A Comprehensive Monograph on ATX-101 (Deoxycholic Acid) for Submental Contouring

Executive Summary

Drug Identity and Indication

This report provides a comprehensive analysis of ATX-101, the investigational designation for a proprietary, injectable formulation of synthetic deoxycholic acid.[1] Deoxycholic acid is a naturally occurring secondary bile acid that functions as a cytolytic agent.[3] ATX-101 is the first and only injectable drug approved by major regulatory bodies for the improvement in the appearance of moderate to severe convexity or fullness associated with submental fat (SMF) in adults, commonly known as a "double chin".[1] It is marketed globally under the brand names Kybella® in the United States and Belkyra® in Canada, Australia, Europe, and South Korea.[7]

Mechanism of Action

The therapeutic effect of ATX-101 is achieved through a process of targeted adipocytolysis. When injected directly into subcutaneous adipose tissue, the deoxycholic acid acts as a detergent, physically disrupting the lipid bilayer of adipocyte cell membranes. This action leads to irreversible cell lysis and the subsequent death of the targeted fat cells.[4] The destruction of adipocytes initiates a localized inflammatory response, characterized by the infiltration of macrophages that clear cellular debris and liberated lipids, followed by the recruitment of fibroblasts, which is thought to stimulate neocollagenesis and contribute to tissue remodeling.[7]

Clinical Efficacy Synopsis

The clinical efficacy of ATX-101 has been robustly established through a comprehensive global development program, culminating in four large-scale, pivotal Phase III, randomized, placebo-controlled trials (REFINE-1, REFINE-2, and two European studies).[1] These trials consistently demonstrated the statistically significant superiority of ATX-101 over placebo in achieving clinically meaningful reductions in SMF. Efficacy was measured using validated clinician- and patient-reported rating scales, with objective confirmation of fat volume reduction provided by magnetic resonance imaging (MRI).[12] Furthermore, the treatment effect has been shown to be durable, with long-term follow-up studies indicating that aesthetic improvements are maintained for at least three years post-treatment.[8]

Safety and Tolerability Overview

The safety profile of ATX-101 is well-characterized and considered manageable. Adverse events are predominantly localized to the injection site, are predictable sequelae of the drug's mechanism of action, and are typically mild to moderate in severity and transient in nature.[12] The most common adverse reactions include injection site swelling, bruising, pain, numbness, and induration.[17] Less frequent but more significant risks include temporary marginal mandibular nerve injury, presenting as an asymmetric smile, and dysphagia (difficulty swallowing).[18] These risks are minimized through meticulous adherence to proper injection technique, which requires a thorough understanding of submental anatomy.[20]

Regulatory Status

ATX-101 was approved by the United States Food and Drug Administration (FDA) on April 29, 2015, establishing it as a first-in-class injectable pharmacologic treatment for submental contouring.[6] It has subsequently received marketing authorization from other major regulatory bodies, including Health Canada and Australia's Therapeutic Goods Administration (TGA), which granted approval on July 21, 2016.[6] These approvals marked a significant advance in aesthetic medicine, providing a validated, non-surgical alternative to invasive procedures for a common cosmetic concern.

Drug Identification, Chemistry, and Formulation

Nomenclature and Disambiguation

A precise and unambiguous identification of the therapeutic agent is foundational to this report. The subject is the small molecule drug deoxycholic acid, a naturally occurring secondary bile acid that is a metabolic byproduct of intestinal bacteria.[3] The specific product under review is a proprietary formulation of

synthetic deoxycholic acid developed for subcutaneous injection under the investigational code ATX-101.[1]

It is critical to resolve several points of ambiguity present in public databases and literature to ensure clarity.

• Resolution of DrugBank ID Conflict: The DrugBank Identifier (ID) DB05780, provided in the initial query, corresponds to S-ribosylhomocysteine lyase, a bacterial protein involved in quorum sensing, and is not related to the subject of this report.[26] The correct and definitive DrugBank ID for the active pharmaceutical ingredient, deoxycholic acid, is DB03619.[4] The association of DB05780 with ATX-101 in some clinical trial records appears to be a database artifact or a legacy entry that does not represent the active drug substance.[27] This report exclusively references the properties associated with DB03619.
• Resolution of Homonym Conflict (ATX-101): The designation ATX-101 is also used for an unrelated investigational anti-cancer peptide that targets Proliferating Cell Nuclear Antigen (PCNA).[28] All information pertaining to this anti-cancer agent is distinct from the deoxycholic acid formulation and is excluded from the scope of this analysis.
• Resolution of Homonym Conflict (REFINE Trials): The acronym "REFINE" has been used for the pivotal Phase III trials of ATX-101 (deoxycholic acid) for submental fat reduction.[8] Coincidentally, the same acronym has been used for Phase II trials of navitoclax, a drug for myelofibrosis.[29] All data related to the navitoclax trials are irrelevant to this report and have been excluded.
• Synonyms and Commercial Names: Deoxycholic acid is known by numerous chemical synonyms, including (3α,5β,12α)-3,12-dihydroxycholan-24-oic acid, 3α,12α-dihydroxy-5β-cholanic acid, and 5β-cholanic acid-3α,12α-diol.[31] The approved pharmaceutical product is marketed globally under two primary brand names: Kybella® in the United States and Belkyra® in Canada, Australia, Europe, and South Korea.[6]

Chemical and Physical Properties

Deoxycholic acid is a C24-steroid and a dihydroxy-5β-cholanic acid, classified as a secondary bile acid.[24] Its chemical and physical properties are well-characterized.

• Molecular Formula and Weight: The molecular formula for deoxycholic acid is C24​H40​O4​.[25] Its average molecular weight is approximately 392.57 g/mol.[4]
• Physicochemical Characteristics: In its solid state, deoxycholic acid is a white to off-white crystalline powder.[24] Its reported melting point falls within the range of 171–178 °C.[24] The molecule's solubility is a key characteristic; it is poorly soluble in water, with a reported solubility of 43.6 mg/L at 20 °C.[24] However, it is soluble in various organic solvents, including ethanol, acetone, and glacial acetic acid, as well as in aqueous solutions of alkali hydroxides and carbonates.[24] The sodium salt form, sodium deoxycholate, is significantly more water-soluble, which is relevant to its formulation as an injectable solution.[24]

Pharmaceutical Formulation (Kybella®/Belkyra®)

The commercial product is a sterile, ready-to-use solution designed for subcutaneous injection.

• Composition and Strength: The formulation is a clear, colorless solution containing 10 mg/mL (1% w/v) of deoxycholic acid as the active pharmaceutical ingredient.[19]
• Excipients and Their Function: The active ingredient is formulated in a sterile, aqueous solution containing several excipients to ensure stability, sterility, and physiological compatibility. These inactive ingredients include: benzyl alcohol (0.9%) as a preservative; dibasic sodium phosphate and sodium hydroxide to buffer the solution to a physiological pH; sodium chloride for tonicity adjustment; and water for injection as the vehicle.[19] During clinical development, two nearly identical formulations were utilized—one preserved with benzyl alcohol and one that was preservative-free.[2]
• Source of Active Ingredient: The development of ATX-101 represents a critical progression in pharmaceutical manufacturing from biologically sourced to fully synthetic production. Initially, the drug substance was derived through the purification of deoxycholic acid from bovine and ovine bile.[19] Subsequently, a robust chemical synthesis process was developed, and the final, approved drug product utilizes this purified synthetic deoxycholic acid.[2] This transition is a significant manufacturing milestone, as it eliminates reliance on animal sources, thereby mitigating risks of supply chain volatility, batch-to-batch inconsistency, and potential biological contamination. The synthetic route ensures a highly pure, consistent, and scalable supply of the active ingredient, a key factor in securing regulatory approval and ensuring commercial viability.

Identifier	Value
Investigational Name	ATX-101 1
Generic Name	Deoxycholic Acid 5
DrugBank ID (Corrected)	DB03619 4
Commercial Names	Kybella® (USA); Belkyra® (Canada, Australia, Europe) 8
Chemical Class	Secondary Bile Acid; C24-Steroid 24
Molecular Formula	C24​H40​O4​ 25
Average Molecular Weight	392.57 g/mol 4
IUPAC Name	(4R)-4-phenanthren-17-yl]pentanoic acid 24
CAS Number	83-44-3 31

Nonclinical and Clinical Pharmacology

Mechanism of Action (Adipocytolysis)

Deoxycholic acid is a cytolytic agent whose pharmacological effect is derived from its fundamental biochemical properties as a detergent molecule.[4] Its mechanism of action in the reduction of submental fat is direct, localized, and physical rather than receptor-mediated.

• Core Cytolytic Effect: Endogenously, deoxycholic acid aids in the emulsification and solubilization of dietary fats in the intestine.[3] When the synthetic formulation is exogenously administered via injection into subcutaneous adipose tissue, it leverages this same detergent property to disrupt the cell membranes of adipocytes.[4] This disruption leads to a loss of cell membrane integrity, resulting in non-specific, irreversible cell lysis and death, a process termed adipocytolysis.[2]
• Local Inflammatory Response and Tissue Remodeling: The destruction of fat cells is not a silent process; it triggers a predictable and localized inflammatory tissue response that is integral to the overall therapeutic outcome.[10] This response involves the infiltration of macrophages and other immune cells into the treatment area. These macrophages serve a crucial cleanup function, phagocytizing the cellular debris and liberated lipids from the lysed adipocytes.[7] This inflammatory cascade also stimulates the recruitment and activity of fibroblasts, the cells responsible for producing collagen.[7] This fibroblast-mediated neocollagenesis is thought to contribute to tissue remodeling and may be responsible for the observed skin tightening, which prevents the development of significant skin laxity after the underlying fat volume has been reduced.[16]

The drug's mechanism of action is directly responsible for both its therapeutic efficacy and its primary adverse effects. The intended therapeutic effect is the destruction of fat cells. This destruction inherently causes a local inflammatory response, which is necessary for clearing cellular debris and promoting tissue remodeling. The most common adverse events reported in clinical trials—such as swelling, pain, and redness—are not off-target side effects but are the direct, expected clinical manifestations of this on-target mechanism. The swelling is the inflammation, and the pain results from tissue disruption and the inflammatory cascade. This understanding is crucial for managing patient expectations, as the signs that the treatment is working are also the source of temporary discomfort and downtime.

Pharmacodynamics

The pharmacodynamic properties of deoxycholic acid are characterized by a notable degree of tissue selectivity, which is a cornerstone of its clinical safety profile.

• Tissue Selectivity: The cytolytic activity of deoxycholic acid is significantly attenuated in protein-rich environments.[4] Its detergent action is effectively neutralized or reduced by binding to albumin and other tissue-associated proteins.[4] This biochemical property results in a selective effect on the targeted subcutaneous fat, which is relatively protein-poor, while sparing adjacent protein-rich tissues such as the dermis, muscle, and glandular tissue.[4] This inherent selectivity helps to confine the drug's destructive effects, contributing to its safety when administered correctly.
• Pharmacodynamic Parameters: Specific pharmacodynamic data, such as receptor binding affinities or enzyme inhibition constants (Ki​), are not applicable, as the drug's effect is based on a physical mechanism of membrane disruption. DrugBank notes that such parameters are "Not Available".[4]

Pharmacokinetics (ADME)

The pharmacokinetic profile of exogenously administered deoxycholic acid is characterized by rapid local absorption, transient systemic exposure, and integration into the body's natural bile acid physiology.

• Absorption: Following subcutaneous injection, synthetic deoxycholic acid is rapidly absorbed into the systemic circulation.[4] Pharmacokinetic studies involving the maximum recommended single treatment dose of 100 mg demonstrated that plasma concentrations of deoxycholic acid peaked quickly. Mean concentrations rose from an average endogenous baseline of approximately 200 ng/mL to nearly 1000 ng/mL within 5 minutes of treatment.[19] However, this systemic exposure is highly transient; plasma levels decline rapidly and return to the normal endogenous range within 24 hours post-dose.[2]
• Distribution: Once in the systemic circulation, deoxycholic acid is highly bound to plasma proteins, primarily albumin, with a protein binding of approximately 98%.[4] The exogenously administered drug is biochemically identical to endogenous deoxycholic acid and readily joins the body's natural bile acid pool, becoming indistinguishable from it.[4] Due to its rapid clearance and integration into this pool, no drug accumulation is expected with the recommended treatment interval of at least one month.[4]
• Metabolism: Under normal physiological conditions, deoxycholic acid is not significantly metabolized by pathways such as the cytochrome P450 system.[4]
• Excretion: Deoxycholic acid is subject to the body's natural enterohepatic circulation. It is taken up by the liver, secreted into the bile, released into the small intestine, and largely reabsorbed in the terminal ileum. The portion that is not reabsorbed is ultimately excreted, along with the endogenous deoxycholic acid pool, unchanged in the feces.[4]

This pharmacokinetic profile reveals a key safety feature. Despite being administered locally to achieve a high concentration in the target tissue, the drug is rapidly absorbed systemically. However, the resulting systemic exposure is brief and the plasma concentrations quickly return to physiological levels. The body's efficient enterohepatic circulation manages this temporary increase by treating the synthetic drug identically to its endogenous counterpart. This rapid clearance minimizes the risk of systemic toxicity and accumulation, and it supports the findings from in vitro studies that clinically significant systemic drug-drug interactions are unlikely, as systemic concentrations are not sustained at levels high enough to meaningfully inhibit or induce metabolic enzymes.[19]

Clinical Efficacy in Submental Fat Reduction

Overview of the Clinical Development Program

The approval of ATX-101 was supported by a comprehensive global clinical development program designed to rigorously evaluate its efficacy and safety. This program included multiple Phase I and Phase II studies, which served to establish the optimal dose (2 mg/cm²), define the treatment paradigm, and characterize the pharmacokinetic and safety profiles.[1] A key Phase I/II study (NCT00618722) provided early evidence of efficacy in the reduction of submental fat.[27] The program culminated in four large-scale, pivotal Phase III trials: two conducted in Europe and two identical trials, known as REFINE-1 and REFINE-2, conducted in the United States and Canada.[6]

Pivotal Phase III Trials: REFINE-1 and REFINE-2

The REFINE-1 (NCT01542034) and REFINE-2 (NCT01546142) trials were the cornerstone studies supporting the FDA approval of ATX-101.[11]

• Study Design: Both were identically designed, multicenter, randomized, double-blind, placebo-controlled trials.[8] This robust design is the gold standard for establishing treatment efficacy.
• Patient Population: The trials enrolled adults who had moderate or severe submental fat, as graded by both a clinician and by themselves, and who were psychologically impacted by their appearance, reporting dissatisfaction with their face and chin.[8]
• Treatment Regimen: Patients were randomized to receive a series of subcutaneous injections of either ATX-101 at a dose of 2 mg/cm² or a matching placebo (saline solution). Patients were eligible to receive up to six treatment sessions, administered at intervals of no less than one month, allowing for individualized treatment based on response.[11]
• Efficacy Endpoints: The trials utilized a set of validated, multi-modal endpoints to assess efficacy 12 weeks after the final treatment session.
• Co-Primary Endpoints: The two co-primary endpoints were composite measures requiring simultaneous improvement on both the 5-point Clinician-Reported Submental Fat Rating Scale (CR-SMFRS) and the 5-point Patient-Reported Submental Fat Rating Scale (PR-SMFRS). The endpoints were the proportion of patients achieving at least a 1-grade improvement on both scales (a clinically meaningful change) and the proportion achieving at least a 2-grade improvement on both scales (a more substantial change).[12]
• Secondary & Other Endpoints: To provide objective and corroborating evidence, secondary endpoints included the proportion of responders as measured by a reduction in submental fat volume confirmed by Magnetic Resonance Imaging (MRI). Additional endpoints assessed the reduction in the psychological impact of SMF using the Patient-Reported Submental Fat Impact Scale (PR-SMFIS) and overall patient satisfaction with treatment.[12]

Efficacy Outcomes from REFINE Trials

Both REFINE-1 and REFINE-2 successfully met all of their primary and secondary endpoints, demonstrating a consistent and statistically significant treatment effect for ATX-101 compared to placebo.

• Primary Endpoint Achievement: In both trials, a significantly higher proportion of patients in the ATX-101 group achieved the co-primary endpoints. The p-value for all primary endpoint comparisons was <.001.[11]
• In REFINE-1, 70.0% of ATX-101-treated patients achieved a ≥1-grade composite response, compared to just 18.6% of placebo patients. A ≥2-grade composite response was achieved by 13.4% of ATX-101 patients versus 0% of placebo patients.[12]
• In REFINE-2, the results were highly consistent, with 66.5% of ATX-101 patients achieving a ≥1-grade composite response versus 22.2% for placebo, and 18.6% achieving a ≥2-grade composite response versus 3.0% for placebo.[14]
• Objective Confirmation with MRI: The subjective clinician and patient ratings were strongly supported by objective MRI data. In REFINE-1, the proportion of MRI responders was more than eight times higher in the ATX-101 group (46.3%) compared to the placebo group (5.3%). Similarly, in REFINE-2, MRI responder rates were 40.0% for ATX-101 versus 5.1% for placebo.[12]
• Psychological Impact and Patient Satisfaction: Treatment with ATX-101 resulted in statistically significant improvements in patient-reported outcomes beyond just appearance. Patients treated with ATX-101 reported a significantly greater reduction in the negative psychological impact of their submental fat (e.g., feeling self-conscious, unhappy, or looking older) and expressed significantly higher satisfaction with their treatment and its outcome compared to those receiving placebo (p<.001 for all assessments).[12]

The clinical trial data also reveal that the treatment paradigm is inherently tailored and response-driven, rather than a fixed course of therapy. While patients were eligible for up to six sessions, a post-hoc pooled analysis of the REFINE trials demonstrated that the majority of patients achieved a clinically significant (≥1-grade) improvement within just two to four treatment sessions.[11] Furthermore, nearly one-fifth (19.1%) of ATX-101-treated patients received fewer than the maximum six treatments specifically because they were satisfied with their results or no longer had sufficient fat to treat safely, compared to only 3.9% of placebo patients.[11] This highlights that the clinical application of ATX-101 is an iterative process where the clinician and patient assess the response after each session to determine the need for further treatment, allowing for individualized aesthetic outcomes.

Endpoint	REFINE-1 ATX-101 (n=256)	REFINE-1 Placebo (n=250)	REFINE-2 ATX-101 (n=258)	REFINE-2 Placebo (n=258)	P-value
≥1-Grade Composite Response	70.0% 12	18.6% 12	66.5% 14	22.2% 14	<.001
≥2-Grade Composite Response	13.4% 12	0% 12	18.6% 14	3.0% 14	<.001
MRI Responders (Volume Reduction)	46.3% 12	5.3% 12	40.0% 13	5.1% 13	<.001

Durability of Effect

A critical question for any aesthetic treatment is the longevity of its results. The mechanism of adipocytolysis, which permanently destroys fat cells, suggests a durable effect. Once destroyed, these cells can no longer store or accumulate fat.[42] This was confirmed in a multicenter, double-blind, non-treatment, long-term follow-up study (NCT02163902) that enrolled patients who had successfully completed the REFINE trials.[8]

The results of this study demonstrated excellent durability. The maintenance of at least a 1-grade improvement as assessed by clinicians (CR-1 response) was significantly higher in the original ATX-101 group compared to the placebo group at every annual time point:

• Year 1: 86.4% vs. 56.8% (p<.001)
• Year 2: 90.6% vs. 73.8% (p=.014)
• Year 3: 82.4% vs. 65.0% (p=.03) [8]

These data confirm that the aesthetic improvements achieved with ATX-101 are long-lasting, with the majority of patients maintaining their results for at least three years. No new safety signals emerged during this long-term follow-up period.[8]

Safety and Tolerability Profile

The safety profile of ATX-101 has been extensively characterized in numerous preclinical studies and a large clinical trial program. The findings consistently show that adverse events are almost entirely localized to the treatment area, are generally mild to moderate in severity, and are transient.[12]

Common Adverse Events (AEs)

The most frequently reported adverse events are the direct and expected clinical manifestations of the drug's adipocytolytic mechanism of action and the associated inflammatory response. In the pivotal clinical trials, the most common AEs included:

• Injection site edema/swelling
• Injection site hematoma/bruising (reported in 72% of subjects)
• Injection site pain
• Injection site numbness
• Injection site erythema (redness)
• Injection site induration (hardness) [17]

These events typically occur shortly after treatment and resolve within the one-month interval between treatment sessions. A pooled analysis of the REFINE trials showed that the incidence and severity of these common AEs tended to decline over subsequent treatment sessions, which corresponds to the decreasing volume of fat being treated.[11]

Adverse Event	ATX-101 Group (%)	Placebo Group (%)
Injection Site Edema/Swelling	87%	44%
Injection Site Hematoma/Bruising	72%	29%
Injection Site Pain	70%	28%
Injection Site Numbness	66%	6%
Marginal Mandibular Nerve Injury	4%	<1%
Dysphagia (Difficulty Swallowing)	2%	<1%
(Incidence data from pooled pivotal clinical trials as reported in prescribing information and safety summaries 17)

Significant Risks and Mitigation Strategies

While the overall safety profile is favorable, there are several less common but more significant risks that require careful attention and are mitigated by precise administration technique.

• Marginal Mandibular Nerve Injury:
• Incidence and Presentation: This was reported in 4% of subjects treated with ATX-101 in the pivotal trials, compared to less than 1% in the placebo group.[18] The injury is to a motor branch of the facial nerve and manifests clinically as an asymmetric smile or weakness of the facial muscles that depress the lower lip.[12]
• Outcome and Mitigation: In all cases reported during the clinical trials, the nerve injury was transient and resolved spontaneously without permanent sequelae. The median time to resolution was 42 to 44 days, though the range was wide (1 to 298 days).[18] This risk is directly related to the injection location. To avoid injury, the prescribing information provides a critical warning: do not inject above the inferior border of the mandible or within a 1 cm to 1.5 cm region below this border.[19]
• Dysphagia (Difficulty Swallowing):
• Incidence and Presentation: Dysphagia was reported in 2% of subjects and typically occurred in the context of other administration-site reactions, such as significant pain, swelling, and induration in the submental area.[18]
• Outcome and Mitigation: All cases reported in the trials were transient, resolving spontaneously with a median duration of approximately 3 days.[18] As a precaution, the use of ATX-101 should be avoided in patients with a current or prior history of dysphagia, as the treatment-related swelling may exacerbate the condition.[18]
• Injection Site Skin Ulceration and Necrosis:
• Cause and Incidence: Though rare in clinical trials, skin ulceration and necrosis are potential risks that have been reported post-marketing.[19] This adverse event occurs if the drug is injected too superficially into the dermis, rather than into the target subcutaneous fat.[20]
• Mitigation: This risk is mitigated by strict adherence to proper injection technique. The needle must be advanced perpendicularly into the pre-platysmal fat, and the administrator must ensure the needle is not withdrawn from the subcutaneous fat during injection, which could lead to intradermal exposure.[21]

Contraindications, Warnings, and Precautions

• Contraindications: ATX-101 is contraindicated in patients with an active infection at the planned injection sites.[17]
• Warnings and Precautions:
• Bleeding Risk: Given the high incidence of bruising, ATX-101 should be used with caution in patients with bleeding abnormalities or those receiving antiplatelet or anticoagulant therapy, as excessive bleeding or bruising may occur.[18]
• Anatomical Considerations: Care must be taken to avoid injecting into or in close proximity (1 cm to 1.5 cm) to vulnerable structures such as salivary glands, lymph nodes, and muscles.[18]
• Patient Selection: Caution should be exercised in patients with excessive skin laxity or prominent platysmal bands, as the reduction of submental fat may result in an aesthetically undesirable outcome.[20]

Drug Interaction Potential

The potential for systemic drug-drug interactions is considered low.

• In Vitro Studies: Comprehensive in vitro studies were conducted to assess the interaction potential with metabolic enzymes and drug transporters. The results indicated that at clinically relevant concentrations, ATX-101 is not likely to induce the activity of CYP1A, CYP2B6, or CYP3A, nor is it likely to inhibit the activity of major CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) or key drug transporters (P-gp, BCRP, OATPs, OCT2, OAT1, OAT3).[19]
• BSEP Inhibition: As expected for a bile acid, ATX-101 was shown to be an inhibitor of the Bile Salt Export Pump (BSEP) transporter, for which it is an endogenous substrate.[19]
• Clinical Significance: Given that systemic plasma concentrations of deoxycholic acid are transient and return to the normal endogenous range within 24 hours of treatment, the risk of clinically significant systemic drug-drug interactions is minimal.[19]

Dosage, Administration, and Patient Selection

The safe and effective use of ATX-101 is highly dependent on a thorough understanding of the proper dosage, administration technique, and patient selection criteria. The treatment functions as a "procedural drug," where the skill and anatomical knowledge of the healthcare professional are as critical to the outcome as the pharmacology of the drug itself.

Recommended Dosing and Treatment Regimen

The dosing for ATX-101 is adjusted based on the surface area of the treatment zone.

• Dosage: The recommended dose is 2 mg/cm².[2]
• Injection Volume and Spacing: The dose is administered via a series of 0.2 mL injections, spaced 1 cm apart from each other within a pre-marked grid on the submental area.[17]
• Maximum Dose Per Session: A single treatment session should not exceed a maximum of 50 injections, which corresponds to a total volume of 10 mL or a total dose of 100 mg of deoxycholic acid.[2]
• Treatment Course: Patients may receive up to a maximum of 6 treatment sessions. The interval between sessions must be no less than 1 month.[17]

Administration Technique

Meticulous technique is paramount to ensure the drug is delivered to the target tissue while avoiding vulnerable structures. The prescribing information provides detailed instructions for healthcare professionals.

• Pre-procedure Assessment and Preparation:

1. The clinician must palpate the submental area to confirm the presence of sufficient subcutaneous fat and to identify the fat layer located between the dermis and the platysma muscle (pre-platysmal fat).[20]
2. The planned treatment area should be outlined with a surgical pen, and a 1 cm injection grid should be applied to mark the individual injection sites.[20]
3. To enhance patient comfort, the use of ice/cold packs, topical anesthesia, and/or injectable local anesthesia (e.g., lidocaine) is recommended before the procedure begins.[20]

• Injection Procedure:

1. The patient should be instructed to tense the platysma muscle, which helps to define the target fat compartment.[20]
2. The clinician should then pinch the submental fat to isolate it.[20]
3. Using a 30-gauge (or smaller), 0.5-inch needle, 0.2 mL of the solution is injected into the pre-platysmal fat at each marked site. The needle should be advanced perpendicular to the skin.[20]
4. It is critical to avoid injecting into the dermis, as this can cause skin ulceration and necrosis, and to avoid injecting into the platysma muscle itself.[21]

The extensive and specific nature of these administration instructions underscores that the safety and efficacy of ATX-101 are inextricably linked to the operator's skill. Unlike a conventional pharmaceutical that a patient self-administers, the delivery of this drug is a medical procedure. The warnings regarding injection depth and location relative to anatomical landmarks like the mandible and platysma mean that successful outcomes and risk mitigation depend entirely on the administrator's anatomical knowledge and technical precision. This positions ATX-101 as a treatment where comprehensive provider training is not merely beneficial but is a critical component of risk management and achieving optimal results.

Patient Selection

Careful patient selection is essential for achieving satisfactory aesthetic outcomes.

• Ideal Candidates: The ideal candidate is an adult with moderate to severe convexity or fullness associated with submental fat who has good to moderate skin quality (i.e., not excessive skin laxity) and is bothered by their submental profile.[13]
• Poor Candidates and Areas to Avoid:
• Patients with very loose skin (excessive laxity) or prominent platysmal bands may not be suitable candidates, as the reduction of underlying fat could result in a less desirable aesthetic outcome.[20]
• Patients who have had prior surgical or aesthetic treatments in the submental area require careful evaluation, as their anatomy may be altered.[20]
• The safe and effective use of ATX-101 for the treatment of subcutaneous fat outside of the submental region has not been established and is not recommended per the approved indication.[18]

Global Regulatory and Commercial Landscape

Regulatory Approvals and Timelines

ATX-101 was the first injectable drug to gain approval for the reduction of submental fat, creating a new category in aesthetic medicine. Its path to market involved securing authorization from major regulatory agencies worldwide.

• United States (FDA): The product, branded as Kybella®, was approved by the U.S. FDA on April 29, 2015. This followed a unanimous recommendation for approval by the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee in March 2015.[22]
• Canada (Health Canada): It was approved in Canada under the brand name Belkyra™.[6]
• Australia (TGA): The Therapeutic Goods Administration (TGA) of Australia granted marketing approval for Belkyra® on July 21, 2016. It is listed on the Australian Register of Therapeutic Goods (ARTG) with the ID 233201.[23]
• Europe: Marketing authorization for Belkyra® was granted in numerous European countries. For example, the Swedish Medical Products Agency (MPA) approved the product in October 2016, with launches across other European nations following in late 2016 and early 2017.[51]

Commercialization and Corporate History

The commercial journey of ATX-101 involves several key corporate entities.

• Original Developer: The drug was developed by Kythera Biopharmaceuticals, Inc., a company focused on aesthetic medicine.[2]
• Acquisition by Allergan: Following the successful development and initial approval of ATX-101, Kythera Biopharmaceuticals was acquired by Allergan plc, a global pharmaceutical leader with a strong portfolio in aesthetics (e.g., Botox® and Juvéderm®).[1]
• Acquisition by AbbVie: Subsequently, Allergan plc was acquired by AbbVie Inc. in a major pharmaceutical merger. As a result, the drug is now part of the AbbVie Aesthetics portfolio and is marketed globally by AbbVie or its affiliates.[8]

Expert Analysis and Conclusion

Synthesis of Findings

ATX-101 (deoxycholic acid) represents a significant and validated innovation in aesthetic medicine. It is a proprietary, synthetic formulation of a naturally occurring bile acid, repurposed as a locally injected adipocytolytic agent. Its mechanism of action is direct and physical, causing the irreversible destruction of adipocyte cell membranes, which leads to a durable reduction in localized fat deposits. The extensive clinical development program, particularly the pivotal Phase III REFINE trials, has provided robust, high-quality evidence of its efficacy. The data demonstrate statistically and clinically significant improvements in submental contour, confirmed by both subjective patient and clinician assessments and objective MRI measurements. Furthermore, these aesthetic improvements are associated with a significant positive impact on patients' psychological well-being. The treatment effect is long-lasting, with results maintained for at least three years. The safety profile is well-understood and manageable; adverse events are overwhelmingly local, transient, and are the predictable consequence of the drug's intended inflammatory mechanism. The more significant risks, such as marginal mandibular nerve injury, are infrequent and can be effectively mitigated through meticulous administration technique, underscoring the procedural nature of the treatment.

Position in Aesthetic Medicine

ATX-101 holds a unique position as a first-in-class, minimally invasive pharmacological treatment for submental contouring.[2] Prior to its approval, patients seeking to address submental fullness were largely limited to more invasive procedures like surgical neck lifts and liposuction, or non-invasive energy-based devices that primarily target skin laxity rather than fat volume.[1] By creating the category of "injectable adipocytolysis," ATX-101 filled a significant unmet need in the market, providing a non-surgical option for a common aesthetic concern that affects a broad demographic and is often resistant to diet and exercise.[48] Its development and approval represent a major advance for non-surgical cosmetic correction, extending the utility of injectable treatments from facial rejuvenation into submental contouring.[1]

Future Directions

While ATX-101 is currently approved solely for the reduction of submental fat, its fundamental mechanism of action suggests potential utility for other small, localized, and unwanted fat deposits. The scientific and clinical interest in expanding its applications is evident.

• Off-Label Use and New Indications: Clinical trials are underway to formally evaluate the safety and efficacy of deoxycholic acid for reducing fat in other body areas, such as the upper inner thighs and the axillary region ("bra strap fat").[53] Success in these trials could lead to expanded indications, further broadening the drug's clinical utility.
• Therapeutic Expansion Beyond Aesthetics: The cytolytic properties of deoxycholic acid may have applications beyond aesthetic fat reduction. Early-phase clinical research is exploring its potential in other therapeutic areas. For instance, a Phase 1 clinical trial (NCT06120036) is currently investigating the dosing and tolerability of deoxycholic acid for the treatment of cutaneous neurofibromas associated with Neurofibromatosis Type 1.[55] This research highlights the potential to leverage its cell-lysing capabilities for non-aesthetic medical conditions, suggesting that the full therapeutic scope of this well-characterized molecule may still be evolving.

Works cited

1. ATX-101 (deoxycholic acid injection) for reduction of submental fat - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/27457304/
2. A Phase I Safety and Pharmacokinetic Study of ATX-101: Injectable, Synthetic Deoxycholic Acid for Submental Contouring - JDDonline - Journal of Drugs in Dermatology, accessed September 26, 2025, https://jddonline.com/articles/a-phase-i-safety-and-pharmacokinetic-study-of-atx-101-injectable-synthetic-deoxycholic-acid-for-subm-S1545961615P0279X
3. ATX-101: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 26, 2025, https://go.drugbank.com/drugs/DB05780
4. Deoxycholic acid: Uses, Interactions, Mechanism of Action ..., accessed September 26, 2025, https://go.drugbank.com/drugs/DB03619
5. Deoxycholic Acid (ATX-101) for Fat Reduction - JDDonline, accessed September 26, 2025, https://jddonline.com/articles/deoxycholic-acid-atx-101-for-fat-reduction-S1545961621P1169X
6. Overview of ATX-101 (Deoxycholic Acid Injection): A Nonsurgical Approach for Reduction of Submental Fat - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/27787266/
7. ATX-101 (Deoxycholic Acid Injection) for Reduction of Submental Fat: Results From a 12-Month Open-Label Study - Beer Dermatology, accessed September 26, 2025, https://www.beerdermatology.com/wp-content/uploads/2024/01/12-month-open-label-study.pdf
8. Improvements in Submental Contour up to 3 Years After ATX-101: Efficacy and Safety Follow-Up of the Phase 3 REFINE Trials - PMC, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8520020/
9. Best Clinical Practices with ATX-101 for Submental Fat Reduction: Patient-related Factors and Physician Considerations - PubMed Central, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8274802/
10. ATX-101 for reduction of submental fat. | DrugBank Online, accessed September 26, 2025, https://go.drugbank.com/articles/A2646
11. Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials - Oxford Academic, accessed September 26, 2025, https://academic.oup.com/asj/article/38/9/998/4833179
12. REFINE-1, a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial With ATX-101, an Injectable Drug for Submental Fat Reduction | Request PDF - ResearchGate, accessed September 26, 2025, https://www.researchgate.net/publication/287213683_REFINE-1_a_Multicenter_Randomized_Double-Blind_Placebo-Controlled_Phase_3_Trial_With_ATX-101_an_Injectable_Drug_for_Submental_Fat_Reduction
13. ATX-101 studies yield favorable findings for reducing submental fat - Dermatology Times, accessed September 26, 2025, https://www.dermatologytimes.com/view/atx-101-studies-yield-favorable-findings-reducing-submental-fat
14. ATX-101 for reduction of submental fat: A phase III randomized controlled trial - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/27430612/
15. Improvements in Submental Contour up to 3 Years After ATX-101: Efficacy and Safety Follow-Up of the Phase 3 REFINE Trials | Aesthetic Surgery Journal | Oxford Academic, accessed September 26, 2025, https://academic.oup.com/asj/article-abstract/41/11/NP1532/6146596
16. Efficacy, safety, and potential industry bias in using deoxycholic acid for submental fat reduction ‒ A systematic review and meta-analysis of randomized clinical trials - PMC, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10570630/
17. About Treatment | KYBELLA® HCP, accessed September 26, 2025, https://hcp.mykybella.com/about-treatment
18. KYBELLA® (deoxycholic acid) injection 10 mg/mL Important Information - Refine Aesthetics, accessed September 26, 2025, http://refineaestheticsllc.com/wp-content/uploads/2021/03/kybella_safety_info_doc.pdf
19. 206333Orig1s000 - accessdata.fda.gov, accessed September 26, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206333Orig1s000SumR.pdf
20. Kybella (deoxycholic acid) dosing, indications, interactions, adverse effects, and more, accessed September 26, 2025, https://reference.medscape.com/drug/kybella-deoxycholic-acid-999993
21. Kybella - VHB - master-uspi-deoxycholic-acid-30OCT2024 - RxAbbVie, accessed September 26, 2025, https://www.rxabbvie.com/pdf/kybella_pi.pdf
22. Kybella (deoxycholic acid) FDA Approval History - Drugs.com, accessed September 26, 2025, https://www.drugs.com/history/kybella.html
23. BELKYRA deoxycholic acid 10 mg/mL injection glass vial (233201), accessed September 26, 2025, https://www.tga.gov.au/resources/artg/233201
24. Deoxycholic Acid | C24H40O4 | CID 222528 - PubChem, accessed September 26, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Deoxycholic-Acid
25. en.wikipedia.org, accessed September 26, 2025, https://en.wikipedia.org/wiki/Deoxycholic_acid
26. S-ribosylhomocysteine lyase | DrugBank Online, accessed September 26, 2025, https://go.drugbank.com/bio_entities/BE0001497
27. Deoxycholic acid Completed Phase 1 / 2 Trials for Moderate or Severe Submental Fullness Treatment - DrugBank, accessed September 26, 2025, https://go.drugbank.com/drugs/DB03619/clinical_trials?conditions=DBCOND0039214&phase=1%2C2&purpose=treatment&status=completed
28. ATX-101 - Apim Therapeutics, accessed September 26, 2025, https://www.apimtherapeutics.com/pipeline/atx-101
29. AbbVie Presents Investigational Navitoclax Preliminary Data in JAK Inhibitor Naïve Myelofibrosis Patients - Jun 10, 2022, accessed September 26, 2025, https://news.abbvie.com/2022-06-10-AbbVie-Presents-Investigational-Navitoclax-Preliminary-Data-in-JAK-Inhibitor-Naive-Myelofibrosis-Patients
30. AbbVie Presents Positive Investigational Navitoclax Combination Data in Phase 2 REFINE Study Suggesting Anti-Fibrosis Activity for Patients with Myelofibrosis - PR Newswire, accessed September 26, 2025, https://www.prnewswire.com/news-releases/abbvie-presents-positive-investigational-navitoclax-combination-data-in-phase-2-refine-study-suggesting-anti-fibrosis-activity-for-patients-with-myelofibrosis-301523415.html
31. Deoxycholic acid | C24H40O4 - ChemSpider, accessed September 26, 2025, https://www.chemspider.com/Chemical-Structure.193196.html
32. Deoxycholic acid - SIELC Technologies, accessed September 26, 2025, https://sielc.com/deoxycholic-acid
33. Definition of deoxycholic acid - NCI Drug Dictionary, accessed September 26, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/deoxycholic-acid
34. Deoxycholic acid | CAS 83-44-3 | SCBT - Santa Cruz Biotechnology, accessed September 26, 2025, https://www.scbt.com/p/deoxycholic-acid-83-44-3
35. Deoxycholic acid =98 HPLC 83-44-3 - Sigma-Aldrich, accessed September 26, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/d2510
36. Sodium deoxycholate | DrugBank Online, accessed September 26, 2025, https://go.drugbank.com/salts/DBSALT003570
37. ATX-101 (DEOXYCHOLIC ACID) INJECTION ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE - cdn.co, accessed September 26, 2025, https://ghk.h-cdn.co/assets/cm/15/11/5500ae2372422_-_ucm436604.pdf
38. belkyra, accessed September 26, 2025, https://www.nps.org.au/assets/medicines/0eb8e67d-8859-4e01-947f-a727004c25ce-reduced.pdf
39. KYBELLA® (kye be lah) (deoxycholic acid) Injection, for subcutaneious use Patient Information - RxAbbVie, accessed September 26, 2025, https://www.rxabbvie.com/content/dam/rxabbvie/cbs/kybella_ecbs.pdf
40. ATX-101 for reduction of submental fat | Request PDF - ResearchGate, accessed September 26, 2025, https://www.researchgate.net/publication/272679394_ATX-101_for_reduction_of_submental_fat
41. ATX-101 (Deoxycholic Acid Injection) for Reduction of Submental Fat: Results From a 12-Month Open-Label Study - Aesthetic Solutions, accessed September 26, 2025, https://aesthetic-solutions.com/wp-content/uploads/2021/01/CV80-ATX1101-Deoxycholic-Acid-Injection-for-reduction-of-Submental-Fat-Results-From-a-12-Month-Open-Label-Study.pdf
42. BELKYRA® is the only non-surgical injectable treatment for reduction of fullness under the chin, known as submental fullness or - Complete Skin Specialists, accessed September 26, 2025, https://completeskinspecialists.com.au/wp-content/uploads/2019/09/BELKYRAR-Information.pdf
43. BELKYRA INFORMATION - Complete Skin Specialists, accessed September 26, 2025, https://completeskinspecialists.com.au/wp-content/uploads/2021/03/Belkyra-General-Information-MAR.21.pdf
44. Phase 2 Study of Deoxycholic Acid Injection (ATX-101) - ClinConnect, accessed September 26, 2025, https://clinconnect.io/trials/NCT00618618
45. BELKYRA® EXPLAINED, accessed September 26, 2025, https://www.jeunesse.co.nz/wp-content/uploads/2018/07/Belkyra-Patient-Brochure-1.pdf
46. Fat Dissolving Injection (Belkyra) | Bare Esthetique | Cosmetic Clinic | Melbourne, accessed September 26, 2025, https://bareesthetique.au/fat-dissolving-injection-belkyra/
47. KYBELLA® (deoxycholic acid) injection 10 mg/mL Before-and-After Photo Files, accessed September 26, 2025, https://sfplasticsurgeon.com/wp-content/uploads/2017/11/KYBELLA%C2%AE-Before-and-After-Photo-Files-MALE.pdf
48. ATX-101 (deoxycholic acid injection) for reduction of submental fat - Sci-Hub, accessed September 26, 2025, https://2024.sci-hub.se/5836/723cc63b373e8a1cb4bbacceb46f2773/ascher2016.pdf
49. belkyra® (deoxycholic acid), accessed September 26, 2025, https://media.allergan.com/actavis/actavis/media/general/Belkyra-piv10.0-ccdsv8-approved.pdf
50. Belkyra - NPS MedicineWise, accessed September 26, 2025, https://www.nps.org.au/medicine-finder/belkyra-solution-for-injection
51. Allergan's Belkyra medicine receives Swedish approval to treat double chin, accessed September 26, 2025, https://www.pharmaceutical-technology.com/news/newsallergans-belkyra-medicine-receives-swedish-approval-to-treat-double-chin-5031952/
52. Allergan's BELKYRA® (Deoxycholic Acid) Receives Marketing Authorisation In Sweden For The Treatment Of Moderate To Severe Fullness Under The Chin (Double Chin) USA - English - PR Newswire, accessed September 26, 2025, https://www.prnewswire.com/news-releases/allergans-belkyra-deoxycholic-acid-receives-marketing-authorisation-in-sweden-for-the-treatment-of-moderate-to-severe-fullness-under-the-chin-double-chin-300344030.html
53. Study Details | NCT04054011 | Safety and Efficacy of Deoxycholic Acid Injection for Reduction of Upper Inner Thigh Fat | ClinicalTrials.gov, accessed September 26, 2025, https://clinicaltrials.gov/study/NCT04054011
54. Study Details | NCT04089722 | Efficacy and Safety of Deoxycholic Acid Injections for Removal of Adipose Tissue in the "Bra Strap Fat" Region | ClinicalTrials.gov, accessed September 26, 2025, https://www.clinicaltrials.gov/study/NCT04089722?term=DEOXYCHOLIC%20ACID&viewType=Table&rank=3
55. Deoxycholic acid Completed Phase 1 Trials for Neurofibromatosis Type 1 Other - DrugBank, accessed September 26, 2025, https://go.drugbank.com/drugs/DB03619/clinical_trials?conditions=DBCOND0029664&phase=1&purpose=other&status=completed