Background There is a need for improved medical approaches to the treatment of actinic keratosis. Ingenol mebutate, a diterpene ester extracted and purified from the plant Euphorbia peplus , is being ...evaluated as a topical therapy for actinic keratosis. Objective Assess the efficacy and safety of ingenol mebutate (formerly PEP005) gel at 3 dosing regimens for the treatment of actinic keratosis. Methods Patients with non-facial actinic keratoses applied vehicle gel for 3 days, ingenol mebutate gel, 0.025% for 3 days, or ingenol mebutate gel, 0.05% for 2 or 3 days, with an 8-week follow-up period. Results All 3 active treatments were significantly more effective than vehicle at clearing actinic keratosis lesions, with a dose response observed. The partial clearance rate (primary efficacy end point) for patients treated with ingenol mebutate gel ranged from 56.0% to 75.4% compared with 21.7% for vehicle gel ( P = .0002 to P < .0001 vs vehicle). The complete clearance rate was also significantly higher ( P ≤ .0006) for patients in the ingenol mebutate gel treatment groups (range: 40.0% to 54.4%) compared with vehicle (11.7%), as was the baseline clearance rate (range: 42.0% to 57.9% for ingenol mebutate gel compared with 13.3% for vehicle, P < .0001 to .0007 vs vehicle). The median percentage reduction in baseline actinic keratosis lesions for patients treated with ingenol mebutate gel ranged from 75% to 100% compared with 0% for vehicle gel ( P < .0001 vs vehicle). Active treatment was well tolerated at all dosages. The mechanism of action of this agent is the localized induction of necrosis followed by a transient inflammatory response, and this was manifested in most patients as transient local skin responses consisting primarily of erythema, flaking/scaling, and crusting. There was no evidence of treatment-related scarring. Limitations Local skin responses may have suggested active treatment to investigators. Conclusions Short-course, field-directed therapy with ingenol mebutate gel for actinic keratoses on non-facial sites seems to be effective with a favorable safety profile and potential benefits over topical agents that require a more prolonged course of treatment.
Background: Topical minoxidil solution 2% stimulates new hair growth and helps stop the loss of hair in individuals with androgenetic alopecia (AGA). Results can be variable, and historical ...experience suggests that higher concentrations of topical minoxidil may enhance efficacy. Objective: The purpose of this 48-week, double-blind, placebo-controlled, randomized, multicenter trial was to compare 5% topical minoxidil with 2% topical minoxidil and placebo in the treatment of men with AGA. Methods: A total of 393 men (18-49 years old) with AGA applied 5% topical minoxidil solution (n = 157), 2% topical minoxidil solution (n = 158), or placebo (vehicle for 5% solution; n = 78) twice daily. Efficacy was evaluated by scalp target area hair counts and patient and investigator assessments of change in scalp coverage and benefit of treatment. Results: After 48 weeks of therapy, 5% topical minoxidil was significantly superior to 2% topical minoxidil and placebo in terms of change from baseline in nonvellus hair count, patient rating of scalp coverage and treatment benefit, and investigator rating of scalp coverage. Hair count data indicate that response to treatment occurred earlier with 5% compared with 2% topical minoxidil. Additionally, data from a patient questionnaire on quality of life, global benefit, hair growth, and hair styling demonstrated that 5% topical minoxidil helped improve patients' psychosocial perceptions of hair loss. An increased occurrence of pruritus and local irritation was observed with 5% topical minoxidil compared with 2% topical minoxidil. Conclusion: In men with AGA, 5% topical minoxidil was clearly superior to 2% topical minoxidil and placebo in increasing hair regrowth, and the magnitude of its effect was marked (45% more hair regrowth than 2% topical minoxidil at week 48). Men who used 5% topical minoxidil also had an earlier response to treatment than those who used 2% topical minoxidil. Psychosocial perceptions of hair loss in men with AGA were also improved. Topical minoxidil (5% and 2%) was well tolerated by the men in this trial without evidence of systemic effects. (J Am Acad Dermatol 2002;47:377-85.)
Onychomycosis is a common nail infection that is difficult to treat successfully. The prevalence increases with age and is associated with diabetes. Oral treatments are limited by drug interactions ...and potential hepatotoxicity; topical treatments, by modest efficacy.
We investigated the efficacy and safety of a solution using a novel topical triazole antifungal, efinaconazole, in distal lateral subungual onychomycosis (DLSO).
Multicenter, randomized, double-blind, vehicle-controlled phase 2 study in mild to moderate toenail DLSO (n=135). Subjects randomized (2:2:2:1 ratio) to receive efinaconazole 10% solution (with or without semiocclusion), efinaconazole 5% solution, or vehicle, once daily for 36 weeks, with one 4-week posttreatment follow-up (week 40). Efficacy assessments included complete cure, mycologic cure, clinical efficacy, and other assessments of overall treatment effectiveness. No efficacy variables were designated as primary.
At follow-up, complete cure was numerically higher in all active groups (16%-26%) compared with vehicle (9%). Mycologic cure rates with efinaconazole 10% semiocclusion, efinaconazole 10%, and efinaconazole 5% were 83%, 87%, and 87%, respectively. Efinaconazole 10% (with or without semiocclusion) demonstrated significantly greater clinical efficacy and treatment effectiveness when compared with vehicle (P=.0088 and .0064; .0056 and .0085, respectively, for both efinaconazole 10% groups). Adverse events were generally similar and mild. Local-site reactions were restricted to few subjects and did not differ meaningfully from those produced by vehicle.
This study provided evidence that once-daily efinaconazole 10% solution (with or without semiocclusion) applied topically for 36 weeks was more effective than vehicle in treating DLSO and was well tolerated. Based on these results, efinaconazole 10% solution was chosen for the phase 3 development program.
Long-term topical treatment is often required for atopic dermatitis (AD), a chronic inflammatory skin disease.
To assess the long-term safety results from a multicenter, open-label, 48-week safety ...study (AD-303) of patients (N = 517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, a topical phosphodiesterase-4 inhibitor, after completing a 28-day phase 3 pivotal study (AD-301, AD-302).
Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28-day treatment period with crisaborole applied twice daily was initiated. Adverse events (AEs), including treatment-emergent AEs (TEAEs), and serious AEs were analyzed.
During the pivotal studies and AD-303, 65% of patients reported ≥1 TEAE, most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment-related AEs (overall, 10.2%) were dermatitis atopic (3.1%), application-site pain (2.3%), and application-site infection (1.2%). Nine patients (1.7%) discontinued the long-term study because of TEAEs.
Long-term efficacy was not analyzed.
Crisaborole ointment had a low frequency of treatment-related AEs over 48 weeks of treatment of patients with AD.
Adverse changes in bone have been reported for patients undergoing high-dose, long-term (several years) isotretinoin therapy for disorders of cornification. The effect of short-term (4-5 months) ...therapy at the lower dose recommended for acne on bone development in younger, growing adolescent (12-17 years) patients has not been well studied.
The purpose of the study was to evaluate the effect of a standard, single course of isotretinoin (Accutane) therapy on bone mineral density (BMD) of the lumbar spine and hip in adolescents ages 12 to 17 years with severe, recalcitrant, nodular acne.
In this open-label, multicenter study, 217 adolescents (81 girls) with severe, recalcitrant, nodular acne were enrolled and treated with isotretinoin twice daily with food at the recommended total dose of approximately 1 mg/kg for 16 to 20 weeks. BMD in the lumbar spine and hip was measured at baseline and at the end of therapy by dual energy radiograph absorptiometry.
There was no clinically significant mean change in BMD measured at the lumbar spine (+1.4%, range: −4.9% to +12.3%) or total hip (−0.26%, range: −11.3% to +15.0%). Hyperostosis was not observed in any patient. Typical efficacy expected in the treatment of acne was observed.
A 16- to 20-week course of isotretinoin treatment at the recommended dose for severe acne has no clinically significant effect on lumbar spine and total hip BMD in the adolescent (12-17 years) population.
Background
Phosphodiesterase‐4 (PDE4) is a promising target in atopic dermatitis (AD) treatment. The pharmacokinetics (PK), safety, and efficacy of crisaborole topical ointment, 2% (formerly AN2728) ...(Anacor Pharmaceuticals, Palo Alto, CA), a boron‐based benzoxaborole PDE4 inhibitor, were evaluated in children with mild to moderate AD.
Methods
This phase 1b, open‐label, maximal‐use study of crisaborole topical ointment, 2% applied twice daily (dose 3 mg/cm2) for 28 days enrolled patients ages 2 to 17 years with extensive AD involving 25% or more or 35% or more treatable body surface area, depending on age. Primary PK and safety assessments included systemic exposure to crisaborole and its metabolites after 7 days of treatment and the incidence of treatment‐emergent adverse events (TEAEs). Secondary efficacy assessments included change from baseline in Investigator Static Global Assessment (ISGA), treatment success (ISGA score ≤1 with a two‐grade or greater improvement from baseline), and improvement in five AD signs and symptoms.
Results
Of 34 patients enrolled, 31 completed the study. Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8. Twenty‐three of 34 patients reported one or more TEAEs; 95% were mild or moderate and one patient discontinued because of a TEAE. Mean ISGA scores declined from 2.65 at baseline to 1.15 at day 29, 47.1% of patients achieved treatment success, and 64.7% of patients achieved ISGA scores of clear (0) or almost clear . Mean severity scores for AD signs and symptoms declined throughout the study.
Conclusions
This open‐label study provides evidence that crisaborole topical ointment, 2% was well tolerated, with limited systemic exposure under maximal‐use conditions in patients ages 2 years and older.
Summary
Background
Onychomycosis is a fungal disease that affects the fingernails and toenails and is predominantly caused by dermatophytes. VT‐1161 is a novel inhibitor of fungal CYP51 through the ...inhibition of lanosterol demethylase, and has demonstrated potent activity against Trichophyton rubrum and Trichophyton mentagrophytes.
Objectives
To evaluate the safety and efficacy of four dosing regimens of orally administered VT‐1161 compared with placebo in patients with moderate‐to‐severe distal and lateral subungual onychomycosis of the toenail.
Methods
This was a phase II, randomized, double‐blind, placebo‐controlled, multicentre study (ClinicalTrials.gov identifier NCT02267356). Patients aged 18–70 years (n = 259) who had 25–75% mycotic involvement were randomized to five treatment groups. They received 300 mg VT‐1161 as a 2‐week daily dose, followed by a once‐weekly dose for either 10 or 22 weeks, or 600 mg VT‐1161 as a 2‐week daily dose, followed by a once‐weekly dose for either 10 or 22 weeks. All treatments were followed by a nontreatment period of 36 weeks. A matching placebo arm was included.
Results
In the intent‐to‐treat population, at week 48 the complete cure rates were 0% in the placebo group and ranged from 32% to 42% in the VT‐1161 treatment groups (P < 0·001 vs. placebo). VT‐1161 was well tolerated, with no evidence of an adverse effect on liver function or QT intervals.
Conclusions
VT‐1161 treatment led to high nail clearance rates and a favourable safety profile. VT‐1161 exhibits characteristics that appear promising for the treatment of this chronic and difficult‐to‐treat condition and warrants further evaluation in larger studies.
What is already known about this topic?
Onychomycosis is a fungal disease that is chronic and difficult to treat.
Topical drugs are currently available but have limited effectiveness. Oral drugs, while effective, suffer from side‐effects including liver function abnormalities.
The majority of patients are elderly on polypharmacy and are at high risk of drug interactions.
An effective and safe oral drug with low potential for liver toxicity and drug interaction is highly desirable.
What does this study add?
This study presents the first large phase II study of a novel tetrazole antifungal, VT‐1161.
The study shows that VT‐1161 has an encouraging safety profile and is highly effective in treating even hard‐to-treat cases of onychomycosis.
The new tetrazole provides a lower overall drug load with an excellent safety and tolerability profile.
VT‐1161 is as effective as or numerically better than the current standard of care, terbinafine.
Linked Comment: Barbieri. Br J Dermatol 2021; 184:191.
Plain language summary available online
Side effects may limit the use of current tetracycline-class antibiotics for acne.
Evaluate the efficacy and safety of once-daily sarecycline, a novel, narrow-spectrum tetracycline-class antibiotic, ...in moderate to severe acne.
Patients 9-45 years with moderate to severe facial acne (Investigator's Global Assessment IGA score ≥ 3, 20-50 inflammatory and ≤ 100 noninflammatory lesions, and ≤ 2 nodules) were randomized 1:1 to sarecycline 1.5 mg/kg/day or placebo for 12 weeks in identically designed phase 3 studies (SC1401 and SC1402).
In SC1401 (sarecycline n=483, placebo n=485) and SC1402 (sarecycline n=519, placebo n=515), at week 12, IGA success (≥ 2-grade improvement and score 0 clear or 1 almost clear) rates were 21.9% and 22.6% (sarecycline), respectively, versus 10.5% and 15.3% (placebo; P less than 0.0001 and P equals 0.0038). Onset of efficacy in inflammatory lesions occurred by the first visit (week 3), with mean percentage reduction in inflammatory lesions at week 12 in SC1401 and SC1402 of -51.8% and -49.9% (sarecycline), respectively, versus -35.1% and -35.4% (placebo; P less than 0.0001). Onset of efficacy for absolute reduction of noninflammatory lesion count occurred at week 6 in SC1401 (P less than 0.05) and week 9 in SC1402 (P less than 0.01). In SC1401, the most common TEAEs (in ≥ 2% of either sarecycline or placebo group) were nausea (4.6% sarecycline; 2.5% placebo), nasopharyngitis (3.1%; 1.7%), headache (2.7%; 2.7%), and vomiting (2.1%; 1.4%) and, in SC1402, nasopharyngitis (2.5%; 2.9%) and headache (2.9%; 4.9%). Most were not considered treatment-related. Vestibular (dizziness, tinnitus, vertigo) and phototoxic (sunburn, photosensitivity) TEAEs both occurred in ≤ 1% of sarecycline patients. Gastrointestinal TEAE rates for sarecycline were low. Among females, vulvovaginal candidiasis (SC1401: 1.1% sarecycline and 0 placebo; SC1402: 0.3% and 0) and mycotic infection (0.7% and 0; 1.0% and 0) rates were low.
The narrow-spectrum antibiotic sarecycline was safe, well tolerated, and effective for moderate to severe acne, with low rates of side effects common with tetracycline antibiotics. J Drugs Dermatol. 2018;17(9):987-996.
Abstract
AN2728, a novel boron-based compound, inhibits phosphodiesterase-4 and reduces proinflammatory cytokine production possibly associated with atopic dermatitis(AD). This open-label maximal-use ...study evaluated systemic exposure, PK, and safety of AN2728 Ointment, 2% BID for 28 days in children and adolescents with mild-to-moderate AD(N=34; 3 cohorts based on age and minimum % treatable body surface area %BSA affected: 2-5y ≥35%; 6-11y ≥35%; 12-17y ≥25%). Disease severity was measured using Investigator’s Static Global Assessment (ISGA; 0, clear to 4, severe), signs/symptoms score (0, none to 3, severe) and %BSA affected. At day 29, 65% of subjects had ISGA scores of clear or almost clear and 47% had scores of clear or almost clear and a ≥2-grade improvement vs baseline. Marked reductions vs baseline were seen for AD signs and symptoms (pruritus, erythema, lichenification, excoriation, exudation) throughout treatment. Mean pruritus scores improved by ~60% vs baseline as early as treatment day 5. Mean %BSA affected decreased by 78% after 4 weeks of treatment. The most common treatment-related adverse events were application site reactions (n=12) which generally were mild or moderate and resolved spontaneously. One patient withdrew due to application site pain. PK results showed low AN2728 blood levels similar to those previously seen in adults after adjusting for %BSA treated. AN2728 Ointment, 2% may be safe and effective in subjects aged ≥2 years with mild-to-moderate AD.
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