(WHS-L2.03) PRECLINICAL AND CLINICAL DEVELOPMENT OF SLI-F06, A NOVEL DERMAL FIBROBLAST MODULATING DRUG, IN CUTANEOUS WOUND HEALING
Thursday, May 16, 2024
10:30 AM – 11:30 AM East Coast USA Time
SLI-F06, a fibromodulin (FMOD)-based peptide, enhances wound healing. In comprehensive animal models, including mice, rats, and Yorkshire pigs (a gold standard for normal human wound healing), SLI-F06 exhibited FMOD's pro-migration, pro-tensile strength, and anti-fibrotic properties. Here, red Duroc pigs, which more closely mimic human hypertrophic scarring, were wounded to further assess the translational potential of SLI-F06 to humans. Large ellipses were designed to create excessive-mechanical-loading (EML) to represent a high-tension wound relative. Primary closed wound edges were immediately injected with 10 mg/ml SLI-F06 or triamcinolone acetonide (TAC), a commonly used corticosteroid for repressing scar. At 8 weeks, TAC did not considerably improve gross scar appearance or reduce scar size, while it significantly reduced scar tensile strength. Meanwhile, SLI-F06 markedly improved visual scar appearance (P < 0.0001; N =12) and significantly reduced scar size, especially in the EML wounds (resulting in 56% Scar Index reduction; P = 0.0024; N = 5). More importantly, SLI-F06 resulted in a 29% and 160% tensile strength increase in the normal (P = 0.0066; N =6) and EML wounds (P < 0.0001; N = 6), respectively. Nonclinical safety studies include a 5-day and a 28-day intravenous bolus repeat-dosing in rats, a 5-day subcutaneous repeat-dosing in pigs, and a 3-day intradermal repeat-dosing in a wounded pigs. All toxicology studies demonstrated no observable adverse effects at maximum feasible doses. Ames and Episkin testing have shown no genotoxicity or local irritation, respectively. After FDA clearance, we performed a multicenter, double-blind, First-in-Man study to compare the safety of the cGMP-compliant SLI-F06 drug product to control formulation buffer (vehicle). Twenty-four (24) subjects were enrolled and 21 completed the study. Each subject served as his or her own control. The study was divided into 2 parts: Part A was a safety and proof-of-concept study of small scars pre-abdominoplasty, and Part B was a phase IIa study of post-abdominoplasty scars. There were no drug-related adverse events or clinically meaningful abnormal laboratory values, and all subjects were negative for antidrug antibodies in immunogenicity testing. Moreover, the POSAS assessment indicated that the non-optimized, low-dose, one-time injection of SLI-F06 led to a 24.6% Surface Area improvement at the high-tension abdominoplasty wound segments (P = 0.0405; N = 42). Therefore, SLI-F06 shows promising preliminary efficacy in minimizing cutaneous scarring and excellent tolerability in human subjects, while further refinement of dosage and treatment regimens are essential for optimal results.