Safety and efficacy of bimekizumab through 2 years in patients with moderate-to-severe plaque psoriasis: longer-term results from the BE SURE randomized controlled trial and the open-label extension from the BE BRIGHT trial.

BACKGROUND: BE SURE 1-year results demonstrated the superior efficacy of bimekizumab compared with adalimumab with no unexpected safety findings. OBJECTIVES: To provide efficacy and safety data over 2 years of bimekizumab treatment compared with adalimumab from BE SURE and the BE BRIGHT open-label extension (OLE) in patients with moderate-to-severe plaque psoriasis. METHODS: The 56-week double-blinded BE SURE phase III randomized controlled trial randomized patients 1 : 1 : 1 to bimekizumab 320 mg every 4 weeks (Q4W), bimekizumab 320 mg Q4W to week 16 then every 8 weeks (Q8W), or adalimumab 40 mg every 2 weeks to week 24 then bimekizumab 320 mg Q4W. After completing BE SURE, patients could enter the ongoing BE BRIGHT OLE, with possible dosing adjustments based on Psoriasis Area and Severity Index (PASI). The primary outcome in BE BRIGHT was incidence of treatment-emergent adverse events (TEAEs); safety data are reported by study period through week 104. Efficacy data are reported for the intention-to-treat population through week 104 by initial randomization group, with ≥ 90% improvement from baseline PASI (PASI 90) and 100% improvement (PASI 100) as key outcomes. RESULTS: Of the patients randomized to bimekizumab, 158 were assigned to Q4W, and 161 to Q4W/Q8W. At week 104, PASI 90 was achieved by 91.2% and 89.7%, and PASI 100 was achieved by 72.3% and 68.1%, for Q4W and Q4W/Q8W, respectively; comparable to week 16 results. Among the 159 patients randomized to adalimumab, responses rapidly and substantially increased after the week 24 bimekizumab switch; at week 104, 96.9% and 70.2% of patients achieved PASI 90 and PASI 100 respectively. Through weeks 24-104, the three most common TEAEs in any bimekizumab-treated group were nasopharyngitis, oral candidiasis and upper respiratory tract infection. Rates of serious TEAEs were low. CONCLUSIONS: Clinical responses observed through week 16 of BE SURE in patients randomized to bimekizumab were sustained through 104 weeks of treatment, regardless of Q4W or Q8W maintenance dosing. Response rates were also sustained through week 104 in patients who switched from adalimumab to bimekizumab at week 24, and were similar to those observed in the bimekizumab groups. Bimekizumab was well tolerated with no new safety signals.

Once-daily roflumilast foam 0.3% for scalp and body psoriasis: a randomized, double-blind, vehicle-controlled phase IIb study.

BACKGROUND: Scalp psoriasis affects most patients with psoriasis, but it can be difficult to treat. OBJECTIVES: To evaluate the efficacy and safety of once-daily roflumilast foam 0.3% on scalp and body psoriasis. METHODS: In a phase IIb randomized controlled trial, adults and adolescents aged ≥ 12 years with scalp and body psoriasis were randomized (2 : 1) to roflumilast foam 0.3% or vehicle for 8 weeks. The primary efficacy endpoint was scalp Investigator Global Assessment (S-IGA) success (score of 'clear' or 'almost clear' plus ≥ 2-grade improvement from baseline) at week 8. Safety and tolerability were also evaluated. RESULTS: Significantly more roflumilast-treated patients (59.1%) than vehicle-treated patients (11.4%) achieved S-IGA success at week 8 (P < 0.001); differences favoured roflumilast as early as the first postbaseline visit at week 2 (P < 0.001). Significant improvements were also seen for secondary endpoints, including body IGA success, Scalp Itch Numeric Rating Scale and the Psoriasis Scalp Severity Index. The safety of roflumilast was generally similar to vehicle. Patients treated with roflumilast experienced low rates of treatment-emergent adverse events (AEs), with few discontinuations due to an AE. Few patients with skin of colour (11%) and few adolescents (0.7%) were included. CONCLUSIONS: The results support the further development of roflumilast foam for treating scalp and body psoriasis.

Effect of Roflumilast Cream vs Vehicle Cream on Chronic Plaque Psoriasis: The DERMIS-1 and DERMIS-2 Randomized Clinical Trials.

Importance: Once-daily roflumilast cream, 0.3%, a potent phosphodiesterase 4 inhibitor, demonstrated efficacy and was well tolerated in a phase 2b trial of patients with psoriasis. Objective: To evaluate the efficacy of roflumilast cream, 0.3%, applied once daily for 8 weeks in 2 trials of patients with plaque psoriasis. Design, Setting, and Participants: Two phase 3, randomized, double-blind, controlled, multicenter trials (DERMIS-1 [trial 1; n = 439] and DERMIS-2 [trial 2; n = 442]) were conducted at 40 centers (trial 1) and 39 centers (trial 2) in the US and Canada between December 9, 2019, and November 16, 2020, and between December 9, 2019, and November 23, 2020, respectively. Patients aged 2 years or older with plaque psoriasis involving 2% to 20% of body surface area were enrolled. The dates of final follow-up were November 20, 2020, and November 23, 2020, for trial 1 and trial 2, respectively. Interventions: Patients were randomized 2:1 to receive roflumilast cream, 0.3% (trial 1: n = 286; trial 2: n = 290), or vehicle cream (trial 1: n = 153; trial 2: n = 152) once daily for 8 weeks. Main Outcomes and Measures: The primary efficacy end point was Investigator Global Assessment (IGA) success (clear or almost clear status plus ≥2-grade improvement from baseline [score range, 0-4]) at week 8, analyzed using a Cochran-Mantel-Haenszel test stratified by site, baseline IGA score, and intertriginous involvement. There were 9 secondary outcomes, including intertriginous IGA success, 75% reduction in Psoriasis Area and Severity Index (PASI) score, and Worst Itch Numeric Rating Scale score of 4 or higher at baseline achieving 4-point reduction (WI-NRS success) at week 8 (scale: 0 [no itch] to 10 [worst imaginable itch]; minimum clinically important difference, 4 points). Results: Among 881 participants (mean age, 47.5 years; 320 [36.3%] female), mean IGA scores in trial 1 were 2.9 [SD, 0.52] for roflumilast and 2.9 [SD, 0.45] for vehicle and in trial 2 were 2.9 [SD, 0.48] for roflumilast and 2.9 [SD, 0.47]) for vehicle. Statistically significantly greater percentages of roflumilast-treated patients than vehicle-treated patients had IGA success at week 8 (trial 1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3%-46.9%]; trial 2: 37.5% vs 6.9%; difference, 28.9% [95% CI, 20.8%-36.9%]; P < .001 for both). Of 9 secondary end points, statistically significant differences favoring roflumilast vs vehicle were observed for 8 in trial 1 and 9 in trial 2, including intertriginous IGA success (71.2% vs 13.8%; difference, 66.5% [95% CI, 47.1%-85.8%] and 68.1% vs 18.5%; difference, 51.6% [95% CI, 29.3%-73.8%]; P < .001 for both), 75% reduction in PASI score (41.6% vs 7.6%; difference, 36.1% [95% CI, 28.5%-43.8%] and 39.0% vs 5.3%; difference, 32.4% [95% CI, 24.9%-39.8%]; P < .001 for both), WI-NRS success (67.5% vs 26.8%; difference, 42.6% [95% CI, 31.3%-53.8%] and 69.4% vs 35.6%; difference, 30.2% [95% CI, 18.2%-42.2%]; P < .001 for both). The incidence of treatment-emergent adverse events was 25.2% with roflumilast vs 23.5% with vehicle in trial 1 and 25.9% with roflumilast vs 18.4% with vehicle in trial 2. The incidence of serious adverse events was 0.7% with roflumilast vs 0.7% with vehicle in trial 1 and 0% with roflumilast vs 0.7% with vehicle in trial 2. Conclusions and Relevance: Among patients with chronic plaque psoriasis, treatment with roflumilast cream, 0.3%, compared with vehicle cream resulted in better clinical status at 8 weeks. Further research is needed to assess efficacy compared with other active treatments and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifiers: NCT04211363, NCT04211389.

Efficacy and safety of topical terbinafine 10% solution (MOB-015) in the treatment of mild to moderate distal subungual onychomycosis: A randomized, multicenter, double-blind, vehicle-controlled phase 3 study.

BACKGROUND: Onychomycosis is a recalcitrant fungal nail infection. Topical antifungal agents may be preferred over systemic agents due to lack of systemic adverse effects. OBJECTIVE: To investigate the efficacy and safety of topical terbinafine 10% solution (MOB-015) for the treatment of distal and lateral subungual onychomycosis. METHODS: In a multicenter, double-blind, phase III, North American study, patients with mild to moderate distal and lateral subungual onychomycosis involving 20% to 60% of at least 1 great toenail were randomized to once daily application of MOB-015 or matching vehicle for 48 weeks. The primary efficacy variable was complete cure, while the secondary efficacy variables were mycological cure and treatment success. Safety evaluations were also performed. RESULTS: At week 52, the mycological cure (negative culture and potassium hydroxide microscopy) rate in the MOB-015 and vehicle groups was 69.9% and 27.7%, respectively (P < .001), and complete cure (0% clinical disease involvement and mycological cure) was achieved in 4.5% and 0% of patients, respectively (P = .0195). At least 1 adverse event leading to discontinuation of treatment occurred in 2.8% of patients in the MOB-015 group and in 4.2% in the vehicle group. LIMITATION: The follow-up period after end of treatment may not be sufficient to accurately reflect cure in distal and lateral subungual onychomycosis. CONCLUSIONS: MOB-015 is a treatment option for onychomycosis with an adverse event profile similar to vehicle.

Serlopitant for psoriatic pruritus: A phase 2 randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Pruritus, a common symptom of psoriasis, negatively affects quality of life; however, treatment of lesional skin does not consistently alleviate psoriatic itch. OBJECTIVE: To examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639). METHODS: Patients (n = 204) were randomized to receive serlopitant, 5 mg, or placebo daily for 8 weeks. Eligible adult patients had plaque psoriasis for ≥6 months, plaques covering ≤10% of body surface area, pruritus for ≥4 weeks, and Worst Itch Numeric Rating Scale (WI-NRS) score ≥7 at the initial screening. RESULTS: Participants (54.2% women) had a mean age of 47.5 years and 85.2% were white. Mean baseline WI-NRS scores were 8.3 for serlopitant and 8.1 for placebo. The WI-NRS 4-point response rate at 8 weeks (primary end point) was 33.3% for serlopitant vs 21.1% for placebo (P = .028); at 4 weeks the rates were 20.8% for serlopitant vs 11.5% for placebo (P = .039). Treatment-related adverse events were reported for 4.9% of serlopitant-treated and 4.0% of placebo-treated patients. LIMITATIONS: This was a phase 2 study with a small study population. Patients with severe psoriasis were excluded. CONCLUSION: Serlopitant significantly reduced pruritus associated with mild to moderate psoriasis, supporting continued development of serlopitant for this patient population.

Long-term efficacy and safety of topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis: Post hoc pediatric subgroup analysis from a 44-week open-label extension study.

BACKGROUND/OBJECTIVES: Glycopyrronium tosylate (GT) cloth, 2.4% is a topical anticholinergic approved in the United States for primary axillary hyperhidrosis in patients ≥9 years. This post hoc analysis evaluated long-term response (efficacy and safety) in pediatric patients (≥9 to ≤16 years) to GT in the 44-week, open-label extension (NCT02553798) of two, phase 3, double-blind, vehicle-controlled, 4-week trials (NCT02530281, NCT02530294). METHODS: In the double-blind trials, patients ≥9 years with primary axillary hyperhidrosis were randomized 2:1 to once-daily GT:vehicle. Those who completed the study could receive open-label GT for up to an additional 44 weeks. Safety assessments included treatment-emergent adverse events (TEAEs) and local skin reactions (LSRs). Descriptive efficacy assessments included gravimetrically measured sweat production, Hyperhidrosis Disease Severity Scale response (≥2-grade improvement), and Children's Dermatology Life Quality Index. RESULTS: Of 43 pediatric patients completing either double-blind trial, 38 (88.4%) entered the open-label extension (age, years: 9 [n = 1], 12 [n = 2], 13 [n = 7], 14 and 15 [n = 9 each], 16 [n = 10]). The safety profile observed was similar to the double-blind trials. Most TEAEs (>95%) were mild/moderate, related to anticholinergic activity, and infrequently led to discontinuation (n = 1/38 [2.6%]). No pediatric patients experienced a serious TEAE. Most anticholinergic TEAEs did not require a dose modification and resolved within 7 days. Approximately, one-third of patients (n = 13/38 [34.2%]) had LSRs; most were mild/moderate in severity. Improvements in efficacy measures were maintained from the double-blind trials. CONCLUSIONS: Long-term, once-daily GT for up to 48 weeks (4-week double-blind plus 44 week open label) provides a noninvasive, well-tolerated treatment option for pediatric patients with primary axillary hyperhidrosis.

Topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis: Results from the ATMOS-1 and ATMOS-2 phase 3 randomized controlled trials.

BACKGROUND: Glycopyrronium tosylate (GT) is a topical anticholinergic developed for once-daily treatment of primary axillary hyperhidrosis. OBJECTIVE: Assess the efficacy and safety of GT for primary axillary hyperhidrosis. METHODS: ATMOS-1 and ATMOS-2 were replicate randomized, double-blind, vehicle-controlled, 4-week phase 3 trials. Patients were randomized 2:1 to GT 3.75% or vehicle applied once daily to each axilla for 4 weeks. Coprimary endpoints were responder rate (≥4-point improvement from baseline) on item 2 (severity of sweating) of the Axillary Sweating Daily Diary (ASDD), which is a newly developed patient-reported outcome measure, and absolute change from baseline in axillary gravimetric sweat production at week 4. Safety evaluation included treatment-emergent adverse events. RESULTS: Pooled data, which are consistent with the individual trial results, show that significantly more GT-treated patients achieved an ASDD-Item 2 response than did those treated with vehicle (59.5% vs 27.6%), and they had reduced sweat production from baseline (-107.6 mg/5 min vs -92.1 mg/5 min) at week 4 (P < .001 for both coprimary end points). Most treatment-emergent adverse events were mild or moderate and infrequently led to discontinuation. LIMITATIONS: Short trial duration and inherent challenges in gravimetrically assessing sweat production. CONCLUSIONS: GT applied topically on a daily basis over 4 weeks reduced the severity of sweating as measured by ASDD-Item 2, reduced sweat production as measured gravimetrically, and was generally well tolerated in patients with primary axillary hyperhidrosis.

Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate and Severe Acne Vulgaris in Females: Effect of Age on Efficacy and Tolerability

BACKGROUND: While it is generally considered to be a disease of adolescence, acne affects an increasing number of adults, especially women. Although data exist on the use of retinoids in adult females, there is no universal agreement as to the age of onset of adult female acne, or data on the efficacy and tolerability dependent on age. A novel tretinoin 0.05% lotion formulation has been shown to be effective and well-tolerated in acne patients with moderate or severe disease. OBJECTIVE: To evaluate the safety and efficacy of once-daily tretinoin 0.05% lotion in women with moderate or severe acne categorized into different age groups (13-19, 20-29, and 30+ years). METHODS: Post hoc analysis of two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies. Women (aged 13-19 years, N=357; 20-29 years, N=352; 30+ years, N=156) with moderate or severe acne were randomized (1:1) to receive tretinoin 0.05% lotion or vehicle, once-daily for 12 weeks. Efficacy assessments included changes in baseline inflammatory/noninflammatory lesions and treatment success (at least 2-grade reduction in Evaluator's Global Severity Score [EGSS] and 'clear'/'almost clear') and Quality of Life (QoL) using the validated Acne-QoL questionnaire. Safety and adverse events (AEs) where evaluated throughout; cutaneous tolerability assessed at each study visit using a 4-point scale (where 0=none and 3=severe). RESULTS: At baseline, 91.9% (N=794) of women in the post hoc analysis had moderate (EGSS=3) and 8.1% (N=70) severe (EGSS=4) acne, with the highest proportion of women (11.1%, N=39) having severe acne being aged 20-29 years. Baseline inflammatory lesion counts were similar across the three age ranges, with more comedonal lesions (44.5) in adolescent females (aged 13-19 years). Quality of life at baseline was much better in adolescent females and may be age-related for some domains (self-perception and role-social). At week 12, there appeared to be an age-related improvement in both inflammatory and noninflammatory lesion counts, and treatment success although the differences between groups were not significant. Mean percent reduction in inflammatory and noninflammatory lesion counts for each age group (13-19, 20-29, and 30+ years old respectively) were 55.3% (P=0.019 versus vehicle), 55.8% (P=0.080) and 63.5%; and 47.1% (P<0.001), 55.2% (P=0.002) and 59.0% (P=0.030). Treatment success for the 3 groups was achieved by 23.2% (P=0.023), 21.3%, and 30.7% of patients, respectively, at week 12; differences between age groups were not significant. Quality of Life improved in all age groups, although changes with tretinoin 0.05% lotion were only significant compared with vehicle in adult females aged 20-29 years (self-perception, role-emotional and acne symptoms); improvements in each domain score by week 12 were also greatest in this age group. The majority of AEs were mild and transient; the most common treatment emergent AEs were application site pain and dryness especially in the older adult females (aged 30+ years). Local cutaneous safety and tolerability assessments were generally mild and improved by week 12. There were transient increases in scaling, burning and stinging in the adolescent females, peaking at week 4; all mean scores were ≤0.6 where 1=mild. CONCLUSIONS: Tretinoin 0.05% lotion was significantly more effective than vehicle in achieving treatment success and reducing inflammatory and comedonal lesions in adult and adolescent females with moderate or severe acne. There appear to be age-related efficacy and tolerability benefits favoring adult females. J Drugs Dermatol. 2019;18(12):1218-1225.

Efficacy of Dupilumab in Different Racial Subgroups of Adults With Moderate-to-Severe Atopic Dermatitis in Three Randomized, Placebo-Controlled Phase 3 Trials

Dupilumab, a monoclonal antibody that blocks the shared receptor subunit for interleukin (IL)-4 and IL-13, is currently approved for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis (AD). The efficacy and safety of dupilumab for AD among racial subgroups is unknown. This post hoc analysis from three phase 3 trials assessed the efficacy and safety of dupilumab vs placebo by racial subgroup (White, Asian, Black/African American). Data from LIBERTY AD SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), and CHRONOS (NCT02260986) were pooled. Outcomes included mean and percent change from baseline to week 16 in the key therapeutic domains Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI), and Patient-Oriented Eczema Measure, as well as Investigator's Global Assessment and pain or discomfort assessed by the European Quality of Life-5 Dimensions 3 level questionnaire. A total of 2,058 patients (White n=1,429, Asian n=501, Black/African American n=128) were included in the current analysis. Baseline demographics and disease characteristics were balanced between treatment groups and racial subgroups. In the three trials, dupilumab significantly (P<0.0001) improved all assessed outcomes compared with placebo in the White and Asian subgroups. In the smaller Black/African American subgroup, dupilumab significantly (P<0.0001) improved EASI endpoints and mean changes in Peak Pruritus NRS and DLQI vs placebo, with positive numeric trends favoring dupilumab in all other endpoints. Dupilumab was generally well tolerated, with an acceptable safety profile in all racial subgroups. Serious adverse events occurred more frequently with placebo; treatment discontinuations due to adverse events were rare in all treatment groups. Significant clinical improvement and a favorable benefit-risk profile can be achieved with dupilumab treatment in patients of White, Asian, and Black/African American racial subgroups with moderate-to-severe AD inadequately controlled with topical medications. ClinicalTrials.gov identifiers: NCT02277743, NCT02277769, NCT02260986

Glycopyrronium tosylate in pediatric primary axillary hyperhidrosis: Post hoc analysis of efficacy and safety findings by age from two phase three randomized controlled trials.

OBJECTIVES: Hyperhidrosis in pediatric patients has been understudied. Post hoc analyses of two phase 3 randomized, vehicle-controlled, 4-week trials (ATMOS-1 [NCT02530281] and ATMOS-2 [NCT02530294]) were performed to assess efficacy and safety of topical anticholinergic glycopyrronium tosylate (GT) in pediatric patients. METHODS: Patients had primary axillary hyperhidrosis ≥ 6 months, average Axillary Sweating Daily Diary (ASDD/ASDD-Children [ASDD-C]) Item 2 (sweating severity) score ≥ 4, sweat production ≥ 50 mg/5 min (each axilla), and Hyperhidrosis Disease Severity Scale (HDSS) ≥ 3. Coprimary end points were ≥ 4-point improvement on ASDD/ASDD-C Item 2 (a validated patient-reported outcome) and change in gravimetrically measured sweat production at Week 4. Efficacy and safety data are shown through Week 4 for the pediatric (≥ 9 to ≤ 16 years) vs older (> 16 years) subgroups. RESULTS: Six hundred and ninety-seven patients were randomized in ATMOS-1/ATMOS-2 (GT, N = 463; vehicle, N = 234); 44 were ≥ 9 to ≤ 16 years (GT, n = 25; vehicle, n = 19). Baseline disease characteristics were generally similar across subgroups. GT-treated pediatric vs older patients had comparable improvements in ASDD/ASDD-C Item 2 (sweating severity) responder rate, HDSS responder rate (≥ 2-grade improvement]), sweat production, and quality of life (mean change from Baseline in Dermatology Life Quality Index [DLQI]/children's DLQI), with greater improvement vs vehicle. Treatment-emergent adverse events were similar between subgroups, and most were mild, transient, and infrequently led to discontinuation. CONCLUSIONS: Topical, once-daily GT improved disease severity (ASDD/ASDD-C, HDSS), sweat production, and quality of life (DLQI), with similar findings in children, adults, and the pooled population. GT was well tolerated, and treatment-emergent adverse events were qualitatively similar between subgroups and consistent with other anticholinergics.

Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients.

BACKGROUND: The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients. METHODS: This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival. RESULTS: The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each). CONCLUSIONS: The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.

Safety and efficacy of a fixed combination of halobetasol and tazarotene in the treatment of moderate-to-severe plaque psoriasis: Results of 2 phase 3 randomized controlled trials.

BACKGROUND: Topical corticosteroids are the mainstay of psoriasis treatment, with long-term safety considerations limiting their use. Combining them with tazarotene may optimize their efficacy and minimize safety and tolerability concerns. OBJECTIVE: To investigate the safety and efficacy of halobetasol propionate 0.01% plus tazarotene 0.045% (HP/TAZ) lotion in moderate-to-severe plaque psoriasis. METHODS: Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies (N = 418) were conducted. Subjects were randomized (2:1) to HP/TAZ lotion or vehicle once daily for 8 weeks with a 4-week follow-up. The primary efficacy assessment end point was treatment success (at least a 2-grade improvement from baseline in Investigator's Global Assessment score and a score of clear or almost clear). Safety and treatment-emergent adverse events were evaluated throughout. RESULTS: HP/TAZ lotion demonstrated statistically significant superiority over vehicle within as few as 2 weeks. By week 8, 35.8% (study 1) and 45.3% (study 2) of subjects were treatment successes compared with 7.0% and 12.5% of those treated with vehicle (P < .001). HP/TAZ lotion was also superior in reducing signs and symptoms of psoriasis and body surface area affected by psoriasis. The most frequently reported treatment-related adverse events were contact dermatitis (6.3%), application site pain (2.6%), and pruritus (2.2%). LIMITATIONS: Studies did not include subjects with more than 12% of their body surface area affected by psoriasis. CONCLUSIONS: HP/TAZ lotion was associated with significant reductions in the severity of the clinical signs of psoriasis, with no safety concerns.

Halobetasol 0.01%/Tazarotene 0.045% Lotion in the Treatment of Moderate-to-Severe Plaque Psoriasis: Maintenance of Therapeutic Effect After Cessation of Therapy.

BACKGROUND: Psoriasis is a chronic, immune-mediated disease that varies widely in its clinical expression. Topical corticosteroids (TCS) are the mainstay of treatment. Long-term safety remains a concern, limiting use, and posttreatment flare is common. Tazarotene has also been shown to be effective in psoriasis, with efficacy maintained several weeks posttreatment. Fixed combination therapy with TCS and tazarotene may improve psoriasis signs and minimize posttreatment flare or rebound. OBJECTIVE: To investigate the maintenance of effect posttreatment with a once-daily application of halobetasol propionate 0.01%/tazarotene 0.045% (HP/TAZ) lotion in comparison with its active ingredients and vehicle in patients with moderate-to-severe plaque psoriasis. METHODS: Multicenter, randomized, double-blind, vehicle-controlled Phase 2 study in moderate or severe psoriasis (N=212). Patients randomized (2:2:2:1 ratio) to receive HP/TAZ, individual active ingredients, or vehicle, once-daily for 8 weeks with a 4-week posttreatment follow-up. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score, and 'clear' or 'almost clear'), and impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion. RESULTS: At the end of the 4-week posttreatment period, 38.2% of patients who had been treated with HP/TAZ were treatment successes; compared with 21.0%, 12.8% and 6.9% of patients who had been treated with HP (P=0.042), TAZ (P=0.004), or vehicle (P=0.002). HP/TAZ lotion was also superior in maintaining reductions in psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. At the end of the 4-week posttreatment period, 49.1%, 54.5%, and 54.5% of patients, respectively, were treatment successes: compared with 38.7% (P=0.26), 48.4% (P=0.51), and 48.4% (P=0.51) of patients who had been treated with HP; 29.8% (P=0.049), 31.9% (P=0.022), and 23.4% (P=0.001) who had been treated with TAZ; and 13.8% (P=0.002), 20.7% (P=0.003), and 20.7% (P=0.003) who had been treated with vehicle. Side effects were minimal and tended to resolve during the posttreatment period. CONCLUSIONS: In conclusion, HP 0.01%/TAZ 0.045% lotion provides synergistic efficacy following 8 weeks' therapy that is sustained after a 4-week posttreatment period. J Drugs Dermatol. 2018;17(7):723-726.

Novel Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Assessment of Efficacy and Safety in Patients Aged 9 Years and Older.

BACKGROUND: Topical tretinoin has been extensively studied in clinical trials, and its essential role in the treatment of acne vulgaris (acne) established through evidence-based guidelines. OBJECTIVE: To evaluate efficacy, safety, and tolerability of a novel tretinoin 0.05% lotion in moderate-to-severe acne in patients aged 9 years and older. METHODS: A total of 1640 patients, 9-58 years of age were randomized to receive tretinoin 0.05% lotion or vehicle in two double-blind, placebo-controlled 12-week, 2-arm, parallel group studies evaluating safety and efficacy (inflammatory and noninflammatory lesion counts and acne severity using Evaluator Global Severity Scores [EGSS]). In addition, patients completed a patient satisfaction survey (PSS), Acne-specific quality of life (QoL) questionnaire and assessed their facial skin for shininess/oiliness improvement. The data from these two independent studies were pooled and analyzed. RESULTS: Tretinoin 0.05% lotion demonstrated statistically significant superiority to vehicle in reducing inflammatory and noninflammatory lesion counts (both P less than .001) at week 12 and improving acne severity (P less than .001). At week 12, mean percent change in inflammatory and noninflammatory lesions were 52% and 46%, respectively. Treatment success (a 2-grade improvement in EGSS and 'clear' or 'almost clear' was reported in 18% of patients. Tretinoin 0.05% lotion also showed significantly greater benefits relative to vehicle control in terms of patient satisfaction (P less than .001) and acne-specific QoL domains. Tretinoin 0.05% lotion was very well tolerated with no substantive differences in cutaneous tolerability among treatment groups. No patients discontinued treatment because of adverse events. LIMITATIONS: Data from controlled studies may differ from clinical practice. CONCLUSIONS: Tretinoin 0.05% lotion provides statistically significant greater efficacy than vehicle with a highly favorable safety and tolerability profile in moderate-to-severe acne patients. J Drugs Dermatol. 2018;17(10):1084-1091.

Planimetric Post-hoc Analysis of Women With Onychomycosis from Tavaborole 5% Phase III Studies: Evidence of Greater Improvements in Patients With >50% Baseline Infection.

Women with onychomycosis may suffer more effects on their quality of life than men. There is limited female-specific data on the treatment of onychomycosis. Tavaborole is a topical treatment option for onychomycosis. This post-hoc study evaluated the nail plates of women using data from the tavaborole 5% Phase III studies at baseline and end of study for the areas of healthy nail and infected nail. Over 52 weeks (48-week treatment, 4-week follow up), women treated with tavaborole had an average 32% increase in healthy nail and 21% decrease in infected nail. Patients with baseline infection involving >50% of the nail plate had an average increase in percentage of unaffected nail surface area of 81% and a corresponding 51% decrease in infected nail. These analyses suggest that patients with the greatest toenail involvement at baseline had greater overall improvements than those who were less affected. This evaluation provides additional clinical guidance for treating women with onychomycosis using tavaborole. J Drugs Dermatol. 2018;17(2):168-172.

From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis.

BACKGROUND: An urgent need exists in the United States to establish treatment goals in psoriasis. OBJECTIVE: We aim to establish defined treatment targets toward which clinicians and patients with psoriasis can strive to inform treatment decisions, reduce disease burden, and improve outcomes in practice. METHODS: The National Psoriasis Foundation conducted a consensus-building study among psoriasis experts using the Delphi method. The process consisted of: (1) literature review, (2) pre-Delphi question selection and input from general dermatologists and patients, and (3) 4 Delphi rounds. RESULTS: A total of 25 psoriasis experts participated in the Delphi process. The most preferred instrument was body surface area (BSA). The most preferred time for evaluating patient response after starting new therapies was at 3 months. The acceptable response at 3 months postinitiation was either BSA 3% or less or BSA improvement 75% or more from baseline. The target response at 3 months postinitiation was BSA 1% or less. During the maintenance period, evaluation every 6 months was most preferred. The target response at every 6 months maintenance evaluation is BSA 1% or less. LIMITATIONS: Although BSA is feasible in practice, it does not encompass health-related quality of life, costs, and risks of side effects. CONCLUSION: With defined treatment targets, clinicians and patients can regularly evaluate treatment responses and perform benefit-risk assessments of therapeutic options individualized to the patient.

A Phase 2, Multicenter, Double-Blind, Randomized, Vehicle Controlled Clinical Study to Assess the Safety and Efficacy of a Halobetasol/Tazarotene Fixed Combination in the Treatment of Plaque Psoriasis.

BACKGROUND: Psoriasis is a chronic, immune-mediated disease that varies widely in its clinical expression. Treatment options focus on relieving symptoms, reducing inflammation, induration, and scaling, and controlling the extent of the disease. Topical corticosteroids are the mainstay of treatment, however long-term safety remains a concern, particularly with the more potent formulations. Combination therapy with a corticosteroid and tazarotene may improve psoriasis signs at a lower corticosteroid concentration providing a superior safety profile. OBJECTIVE: To investigate the efficacy and safety of a once-daily application of a fixed combination halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) lotion in comparison with its monads and vehicle in subjects with moderate-to-severe plaque psoriasis. METHODS: Multicenter, randomized, double-blind, vehicle-controlled Phase 2 study in moderate or severe psoriasis (N=212). Subjects randomized (2:2:2:1 ratio) to receive HP/TAZ, individual monads, or vehicle, once-daily for 8 weeks. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score and a score of 'Clear' or 'Almost Clear'), and impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion. Safety and treatment emergent adverse events (TEAEs) were evaluated throughout. RESULTS: HP/TAZ lotion demonstrated statistically significant superiority over vehicle as early as 2 weeks. At week 8, 52.5% of subjects had treatment success compared with 33.3%, 18.6%, and 9.7% in the HP (P=0.033), TAZ (P less than 0.001), and vehicle (P less than 0.001) groups, respectively. HP/TAZ lotion was superior to its monads and vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. At week 8, a 2-grade improvement in IGA was achieved by 54.2% of subjects for erythema, 67.8% for plaque elevation, and 64.4% for scaling. Most frequently reported TEAEs were application site reactions, and were more likely associated with the tazarotene component. Side effects such as skin atrophy were rare. CONCLUSIONS: HP/TAZ lotion was consistently more effective than its monads or vehicle in achieving treatment success and reducing psoriasis signs of erythema, plaque elevation, and scaling at the target lesion. Safety data were consistent with the known safety profile of halobetasol propionate and tazarotene, and did not reveal any new safety concerns with the combination product.

J Drugs Dermatol. 2017;16(3):197-204.

Randomized, Placebo- and Active-Controlled Crossover Study of the Safety and Efficacy of THVD-102, a Fixed-dose Combination of Oxybutynin and Pilocarpine, in Subjects With Primary Focal Hyperhidrosis.

BACKGROUND: While muscarinic antagonists (anticholinergics) have shown efficacy in treating primary focal hyperhidrosis (PFH), side effects - most commonly dry mouth - are intolerable for most patients. THVD-102, a fixed-dose combination product has been developed combining oxybutynin, a muscarinic antagonist, and pilocarpine, a muscarinic agonist. The pilocarpine is at a dose level and release profile optimized to correct salivary flow impaired by oxybutynin yet not interfere with the therapeutic muscarinic antagonist effect of oxybutynin upon the sweat glands. OBJECTIVES: This study evaluated safety, efficacy, dry mouth and quality of life with THVD-102 (oxybutynin 7.5 mg / pilocarpine 7.5 mg) in subjects with axillary and / or palmar PFH. METHODS: After a 21-day open label treatment period with oxybutynin 5 mg twice daily to determine susceptibility of subjects to develop dry mouth, eligible subjects were randomized to 1 of 6 sequences of 3 study treatments (THVD-102, oxybutynin 7.5 mg, and placebo) in sequential 21day double-blind crossover treatment periods, each preceded by a washout period of at least 7 days. RESULTS: A total of 24 subjects were randomized and 19 finished all crossover treatments. Changes from baseline to end of treatment in symptoms associated with PFH were statistically significant for both THVD-102 versus placebo and for oxybutynin versus placebo as assessed by multiple measures. Beneficial trends, not statistically significant, for gravimetric measurements were also observed. There were no statistically significant differences between THVD-102 and oxybutynin in PFH efficacy. Fewer subjects reported moderate to severe dry mouth while receiving THVD-102 compared to oxybutynin and more subjects categorized their dry mouth as none or mild while receiving THVD-102 compared to oxybutynin. Differences in reported dry mouth were statistically significant. CONCLUSION: THVD-102 was generally well-tolerated. Both THVD-102 and oxybutynin 7.5 mg twice daily were effective in treating PFH. THVD-102 was associated with significantly reduced dry mouth compared to oxybutynin. J Drugs Dermatol. 2017;16(2):127-132..

Safety and Efficacy of Escalating Doses of Ingenol Mebutate for Field Treatment of Actinic Keratosis on the Full Face, Full Balding Scalp, or Chest.

Background: Actinic keratosis (AK) can affect large skin areas. Ingenol mebutate (IngMeb) gel (0.015% and 0.05%) is approved for topical treatment of AK in a single contiguous area of ~25 cm2.

Objective: The study sought to determine the maximum tolerated dose (MTD), efficacy, and tolerability of IngMeb applied to AK on a contiguous area less than equal to 250 cm2.

Methods: Part 1 determined the MTD of IngMeb at 7 concentrations for 2 or 3 days. Part 2 assessed efficacy and tolerability at the MTD and one dose lower for 2 or 3 days vs vehicle.

Results: Four dosing regimens with an acceptable benefit-to-risk ratio were identified: 0.018% and 0.027% once daily for 2 or 3 days. Complete clearance at 8 weeks was achieved by 21.3% to 39.1% of IngMeb-treated patients vs 0% to 3.2% treated with vehicle. Composite local skin response scores peaked on the day after the last application, rapidly declined, and were near baseline at 2 weeks. Adverse events were predominantly mild or moderate.

Limitations: The study evaluated a limited number of doses in a population of only white patients.

Conclusion: IngMeb gel was effective and well tolerated as field treatment of AK on the full face, full scalp, and up to 250 cm2 on the chest.

J Drugs Dermatol. 2017;16(5):438-444.