ATX-101 (deoxycholic acid injection; Kybella in the United States and Belkyra in Canada; Kythera Biopharmaceuticals, Inc., Westlake Village, CA [an affiliate of Allergan plc, Dublin, Ireland]) was approved in 2015 as a first-in-class injectable drug for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat (SMF).1 The initial insight leading to the development of ATX-101 as a pharmacologic treatment for reduction of SMF was the identification by Rotunda and colleagues of deoxycholic acid as the primary mediator of adipocyte lysis in compounded phosphatidylcholine/sodium deoxycholate.2 Subsequent studies additionally demonstrated that deoxycholic acid physically disrupts the cell membrane of adipocytes causing cell death and that relatively protein-poor tissue such as fat is more sensitive to the cytolytic effects of deoxycholic acid than relatively protein-rich tissues such as skin and muscle.3,4 Based on these data and other scientific insights, Kythera Biopharmaceuticals, Inc. developed ATX-101 as the first minimally invasive, nonsurgical treatment for reduction of SMF.
Endogenous deoxycholic acid is a secondary bile acid that emulsifies and solubilizes dietary fat to aid in its breakdown and absorption within the gastrointestinal tract.5 The deoxycholic acid in ATX-101 is manufactured through a multistep chemical synthesis, is biologically equivalent to endogenous deoxycholic acid, and is without risk of human- or animal-derived pathogens. Overall, the manufacturing process used to generate ATX-101 is designed to ensure a consistent and safe product for use in patients.
ATX-101 has been evaluated in a clinical development program that included 18 Phase 1 to 3 clinical studies to support the current indication.6 Since 2007, the toxicity and safety profiles of ATX-101 have been characterized in numerous preclinical studies,6 its pharmacokinetics, pharmacodynamics, and optimal treatment paradigm have been defined in multiple Phase 1 and 2 studies,6–10 and its efficacy and clinical safety have been confirmed in 4 large Phase 3 trials.11–14
Results from 2 single-center, open-label Phase 1 studies (ClinicalTrials.gov identifiers: NCT01319916 and NCT01632917) demonstrated that ATX-101 is rapidly absorbed when injected subcutaneously into either SMF or abdominal fat in healthy subjects.9,10 After subcutaneous injection of 100 mg ATX-101 (administered through 0.2-mL injections at 1-cm intervals) into fat, plasma levels of deoxycholic acid rapidly increased, remained within the physiologic range for endogenous deoxycholic acid, and returned to baseline levels within 12 to 24 hours.9,10 Importantly, these Phase 1 studies also showed that administration of ATX-101 had no clinically meaningful effect on heart rate9 or plasma concentrations of total cholesterol, triglycerides, free fatty acids, or proinflammatory cytokines.10 Rather, fluctuations observed in total cholesterol, triglyceride, and free fatty acid levels after ATX-101 administration were short lived and similar to those observed after ingestion of a meal.10 In addition, no clinically significant changes in low-density lipoprotein, high-density lipoprotein, or very–low-density lipoprotein cholesterol concentrations were noted after ATX-101 administration. Furthermore, all clinical laboratory values for liver and renal function were considered unremarkable, including those for alanine transaminase, aspartate transaminase, and creatinine (Data on file; Kythera Biopharmaceuticals, Inc. [an affiliate of Allergan plc]). An additional Phase 1 study (NCT01706679), which specifically evaluated QT/QTc intervals after subcutaneous administration of ATX-101 (100 and 200 mg), demonstrated that neither dose prolonged QTcF intervals nor resulted in clinically significant changes in other electrocardiogram parameters.6
Based on previous findings,2–4 it was hypothesized that subcutaneous injection of ATX-101 into SMF would result in adipocytolysis leading to localized fat reduction. Furthermore, ATX-101 treatment was predicted to result in a durable effect as the targeted fat cells are destroyed within the treatment area. Histological data from a multicenter, open-label Phase 1 study (NCT00835952) support this proposed mechanism of action for ATX-101.6 Various doses of ATX-101 (1–8 mg/cm2) were injected subcutaneously into abdominal fat and abdominoplasty was performed on subjects at 1, 3, 7, or 28 days posttreatment. Histological analysis of the ATX-101–treated and resected tissue was then performed. Adipocyte lysis was observed on Day 1. This was followed by acute local neutrophilic inflammation visible on Day 3. By Day 7, few neutrophils remained and infiltrating macrophages were visible scavenging (through phagocytosis) cellular debris and liberated lipids. The local inflammation was largely resolved by Day 28. Fibroblasts were also recruited to the treatment area, and thickening of fibrous septae, indicative of neocollagenesis, was observed in the Day 28 sections.6Figure 1 illustrates the proposed mechanism of action for ATX-101 and the associated local tissue response.
Phase 2 studies established the appropriate ATX-101 dose strength and optimal treatment paradigm for reducing SMF. Results from 2 multicenter, randomized, double-blind, placebo-controlled studies (NCT00618722 and NCT00618618) demonstrated that increasing the area-adjusted dose of ATX-101 (to 4 mg/cm2 [vs 2 mg/cm2]) by administering a higher concentration (20 mg/mL [vs 10 mg/mL]), larger injection volume (0.4 mL [vs 0.2 mL]), or more closely spaced injections (0.7-cm intervals [vs 1.0-cm intervals]) did not produce greater efficacy and resulted in injection site adverse events (AEs) of greater intensity and longer duration. Moreover, a 2 mg/cm2 dose of ATX-101 consistently resulted in greater efficacy on all measures relative to a lower 1-mg/cm2 dose.6,8 A subsequent dose-ranging Phase 2 study (NCT01032889) established a reproducible magnetic resonance imaging (MRI) protocol for measuring changes in submental volume after ATX-101 treatment and the validity of patient-reported outcome measures of SMF reduction (i.e., Patient-Reported SMF Rating Scale [PR-SMFRS]; Table 1) and the psychological impact of SMF (i.e., Patient-Reported SMF Impact Scale [PR-SMFIS]).6,7 Overall, results from the Phase 2 program established the optimal dose strength (2 mg/cm2) and treatment paradigm for ATX-101 administration (0.2-mL injections spaced at 1-cm intervals within the submental area) and appropriate outcome measures for Phase 3.6–8 In addition, a treatment interval of 28 days was adopted based on the histological evidence that posttreatment inflammation was largely resolved by this time.6
Four randomized, double-blind, placebo-controlled Phase 3 trials evaluated the efficacy and clinical safety of ATX-101—2 conducted in Europe (NCT01305577 and NCT01294644) before completion of the dose-ranging Phase 2 study and 2 conducted in the United States and Canada (NCT01542034 [REFINE-1] and NCT01546142 [REFINE-2]), which evaluated the 2 mg/cm2 dose of ATX-101 for which approval was sought.11–14 All 4 Phase 3 trials enrolled adults who had moderate or severe SMF based on clinician assessment (using the validated 5-point Clinician-Reported SMF Rating Scale [CR-SMFRS]; Figure 2). In the US and Canadian REFINE trials, the presence of a moderate or large amount of chin fat based on subject assessment (using the validated 5-point PR-SMFRS) was included as an additional eligibility criterion.11,13 Across all 4 Phase 3 trials, subjects randomized to ATX-101 treatment could receive up to 10 mL, delivered in 0.2-mL injections spaced 1-cm apart, at each treatment session depending on the amount and distribution of their SMF.11–14
The efficacy of ATX-101 for reducing SMF was evaluated across all 4 Phase 3 trials through a validated scale-based assessment of SMF severity by the clinician (CR-SMFRS) and subject (PR-SMFRS) and through a simple tool-based objective assessment of SMF thickness using calipers.11–14 In the REFINE trials, MRI was used as an additional imaging-based objective assessment of the change in submental volume after ATX-101 treatment.11,13 In addition to these diverse measurements of SMF reduction, the Phase 3 trials included multiple patient-reported outcome measures to assess satisfaction with appearance and treatment and the psychological impact of SMF (Table 2).11–14
All 4 Phase 3 trials met their primary and secondary efficacy endpoints (summarized in Table 3), evaluated at 12 weeks after last treatment, demonstrating that ATX-101 significantly reduced SMF.11–14 In addition, satisfaction with the appearance of the face and chin was high and the negative psychological impact of SMF was significantly reduced after ATX-101 treatment.11–14 Furthermore, data from the REFINE trials demonstrated that ATX-101 treatment significantly reduced submental volume based on MRI.11,13 Representative photographs of subjects treated with ATX-101 in the REFINE-1 trial are shown in Figure 3A,B. Overall, results from the Phase 3 trials support the efficacy of ATX-101 (2 mg/cm2) for reducing SMF and improving the submental profile.11–14
Most subjects achieved a clinically meaningful treatment response to ATX-101 within 2 to 4 treatment sessions (52% of ATX-101–treated subjects achieved a ≥1-grade improvement in SMF based on clinician assessment after the second treatment which increased to 72% after the fourth treatment, whereas 47% achieved a ≥1-grade improvement in SMF based on subject assessment after the second treatment which increased to 74% after the fourth treatment [Data on file; Kythera Biopharmaceuticals, Inc. (an affiliate of Allergan plc)]). Results from the Phase 3 trials underscore the importance and benefit of tailoring ATX-101 treatment for each individual. In addition to varying the number of treatment sessions, the amount of drug administered (determined by the area to be treated) at each treatment session is customized to each patient based on the presentation of submental fullness (i.e., amount and distribution of SMF). As the amount of SMF is reduced over successive treatment sessions, less ATX-101 is required. Therefore, it is also necessary to thoroughly evaluate the patient's submental region at each treatment session to ensure that there is sufficient SMF remaining to treat.
Long-term follow-up of subjects from multiple Phase 2 and Phase 3 trials has demonstrated that the reduction in SMF and resulting improvement in the submental profile achieved with ATX-101 treatment is maintained in most subjects over time. This finding is not unexpected given the mechanism of action of ATX-101 (i.e., lysis and destruction of adipocytes). Currently available data support a durable treatment response with maintenance of efficacy observed for up to 4 years after last treatment.6 Additional long-term follow-up studies are ongoing (NCT02159729 and NCT02163902), with data being collected for up to 5 years after last treatment with ATX-101.
Overall, AEs in the ATX-101 clinical trials were mostly mild or moderate in intensity, temporary, and resolved without sequelae.11–14 The most common AEs reported with ATX-101 were associated with the treatment area (injection site) and included pain, swelling, bruising, numbness, erythema, and induration. The frequency of the common injection site AEs tended to decrease over subsequent treatment sessions. Furthermore, the injection site AEs observed with ATX-101 treatment were expected based on its route of administration (subcutaneous injection), mechanism of action (lysis of adipocytes), and anticipated local tissue response (mild inflammation). In the REFINE trials, marginal mandibular nerve paresis was reported in 4.3% of ATX-101–treated subjects and 0.4% of placebo-treated subjects.6 All events were temporary and resolved without sequelae; however, their incidence highlights the importance of physician education on relevant submental anatomy to minimize risk of complications, such as nerve paresis, after ATX-101 administration. Long-term follow-up of subjects from Phase 2 and Phase 3 trials has not identified any new safety signals.6
Increased skin laxity is a potential concern when subcutaneous fat is removed from a targeted area such as the submentum. However, in the Phase 3 trials, despite the significant reduction in SMF, skin laxity was maintained or improved in the large majority of subjects treated with ATX-101 (as evaluated by the clinician using the Skin Laxity Rating Scale12,14 or Submental Skin Laxity Grade scale6,11,13). The absence of an observed worsening of skin laxity in most ATX-101–treated subjects suggests that skin retraction is occurring in the treatment area as fat is destroyed. Histological documentation of thickened fibrous septae and increased total collagen within the treatment area may partially explain this effect.6 Overall, these results suggest that secondary or adjunctive procedures for skin tightening are not needed in appropriately indicated subjects after reduction of SMF with ATX-101.
ATX-101 is approved for injection into SMF.1 It is not approved for use in other areas of the face or body. Care should be taken when injecting ATX-101 to avoid injury to important anatomic structures adjacent to the treatment area, such as the marginal mandibular nerve. Examination of the submental region before each treatment session is necessary to eliminate other potential contributing factors to submental fullness, to confirm the presence of sufficient SMF to warrant ATX-101 treatment, and to define the appropriate target treatment area. Article #3 of this supplement titled “Anatomy of the cervicomental region: insights from an anatomy lab and roundtable discussion” will review relevant external landmarks and internal anatomic structures within the submental region, whereas article #4 titled “Proper technique for administration of ATX-101 (deoxycholic acid injection): insights from an injection practicum and roundtable discussion” will review the proper technique for administration of ATX-101 in the treatment of submental fullness, including appropriate selection of patients.
ATX-101 is a first-in-class injectable drug for reduction of SMF and represents a minimally invasive, tailorable alternative to liposuction and surgery for patients with moderate to severe submental fullness. As ATX-101 destroys undesired fat within the treatment area, it leads to durable improvement in the appearance of the submental profile, and likely without the need for adjunctive treatments to address skin laxity.
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3. Rotunda AM, Ablon G, Kolodney MS. Lipomas treated with subcutaneous deoxycholate injections. J Am Acad Dermatol 2005;53:973–8.
4. Thuangtong R, Bentow JJ, Knopp K, Mahmood NA, et al. Tissue-selective effects of injected deoxycholate. Dermatol Surg 2010;36:899–908.
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7. Dover J, Schlessinger J, Young L, Walker P. Reduction of submental fat with ATX-101: results from a phase IIB study using investigator, subject, and magnetic resonance imaging assessments (P4787). J Am Acad Dermatol 2012;2:AB29.
8. 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:AB23.
9. Walker P, Fellmann J, Lizzul PF. A phase I safety and pharmacokinetic study of ATX-101: injectable, synthetic deoxycholic acid submental contouring. J Drugs Dermatol 2015;14:279–87.
10. 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.
11. Humphrey S, Sykes J, Kantor J, Bertucci V, et al. ATX-101 for reduction of submental fat: a phase III randomized controlled trial. J Am Acad Dermatol 2016;75:788–97.
12. Ascher B, Hoffmann K, Walker P, Lippert S, et al. Efficacy, patient-reported outcomes and safety profile of ATX-101 (deoxycholic acid), an injectable drug for the reduction of unwanted submental fat: results from a phase III, randomized, placebo-controlled study. J Eur Acad Dermatol Venereol 2014;28:1707–15.
13. Jones DH, Carruthers J, Joseph JH, Callender VD, 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.
14. Rzany B, Griffiths T, Walker P, Lippert S, 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.
© 2016 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
15. McDiarmid J, Ruiz JB, Lee D, Lippert S, 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. Aesthet Plast Surg 2014;38:849–60.