Novel Approach to Fat Reduction: A Phase I Study Evaluating Safety and Tolerability of STP705 in Abdominoplasty

Abstract

Background: RNAi therapeutics are a rapidly developing technology with broad medical applications predicated on reducing the expression of genes with key links to disease pathogenesis. The TGF-β1/Smad3 and COX-2 signaling pathways are strongly implicated in obesity and type 2 diabetes. Reducing the expression of TGF-β1 and COX-2 may have benefits in fat reduction procedures. The aim of this study was to assess the safety and tolerability of STP705 (a TGF-β1/COX-2 siRNA complex in a polypeptide nanoparticle vehicle) injections in persons undergoing abdominoplasty. A secondary aim was to make initial histologic observations on the efficacy of STP705 injections in inducing adipocyte apoptosis for the purpose of focal fat reduction. Methods: The study treatment consisted of 3 rounds of treatment with 7 subcutaneous abdominal injections of STP705 or placebo. Eight female subjects aged 18-65 years received 120 μg, 240 μg, or 360 μg STP705 in 0.5 or 1.0 ml doses (per injection) or an equivalent amount of placebo injected randomly across seven 1 cm2 areas. Treatments were administered 28 days apart with follow-ups occurring at 2 and 7 days’ post-procedure. Tissue samples from each of the 7 injection sites were harvested from total abdominoplasty excisional specimens obtained 28 days after the final injection. Safety assessments were conducted, including physical examination, clinical laboratory tests, electrocardiograms, evaluation of local skin reactions (LSRs), and collection of adverse events (AEs). Lipolytic and inflammatory effects of STP705 were assessed by blinded histologic analysis of harvested tissue samples. Results: There were no clinically significant changes in clinical labs, vital signs, or ECGs. The incidence of LSRs was low throughout the study. There were 3 moderate AEs deemed likely to be related to STP705 injection; none required intervention, and all resolved without dose modification. Histology revealed marginally dose-dependent tissue response with adipocyte destruction and fat remodeling. Conclusion: In general, STP705 was well tolerated at all concentrations and volumes studied. STP705 demonstrated excellent safety, and initial histologic analysis is suggestive of its efficacy in adipocyte destruction. The lack of cutaneous side effects with STP705 injection is an advantage over current treatments for similar indications.