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

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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: [email protected]
†
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
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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

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 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
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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

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 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
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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

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 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].
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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].

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 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
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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,

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 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
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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

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 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
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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

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 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
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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

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 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).
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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

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 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
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(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].

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 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
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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
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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
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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

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 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-
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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
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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
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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
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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
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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
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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
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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
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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.

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 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,
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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.

Downloaded by [Weill Cornell Medical College] at 19:14 28 July 2016

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

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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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Committee Briefing Document: ATX-101 (deoxycholic acid) injection, Available at:

http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/d

ermatologicandophthalmicdrugsadvisorycommittee/ucm436604.pdf. [Last accessed 26

October 2015].

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57. Walker P, Havlickova B, Lee D. ATX-101 for reduction of submental fat:

pharmacokinetic and safety findings from a phase I trial [abstract]. Presented at: 8th

European Masters in Aesthetic and Anti-Ageing Medicine; 12–14 October 2012; Paris,

France.

**58. 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;14:279–87.

Summarizes the pharmacokinetic and safety profile of ATX-101, the only injectable

drug approved in the United States and Canada for reduction of submental fat.

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 59. Walker P, Lee D. A phase I pharmacokinetic study of ATX-101: serum lipids and

adipokines following synthetic deoxycholic acid injections. J Cosmet Dermatol

2015;14:33–9.

60. Goodman G, Smith K, Walker P, Lee D. Reduction of submental fat with ATX-101: a

pooled analysis of two international multicenter, double-blind, randomized, placebo-

controlled studies. J Am Acad Dermatol 2012;66:AB11.

61. Dover J, Schlessinger J, Lee D, et al. Reduction of submental fat with ATX-101: results
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from a phase IIB study using investigator, subject, and magnetic resonance imaging

assessments. J Am Acad Dermatol 2012;66:AB29.

**62. Ascher B, Hoffmann K, Walker P, et al. Efficacy, patient-reported outcomes and safety

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submental fat: results from a phase III, randomized, placebo-controlled study. J Eur Acad

Dermatol Venereol 2014;28:1707–15.

Reports the results from a European Phase III clinical trial of ATX-101

demonstrating its efficacy for reducing submental fat, reducing the pyschological

impact of submental fat, and improving the appearance in adults with moderate or

severe submental fat.

**63. Rzany B, Griffiths T, Walker P, et al. Reduction of unwanted submental fat with ATX-

101 (deoxycholic acid), an adipocytolytic injectable treatment: results from a phase III,

randomized, placebo-controlled study. Br J Dermatol 2014;170:445–53.

Reports the results from a European Phase III clinical trial of ATX-101

demonstrating its efficacy for reducing submental fat, reducing the pyschological

35
 impact of submental fat, and improving the appearance in adults with moderate or

severe submental fat.

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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
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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.

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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
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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

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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
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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

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 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

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 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

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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*

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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-

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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

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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
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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].

REFINE-1 [65] REFINE-2 [66]

ATX-101 ATX-101

2 mg/cm2 Placebo p value* 2 mg/cm2 Placebo p value*

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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, %
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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

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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].

REFINE-1 [65] REFINE-2 [66]

ATX-101 ATX-101
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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.

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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
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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].

Downloaded by [Weill Cornell Medical College] at 19:14 28 July 2016

54