ATX-101 (Deoxycholic Acid Injection) For Reduction of Submental Fat

Expert Review of Clinical Pharmacology
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20
ATX-101 (deoxycholic acid injection) for reduction

of submental fat
Benjamin Ascher, Jere Fellmann & Gary Monheit
To cite this article: Benjamin Ascher, Jere Fellmann & Gary Monheit (2016): ATX-101
(deoxycholic acid injection) for reduction of submental fat, Expert Review of Clinical
Pharmacology, DOI: 10.1080/17512433.2016.1215911
To link to this article: http://dx.doi.org/10.1080/17512433.2016.1215911
Accepted author version posted online: 26

Jul 2016.
Published online: 26 Jul 2016.
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Download by: [Weill Cornell Medical College] Date: 28 July 2016, At: 19:14
Publisher: Taylor & Francis
Journal: Expert Review of Clinical Pharmacology
DOI: 10.1080/17512433.2016.1215911
Drug Profile
ATX-101 (deoxycholic acid injection) for reduction of submental fat
Benjamin Ascher*1, Jere Fellmann†2 and Gary Monheit3

Downloaded by [Weill Cornell Medical College] at 19:14 28 July 2016
1
Clinic of Aesthetic Surgery IENA, 11 Rue Fresnel, 75116 Paris, France; 2Kythera
Biopharmaceuticals, Inc., 30930 Russell Ranch Road, Third Floor, Westlake Village, CA 91362,
USA (an affiliate of Allergan plc, Dublin, Ireland); 3Private Practice (Total Skin & Beauty
Dermatology Center, P.C.) and Department of Dermatology, Department of Ophthalmology,
University of Alabama at Birmingham, 2100 16th Avenue South, Suite 202, Birmingham, AL
35205, USA
*Author for correspondence:
Benjamin Ascher
11 Rue Fresnel
75116 Paris, France
T: +33 (0) 1 40 70 00 33
F: +33 (0) 1 40 70 92 40
E: benjaminascher@wanadoo.fr
†
former employee of Kythera Biopharmaceuticals, Inc.
1
Abstract
Introduction: The shape and contour of the chin and neck play an important role in facial
aesthetics. As such, excess fat within the submental area (double chin) can negatively affect
facial aesthetics and body image. Common treatments for submental contouring include invasive
procedures such as surgical rejuvenation and targeted liposuction. Energy devices (lasers,
radiofrequency, and ultrasound) may be used to improve submental skin laxity while
cryolipolysis was recently cleared in the United States for use in the submental area. However,
ATX-101 (deoxycholic acid injection) is the only injectable drug approved in the United States
and Canada for reduction of submental fat.
Areas Covered: The efficacy and safety of ATX-101 have been extensively evaluated in a global
clinical development program including multiple Phase I/II studies and four large Phase III trials.
Available data from ATX-101 trials are reviewed.
Expert Review: Injectables have been well established for facial rejuvenation. Extending
injectable treatment into the chin and neck is a major advance for nonsurgical cosmetic
correction. Overall, the evidence supports ATX-101 as a safe and effective, minimally invasive
treatment alternative for reduction of submental fat that will provide a major tool for the
aesthetic physician.
Keywords: adipocyte lysis; ATX-101; deoxycholic acid; efficacy; facial aesthetics; injectable;
nonsurgical; safety; submental fat
2
1. Introduction
The ideal shape of the youthful female face has been described as an upside-down triangle with a
full and wide mid-face narrowing towards the chin [1]. In addition, the shape and contour of the
chin and neck play an important role in facial aesthetics [2-4]. Furthermore, a strong chin has
been associated with self-confidence, authority, and trustworthiness [5], whereas submental
convexity or fullness can make an individual appear overweight and older. One common cause
of submental fullness is the accumulation of submental fat (SMF) which often presents as a
double chin [6,7]. Although weight gain secondary to diet and lifestyle can contribute to the
accumulation of SMF [8,9], aging [8,10,11] and genetics [8,9] play a major role. For some
individuals (both males and females), fat deposited in the submental area is disproportionate with
their overall fat profile and diet and exercise are not sufficient to reduce SMF in these individuals
[3,9]. According to data from a blinded online consumer survey conducted by the American
Society for Dermatologic Surgery in 2015, 67% of the 7315 respondents indicated that they were
somewhat to extremely bothered by excess fat under their chin/neck [12]. In addition, the number
of chin augmentation procedures increased by 71% between 2010 and 2011 based on statistics
from the American Society of Plastic Surgeons [13]. In combination, these data highlight an
increasing focus on the submental area among patients as well as within the field of facial
aesthetics. As such, a pharmacologic treatment for submental contouring may be of interest to
the population currently dissatisfied with their submental profile.
The neck is divided by the sternocleidomastoid muscle into the anterior and posterior
triangles with the submental area being part of the anterior triangle [14]. Within the submental
area, fat is separated into two distinct compartments by the platysma which is composed of two
broad muscles located on either side of the neck [15]. Preplatysmal (supraplatysmal) fat is
3
located between the dermis and platysma, while postplatysmal (subplatysmal) fat is located
between the platysma and submental musculature [16]. The overall distribution of SMF between
the preplatysmal and postplatysmal fat compartments has been investigated via cadaver
dissection studies [16,17]. Renaut and colleagues found that, on average, approximately 70% of
SMF was contained within the preplatysmal fat compartment (mean, 8.4 g [vs 3.7 g within the
postplatysmal fat compartment]) [17]. However, the distribution of SMF was closer to 50%
preplatysmal: 50% postplatysmal in 15% of their samples (n = 3/20) [17], suggesting variability
among individuals. Larson et al. also found variability in the distribution of SMF between the
preplatysmal and postplatysmal fat compartments in their study [16]. It is worth noting that both
the Renaut and Larson studies evaluated a small number of cadavers (20 and 10, respectively)
[16,17]. Therefore, it is difficult to draw conclusions about the distribution of SMF between the
preplatysmal and postplatysmal fat compartments in the general population from these limited
data.
Current treatment options for submental contouring often target preplatysmal fat (as
extensive removal of postplatysmal fat can result in a concave and distorted neck shape [4,18])
and include invasive procedures such as surgical rejuvenation [2,4,18-21] and targeted
liposuction [2,19,21-23]. Although energy devices (lasers, radiofrequency, and ultrasound) offer
a noninvasive option for submental contouring [24-26], these treatments focus on tightening the
skin within the submental area versus reducing SMF. Cryolipolysis was recently cleared in the
United States for use in the submental area (using the CoolMini™ applicator; Zeltiq Aesthetics,
Inc., Pleasanton, CA, USA) and may offer a less invasive alternative to surgery or liposuction for
reduction of SMF [27]. Injectable therapy with phosphatidylcholine/deoxycholate also offers a
less invasive option for reduction of SMF [28,29]; however, these products are produced by
4
chemical compounding and are not regulated by the US Food and Drug Administration (FDA)
[30], Health Canada, or the CE commission. In contrast, ATX-101 (deoxycholic acid [DCA])
injection; KYBELLA® in the United States and BELKYRA™ in Canada; Kythera
Biopharmaceuticals, Inc., Westlake Village, CA, USA [an affiliate of Allergan plc, Dublin,
Ireland]) is the first injectable drug approved by the FDA and Health Canada for improvement in
the appearance of moderate to severe convexity or fullness associated with SMF [31].
2. Background on ATX-101
Since 2007, ATX-101 has been the focus of an extensive preclinical and clinical development
program that has enrolled more than 2500 subjects worldwide, of whom, more than 1600 have
been treated with ATX-101. One of the initial insights leading to development of ATX-101 for
reduction of SMF was generated by Rotunda and colleagues, who identified DCA as the active
adipocytolytic ingredient in compounded phosphatidylcholine/sodium deoxycholate [32]. Using
cell viability and cell membrane lysis assays, significant cell death, membrane lysis, and
disruption of fat architecture was observed in human keratinocyte cell cultures and porcine tissue
samples treated with isolated sodium deoxycholate. Furthermore, the adipocyte cytolytic effects
observed with isolated sodium deoxycholate were comparable to those observed with a
phosphatidylcholine/sodium deoxycholate formulation in clinical use for reduction of localized
fat deposits (5.0% phosphatidylcholine, 4.75% sodium deoxycholate, 0.9% benzyl alcohol [BA])
[32]. Subsequent in vitro studies (using primary human subcutaneous adipocytes and human
dermal fibroblasts) and in vivo studies (using genetically obese mice) conducted by Thuangtong
et al. demonstrated that protein-poor tissue (e.g., fat) is more sensitive to the cytolytic effects of
deoxycholate while protein-rich tissue (e.g., muscle and skin) is largely unaffected [33].
5
Although deoxycholate had initially been used as an emulsifier for phosphatidylcholine, these
findings suggested that sodium deoxycholate was the primary mediator of adipocyte lysis in
compounded phosphatidylcholine/sodium deoxycholate and led to the development of ATX-101,
a proprietary formulation containing pure synthetic DCA.
3. Chemistry and manufacturing of ATX-101
FIGURE 1 shows the chemical structure of DCA. Endogenous DCA is a secondary bile acid
produced in the intestine [34]. The active ingredient (DCA) in ATX-101 is manufactured via a
proprietary process that creates a synthetic compound identical in chemical structure to
endogenous DCA and without human- or animal-derived contaminants. ATX-101 (DCA
injection) is produced according to current Good Manufacturing Practice (cGMP) regulations in
facilities approved for manufacture of parenteral pharmaceuticals [35]. This manufacturing
process ensures a consistent formulation of DCA, which is in contrast to formulations produced
by chemical compounding of phosphatidylcholine and sodium deoxycholate. Although sodium
deoxycholate has been used in globally approved drug products for decades as either a
solubilizing excipient, such as in Lipostabil® (phosphatidylcholine [Nattermann & Cie [GmbH]
and Aventis Pharma]) [36] and Fungizone® (amphotericin B [Bristol-Myers Squibb Canada,
Montreal, Canada]) [37], or to disrupt the virus during manufacturing of influenza vaccines, such
as Fluarix® (GlaxoSmithKline Australia Pty Ltd, Abbotsford, Victoria, Australia) [38], Fluviral®
(GlaxoSmithKline Inc., Mississauga, Ontario, Canada) [39], and Arepanrix® (GlaxoSmithKline
Inc., Mississauga, Ontario, Canada) [40], ATX-101 is the first formulation of pure synthetic
DCA produced under cGMP regulations and whose safety and efficacy have been thoroughly
evaluated in well-designed and controlled clinical trials. ATX-101 is supplied in ready-to-use,
6
single-use vials containing 10 mg/mL DCA in phosphate-buffered saline with 0.9% BA as a
preservative [31].
4. Mechanism of action of ATX-101 for reduction of submental fat
As mentioned, endogenous DCA is a secondary bile acid that serves to emulsify and solubilize
dietary fat, thereby aiding in its breakdown and absorption within the gastrointestinal tract [34].
The initial mechanism of action proposed for ATX-101 was that administration of exogenous
DCA to subcutaneous fat (adipose tissue) within the submental area would lead to adipocyte
lysis, the targeted destruction of fat cells, and ultimately a reduction in SMF. Deoxycholic acid
has been shown to mediate adipocyte lysis via disruption of the cell membrane leading to cell
death [32,33]. As DCA destroys adipocytes, administration of exogenous DCA would be
expected to result in a reduction in the overall number of adipocytes within the treatment area
(preplatysmal fat) and a durable treatment response over time. Support for this proposed
mechanism of action was provided by a Phase I clinical study (ClinicalTrials.gov identifier,
NCT00835952) that evaluated the histological effect of ATX-101 (TABLE 1) [41-43].
In this open-label study, a BA-preserved formulation of ATX-101 was administered
subcutaneously into the abdominal fat of healthy subjects (n = 14) aged 25 to 65 years who were
planning to undergo abdominoplasty and had 3 to 6 cm (thickness) of abdominal fat for excision
[40-42]. The abdominal fat was divided into predefined segments and subjects were assigned to
one of two ATX-101 dosing groups: group 1 received two injections per segment administered at
least 1.5 cm apart while group 2 received four injections per segment administered in a grid
pattern. Varying concentrations of ATX-101 (1, 2, 4, and 8 mg/cm2) were administered to each
subject. At 1, 3, 7, or 28 days post ATX-101 administration, abdominoplasty was performed with
7
the resected abdominal fat preserved for histology. Tissue samples were stained with
hematoxylin and eosin (for cellular, vascular, and inflammation assessment) and Masson’s
trichrome stain (for collagen assessment) [41-43].
Consistent with the proposed mechanism of action for ATX-101, adipocyte lysis was
noted as early as 1 day post ATX-101 administration, and was followed by local tissue response
and septal thickening [41-43]. Neutrophilic infiltration was observed on days 1 and 3, with lipid-
laden macrophages and mild septal inflammation of the adipocyte layer noted on day 7. By day
28, inflammation was nearly resolved while neovascularization, thickening of fibrous septae
indicative of collagen production (neocollagenesis), and fat lobule atrophy were noted. The
effects of ATX-101 were dose dependent and confined to the subcutaneous fat layer across all
doses evaluated with no changes observed in either the dermis or epidermis [41-43]. Overall, the
results of this study supported the proposed mechanism of action of ATX-101 for reduction of
localized fat and established the 28-day interval between ATX-101 treatment sessions used in the
Phase II/III clinical trials [31].
5. Pharmacokinetics and pharmacodynamics of ATX-101
Exogenous DCA, administered as ATX-101, is indistinguishable from endogenous DCA.
Therefore, the elimination of exogenous DCA from the systemic circulation and its metabolic
fate are expected to be identical to that for endogenous DCA. In mammals, the biosynthetic and
elimination pathways of endogenous DCA are well known [34,44-52]. Endogenous DCA is
secreted into the gastrointestinal tract where it aids in digestion. The majority of endogenous
DCA is resorbed within the small intestine and recycled via the enterohepatic circulation while a
minor portion is eliminated without modification (primarily via feces). A tissue distribution
8
study conducted in Sprague-Dawley rats found that [3H]-labeled ATX-101 was primarily
associated with the small intestine and liver following subcutaneous administration suggesting
exogenous DCA is recycled via the enterohepatic circulation similar to endogenous DCA [53].
The pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of ATX-101
were extensively characterized in Phase I clinical studies (summarized in TABLE 1). Across all
three Phase I studies, substantial variability in the plasma concentration of endogenous DCA was
noted at baseline which is consistent with previous reports in the literature [54-56]. This
variability was maintained following ATX-101 administration, though often not as marked as at
baseline.
A Phase I clinical study (NCT00618709) investigated the PK profile of a single dose of
the BA-preserved formulation of ATX-101 when injected subcutaneously into the SMF of
healthy subjects [53]. In this study, four doses of ATX-101 were evaluated (24 mg [n = 3], 48
mg [n = 3], 96 mg [n = 9], and 192 mg [n = 9] total dose). Across all subjects, ATX-101 was
administered via multiple injections using a grid; however, the number and volume of injections
varied by subject. By varying the drug concentration, injection volume, and injection spacing,
the area-adjusted dose of ATX-101 was varied from 1 to 8 mg/cm2 [57].
Following ATX-101 administration, the mean maximum plasma concentration (Cmax) of
DCA increased in a dose-dependent manner (490, 563, 734, and 975 ng/mL for the 24, 48, 96,
and 192-mg doses of ATX-101, respectively, vs 292 ng/mL at baseline) [57]. Across all doses,
ATX-101 was rapidly absorbed with a median time to Cmax (tmax) of 0.4 hours. Furthermore,
plasma concentrations of DCA returned to baseline levels by 12 hours post ATX-101
administration with the 24- and 48-mg doses and by 24 hours post ATX-101 administration with
the 96- and 192-mg doses [57]. Overall, the results from this study indicated the PK profile for
9
ATX-101 was linear at lower doses and nonlinear at higher doses. In addition, the PK profile was
similar for each treatment paradigm regardless of the number and volume of injections
administered.
In another Phase I clinical study (NCT01632917), the PK profile of a single dose of two
formulations of ATX-101 (BA-preserved and BA-free) were evaluated [58]. Both formulations
were injected subcutaneously into the SMF of healthy subjects aged 18 to 65 years. Subjects
were randomized 1:1 to either BA-preserved ATX-101 (n = 12) or BA-free ATX-101 (n = 12).
Both formulations of ATX-101 were administered via 0.2-mL injections spaced 1 cm apart (2
mg/cm2) using a grid for a total dose of 100 mg. The formulations evaluated in this study were to
be the marketed formulations and the dose studied (100 mg) was the proposed maximum clinical
dose. The mean Cmax of DCA was 324 ± 182 ng/mL at baseline and 1024 ± 304 ng/mL after
administration of the BA-preserved ATX-101 formulation. The Cmax of DCA was lower post
administration of BA-preserved ATX-101 in some subjects compared with baseline plasma
concentrations of DCA in other subjects, underscoring the inherent variability in plasma
concentrations of DCA among individuals. The BA-preserved ATX-101 formulation was rapidly
absorbed with a median tmax of 0.3 (range, 0.1–1.1) hours. Plasma concentrations of DCA
returned to baseline levels by 24 hours post administration of BA-preserved ATX-101. Overall,
the PK results for the BA-free ATX-101 formulation were comparable to those reported above
for the BA-preserved formulation (mean Cmax, 441 ± 293 ng/mL [baseline] vs 1036 ± 254 ng/mL
[post ATX-101 administration]; median tmax, 0.1 [range, 0.1–16.0] hours) [58], suggesting that
the addition of BA as a preservative has no effect on the overall PK profile of ATX-101. In
addition, routine cardiovascular monitoring showed no clinically meaningful change in heart
10
rate, assessed using a Holter monitor, following administration of either ATX-101 formulation
[58].
In another Phase I clinical study (NCT01319916), a single dose of ATX-101 was injected
subcutaneously into the abdominal fat of healthy subjects aged 18 to 65 years (n = 10) [59].
ATX-101 2 mg/cm2 was administered via 0.2-mL injections spaced 1 cm apart using a grid for a
total dose of 100 mg. At baseline, the mean plasma concentration of DCA was 249 ± 161 ng/mL.
Following ATX-101 administration, the mean Cmax of DCA increased approximately 3.6-fold
(902 ± 153 ng/mL) but remained within the normal physiological range for endogenous DCA.
The median tmax of DCA was 0.75 (range, 0.25–1.50) hours. By 12 hours post ATX-101
administration, plasma concentrations of DCA returned to baseline levels [59]. Again, the
plasma concentration of DCA was lower following ATX-101 administration in some subjects
compared with baseline plasma concentrations in other subjects [59].
In addition, extensive assessment of plasma lipid concentrations was conducted in this
study. No clinically meaningful changes in total cholesterol (193 ± 30 mg/dL [baseline] vs 184 ±
26 mg/dL [post ATX-101 administration]), triglycerides (136 ± 55 mg/dL vs 153 ± 61 mg/dL,
respectively), or free fatty acids (0.74 ± 0.20 meq/L vs 0.86 ± 0.27 meq/L, respectively) were
noted following ATX-101 administration [59]. Rather, the changes observed in plasma lipid
concentrations after ATX-101 administration were similar to those expected after consumption
of a meal or snack. In addition, there were no clinically meaningful changes in the plasma
concentrations of various proinflammatory cytokines, including interleukin 15, tumor necrosis
factor , adiponectin, apolipoprotein B, insulin, leptin, and resistin, following ATX-101
administration [59].
11
6. Identification of the optimal safe and effective dose of ATX-101 for reduction of
submental fat
The Phase II clinical program for ATX-101 included dose-ranging studies that evaluated various
concentrations and injection volumes, different spacing of injections, and four and six maximum
treatment sessions with ATX-101 (summarized in TABLE 1). The first double-blind, placebo-
controlled Phase II clinical study (NCT00618722) evaluated the safety and efficacy of various
ATX-101 concentrations injected at a fixed volume and spacing [53,60]. Subjects aged 25 to 65
years who exhibited moderate or severe SMF were randomized 1:1:1:1 to receive one of three
dose strengths of ATX-101 (1 mg/cm2 [n = 20], 2 mg/cm2 [n = 20], or 4 mg/cm2 [n = 22]) or
placebo (n = 22). Study drug was administered by subcutaneous injection into the SMF of 0.2
mL at 1-cm intervals with up to 24 injections permitted per treatment session. Treatments were
administered every 28 ± 5 days for four treatments. Results from this clinical study demonstrated
that a 1 or 2 mg/cm2 concentration of ATX-101 was likely to be effective for reduction of SMF
and that a higher concentration (4 mg/cm2) did not appear to be warranted [53,60].
A second double-blind, placebo-controlled Phase II clinical study (NCT00618618)
evaluated the safety and efficacy of a fixed concentration of ATX-101 administered via different
injection volumes and spacing [53,60]. All subjects in the ATX-101 group received ATX-101 2
mg/cm2; however, the dose was increased locally by increasing the injection volume (from 0.2 to
0.4 mL) or reducing the spacing between injections (from 1.0 to 0.7 cm). In this study, subjects
aged 25 to 65 years who exhibited moderate or severe SMF were randomized to receive one of
three dosing paradigms of ATX-101 (0.2-mL injections/0.7-cm spacing [n = 24], 0.2-mL
injections/1.0-cm spacing [n = 13], or 0.4-mL injections/1.0-cm spacing [n = 20]) or placebo (n =
14). Treatments were administered every 28 ± 5 days for up to four treatments. Results indicated
12
that increasing the injection volume and decreasing the spacing between injections only slightly
improved the efficacy of ATX-101 for reducing SMF and was countered by more severe and/or
prolonged adverse events (AEs) [53,60].
Overall, the results from the two preceding Phase II clinical studies established the dosing
paradigm for ATX-101 as 0.2-mL injections spaced at 1.0-cm intervals. In combination with the
results from the Phase I clinical study that indicated inflammation was nearly resolved by 28
days post ATX-101 administration, the ATX-101 treatment paradigm was established as 0.2-mL
injections at 1.0-cm spacing with at least 28 days between treatment sessions. This treatment
paradigm was subsequently evaluated in a third Phase II clinical study.
A third double-blind, placebo-controlled Phase II clinical study (NCT01032889) was
conducted to evaluate the safety and efficacy of two doses of ATX-101 for reduction of SMF
[53,61]. Subjects aged 18 to 65 years who exhibited moderate or severe SMF were randomized
1:1:1 to receive one of two dose strengths of ATX-101 (1 mg/cm2 [n = 41] or 2 mg/cm2 [n = 43])
or placebo (n = 45). Study drug was administered by subcutaneous injection (0.2 mL per
injection) into the SMF at 1-cm intervals with up to 50 injections allowed per treatment session.
Treatments were administered every 28 ± 5 days with up to six treatments permitted [53,61].
In this study, the efficacy of ATX-101 for reducing SMF was evaluated by both the
investigator (using the validated 5-point Clinician-Reported Submental Fat Rating Scale [CR-
SMFRS]) and by the subject (using the validated 5-point Patient-Reported Submental Fat Rating
Scale [PR-SMFRS]). Details regarding the scales used to evaluate efficacy in the ATX-101
clinical trials are summarized in TABLE 2. In addition to investigator and subject assessment of
improvements in SMF, changes in the thickness and volume of SMF were independently
13
assessed via magnetic resonance imaging (MRI). The correlation between change from baseline
in SMF thickness as assessed by MRI versus calipers also was evaluated [53,61].
Both ATX-101 doses resulted in an improvement from baseline in SMF based on
investigator, subject, and MRI assessment at 12 weeks after last treatment [53,61]. As expected
(based on results from the Phase I dose-ranging study [57]), a dose-response relationship was
observed with the 2-mg/cm2 dose of ATX-101 associated with larger reductions in SMF
compared with the 1-mg/cm2 dose. At 12 weeks after last treatment, ATX-101 2 mg/cm2 resulted
in significantly greater improvements from baseline in SMF compared with placebo based on
CR-SMFRS (p < 0.01 vs placebo), PR-SMFRS (p < 0.05), and MRI (p < 0.01) [53,61]. Overall,
the results from the Phase II clinical studies helped identify the optimal dose concentration and
treatment paradigm for ATX-101 (2-mg/cm2 dose administered via 0.2-mL injections at 1-cm
spacing every 28 days for up to six treatments), which were subsequently evaluated in the Phase
III clinical trials conducted in the United States and Canada.
7. Efficacy of ATX-101 in Phase III clinical trials conducted in Europe
Based on results from Phase II studies (NCT00618722 and NCT00618618), two large
multicenter, double-blind, placebo-controlled Phase III clinical trials were initiated in Europe to
further evaluate the efficacy and safety of the 1- and 2-mg/cm2 dose strengths of the BA-free
formulation of ATX-101 (NCT01305577 and NCT01294644) [62,63]. As these clinical trials
were initiated before completion of the final Phase II clinical trial (NCT01032889), two
concentrations of ATX-101 were evaluated. The two European Phase III trials were identical in
study design with both enrolling subjects aged 18 to 65 years who had moderate or severe SMF
based on investigator assessment (i.e., grade of 2 or 3 on the CR-SMFRS) and were dissatisfied
14
with the appearance of their face and chin (i.e., score of 0–3 on the 7-point Subject Self-Rating
Scale [SSRS]; description provided in TABLE 2). Subjects were randomized 1:1:1 to ATX-101 1
mg/cm2, ATX-101 2 mg/cm2, or placebo. Study drug was administered subcutaneously into the
SMF via 0.2-mL injections spaced 1 cm apart to ensure even distribution. Subjects were eligible
to receive up to four treatments every 28 ± 5 days [62,63].
There were two co-primary efficacy endpoints in the European Phase III clinical trials:
the proportion of subjects who achieved a ≥1-grade improvement from baseline on the CR-
SMFRS (CR-1 response) and the proportion of subjects who were satisfied with the appearance
of their face and chin (i.e., achieved a score ≥4 based on the SSRS [SSRS response]). Secondary
efficacy endpoints included the proportion of subjects who achieved a ≥1-grade improvement
from baseline on the PR-SMFRS (PR-1 response), change from baseline in SMF thickness based
on caliper assessment, effect of treatment on the psychological impact of SMF using the Patient-
Reported Submental Fat Impact Scale (PR-SMFIS), and subject responses to the modified
Derriford Appearance Scale 24 (DAS 24) and Subject Global Questions (SGQ). All efficacy
endpoints were evaluated at 12 weeks after last treatment [62,63].
Demographic characteristics of subjects enrolled in the European Phase III clinical trials
are summarized in TABLE 3 [62,63]. Across both trials, the majority of subjects were white
(94%) and female (74%) with a mean age of 46 years and a mean body mass index of 26 kg/m2
[64]. In both European Phase III clinical trials, all primary and secondary endpoints were met,
supporting the efficacy of ATX-101 for reducing SMF (TABLE 4) [62,63]. ATX-101 treatment
was consistently associated with clinically meaningful SMF reduction based on outcome
measures assessed by the investigator and subject as well as by objective caliper assessment.
Subjects reported substantial and significant reductions in the psychological impact of SMF
15
based on the PR-SMFIS Total Scale Score (TSS). Overall, results from the European Phase III
clinical trials indicated that both the 1- and 2-mg/cm2 dose strengths of ATX-101 were effective
for reducing SMF compared with placebo (p values listed in TABLE 4); however, improvements
were greater with the 2-mg/cm2 dose.
8. Efficacy of ATX-101 in Phase III clinical trials conducted in the United States and
Canada
Based on results from a Phase II clinical study (NCT01032889), two large multicenter, double-
blind, placebo-controlled pivotal Phase III clinical trials were initiated in the United States and
Canada to evaluate the efficacy and safety of ATX-101 2 mg/cm2 (NCT01542034 [REFINE-1]
and NCT01546142 [REFINE-2]) [65,66]. The REFINE trials were identical in study design. In
addition, the REFINE trials were generally similar in study design to the Phase III clinical trials
conducted in Europe. However, a single dose strength (2 mg/cm2) of BA-preserved ATX-101
was evaluated in the REFINE trials (vs two dose strengths [1 and 2 mg/cm2] of BA-free ATX-
101 in the European trials) and subjects were eligible to receive up to six treatments (every 28 ±
5 days) in the REFINE trials (vs up to four treatments in the European trials). Although the
efficacy endpoints were slightly different in the REFINE trials compared with the European
trials, all endpoints focused on reductions in SMF at 12 weeks after last treatment.
In the REFINE trials, subjects were enrolled who were 18 to 65 years of age, had
moderate or severe SMF based on both investigator and subject assessment (i.e., grade of 2 or 3
on the CR-SMFRS and PR-SMFRS, respectively), and were dissatisfied with the appearance of
their face and chin. Subjects were randomized 1:1 to ATX-101 2 mg/cm2 or placebo. There were
two coprimary efficacy endpoints in the REFINE trials: the proportion of subjects who achieved
16
a ≥1-grade improvement from baseline on both the CR-SMFRS and PR-SMFRS (composite CR-
1/PR-1 response) and the proportion of subjects who achieved a ≥2-grade improvement from
baseline on both scales (composite CR-2/PR-2 response). Secondary efficacy endpoints included
the proportion of subjects who achieved a ≥10% reduction in SMF volume based on MRI
assessment (MRI response) and the effect of treatment on the psychological impact of SMF
based on the PR-SMFIS TSS. Additional efficacy endpoints included the proportion of subjects
who were satisfied with the appearance of their face and chin (SSRS responders), the change
from baseline in SMF thickness based on caliper assessment, and subject responses to SGQ. All
efficacy endpoints were evaluated at 12 weeks after last treatment [65,66].
Demographic characteristics of subjects enrolled in the REFINE trials are summarized in
TABLE 5 [65,66]. Across both trials, the majority of subjects were white and female. All primary,
secondary, and other efficacy endpoints were met in the REFINE trials with ATX-101 2 mg/cm2
demonstrating significant efficacy compared with placebo (p < 0.001 for all assessments listed in
TABLE 6) [65,66]. ATX-101 treatment was consistently associated with clinically meaningful
SMF reductions (both ≥1- and ≥2-grade improvements) based on assessment by the investigator
and subject as well as objective measures (MRI and calipers). Inclusion of the composite CR-
2/PR-2 response was a more stringent regulatory endpoint that was anticipated to have a low
placebo response. Most CR-1/PR-1 responders reported satisfaction with the appearance of their
face and chin, satisfaction with treatment, and reduction in the psychological impact of their
SMF, supporting the clinical meaningfulness of a 1-grade response [65]. In addition, ATX-101–
treated subjects were eight times more likely to have a MRI response than placebo-treated
subjects in both REFINE trials [65,66]. A representative example of an ATX-101–treated subject
from the REFINE-1 trial is shown in FIGURE 2. Furthermore, subjects treated with ATX-101 in
17
the REFINE trials reported substantial and significant reductions in the psychological impact of
their SMF [65,66].
Overall, the results from the REFINE trials demonstrated the efficacy of ATX-101 2
mg/cm2 for reducing SMF and improving the submental profile. The majority of ATX-101–
treated subjects in the REFINE trials achieved a CR-1 or PR-1 response within two to four
treatments. As significant improvements in SMF were achieved in fewer than six ATX-101
treatments (i.e., the maximum permitted in the Phase III REFINE trials), these results highlight
the importance of tailoring ATX-101 treatment (both number of injections/treatment session and
overall number of treatments) to each individual based on their specific submental anatomy and
treatment goals. The REFINE trials were novel in their use of MRI as an objective assessment to
support the reduction in SMF noted by both the investigator (using the CR-SMFRS) and subject
(using the PR-SMFRS). In addition, the results from the REFINE trials further confirmed the
efficacy of ATX-101 2 mg/cm2 as demonstrated in the European Phase III trials. In combination,
the results from the European and US/Canadian Phase III trials demonstrated that ATX-101 2
mg/cm2 significantly reduced SMF regardless of the presence or absence of BA as a
preservative.
9. Durability of response to ATX-101 treatment
Long-term follow-up of treatment responders from ATX-101 clinical trials has been conducted
to evaluate the durability of the ATX-101 treatment response [67]. Subjects from an open-label
Phase IIIb clinical trial who responded to treatment with ATX-101 2 mg/cm2 at the initial time
point (12 weeks after last treatment) were subsequently followed for 1 year to determine whether
the treatment effect was maintained. In the subset of subjects who were either CR-1 or PR-1
18
responders at 12 weeks after last treatment, 90.4% (113/125) and 80.7% (96/119) maintained a
CR-1 and PR-1 response, respectively, at 1 year after last treatment [67].
Subjects who were either CR-1 or PR-1 responders at 12 weeks after last treatment in the
two European Phase III clinical trials were followed for 2 years [66]. For subjects from the ATX-
101 2 mg/cm2 treatment group who achieved a CR-1 or PR-1 response at 12 weeks after last
treatment, 87.0% (47/54) maintained a CR-1 response and 90.7% (49/54) maintained a PR-1
response after 1 year. After 2 years, 87.0% (47/54) and 88.9% (48/54) maintained a CR-1 and
PR-1 response, respectively, supporting the durability of the response to ATX-101 treatment
[67]. Similarly, subjects who were CR-1 or PR-1 responders in the US/Canadian Phase III
REFINE trials were followed for 2 years after last treatment. Overall, 87.4% (76/87) of ATX-
101–treated responders maintained a CR-1 response and 95.4% (83/87) maintained a PR-1
response at 1 year after last treatment, while 90.4% (75/83) maintained a CR-1 response and
87.5% (77/88) maintained a PR-1 response at 2 years after last treatment [67].
Subjects who responded to ATX-101 treatment in three Phase II clinical studies are
currently being followed for up to 5 years after last treatment. In the Phase II studies, the ATX-
101 dose ranged from 1 to 4 mg/cm2. For the long-term follow-up analyses, data were pooled
across all ATX-101 doses with data currently available for up to 4 years after last treatment [67].
After 1 year, 94.0% (79/84) of ATX-101 treatment responders maintained a CR-1 response and
84.6% (33/39) maintained a PR-1 response. After 2 years, 89.3% (67/75) and 90.9% (30/33)
maintained a CR-1 and PR-1 response, respectively. After 3 and 4 years, 80.8% (63/78) and
89.1% (49/55), respectively, maintained a CR-1 response, and 81.8% (27/33) and 80.0% (20/25),
respectively, maintained a PR-1 response [67]. Overall, these data indicate that the initial
improvement in the submental profile achieved with ATX-101 treatment is maintained over
19
time. Furthermore, these data are consistent with the mechanism of action of ATX-101, which
would predict that adipocyte lysis results in a reduction in the overall number of adipocytes
within the submental area and a durable treatment effect. A steady-state population of adipocytes
likely remains within the submental area including stem cells following ATX-101 treatment.
10. Safety and tolerability of ATX-101 treatment in Phase III clinical trials
Across the four Phase III clinical trials, the majority of AEs that occurred in the ATX-101
treatment group were localized to the injection site. Injection site AEs reported in ≥10% of
subjects in the European and US/Canadian Phase III clinical trials are summarized in TABLES 7a
and 7b, respectively, and included pain, swelling/edema, hematoma (bruising), anesthesia
(numbness), erythema, induration, paresthesia, and nodule [62,63,65,66]. Overall, these AEs are
those expected based on the route of administration (subcutaneous injection) and mechanism of
action of ATX-101.
Most AEs were mild or moderate in severity, transient in nature, and resolved within the
28-day interval between treatment sessions without interventions. The incidence, severity, and
duration of the most common AEs (pain, swelling/edema, hematoma [bruising], and anesthesia
[numbness]) were generally highest after the first treatment session and decreased as treatment
continued. Adverse events of special interest including marginal mandibular nerve paresis
(which often presented as an asymmetric smile), superficial skin ulceration, and dysphagia
(which often presented as a sensation of swallowing deficiency related to the volume of injection
and post-treatment swelling/edema) were rare occurrences in the Phase III clinical trials; all AEs
resolved without sequelae [62,63,65,66]. Few serious AEs were reported and were equally
distributed between the ATX-101 and placebo groups with no trends noted [62,63,65,66]. In
20
addition, there were no clinically meaningful changes in vital signs, physical examination, or
laboratory tests as a result of ATX-101 treatment [62,63,65,66]. In spite of significant SMF
reductions in both the European and US/Canadian Phase III trials, submental skin laxity was
improved or unchanged in the majority of subjects, suggesting that the skin within the submental
area retracts as SMF is reduced during ATX-101 treatment.
Both marginal mandibular nerve paresis and superficial skin ulceration likely result from
improper injection technique, emphasizing the importance of adequate training and knowledge of
key anatomic landmarks within the submental area before ATX-101 administration. The
marginal mandibular nerve is a branch of the facial nerve [68]. At the antegonial notch (located
approximately 2 cm posterior to the corner of the mouth), the marginal mandibular nerve angles
upward and becomes more superficial to innervate the lip depressors [69]. Posterior to the facial
artery, the marginal mandibular nerve is typically found 1 to 2 cm below the mandibular border
[70] while anterior to the facial artery, the nerve is commonly located above the mandible [71].
Identification of the probable location of the marginal mandibular nerve is critical before
injecting ATX-101. To reduce the risk of nerve paresis, ATX-101 should not be injected superior
to the inferior border of the mandible or within a region defined by a 1.0- to 1.5-cm line below
the inferior border (from the angle of the mandible to mentum) [31]. In addition, the submental
area should be palpated to ensure the presence of sufficient preplatysmal fat before each
treatment session to avoid injection of ATX-101 into the platysma. ATX-101 should be injected
midway into the preplatysmal fat to avoid the risk of superficial skin ulceration resulting from
exposure of the dermis to ATX-101.
21
11. Expert commentary and five-year view
The scientific and clinical study of DCA and ATX-101 have taken over a decade for final
objective proof of efficacy and safety. The results were so overwhelming that the Dermatologic
and Ophthalmic Drugs Advisory Committee gave a 100% agreement to recommend approval of
ATX-101. Overall, the clinical development program for ATX-101 has been an exciting
evolution from experimental drug to well-developed treatment for reduction of SMF.
Injectables have been well established for facial treatment with both neuromodulators and
injectable facial fillers. Extending injectable treatment for cosmetic correction into the neck is a
major advance for nonsurgical cosmetic correction. Up to this point, only invasive surgical
modalities have been effective to correct SMF and contour the aging neck. The use of ATX-101
as an injectable adipocytolytic agent has resulted in removal of unwanted SMF and used
correctly can recontour the shape of the neck to deliver a more youthful and pleasing appearance.
ATX-101 represents a safe, nonaggressive treatment for reduction of SMF that will provide a
major tool for the aesthetic physician.
12. Conclusion
The submental area is a region of increasing focus among patients and within the field of facial
aesthetics. However, treatment options for submental contouring have been limited with invasive
procedures such as surgical rejuvenation and targeted liposuction being the standard of care. The
recent approval of ATX-101, a first-in-class injectable drug for reduction of SMF, offers a
minimally invasive treatment alternative for patients.
22
13. Key issues
 Excess submental fat (SMF), which commonly presents as a double chin, can negatively
affect facial aesthetics. Treatments for submental contouring primarily consist of invasive
procedures such as surgical rejuvenation and targeted liposuction.
 ATX-101 (deoxycholic acid [DCA] injection) is the only injectable drug approved in the
United States and Canada for improvement in the appearance of moderate to severe
convexity or fullness associated with SMF.

 The mechanism of action for reduction of SMF with ATX-101 treatment is that
administration of exogenous DCA to SMF leads to adipocyte lysis, the targeted destruction
of fat cells, and a reduction in localized fat content. Histological data support this mechanism
of action for ATX-101. In addition, as DCA destroys adipocytes, ATX-101 administration
would be expected to result in a reduction in the overall number of adipocytes within the
treatment area (i.e., preplatysmal fat) and a durable treatment response over time.
 Data from Phase I clinical studies support the rapid absorption of ATX-101 with plasma
concentrations of DCA returning to endogenous levels within 12 to 24 hours post
administration. As expected, plasma concentrations of DCA increased following ATX-101
administration; however, the increases were within the range of endogenous levels seen
across individual subjects. In addition, changes observed in plasma lipid concentrations
following ATX-101 administration were similar to changes expected after consumption of a
meal or snack.
 Data from Phase II and III dose-ranging clinical trials support ATX-101 2 mg/cm2 as the
optimal safe and effective dose strength for reduction of SMF.
23
 The efficacy and safety of ATX-101 2 mg/cm2 was evaluated in two large multicenter,
randomized, double-blind, placebo-controlled pivotal Phase III clinical trials conducted in the
United States and Canada (REFINE-1 and REFINE-2). In the REFINE trials, ATX-101
demonstrated significant and clinically meaningful efficacy compared with placebo based on
investigator, subject, and objective (magnetic resonance imaging and caliper) assessments.
 Across the four Phase III clinical trials, the majority of adverse events (AEs) reported in the
ATX-101 treatment group were localized to the injection site, mild or moderate in severity,
transient in nature, and resolved without sequelae. AEs of special interest, including marginal
mandibular nerve paresis, superficial skin ulceration, and dysphagia, as well as serious AEs,
were infrequently observed.
 The presence or absence of benzyl alcohol in the formulation has no effect on the clinical
pharmacokinetics or efficacy of ATX-101, with both formulation showing acceptable safety
profiles.
 Appropriate training on injection technique and key anatomic structures within the submental
area is critical to ensure that ATX-101 is administered safely and effectively.
Funding
This review was sponsored by Allergan plc, Dublin, Ireland.
Declaration of Interest
B Ascher was an investigator for Kythera Biopharmaceuticals, Inc.* J Fellmann is a former
employee of Kythera Biopharmaceuticals, Inc.* G Monheit was an advisor and investigator for
Kythera Biopharmaceuticals, Inc.* *An affiliate of Allergan plc, Dublin, Ireland. All authors met
the ICMJE authorship criteria. Neither honoraria nor payments were made for authorship.
24
Allergan was not involved in the development of the manuscript with the authors or the vendor.
Allergan had the opportunity to review the final version of the manuscript and provide
comments; however, the authors maintained complete control over the content of the paper.
Writing assistance was utilized in the production of this manuscript and performed by Karen
Stauffer, PhD, CMPP, of Evidence Scientific Solutions, Philadelphia, PA, USA, and funded by
Allergan plc, Dublin, Ireland.

Abbreviations
AE: adverse event
BA: benzyl alcohol
BMI: body mass index
cGMP: Current Good Manufacturing Practice
CR-1: ≥1-grade improvement from baseline on Clinician-Reported Submental Fat Rating Scale
CR-2: ≥2-grade improvement from baseline on Clinician-Reported Submental Fat Rating Scale
Cmax: maximum plasma concentration
CR-SMFRS: Clinician-Reported Submental Fat Rating Scale
DAS 24: Derriford Appearance Scale 24
DCA: deoxycholic acid
FDA: US Food and Drug Administration
MRI: magnetic resonance imaging
NA: not available
PD: pharmacodynamics
PK: pharmacokinetics
25
PR-1: ≥1-grade improvement from baseline on Patient-Reported Submental Fat Rating Scale
PR-2: ≥2-grade improvement from baseline on Patient-Reported Submental Fat Rating Scale
PR-SMFIS: Patient-Reported Submental Fat Impact Scale
PR-SMFRS: Patient-Reported Submental Fat Rating Scale
SD: standard deviation
SGQ: Subject Global Questions
SMF: submental fat

SMSLG: Submental Skin Laxity Grade
SSRS: Subject Self-Rating Scale
tmax: time to maximum plasma concentration
TSS: Total Scale Score
26
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severe submental fat.
64. McDiarmid J, Ruiz JB, Lee D, et al. Results from a pooled analysis of two European,
randomized, placebo-controlled, phase 3 studies of ATX-101 for the pharmacologic
reduction of excess submental fat. Aesthetic Plast Surg 2014;38:849–60.
65. Jones DH, Carruthers J, Joseph JH, et al. REFINE-1, a multicenter, randomized, double-
blind, placebo-controlled, phase 3 trial with ATX-101, an injectable drug for submental
fat reduction. Dermatol Surg 2016;42:38–49.
**Summarizes the results from a Phase III clinical trial of ATX-101 (REFINE-1)
conducted to support approval of ATX-101 in the United States and Canada. In addition
to further demonstrating that ATX-101 treatment reduces submental fat, reduces the
pyschological impact of submental fat, and improves the appearance, this clinical trial
used magnetic resonance imaging to objectively assess reduction in submental volume
following an injectable cosmetic treatment.
**66. Humphrey S, Sykes J, Kantor J, et al. ATX-101 for reduction of submental fat: a phase
III randomized controlled trial. J Am Acad Dermatol. In press.
Summarizes the results from a Phase III clinical trial of ATX-101 (REFINE-1)
conducted to support approval of ATX-101 in the United States and Canada. In
addition to further demonstrating that ATX-101 treatment reduces submental fat,
reduces the pyschological impact of submental fat, and improves the appearance,
this clinical trial used magnetic resonance imaging to objectively assess reduction in
submental volume following an injectable cosmetic treatment.
36
67. Bhatia AC, Dayan SH, Hoffmann K, et al. Reductions in submental fat achieved with
deoxycholic acid injection (ATX-101) are maintained over time: results from long-term,
follow-up studies. Presented at: Annual Meeting of the American Society for
Dermatologic Surgery; 15–18 October 2015; Chicago, IL.
68. Woltmann M, Faveri R, Sgrott EA. Anatomosurgical study of the marginal mandibular
branch of the facial nerve for submandibular surgical approach. Braz Dent J 2006;17:71–
4.
69. Allen S, Senglemann R. Nerve injury. In: Gloster HM, editor. Complications in
Cutaneous Surgery. Springer; New York, NY: 2008. p. 21–35.
70. Baker DC, Conley J. Avoiding facial nerve injuries in rhytidectomy. Anatomical
variations and pitfalls. Plast Reconstr Surg 1979;64:781–95.
71. Dingman RO, Grabb WC. Surgical anatomy of the mandibular ramus of the facial nerve
based on the dissection of 100 facial halves. Plast Reconstr Surg Transplant Bull
1962;29:266–72.
37
Table 1. Summary of Phase I and II ATX-101 clinical studies [41-43,53,58-61].
ATX-101
dosage Injection Number of
Phase Study design (total dose) site Enrollment criteria subjects Region Reference
I Multicenter, 1, 2, 4, and 8 Abdominal  Healthy subjects 14 US [41-43]
open-label mg/cm2 fat  25–65 years
 3-6 cm (thickness) of
abdominal fat
I Single-center, 1, 2, 4, or 8 SMF  Healthy subjects  24 mg (n = 3) US [53]
open-label, mg/cm2  SMF of at least moderate  48 mg (n = 3)
dose-escalation (24, 48, 96, or convexity  96 mg (n = 9)
192 mg)  192 mg (n = 9)
I Single-center, 2 mg/cm2 SMF  Healthy subjects  BA-preserved US [58]
open-label (100 mg)  18–65 years formulation (n =
 Sufficient SMF for ~50 12)
injections spaced 1 cm  BA-free
38
apart formulation (n =
12)
I Single-center, 2 mg/cm2 Abdominal  Healthy subjects 10 US [59]
open-label (100 mg) fat  18–65 years

II Multicenter, 1, 2, or 4 SMF  25–65 years  ATX-101 1 UK, [60]
randomized, mg/cm2  Moderate or severe SMF mg/cm2 (n = 20) Australi
double-blind,  No prior intervention for  ATX-101 2 a,
placebo- SMF reduction mg/cm2 (n = 20) Canada
controlled  ATX-101 2
mg/cm2 (n = 22)
 Placebo (n = 22)
II Multicenter, 2 or 4 mg/cm2 SMF  25–65 years  ATX-101 (4 UK, [60]
randomized,  Moderate or severe SMF mg/cm2/ 0.2 Australi
double-blind,  No prior intervention for mL/0.7 cm [n = a,
placebo- SMF reduction 24]) Canada
controlled  ATX-101 (2
39
mg/cm2/ 0.2
mL/1.0 cm [n =
13])
 ATX-101 (4
mg/cm2/ 0.4
mL/1.0 cm [n =
20])
Placebo (n = 14)
II Multicenter, 1 or 2 mg/cm2 SMF  18–65 years  ATX-101 1 US [61]
randomized,  Moderate or severe SMF mg/cm2 (n = 41)
double-blind,  No prior intervention for  ATX-101 2
placebo- SMF reduction mg/cm2 (n = 43)
controlled  Placebo (n = 45)
BA: benzyl alcohol; SMF: submental fat
40
Table 2. Scales used to evaluate the efficacy of ATX-101 in clinical trials [62,63,65,66].
Scale Description
CR-SMFRS*  Submental size evaluated by the clinician on a 5-point ordinal scale (0–4) with 0 = absent, 1 = mild, 2 =
moderate, 3 = severe, and 4 = extreme

 Photonumeric guide included to assist clinicians in applying the ratings (FIGURE 3)
PR-SMFRS*  Submental size evaluated by the subject on a 5-point ordinal scale (0–4) with 0 = no chin fat at all, 1 = a slight
amount of chin fat, 2 = a moderate amount of chin fat, 3 = a large amount of chin fat, and 4 = a very large
amount of chin fat
PR-SMFIS*  Psychological impact of SMF evaluated by the subject based on self-perception of 6 emotional and visual
characteristics related to the appearance of submental fullness (unhappy, bothered, self-conscious,
embarrassed, look older, and look overweight)
 Each item rated on an 11-point numeric scale (0–10). Scores for the 6 items were combined to generate a PR-
SMFIS Total Scale Score
Modified DAS  Psychological impact of SMF and perceived visual self-image evaluated by the subject (in the European Phase
24 III trials)
 Consisted of 24 questions related to the way a subject feels or acts in reference to their physical appearance in
41
general and to the appearance of their chin. In addition, pain and functional limitations were assessed
SSRS  Overall satisfaction with the appearance of face and chin evaluated by the subject on a 7-point scale (0–6) with
0 = extremely dissatisfied, 1 = dissatisfied, 2 = slightly dissatisfied, 3 = neither satisfied nor dissatisfied, 4 =
slightly satisfied, 5 = satisfied, and 6 = extremely satisfied

 A responder was a subject whose response was positive relative to the instrument’s neutral response option
(i.e., response of 4, 5, or 6)
SGQ  Fat under chin (SGQ #1) and definition between chin and neck (SGQ #2) compared with how they were
before treatment, and satisfaction with treatment (SGQ #3) evaluated by the subject
 Response options for SGQ #1 and #2: a great deal worse; moderately worse; a little worse; about the same; a
little better; moderately better; and a great deal better
 Response options for SGQ #3: extremely dissatisfied; moderately dissatisfied; a little dissatisfied; neither
dissatisfied or satisfied; a little satisfied; moderately satisfied; and extremely satisfied
 A responder was a subject whose response was one of the two highest positive categories
CR-SMFRS: Clinician-Reported Submental Fat Rating Scale; DAS 24: Derriford Appearance Scale 24; PR-SMFIS: Patient-Reported
Submental Fat Impact Scale; PR-SMFRS: Patient-Reported Submental Fat Rating Scale; SGQ: Subject Global Question; SMF:
submental fat; SSRS: Subject Self-Rating Scale.
42
Table 3. Demographic characteristics of subjects enrolled in the European Phase III ATX-101 clinical trials [62,63].
European Phase III – study 1 [63] European Phase III – study 2 [62]
ATX-101 ATX-101 ATX-101 ATX-101
1 mg/cm2 2 mg/cm2 Placebo 1 mg/cm2 2 mg/cm2 Placebo

N = 119 N = 121 N = 122 N = 121 N = 122 N = 117
Age, mean (SD), years 45.9 (10.96) 46.7 (9.78) 46.6 (10.17) 45.9 (10.21) 45.9 (9.95) 46.1 (9.50)
Female, % 79.8 78.5 71.3 75.4 72.1 68.4
White, % 92.4 95.9 95.9 94.1 93.4 91.2
BMI, mean (SD), kg/m2 25.9 (2.72) 25.7 (3.06) 25.5 (2.76) 26.3 (2.71) 26.5 (2.67) 26.1 (2.55)
BMI: body mass index; SD: standard deviation.
43
Table 4. Efficacy results in the European Phase III ATX-101 clinical trials [62,63].
European Phase III – study 1 [63] European Phase III – study 2 [62]
ATX-101 ATX-101 p ATX-101 ATX-101
1 mg/cm2 2 mg/cm2 Placebo value* 1 mg/cm2 2 mg/cm2 Placebo p value*

Coprimary endpoints
CR-1 response, % 59.2 65.3 23.0 < 0.001 58.3 62.3 34.5 < 0.001
SSRS response, % 53.3 66.1 28.7 < 0.001 68.3 64.8 29.3 < 0.001
Secondary endpoints
PR-1 response, % 67.0 73.6 32.4 < 0.001 64.9 67.3 44.1 = 0.009
(1 mg/cm2);
< 0.001
(2 mg/cm2)
SMF thickness (caliper), 3.8 4.2 1.7 < 0.001 NA NA NA NA
mean decrease from
baseline, mm
PR-SMFIS, mean change NA NA NA < 0.001 NA NA NA < 0.001
44
from baseline for TSS and for all for all
individual items that compar comparison
included feeling happier, isons s
less bothered, less self-

conscious, less
embarrassed, looking less
old, and looking less
overweight
DAS 24
Improved confidence NA NA NA NA NA NA NA = 0.018
(2 mg/cm2)
Females feeling more NA NA NA NA NA NA NA = 0.042
feminine/males feeling (2 mg/cm2)
more masculine
Subjects feeling less self- NA NA NA NA NA NA NA = 0.045
conscious about their chin (2 mg/cm2)
45
SGQ response, %
SGQ #2 (definition NA NA NA NA 24.3 25.2 4.9 < 0.001
between chin and neck)
SGQ #3 (satisfaction with NA NA NA NA 43.2 45.0 35.0 = 0.008

treatment) (1 mg/cm2);
= 0.049
(2 mg/cm2)
DAS 24: Derriford Appearance Scale 24; NA: not available; CR-1: ≥1-grade improvement from baseline on Clinician-Reported
Submental Fat Rating Scale; PR-1: ≥1-grade improvement from baseline on Patient-Reported Submental Fat Rating Scale; PR-
SMFIS: Patient-Reported Submental Fat Impact Scale; SGQ: Subject Global Questions; SMF: submental fat; SSRS, Subject Self-
Rating Scale; TSS: Total Scale Score.
*ATX-101 versus placebo.
46
Table 5. Demographic characteristics of subjects enrolled in the US/Canadian Phase III ATX-101 clinical trials (REFINE-1
and REFINE-2) [65,66].
REFINE-1 [65] REFINE-2 [66]
ATX-101 ATX-101
2 mg/cm2 Placebo 2mg/cm2 Placebo
N = 256 N = 250 N = 258 N = 258
Age, mean (SD), years 49.5 (9.3) 49.4 (9.3) 48.2 (9.3) 47.6 (9.0)
Female, % 83.2 83.2 85.7 86.8
White, % 85.2 90.8 86.0 86.0
BMI, mean (SD), kg/m2 29.2 (4.4) 29.3 (4.3) 29.2 (4.8) 29.3 (4.3)
BMI: body mass index; SD: standard deviation.
47
Table 6. Efficacy results in the US/Canadian Phase III ATX-101 clinical trials (REFINE-1 and REFINE-2) [65,66].
ATX-101 ATX-101
2 mg/cm2 Placebo p value* 2 mg/cm2 Placebo p value*

Co-primary endpoints
Composite CR-1/PR-1 response, % 70.0 18.6 < 0.001 66.5 22.2 < 0.001
Composite CR-2/PR-2 response, % 13.4 0 < 0.001 18.6 3.0 < 0.001
Secondary endpoints
MRI response, % 46.3 5.3 < 0.001 40.2 5.2 < 0.001
PR-SMFIS TSS, mean change from baseline –3.7 –1.2 < 0.001 –3.7 –1.5 < 0.001
Other endpoints
PR-SMFIS scores for individual items that NA NA < 0.001 NA NA < 0.001
included feeling happier, less bothered, less
self-conscious, less embarrassed, looking less
old, and looking less overweight, % change
from baseline
48
SSRS response, % 82.8 31.0 < 0.001 75.1 36.2 < 0.001
SMF thickness (caliper), mean change from –21.9 –6.2 < 0.001 –17.8 –8.4 < 0.001
baseline, mm
SGQ response, %
SGQ #1 (improvement in fat under chin) 74.7 16.6 < 0.001 70.7 24.7 < 0.001
SGQ #2 (definition between chin and neck) 68.9 16.2 < 0.001 67.4 21.6 < 0.001
SGQ #3 (satisfaction with treatment) 77.8 30.3 < 0.001 75.3 33.9 < 0.001
CR-1: ≥1-grade improvement from baseline on Clinician-Reported Submental Fat Rating Scale (CR-SMFRS); CR-2: ≥2-grade
improvement from baseline on CR-SMFRS; MRI: magnetic resonance imaging; NA: not available; PR-1: ≥1-grade improvement from
baseline on Patient-Reported Submental Fat Rating Scale (PR-SMFRS); PR-2: ≥2-grade improvement from baseline on PR-SMFRS;
PR-SMFIS: Patient-Reported Submental Fat Impact Scale; SGQ: Subject Global Questions; SMF: submental fat; SSRS: Subject Self-
Rating Scale; TSS: Total Scale Score.
*ATX-101 versus placebo.
49
Table 7a. Incidence of injection site AEs reported in ≥10% of subjects in the European Phase III ATX-101 clinical trials
[62,63].
European Phase III – study 1 [63] European Phase III – study 2 [62]*
ATX-101 ATX-101 ATX-101 ATX-101

1 mg/cm2 2 mg/cm2 Placebo 1 mg/cm2 2 mg/cm2 Placebo
AE, % N = 120 N = 121 N = 122 N = 118 N = 122 N = 114
Pain including burning 77.3 80.2 25.4 88.1 87.7 29.8
Swelling including edema 65.5 66.1 30.3 55.9 54.9 21.9
Hematoma (bruising) including 55.5 53.7 41.0 60.2 54.9 50.0
bleeding
Anesthesia (numbness) 47.9 51.2 2.5 44.1 52.5 0.9
Erythema 38.7 37.2 23.0 42.4 42.6 21.9
Induration including fibrosis 18.5 26.4 2.5 13.6 19.7 0.9
AE: adverse event.
*Actual values provided by Kythera Biopharmaceuticals, Inc.
50
Table 7b. Incidence of injection site AEs reported in ≥10% of subjects in the US/Canadian Phase III ATX-101 clinical trials
(REFINE-1 and REFINE-2) [65,66].
ATX-101 ATX-101
2 mg/cm2 Placebo 2 mg/cm2 Placebo
AE, % N = 256 N = 250 N = 258 N = 256
Pain 65.4 23.4 73.6 39.1
Swelling 37.4 15.7 29.1 15.6
Edema 52.9 21.8 67.8 36.3
Hematoma (bruising) 70.0 67.3 72.9 72.7
Anesthesia (numbness) 66.9 4.4 65.5 7.0
Erythema 17.9 10.1 35.3 25.4
Induration 18.3 1.6 28.3 3.5
Paresthesia 12.8 3.2 14.7 4.3
Nodule 12.5 0.8 14.3 4.3
AE: adverse event.
51
Figure legends
Figure 1. Chemical structure of deoxycholic acid
52
Figure 2. Standardized photographs and magnetic resonance images (MRI) of a 50-year-
old female subject who underwent five treatment sessions with ATX-101 and achieved ≥2-
grade improvement in composite Clinician-Reported Submental Fat Rating Scale (CR-
SMFRS)/Patient-Reported Submental Fat Rating Scale (PR-SMFRS) response rates at 12
weeks after last treatment. Percentage reduction in submental volume as assessed by MRI was
22.4%. BMI: body mass index; PR-SMFIS: Patient-Reported SMF Impact Scale; SMSLG:
Submental Skin Laxity Grade; SSRS: Subject Self-Rating Scale. Reproduced with permission
from Jones DH, Carruthers J, Joseph JH, Callender V, Walker P, Lee DR, Subramanian M,
Lizzul PF, Gross TM, Beddingfield, III FC. REFINE-1, a multicenter, randomized, double-blind,
placebo-controlled, phase 3 trial with ATX-101, an injectable drug for submental fat reduction.
Dermatol Surg. 2016;42:38–49 [64].
53
Figure 3. Photonumeric guide for assessment of submental fat using the Clinician-Reported
Submental Fat Rating Scale. Adapted from McDiarmid J, Ruiz JB, Lee D, Lippert S, Hartisch
C, Havlickova B. Results from a pooled analysis of two European, randomized, placebo-
controlled, phase 3 studies of ATX-101 for the pharmacologic reduction of excess submental fat.
Aesthetic Plast Surg. 2014;38:849–60 [63].

54

ATX-101 (Deoxycholic Acid Injection) For Reduction of Submental Fat

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Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

ATX-101 (deoxycholic acid injection) for reduction

Benjamin Ascher, Jere Fellmann & Gary Monheit

To link to this article: http://dx.doi.org/10.1080/17512433.2016.1215911

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ATX-101 (deoxycholic acid injection) for reduction of submental fat

Benjamin Ascher*1, Jere Fellmann†2 and Gary Monheit3

Dermatology Center, P.C.) and Department of Dermatology, Department of Ophthalmology,

*Author for correspondence:

75116 Paris, France

and Canada for reduction of submental fat.

Available data from ATX-101 trials are reviewed.

nonsurgical; safety; submental fat

aesthetics. As such, a pharmacologic treatment for submental contouring may be of interest to

the population currently dissatisfied with their submental profile.

reduction of SMF [27]. Injectable therapy with phosphatidylcholine/deoxycholate also offers a

injection; KYBELLA® in the United States and BELKYRA™ in Canada; Kythera

adipocytolytic ingredient in compounded phosphatidylcholine/sodium deoxycholate [32]. Using

phosphatidylcholine/sodium deoxycholate formulation in clinical use for reduction of localized

compounded phosphatidylcholine/sodium deoxycholate and led to the development of ATX-101,

a proprietary formulation containing pure synthetic DCA.

3. Chemistry and manufacturing of ATX-101

proprietary process that creates a synthetic compound identical in chemical structure to

endogenous DCA and without human- or animal-derived contaminants. ATX-101 (DCA

injection) is produced according to current Good Manufacturing Practice (cGMP) regulations in

facilities approved for manufacture of parenteral pharmaceuticals [35]. This manufacturing

process ensures a consistent formulation of DCA, which is in contrast to formulations produced

by chemical compounding of phosphatidylcholine and sodium deoxycholate. Although sodium

solubilizing excipient, such as in Lipostabil® (phosphatidylcholine [Nattermann & Cie [GmbH]

(GlaxoSmithKline Inc., Mississauga, Ontario, Canada) [39], and Arepanrix® (GlaxoSmithKline

evaluated in well-designed and controlled clinical trials. ATX-101 is supplied in ready-to-use,

4. Mechanism of action of ATX-101 for reduction of submental fat

death [32,33]. As DCA destroys adipocytes, administration of exogenous DCA would be

mechanism of action was provided by a Phase I clinical study (ClinicalTrials.gov identifier,

NCT00835952) that evaluated the histological effect of ATX-101 (TABLE 1) [41-43].

In this open-label study, a BA-preserved formulation of ATX-101 was administered

subject. At 1, 3, 7, or 28 days post ATX-101 administration, abdominoplasty was performed with

trichrome stain (for collagen assessment) [41-43].

Phase II/III clinical trials [31].

5. Pharmacokinetics and pharmacodynamics of ATX-101

Exogenous DCA, administered as ATX-101, is indistinguishable from endogenous DCA.

The pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of ATX-101

A Phase I clinical study (NCT00618709) investigated the PK profile of a single dose of

the area-adjusted dose of ATX-101 was varied from 1 to 8 mg/cm2 [57].

Following ATX-101 administration, the mean maximum plasma concentration (Cmax) of

plasma concentrations of DCA returned to baseline levels by 12 hours post ATX-101

administration of BA-preserved ATX-101 in some subjects compared with baseline plasma

concentrations of DCA in other subjects, underscoring the inherent variability in plasma

returned to baseline levels by 24 hours post administration of BA-preserved ATX-101. Overall,

the addition of BA as a preservative has no effect on the overall PK profile of ATX-101. In

addition, routine cardiovascular monitoring showed no clinically meaningful change in heart

compared with baseline plasma concentrations in other subjects [59].

In addition, extensive assessment of plasma lipid concentrations was conducted in this

26 mg/dL [post ATX-101 administration]), triglycerides (136 ± 55 mg/dL vs 153 ± 61 mg/dL,

concentrations of various proinflammatory cytokines, including interleukin 15, tumor necrosis

factor , adiponectin, apolipoprotein B, insulin, leptin, and resistin, following ATX-101

dose strengths of ATX-101 (1 mg/cm2 [n = 20], 2 mg/cm2 [n = 20], or 4 mg/cm2 [n = 22]) or

A second double-blind, placebo-controlled Phase II clinical study (NCT00618618)