ATX-101, a Submental Contouring Injectable Drug for the Reduction of Submental Fat: A Pooled Analysis of Two Pivotal Phase 3 (REFINE-1 And REFINE-2) Multicenter, Double-Blind, Randomized, Placebo-Controlled Trials

 

Goals/Purpose: The submental region affects facial harmony, balance, and attractiveness and, therefore, is important for facial aesthetics. The submental profile is typically characterized by the distribution of pre- and postplatysmal fat as well as skin laxity and other anatomical features. An undesirable submental profile can negatively affect self-perception and can be influenced by multiple factors, including aging and genetics, and often cannot be changed by diet and exercise. Currently, no FDA-approved injectable drug is available to reduce submental fat (SMF). ATX-101 is an investigational first-in-class submental contouring injectable drug in late-stage clinical trials for the reduction of SMF.

ATX-101 is a proprietary formulation of a purified synthetic version of deoxycholic acid, which is a well characterized naturally occurring molecule that aids in the breakdown of dietary fat. When injected into subcutaneous fat, ATX-101 causes focal adipocytolysis, the destruction of adipocytes. The resulting expected local tissue response involves macrophages eliminating cell debris and lipids from the treatment area, and the recruitment of fibroblasts, which are believed to be responsible for neocollagenesis. The action of ATX-101 is attenuated by protein binding, making protein-poor fat more sensitive to its effects than protein-rich tissues such as skin, muscle, and blood vessels. Kinetically, its action on protein-poor fat is immediate. It is then rapidly cleared from the injection site, presumably bound by interstitial albumin. REFINE-1 and REFINE-2 were pivotal phase 3 studies conducted in the United States and Canada, which evaluated the efficacy and safety of 2 mg/cm² ATX-101 for the reduction of SMF. Each study met its a priori primary and secondary endpoints. A pooled analysis of REFINE-1 and REFINE-2 is reported here.

Methods/Technique: REFINE-1 and REFINE 2 were conducted in 70 centers in the United States and Canada. These double-blind, randomized, placebo-controlled studies enrolled 1022 subjects with moderate-to-severe SMF as rated by clinicians and subjects, of which 1019 were treated. Subjects were randomized (1:1) to receive subcutaneous injections of 2 mg/cm² ATX-101 or placebo into the SMF for up to 6 treatment sessions, approximately 28 days apart. Treatment considerations were based on the size and volume of the submental area. Primary and secondary efficacy endpoints were assessed 12 weeks after the last treatment. REFINE-1 and REFINE-2 had 2 primary composite efficacy endpoints: the proportion of subjects with simultaneous improvement of ≥2 grades and ≥1 grade from baseline, respectively, on 2 validated scales, the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and the Patient-Reported Submental Fat Rating Scale (PR-SMFRS). Secondary endpoints were changes from baseline (proportion of subjects with ≥10% reduction in volume) in a predefined section of the magnetic resonance imaging (MRI)-measured submental area and improvements from baseline on the validated Patient-Reported Submental Fat Impact Scale (PR-SMFIS). MRIs were performed on an a priori defined 449 of the enrolled 1022 subjects. Additional efficacy assessments included other patient-reported outcome measures such as subject satisfaction with treatment. Subjects were followed for up to 24 weeks after the last treatment. Adverse events (AEs) and changes from baseline in vital signs and laboratory values were recorded throughout the studies.

 

Results/Complications: Individually, REFINE-1 and REFINE-2 met their predefined primary and secondary efficacy endpoints. ATX-101 resulted in statistically significant reductions in SMF based on the CR-SMFRS and PR-SMFRS (p<.001) with 70.3% and 66.9% of ATX-101-treated subjects in REFINE-1 and REFINE-2, respectively, demonstrating a ≥1-grade improvement versus placebo (18.7% and 22.4%) and 13.4% and 18.7% demonstrating a ≥2-grade improvement versus placebo (0% and 3.2%) from baseline for the 2 composite primary efficacy endpoints (all p<.001). Subjects also achieved a statistically significant reduction in the volume of a predefined area of the submental region as measured through MRI (p<.001). Additionally, subjects treated with ATX-101 reported statistically significant improvements in the visual and psychologic impact of SMF using PR-SMFIS (p<.001), and reported satisfaction with treatment (p<.001). Most AEs with ATX-101 were transient, mild to moderate in severity, and primarily associated with the treatment area. Less than 4% of subjects discontinued the studies due to AEs. Data for this pooled analysis of efficacy and safety endpoints for REFINE-1 and REFINE-2 are being analyzed and will be reported at the time of presentation.

 

Conclusion: Current facial injectable products do not adequately address the submental region. ATX-101 is the first submental contouring injectable drug to be investigated for the reduction of SMF in a rigorous clinical development program that has enrolled more than 2500 subjects to date. Results from these 2 US/Canada phase 3 pivotal studies suggest that ATX-101 may address subjects' unmet need for a nonsurgical, injectable drug option to improve their submental profile, thereby enhancing overall facial harmony and balance and, in turn, leading to improvements in self-perception.

Support Statement:  Support was provided by KYTHERAŽ Biopharmaceuticals, Inc.

Figure: 45-year-old female REFINE-1 subject before (top, weight 156 lb) and 12 weeks after 6 treatment sessions with ATX-101 (bottom, weight 167 lb).