; base; bench to bedside; Biological Assay; Birth; Bone Tissue; Burn injury; Businesses; Bypass; Caucasians; Cells; Chemistry; Cicatrix; Cleaved cell; Cleft Lip; cleft lip and palate; Clinical; Clinical Trials; commercialization; comparative efficacy; Complication; Congenital Abnormality; congenital anomaly; craniofacial; cytotoxicity; Deformity; Development; Dose; Drug Evaluation; Drug Formulations; Esthetics; Evaluation Research; Exhibits; expectation; Extracellular Matrix; Family suidae; fetal; Fibroblasts; fibromodulin; Future; genotoxicity; Goals; Growth; Hand; Head; Health; Human; Hypertrophic Cicatrix; improved; In Vitro; in vitro Assay; in vivo; infancy; Intention; Investigational Drugs; Investigational New Drug Application; Jaw; Knock-out; Lip structure; Live Birth; Maintenance; Malignant Neoplasms; man; meetings; Methodology; migration; Modeling; Mus; Muscle; Myofibroblast; novel; Operative Surgical Procedures; Outcome Measure; palate repair; Patients; Peptides; Phase; phase 1 study; Postoperative Complications; Preparation; primary outcome; Production; protein aminoacid sequence; Proteins; psychologic; Quality Control; Quality of life; Radiation; Rattus; Regimen; repaired; Reporting; Risk; Safety; safety study; Second Look Surgery; Skin; Small Business Innovation Research Grant; soft tissue; technological innovation; Tensile Strength; Testing; Time; Tissues; Toxic effect; Toxicology; Translations; Trauma; Treatment outcome; United States Food and Drug Administration; Visual; wound; Wound Healing
