A Phase I Safety and Pharmacokinetic Study of ATX-101: Injectable, Synthetic Deoxycholic Acid for Submental Contouring
March 2015 | Volume 14 | Issue 3 | Original Article | 279 | Copyright © 2015
Patricia Walker MD PhD,a,b Jere Fellmann PhD,b and Paul F. Lizzul MD PhD MBA MPHb
aPrivate Practice, Carpinteria, CA
bClinical Department, Kythera Biopharmaceuticals, Inc., Westlake Village, CA
ATX-101 (deoxycholic acid [DCA] injection) is a proprietary formulation of pure synthetic DCA. When injected into subcutaneous fat, ATX-101 results in focal adipocytolysis, the targeted destruction of fat cells. ATX-101 is undergoing investigation as an injectable drug for contouring the submental area by reducing submental fat (SMF). The purpose of this study was to evaluate the safety and pharmacokinetics (PK) of the maximal therapeutic dose of ATX-101 (100 mg total dose). Following PK evaluation of endogenous DCA, subjects (N = 24) received subcutaneous injections of ATX-101 (2 mg/cm2, with or without 0.9% benzyl alcohol) into SMF; PK evaluation was repeated periodically over 24 hours. Endogenous DCA plasma concentrations measured prior to injection were highly variable within and between subjects. Similarly, following ATX-101 injection, DCA plasma concentrations were highly
variable, peaked rapidly, and returned to the range observed for endogenous values by 24 hours postdose. All subjects experienced at least 1 adverse event (AE). No death, serious AE, or AE-related discontinuations occurred. The majority of AEs were transient, associated with the area treated, and of mild or moderate severity. No clinically significant changes were reported for laboratory test results, vital signs, or Holter electrocardiograms postdosing. These data support the favorable safety and efficacy observations of ATX-101 as an injectable drug to reduce SMF.
J Drugs Dermatol. 2015;14(3):279-284.
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Accumulation of subcutaneous fat under the chin (submental fat; SMF) may result in unappealing submental convexity and fullness, negatively affecting an individual’s satisfaction with appearance and sense of well-being.1,2 Additionally, SMF accumulation and the resulting appearance of the submental area may adversely influence perceptions of overall facial attractiveness.3,4
Although surgical options for reducing SMF such as liposuction (with or without platysmaplasty) or “neck lift” (cervical rhytidectomy) are available to reduce SMF, currently, no approved pharmacologic treatment options are available to patients.2,5 Interest in nonsurgical options for addressing submental convexity and fullness, which have not been a primary focus in aesthetic medicine, is increasing.5,6 ATX-101 (deoxycholic acid [DCA] injection), an injectable drug currently under development by Kythera Biopharmaceuticals, Inc. (Westlake Village, CA), has the potential to address this unmet need, providing a nonsurgical and less invasive alternative for SMF reduction and submental contouring.
ATX-101 is a proprietary, potential first-in-class formulation of pure synthetic DCA, a well-characterized, tightly regulated endogenous secondary bile acid that emulsifies and solubilizes dietary fat.7,8 Both in vivo and in vitro studies show that DCA physically disrupts the cell membranes of adipocytes and causes adipocytolysis, the targeted destruction of fat cells, when it is injected into subcutaneous fat tissue.9-11 This, in turn, elicits an expected tissue response, characterized by mild and local inflammation, including the attraction of macrophages to the area to clear cellular debris and lipids, which are then eliminated through natural processes.11,12 The cytolytic activity of DCA is attenuated by albumin and tissue-associated protein; therefore, when injected into subcutaneous fat tissue (protein poor) nearby, relatively protein-rich tissues such as skin and muscle are largely unaffected by ATX-101, which may contribute to enhanced product safety.11
Two nearly identical formulations of ATX-101 have been used during its clinical development globally, benzyl alcohol (BA)-preserved and BA-free. The objectives of this trial were (1) to evaluate the safety and tolerability of subcutaneous injections of these formulations of ATX-101 into SMF and (2) to characterize the pharmacokinetic (PK) profile of plasma DCA concentrations prior to and following subcutaneous injections of these formulations of ATX-101 into the submental area.
MATERIALS AND METHODS
Study Design and Subjects
This study was conducted in compliance with the International Conference on Harmonisation Guidelines for Good Clinical