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Sodium Deoxycholate for Submental Contouring

Shannon Humphrey, MD, FRCPC, FAAD1; Katie Beleznay, MD, FRCPC, FAAD1; Jean D. A. Carruthers MD, FRCSC, FRC (OPHTH), FASOPRS2
1Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
2Department of Ophthalmology and Visual Science, University of British Columbia, Vancouver, BC, Canada


Conflict of interest disclosure: Dr. Humphrey and Dr. Carruthers are investigators, speakers and consultants for Kythera Biopharmaceuticals and Allergan Inc.

ABSTRACT

The chin and jaw line are integral parts of an individual's aesthetic profile, and the presence of submental fat detracts from this and can lead to displeasure with one's facial appearance. While liposuction and cosmetic surgery are regarded as the gold standard in treating submental fat, surgical intervention is not appealing to all patients and has potential surgical complications including longer recovery, and contour irregularities. Despite ample advances in aesthetic medicine to enhance the appearance of the face, very little is available in non-invasive options to reduce submental fat that has been supported by robust evidence. ATX-101, a proprietary formulation of deoxycholic acid that is synthetically derived, has been extensively explored in a vigorous clinical development program that has established the safety and efficacy of the injectable. It has recently received approval by regulatory authorities in Canada (Belkyra™) and the US (Kybella®) for the treatment of submental fat.

Key Words: adipocytolysis, ATX-101, deoxycholic acid, injectable, nonsurgical, submental fat

Introduction

Desirable features of the face are thought to follow the "golden ratio" or Phi that is seen in natural formations.1,2 What is viewed as an attractive face in contemporary culture does not significantly differ from ancient times.3 Think of the bust of Egyptian queen Nefertiti. The ideal face appears as an inverted triangle that contains a wide mid-face that tapers toward the chin.4,5 A defined chin denotes assertiveness, credibility, and leadership.6 A face that has aesthetic balance is thought to feature a neck contour that is pleasing to the eye.7 Individuals who have submental fullness may be perceived as having an unattractive profile of the chin and may experience reduced satisfaction with their appearance which erodes their sense of well-being.8,9 The presence of submental fat superficially and deep to the platysma muscle is regarded as a sign of aging of the lower face,10,11 but there are individuals, both young and old, whose morphology involves a round face which includes deposits of submental fat. Still for others, a genetic predisposition produces undesired submental fat that detracts from their profile and remains even with weight loss and exercise.1,7

Surgery has been the mainstay to treat submental fullness, colloquially referred to as the "double chin".8 Complications from surgery however make it somewhat unappealing to patients.12 Indeed, alternatives to surgery would be well-received by both clinicians and patients.

Discussion

It was first observed in cell cultures and porcine skin that sodium deoxycholate, a bile salt that occurs in the body, acts as the active ingredient in an injectable phosphatidylcholine and sodium deoxycholate solution that treats the accumulation of localized fat through adipocytolysis.13 Other investigators later concluded that deoxycholic acid selectively targets fat tissue while sparing other tissues like skin and muscle in the local environment.14 The encouraging basic research has prompted Kythera Biopharmaceuticals, Inc. to develop a synthetic form of deoxycholic acid, with an aim to introduce a non-injectable therapy designed to contour the chin-neck area through decreasing submental fat.

The synthetic compound, known as ATX-101, is manufactured using a proprietary process, is indistinguishable from endogenous deoxycholic acid given it possesses an identical chemical structure, and does not contain any substances derived from humans or animals. Chemical compounding that produces phosphatidylcholine/sodium deoxycholate formulations is not a process that guarantees a consistent formulation15 while the proprietary manufacturing process to prepare synthetic deoxycholic acid does achieve this.

In-depth study and evaluation of deoxycholic acid for the purposes of decreasing submental fat began in 2007 with preclinical investigations to first assess the safety and side effect profile of the compound, followed by research to elucidate the pharmacokinetic, pharmacodynamic, and optimal dosing of deoxycholic acid in a clinical setting. Safety data has assured that the subcutaneous injection of 100 mg deoxycholic acid, given via 0.2-ml injections spaced at 1-cm intervals, sees a temporary rise in deoxycholic acid plasma levels, but no increase beyond the normal range of variability for endogenous deoxycholic acid, with a return to baseline levels by 24 hours post dose.16,17 Chief among the safety observations is that injection of synthetic deoxycholic acid does not result in elevations in lipids and adipokine concentrations that are clinically significant.17

The clinical development program associated with ATX-101 has enrolled more than 2,600 patients, of whom 1,600 patients have been treated with the synthetic compound. Investigators have witnessed fast absorption of the compound, as well as a decline in overall fat in the treated area. Where needed in clinical studies, anesthesia with topical lidocaine preparations together with ice were provided to patients and local lidocaine injections were performed in some cases.17

Histological data reinforce the proposed mechanism of action, adipocytolysis (Figure 1), for deoxycholic acid.18 Injections of the synthetic compound into abdominal fat were observed to result in fat lobule atrophy amongst other outcomes as well as near resolution of inflammation at 28 days, which determined the spacing of treatments of just under one month.18 The treatment schedule was assessed in phase III clinical trials. No histological effects were seen in the dermis or epidermis.18



Figure 1

Figure 1. Mechanism of action of deoxycholic acid. Subcutaneous administration causes the destruction of fat cells.
Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

Of note, submental fat was not decreased any further when the area-adjusted dose of deoxycholic acid was increased through administration of a stronger concentration, larger injection volume, or shorter intervals between injections.19,20 Self-reported scales, which denoted patient dissatisfaction with appearance, and clinician-reported scales, which reflect investigator evaluations of submental fat were employed to determine baseline appearance as it relates to the chin in randomized, double-blind, placebocontrolled, phase III clinical trials.21-25 In the two North American trials, magnetic resonance imaging (MRI) was also employed to assess a decrease in submental volume subsequent to deoxycholic acid injection where MRI images were interpreted in a blinded fashion.23,24 Post-treatment evaluations were conducted using patient-reported instruments to determine approval with facial appearance and appearance of the chin. Submental fat change and its psychological effect were also evaluated, and the adverse psychological impact of submental fat was diminished with deoxycholic acid injection. Assessments performed at 12 weeks after the last treatment showed that the synthetic compound decreased submental fat based on patient, clinician, and objective evaluations. In the North American phase III trials 68.2% of ATX-101 (2 mg/cm2) subjects demonstrated a simultaneous improvement of at least one grade from baseline on clinician and patient reported rating scales vs. 20.5% in placebo (p<0.001). The proportion of MRI responders was more than eight-fold greater with the compound than placebo in the REFINE-1 trial.21-24

While there are predefined maximum treatments based on phase III clinical data – four treatments based on European data and six treatments based on North American data – fewer treatments may be administered if efficacy is achieved earlier or if there are safety concerns. After two treatments, 52.2% of subjects achieved at least a one grade change from baseline in the clinician submental fat ratings, and 71.5% after four treatments21-24, endorsing the concept of tailored treatment of deoxycholic acid for each patient, taking into account factors such as individual anatomy and the fact the quantity of submental fat decreases over time with successive treatments. See Figures 2a and 2b for before and after images.23,24 Durability is another favorable property of deoxycholic acid therapy.24 Data bear out that the effect of treatment is sustained for up to 4 years after the last injection.24



Figure 2a

Figure 2a. REFINE-2 (ATX-101-11-23) study – unretouched photos of clinical trial patient taken before and after treatment with ATX-101.
Subject details: Age: 35, Sex: F, Number of treatment cycles: 4, Composite grade change: 1-grade, Total dose: 16.2 ml
CR-SMFRS = Clinician-Reported Submental Fat Rating Scale; PR-SMFRS = Patient-Reported Submental Fat Rating Scale
Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

Figure 2b

Figure 2b. REFINE-1 (ATX-101-11-22) study – unretouched photos of clinical trial patient taken before and after treatment with ATX-101.
Subject details: Age: 55, Sex: F, Number of treatment cycles: 5, Composite grade change: 1-grade, Total dose: 22.0 ml
Copyright 2015, Kythera Biopharmaceuticals, Inc., Used by permission. All rights reserved.

The majority of adverse events in the four phase III trials associated with deoxycholic acid injections were mild or moderate, and transient. Pain, swelling, bruising, numbness, erythema, and induration were some of the most frequent side effects and were linked to the treatment area, route of administration, the mechanism of action of the compound, and expected tissue response. With repeated treatments, the incidence and severity of pain and swelling declined.23 Serious adverse events were infrequent.23 One adverse event, albeit rare, that did differ between placebo-treated patients and deoxycholic acidtreated patients was marginal mandibular nerve (MMN) paresis, but most instances of MMN paresis were mild or moderate in severity, lasting a median duration of 47.5 days.23 No new signals related to safety have been detected in extended follow up.

Phase III clinical trials demonstrated no exacerbation of skin laxity, which is traditionally a worry when fat is extracted from a targeted zone. In actual fact, skin laxity remained the same or was improved in phase III clinical trials.21,24 It has been suggested the absence of exacerbation of skin laxity could be attributed to the phenomenon of neocollagenesis,18 which was observed in histologic samples after treatment with deoxycholic acid. Happily for patients, the data indicate procedures for skin tightening to address skin laxity are not necessary after submental fat decrease with deoxycholic acid therapy.

Conclusion

As a first-in-class injectable therapy, deoxycholic acid, was recently approved by Health Canada and the US Food and Drug Administration, as Belkyra™ and Kybella®, respectively, to treat submental fullness. It is not approved for use in other facial areas or sites on the body. As a minimally invasive treatment, it can be performed in the office, results are visible in two to four treatments, and recovery is relatively quick. Different from facial injectables like fillers and neuromodulators, maintenance treatments with deoxycholic acid are not required to sustain the effect over time or to reduce skin laxity. Clinicians should ensure sufficient submental fat is present to justify injection of deoxycholic acid. They should also be cautious to avoid injuring anatomic structures in the submental region when injecting the synthetic compound.

Acknowledgement

The authors wish to acknowledge Louise Gagnon for her editorial assistance in the preparation of this manuscript.

References

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  15. Gupta A, Lobocki C, Singh S, et al. Actions and comparative efficacy of phosphatidylcholine formulation and isolated sodium deoxycholate for different cell types. Aesthetic Plast Surg. 2009 May;33(3):346-52.
  16. Walker P, Fellmann J, Lizzul PF. A phase I safety and pharmacokinetic study of ATX-101: injectable, synthetic deoxycholic acid for submental contouring. J Drugs Dermatol. 2015 Mar;14(3):279-87.
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  19. KYTHERA Biopharmaceuticals, Inc. FDA briefing document, April 30, 2015.
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In this issue:

  1. Sodium Deoxycholate for Submental Contouring
  2. Rituximab: Uses in Dermatology
  3. Update on Drugs and Drug News - September-October 2016