Variables in Cryosurgery Technique Associated With Clearance of Actinic Keratosis.

BACKGROUND: Cryosurgery is the most commonly used method to treat actinic keratosis (AK). Cryosurgical methods are not standardized. OBJECTIVE: To examine differences in the spray techniques used for liquid nitrogen cryosurgery when treating AKs of the head, and the effect of these variations in technique on rates of complete clearance of AKs. MATERIALS AND METHODS: Patients were those from the FIELD-1 study, who received cryosurgery as per the investigators' usual practice to all AKs. This was followed by topical treatment with either vehicle gel or ingenol mebutate gel, 0.015%, after 3 weeks. The investigator recorded the average duration of cryosurgery spray used, the number of freeze-thaw cycles, and the distance from the tip of the spray device to the AK. Clearance rates were determined at Week 11. RESULTS: Less-aggressive freezing techniques were used for AKs on the face than for those on the scalp. However, higher rates of complete clearance on the face and scalp were associated with more-aggressive freezing techniques. CONCLUSION: Patients with AKs on the face receive less-aggressive cryosurgery than do patients with AKs on the scalp.

Regression Analysis of Local Skin Reactions to Predict Clearance of Actinic Keratosis on the Face in Patients Treated With Ingenol Mebutate Gel: Experience from Randomized Controlled Trials.

Ingenol mebutate gel, a topical field treatment for actinic keratosis (AK), elicits inflammatory application-site reactions in most patients. This analysis explored the relationship between the intensity of local skin reactions (LSRs) and AK clearance, measured by the reduction in AK count from baseline in 218 patients who were treated for AK on the face in the pivotal Phase 3 studies. The analysis modeled the AK count at week 8, adjusted for baseline count, with the composite LSR score at 1 day after the last treatment application for each patient as a predictor to estimate the mean and 90% prediction interval for the percent reduction in AK count. The predicted mean percent reduction in AK count was higher in patients with higher composite LSR scores. Lower composite scores demonstrated a variable, less predictive percentage reduction in efficacy. Therefore, a large inflammatory reaction from ingenol mebutate gives a more reliable prognosis for improved AK clearance.

J Drugs Dermatol. 2017;16(2):112-114.

Ingenol mebutate gel for actinic keratosis: the link between quality of life, treatment satisfaction, and clinical outcomes.

BACKGROUND: Actinic keratosis therapy can elicit unsightly and painful local skin responses; assessment of treatment satisfaction and health-related quality of life (QoL) is important. Ingenol mebutate gel is a novel topical field therapy for actinic keratosis. OBJECTIVE: Post-hoc analyses were performed based on patient-reported outcomes from phase-III trials (n = 1005) to assess the effects of ingenol mebutate on QoL and the relationship between both QoL and treatment satisfaction, and degree of lesion clearance. METHODS: Patients received ingenol mebutate or vehicle for self-application to a 25-cm(2) contiguous area: 0.015% once daily for 3 consecutive days (face/scalp) or 0.05% once daily for 2 consecutive days (trunk/extremities). QoL (Skindex-16) and Treatment Satisfaction Questionnaire for Medication data were recorded. RESULTS: Significant, positive associations between Treatment Satisfaction Questionnaire for Medication score and degree of clearance were identified for patients in the face/scalp (effectiveness P < .0001 and global satisfaction P = .0002) and trunk/extremities (P < .0001 and P = .0014, respectively) groups. There was a significant association between Skindex-16 score and clearance for patients in the face/scalp group for change in symptoms (P = .0218), emotions (P = .0002), and overall Skindex-16 score (P = .0006) from baseline. LIMITATIONS: Clinical trial population findings may not be generalizable to clinical practice. CONCLUSION: Ingenol mebutate significantly improved patients' QoL and treatment satisfaction. Improvements were associated with higher degrees of actinic keratosis lesion clearance.

Efficacy and safety of ingenol mebutate 0.015% gel after cryosurgery of actinic keratosis: 12-month results.

INTRODUCTION: Recurrence rates of actinic keratosis (AK) lesions after cryosurgery are high, and this treatment does not address field cancerization. We investigated the efficacy and safety of field treatment of AKs with ingenol mebutate gel following cryosurgery. METHODS: In this phase 3, randomized, double-blind, vehicle-controlled study (NCT01541553), patients ≥18 years with four to eight clinically typical, visible, discrete AKs within a contiguous 25-cm2 treatment area on the face or scalp underwent cryosurgery followed 3 weeks later by once-daily ingenol mebutate 0.015% or vehicle gel for 3 consecutive days. Endpoints included complete clearance at week 11 and safety and efficacy over 12 months. RESULTS: In 329 randomized patients, complete clearance rates were greater with ingenol mebutate than vehicle (week 11: 60.5% vs 49.4%; P=.04; month 12: 30.5% vs 18.5%; P=.01). Fewer patients experienced the emergence of new lesions with ingenol mebutate than with vehicle (38.9% vs 51.9%; P =.02). At month 12, mean percentage reduction of AKs was higher with ingenol mebutate than with vehicle (68.2% vs 54.1%; P =.002). The probability of remaining free of lesions was sustained longer with ingenol mebutate compared with vehicle gel: 78% vs 68% at 6 months; 64% vs 57% at 9 months; 55% vs 40% at month 12, respectively. Ingenol mebutate 0.015% gel was well tolerated and no unexpected adverse events occurred; all adverse events resolved within 2 weeks of starting treatment. CONCLUSIONS: Field treatment with ingenol mebutate 0.015% gel following cryosurgery significantly enhanced clearance of baseline lesions, and was well tolerated. Furthermore, ingenol mebutate 0.015% gel following cryosurgery reduced development of new lesions in the treated field.

Efficacy and safety of ingenol mebutate 0.015% gel 3 weeks after cryosurgery of actinic keratosis: 11-week results.

INTRODUCTION: Cryosurgery is the most common treatment for actinic keratosis (AK) in the United States. Efficacy with cryosurgery is variable, and is a modality for treating individual, visible lesions while failing to treat subclinical lesions. METHODS: FIELD Study 1 (NCT01541553) is a phase 3, multicenter, randomized, double-blind study that evaluated the short- (11-week) and long- (12-month) term efficacy and safety of sequential AK treatment using cryosurgery with liquid nitrogen followed by ingenol mebutate gel, versus cryosurgery followed by vehicle. RESULTS: Overall, 329 patients were randomized to ingenol mebutate 0.015% gel (n=167) or vehicle (n=162) 3 weeks after cryosurgery. Baseline characteristics were balanced across groups. At week 11, complete clearance rate (100%) in the treatment area was higher for ingenol mebutate gel compared with vehicle (60.5% vs 49.4%, respectively; P=.04). Mean percentage reduction in number of AKs versus baseline was also numerically higher for ingenol mebutate gel (82.7% vs 75.6%). A general reduction from baseline lesion count was observed 3 weeks after cryosurgery. Treatment after cryosurgery was well tolerated. CONCLUSIONS: Short-term (11-week) AK clearance rates on the face or scalp with ingenol mebutate gel after cryosurgery were higher than with cryosurgery alone.

Pharmacokinetics, Safety, and Tolerability of Glepaglutide, a Long-Acting GLP-2 Analog, in Subjects with Renal Impairment.

BACKGROUND: Glepaglutide is a novel, ready-to-use, long-acting, glucagon-like peptide-2 (GLP-2) analog intended for the treatment of patients with short bowel syndrome (SBS). This study investigated the impact of renal function on the pharmacokinetics and safety of glepaglutide. METHODS: In this 3-site, non-randomized, open-label study, 16 subjects were enrolled: 4 with severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), 4 with end stage renal disease (ESRD) not on dialysis (eGFR < 15 mL/min/1.73 m2), and 8 matching controls with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). Blood samples were collected over a 14-day period following a single subcutaneous (SC) dose of glepaglutide 10 mg. Safety and tolerability were assessed throughout the study. The primary pharmacokinetic parameters were area under the curve between dosing and 168 h (AUC0-168 h) and the maximum plasma concentration (Cmax). RESULTS: There was no clinically relevant difference between subjects with severe renal impairment/ESRD and normal renal function with respect to total exposure (AUC0-168 h) and peak plasma concentrations (Cmax) of glepaglutide following a single SC dose. A single SC dose of glepaglutide 10 mg appeared safe and well tolerated in subjects with normal renal function and subjects with severe renal impairment or ESRD. No serious adverse events were reported, and no safety issues were identified. CONCLUSIONS: No difference in glepaglutide pharmacokinetics was seen between renal impaired and normal subjects. Based on this trial, dose adjustment appears not to be warranted in SBS patients with renal impairment. TRIAL REGISTRATION: The trial is registered at http://www. CLINICALTRIALS: gov (NCT04178447) and has the EudraCT number: 2019-001466-15.

Pharmacokinetics of Glepaglutide, A Long-Acting Glucagon-Like Peptide-2 Analogue: A Study in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Glepaglutide is a novel, long-acting, glucagon-like peptide-2 analogue in a stable aqueous formulation for subcutaneous dosing to treat patients with short bowel syndrome. This study was conducted primarily to characterise the pharmacokinetics of glepaglutide in healthy subjects. METHODS: In this open-label, partially randomised, parallel-group study, healthy subjects were evenly randomised to glepaglutide 5 or 10 mg dosed subcutaneously once weekly for 6 weeks or to a single intravenous infusion of glepaglutide 1 mg. Each group comprised 15 subjects. Blood samples were drawn to determine plasma concentrations of the parent drug and its two main metabolites. Concentrations of glepaglutide were calculated as the sum of these three analytes. Citrulline was included as a pharmacodynamic biomarker. Safety was assessed throughout the study. RESULTS: From a comparison of pharmacokinetic parameters following subcutaneous versus intravenous dosing, it is concluded that the pharmacokinetics of glepaglutide following subcutaneous dosing are primarily determined by slow release of the two main glepaglutide metabolites from a subcutaneous depot. For subcutaneous dosing once weekly, the two main metabolites accounted for >98% of the overall glepaglutide exposure at steady state, with the parent drug contributing to less than 1% of exposure. The estimated mean (95% confidence interval) effective half-life for glepaglutide 5 and 10 mg was 124 (73-185) h and 88 (31-146) h, respectively. There was an increase in the citrulline concentration for both glepaglutide subcutaneous dose levels. No safety issues were identified. CONCLUSIONS: Slow release of active metabolites following subcutaneous dosing leads to a significantly protracted pharmacokinetic profile for glepaglutide. These results support that once- or twice-weekly subcutaneous dosing of glepaglutide could be an efficacious therapy for intestinal rehabilitation. GOV IDENTIFIER: NCT03279302.

Relationship between severity of the local skin reactions and the rate of local skin reaction resolution in patients treated with ingenol mebutate gel.

BACKGROUND: Ingenol mebutate gel is a topical field treatment for actinic keratosis (AK). The treatment elicits application-site reactions in most patients. This analysis evaluated the relationship between the severity of reactions and the speed of their resolution. METHODS: Patients in Phase III studies were treated for AKs on the face (n=218), scalp (n=56), and trunk and extremities (n=209). All of the patients were treated with either ingenol mebutate gel 0.015% once daily for three consecutive days (face/scalp) or ingenol mebutate gel 0.05% once daily for two consecutive days (trunk/extremities). Local skin reactions (LSRs) were assessed on a 5-point scale from 0 to 4 in six categories, yielding composite scores in the range of 0 to 24. RESULTS: The composite LSR score on the day after the last application of ingenol mebutate gel was an important predictor of the speed of resolution of LSRs. The rate of resolution was greatest for AKs treated on the face, followed by the scalp, and then the trunk and extremities. All patients were expected to have minimal LSR scores for the face and scalp at 2 weeks, and for the trunk and extremities at 4 weeks. CONCLUSION: The absolute reduction in LSR scores was proportional to the composite LSR score on the day after the last application of ingenol mebutate gel treatment. The rate of resolution for LSRs was dependent on the anatomic site treated as well as the day 4 composite score.

Association of metabolic syndrome and hidradenitis suppurativa.

IMPORTANCE An association between the metabolic syndrome (MetS) and chronic inflammatory diseases, such as psoriasis or rheumatoid arthritis, has been suggested.Hidradenitis suppurativa (HS), a more localized chronic inflammation of the skin, has been speculated to have a similar association. Hidradenitis suppurativa is a substantial burden for the individual and a socioeconomic burden globally. Information about the burden of possible comorbidities is scarce.OBJECTIVE To investigate the possibility of an association between HS and MetS.DESIGN, SETTING, AND PARTICIPANTS Cross-sectional population- and hospital-based study of HS and MetS.We identified 32 patients with physician-verified HS from the outpatient clinic at the Department of Dermatology, Roskilde Hospital, and 326 patients with HS and 14 851 individuals without HS from the general population. Individuals with HS were younger,predominantly female, and more often smokers compared with the non-HS group.EXPOSURE Hidradenitis suppurativa.MAIN OUTCOMES AND MEASURES Metabolic syndrome and its components of diabetes mellitus, hypertension, dyslipidemia, and obesity.RESULTS When compared with the non-HS group, the odds ratios (ORs) for the hospital HS and population HS groups were 3.89 (95%CI, 1.90-7.98) and 2.08 (95%CI, 1.61-2.69),respectively, for MetS; 5.74 (95%CI, 1.91-17.24) and 2.44 (95%CI, 1.55-3.83), respectively, for diabetes mellitus; 6.38 (95%CI, 2.99-13.62) and 2.56 (95%CI, 2.00-3.28), respectively, for general obesity; and 3.62 (95%CI, 1.73-7.60) and 2.24 (95%CI, 1.78-2.82), respectively, for abdominal obesity. With regard to dyslipidemia, significant results were found for decreased levels of high-density lipoprotein cholesterol, with ORs of 2.97 (95%CI, 1.45-6.08) and 1.94(95%CI, 1.52-2.48) for the hospital HS and general population HS groups, respectively, when compared with the non-HS group. With regard to increased triglyceride levels, only the result for the population HS group compared with the non-HS group was significant, with an OR of1.49 (95%CI, 1.18-1.87). The OR for hypertension, which was only significant for the hospital HS group compared with the non-HS group, was 2.14 (95%CI, 1.01-4.53). Obesity and inflammation acted as possible confounders. The ORs were higher for the hospital HS group compared with the population HS group. The association between HS and MetS was not influenced by the degree of HS severity.CONCLUSIONS AND RELEVANCE As with more systemic inflammatory diseases, HS appears to be associated with MetS, indicating substantial comorbidities. Because this study is cross-sectional, causality remains to be explored.