Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials.

BACKGROUND: ATX-101 (deoxycholic acid injection) is the only injectable drug approved for submental fat (SMF) reduction. In the phase 3 REFINE trials, adults with moderate or severe SMF who were dissatisfied with the appearance of their face/chin were eligible to receive up to 6 treatment sessions with ATX-101 (2 mg/cm2) or placebo. Primary and secondary endpoints, evaluated at 12 weeks after last treatment, significantly favored ATX-101 supporting its efficacy for reducing SMF and the psychological impact of SMF, and increasing satisfaction with the appearance of the face/chin. OBJECTIVES: To evaluate the efficacy and safety of ATX-101 by treatment session. METHODS: This post hoc analysis used pooled data from the REFINE trials to evaluate efficacy endpoints and adverse events following each treatment session to further characterize the ATX-101 treatment response and safety profile. RESULTS: In both treatment groups, mean injection volume declined over subsequent treatment sessions, though more markedly in the ATX-101 group. The majority of ATX-101-treated patients achieved a ≥1-grade improvement in SMF within 2 to 4 treatment sessions based on either clinician or patient assessment. Furthermore, 19.1% of ATX-101-treated patients (vs 3.9% of placebo-treated patients) received fewer than 6 treatment sessions owing to patient satisfaction with treatment or lack of sufficient SMF for further treatment. In both treatment groups, the incidence/severity of common injection-site adverse events declined over subsequent treatment sessions. CONCLUSIONS: Although up to 6 treatment sessions were permitted in the REFINE trials, most ATX-101-treated patients achieved an improvement in SMF within 2 to 4 treatment sessions. Level of Evidence: 3.

Overview of ATX-101 (Deoxycholic Acid Injection): A Nonsurgical Approach for Reduction of Submental Fat.

In 2015, 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 as a first-in-class injectable drug for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat. ATX-101 has been evaluated in a clinical development program that included 18 Phase 1 to 3 studies supporting the current indication. Since 2007, the toxicity and safety profiles of ATX-101 have been characterized in numerous preclinical studies, its pharmacokinetics, pharmacodynamics, and optimal treatment paradigm have been defined in multiple Phase 1 and 2 studies, and its efficacy and clinical safety have been confirmed in 4 large Phase 3 trials (2 conducted in Europe and 2 in the United States and Canada [REFINE-1 and REFINE-2]). As subcutaneous injection of deoxycholic acid has been shown to cause adipocytolysis, the reduction in submental fat achieved after ATX-101 treatment is expected to be long lasting. This prediction is confirmed by data from long-term follow-up studies of up to 4 years after last treatment with ATX-101, which demonstrate that the treatment response is maintained over time in most subjects. ATX-101 offers a durable, minimally invasive alternative to liposuction and surgery for addressing submental fullness.

Management of Patient Experience With ATX-101 (Deoxycholic Acid Injection) for Reduction of Submental Fat.

BACKGROUND: ATX-101 (deoxycholic acid injection; Kythera Biopharmaceuticals, Inc., Westlake Village, CA [an affiliate of Allergan plc, Dublin, Ireland]) was recently approved for submental fat (SMF) reduction in the United States (Kybella) and Canada (Belkyra). The pivotal trials supporting these approvals revealed that ATX-101 is associated with common injection-site treatment reactions consistent with its mechanism of action and administration procedure. OBJECTIVE: The purpose of this study was to evaluate 4 patient experience management paradigms targeting the common injection-site adverse events of pain, swelling/edema, and bruising after a single treatment session with ATX-101. METHODS: In this double-blind, parallel-group, exploratory Phase 3b study (ClinicalTrials.gov identifier: NCT02007434), subjects with moderate to severe SMF were randomized 4:1 within each paradigm to receive ATX-101 2 mg/cm or placebo. In Paradigm 1, subjects received a cold pack application to the treatment area. In Paradigm 2, in addition to cold pack application, subjects were treated with topical lidocaine and injectable lidocaine containing epinephrine. In Paradigm 3, in addition to the interventions of Paradigm 2, subjects received loratadine and ibuprofen. Subjects in Paradigm 4 received the same interventions in Paradigm 3, plus application of a chin strap. RESULTS: Eighty-three subjects were treated. In ATX-101-treated subjects, peak pain occurred within 1 to 5 minutes of treatment, with median values at these time points ranging from 21.4 to 35.7 mm on a 100-mm pain visual analog scale ("mild"). Pain ratings reduced substantially by 15 minutes; at 4 hours after injection, pain was characterized as mild tenderness or mild achiness. Compared with cold alone, treatment with topical and injectable lidocaine reduced median peak pain by 17%. Addition of ibuprofen and loratadine resulted in a total reduction in pain by 40%. Peak swelling/edema in ATX-101-treated subjects was "modest," with mean values ≤1.7 (on a 0-5 scale) across all paradigms. Swelling/edema was not substantially mitigated by the interventions, including ibuprofen, loratidine, and the use of a chin strap. Bruising associated with ATX-101 treatment was confined to the treatment area, with mean values between 1.0 and 1.4 on a 0-to-5 scale. Bruising was modestly reduced by injectable lidocaine with epinephrine. CONCLUSION: Results from this study support the safety of ATX-101 for SMF reduction, and demonstrate that pain and bruising associated with ATX-101 treatment can be mitigated by a series of simple measures.

REFINE-1, a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial With ATX-101, an Injectable Drug for Submental Fat Reduction.

BACKGROUND: ATX-101, an injectable form of deoxycholic acid, is approved in the United States and Canada for submental fat (SMF) reduction. OBJECTIVE: To report results of REFINE-1, a randomized, double-blind, placebo-controlled, Phase 3 trial investigating the efficacy and safety of ATX-101. METHODS: Subjects dissatisfied with their moderate or severe SMF received ATX-101 (2 mg/cm) or placebo. Coprimary outcome measures were composite ≥1-grade and ≥2-grade improvements in clinician-assessed and subject-assessed SMF severity using validated scales at 12 weeks after last treatment. Magnetic resonance imaging (MRI) provided an objective measure of submental volume reduction. Patient-reported outcomes were assessed. RESULTS: Among 256 ATX-101-treated and 250 placebo-treated subjects, a ≥1-grade composite response was achieved in 70.0% and 18.6%, and a ≥2-grade composite response in 13.4% and 0%, respectively (p < .001 for both). The proportion of MRI responders was more than 8 times higher with ATX-101 than placebo (46.3% vs 5.3%; p < .001). ATX-101-treated subjects reported improvement in the psychological impact of SMF and satisfaction with treatment (p < .001 for all assessments vs placebo). Of note, 55% and 75% of ATX-101-treated subjects reported 1-grade improvement in clinician-assessed SMF after 2 and 4 treatments, respectively. Adverse events (primarily localized to the injection site) were mostly mild or moderate, and transient. Marginal mandibular nerve paresis reported in 4.3% of ATX-101-treated subjects (1.0% of all ATX-101 treatment sessions) was mostly mild, transient, and resolved without sequelae. CONCLUSION: ATX-101 is a safe and efficacious, first-in-class, injectable drug for SMF reduction.

Prevalence of the metabolic syndrome in children with psoriatic disease.

Adults with psoriasis have a greater risk of developing metabolic syndrome (MetS) and cardiovascular disease (CVD), but few studies have investigated the prevalence of MetS and other risk factors for CVD in children with psoriasis. In an assessor-blinded study, 20 children ages 9-17 years with a current or previously documented history of psoriasis involving 5% or more of their body surface area or psoriatic arthritis were compared with a cohort of age- and sex-matched controls with benign nevi, warts, or acne. MetS, our primary endpoint, was defined by the presence of abnormal values in at least three of the following measures: triglycerides, high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), waist circumference, and blood pressure. Secondary endpoints included high-sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Thirty percent (6/20) of children with psoriasis met the criteria for MetS, compared with 5% (1/20) of the control group (p < 0.05). Subjects with psoriasis had higher mean FBG (91.1 mg/dL) than the control group (82.9 mg/dL) (p = 0.01). There were no statistically significant differences in the other four components of MetS, BMI, BMI percentile, hs-CRP, TC, or LDL-C. The results of this trial demonstrate that children with psoriasis have higher rates of MetS than age- and sex-matched controls. It may therefore be important to evaluate children with psoriasis for components of MetS to prevent future CVD morbidity and mortality.

Cutaneous clues to renal cell carcinoma: hereditary leiomyomatosis and renal cell carcinoma.

We present a case of a 33-year-old female who was incidentally found to have cutaneous leiomyomata during a routine skin examination. Further history revealed that she also suffered from uterine fibroids and that her mother had died at an early age from renal cell carcinoma. This case serves as a reminder of the often-subtle cutaneous clues, as well as the importance of a multidisciplinary approach, for early diagnosis of potentially fatal conditions.

Management of psoriatic arthritis from the view of the dermatologist.

Psoriatic arthritis (PsA) is an inflammatory seronegative spondyloarthropathy associated with psoriasis. Although the main assessment measures for PsA are borrowed from the standard criteria used to assess rheumatoid arthritis, a number of new criteria such as the PsAJAI and CPDAI are being developed specifically for PsA. Long-term consequences of untreated PsA include persistent inflammation, progressive joint damage and, in many cases, substantial functional limitations, pain and disability. Moreover, patients with PsA have an increased mortality risk and an increased risk of developing cardiovascular disease and metabolic syndrome. Both GRAPPA and the AAD have developed treatment guidelines, which are discussed here. Psoriasis commonly precedes arthritic symptoms; thus, dermatologists are ideally placed to make the initial diagnosis of PsA and treat it appropriately, affording the opportunity to slow disease progression, improve physical function and enhance quality of life. This Review explores the management of patients with PsA, with a particular emphasis on assessment tools, long-term consequences and treatment issues from the viewpoint of the dermatologist.

Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept.

Etanercept, a recombinant human tumor necrosis factor (TNF) receptor fusion protein, is FDA approved for psoriasis and psoriatic arthritis. TNFalpha increases the synthesis of proinflammatory cytokines and leads to the activation of multiple signaling pathways, including nuclear factor kappa B (NF-kappaB). The Rel/NF-kappaB transcription factors play a central role in numerous cellular processes, including the stress response and keratinocyte proliferation and differentiation. Utilizing a phosphorylation-specific antibody, we examined the expression of active nuclear NF-kappaB/RelA via immunohistochemistry in normal skin, non-lesional psoriatic skin, lesional psoriatic skin, and lesional skin from patients treated with etanercept. There was no expression of active nuclear NF-kappaB in the normal epidermis, whereas a basal level of constitutive active phosphorylated NF-kappaB/RelA was present in uninvolved epidermis from psoriasis patients. There was also significant upregulation of active phosphorylated NF-kappaB/RelA in the epidermis from psoriatic plaques. Serial biopsies from psoriasis patients treated with etanercept at 1, 3, and 6 mo demonstrated a significant downregulation of phosphorylated NF-kappaB/RelA, which correlated with decreases in epidermal thickness, restoration of normal markers of keratinocyte differentiation, and clinical outcomes. These data suggest that activation of NF-kappaB plays a significant role in the pathogenesis of psoriasis and that a potential mechanism of action for TNF-targeting agents is downregulation of NF-kappaB transcriptional activity.