Biomarkers and clinical outcomes after tezepelumab cessation: Extended follow-up from the 2-year DESTINATION study.

BACKGROUND: Long-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma. OBJECTIVE: To explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment. METHODS: DESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma. Patients received their last treatment doses at week 100 and could enroll in an extended follow-up period from weeks 104 to 140. Change over time in key biomarkers and clinical outcomes were assessed in tezepelumab vs placebo recipients for 40 weeks after stopping treatment. RESULTS: Of 569 patients enrolled in the extended follow-up period, 426 were included in the analysis (289 received tezepelumab and 137 placebo). In the 40-week period after the last tezepelumab dose, blood eosinophil counts, fractional exhaled nitric oxide levels, and Asthma Control Questionnaire-6 scores gradually increased from weeks 4 to 10, with a gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that blood eosinophil counts, fractional exhaled nitric oxide levels, and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels. Total IgE levels increased later from week 28 and remained well below placebo and baseline levels during the 40-week period after the last tezepelumab dose. CONCLUSION: This analysis reveals the benefits of continued tezepelumab treatment in the management of patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03706079.

Effect of Tezepelumab on the Humoral Immune Response to Seasonal Quadrivalent Influenza Vaccination in Patients with Moderate to Severe Asthma: The Phase 3b VECTOR Study.

INTRODUCTION: Annual influenza vaccinations are recommended for adolescents and adults with moderate to severe asthma. This study investigated the effect of tezepelumab, a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, on the humoral immune response to the quadrivalent seasonal influenza vaccine in patients with moderate to severe asthma. METHODS: VECTOR was a phase 3b, randomized, multicenter, double-blind, parallel-group, placebo-controlled study. Adolescents (aged 12-17 years) and young adults (aged 18-21 years) with moderate to severe asthma were enrolled across 15 centers in the USA. Patients received tezepelumab 210 mg or placebo subcutaneously at weeks 0, 4, 8, and 12, and a single dose of inactivated quadrivalent seasonal influenza vaccine at week 12 before receiving study treatment. Immediately before vaccination and at 4 weeks postvaccination (week 16), strain-specific antibody responses were assessed for four influenza antigens by hemagglutination inhibition (HAI) and microneutralization (MN) assays. Safety was assessed. RESULTS: Seventy patients were randomized to tezepelumab (n = 35) or placebo (n = 35). There were no meaningful differences in HAI or MN antibody responses between treatment groups at week 16. HAI assay geometric mean fold rises (GMFRs) for influenza strains were 1.76-7.34 for tezepelumab and 1.46-4.75 for placebo. MN assay GMFRs were 4.00-14.56 for tezepelumab and 3.56-10.62 for placebo. In the HAI assay, a fourfold or larger rise in antibody titer from weeks 12 to 16 occurred in 15.2-78.8% and 15.2-51.5% of tezepelumab and placebo recipients, respectively, and 97.0-100% of patients in both treatment groups achieved an antibody titer of at least 40 at week 16. No unexpected safety findings occurred. CONCLUSION: There was no observed suppression of the humoral immune response after influenza vaccination in adolescents and young adults with moderate to severe asthma treated with tezepelumab. Therefore, the influenza vaccine can be administered to this patient population during tezepelumab treatment. GOV IDENTIFIER: NCT05062759.

Tezepelumab Efficacy in Patients with Severe, Uncontrolled Asthma with Comorbid Nasal Polyps in NAVIGATOR.

Purpose: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR. Methods: Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc). Results: Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (-12.57 points [-19.40, -5.73]) and 52 weeks (-10.58 points [-17.75, -3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status. Conclusion: Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.

Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin. The drug has been tested previously in the phase 3 NAVIGATOR (NCT03347279) and SOURCE (NCT03406078) studies, and was subsequently approved as a treatment for severe asthma. This extension study recruited from NAVIGATOR and SOURCE and aimed to evaluate the long-term safety and efficacy of tezepelumab in individuals with severe, uncontrolled asthma. METHODS: DESTINATION was a phase 3, multicentre, randomised, double-blind, placebo-controlled, long-term extension study. The study was done across 182 sites (including hospitals, clinics, medical centres, clinical trial centres, and private practices) in 18 countries. Participants (aged 12-80 years) were required to have good treatment compliance in the parent study. Randomisation was stratified by the parent study and all participants were re-randomised. Those who were previously randomised to receive tezepelumab in either parent study continued treatment of subcutaneous tezepelumab (210 mg every 4 weeks); those who were previously randomised to receive placebo in either parent study were re-randomised 1:1 to receive either subcutaneous tezepelumab (210 mg every 4 weeks) or placebo (every 4 weeks) using a randomisation list prepared by a computerised system. Total treatment duration (including the parent studies) was 104 weeks for all groups. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoints were exposure-adjusted incidence of adverse events and serious adverse events and the secondary endpoint was the annualised asthma exacerbation rate; these were assessed from week 0 of the parent studies to week 104 of DESTINATION in all participants who were randomised and who received at least one dose of tezepelumab or placebo in either of the parent studies. The trial is registered with ClinicalTrials.gov, NCT03706079, and is closed to new participants. FINDINGS: Participants were recruited between Jan 7, 2019, and Oct 15, 2020. For individuals who initially received tezepelumab (n=528) in NAVIGATOR, incidence of adverse events over 104 weeks was 49·62 (95% CI 45·16 to 54·39) per 100 patient-years, compared with 62·66 (56·93 to 68·81) for those receiving placebo (n=531; difference -13·04, 95% CI -17·83 to -8·18). For serious adverse events, incidence was 7·85 (6·14 to 9·89) per 100 patient-years for individuals who initially received tezepelumab and 12·45 (9·97 to 15·35) for those who received placebo (difference -4·59, -7·69 to -1·65). In SOURCE, incidence of adverse events was 47·15 (36·06 to 60·56) per 100 patient-years for those who initially received tezepelumab (n=74) and 69·97 (54·54 to 88·40) for those who received placebo (n=76; difference -22·82, -34·77 to -10·01). For serious adverse events, incidence was 13·14 (7·65 to 21·04) per 100 patient-years for those who initially received tezepelumab and 17·99 (10·66 to 28·44) for those who received placebo (difference -4·85, -14·88 to 4·53). Tezepelumab reduced the annualised asthma exacerbation rate over 104 weeks compared with placebo. In participants initially from NAVIGATOR, the annualised asthma exacerbation rate ratio over 104 weeks was 0·42 (95% CI 0·35 to 0·51); in those initially from SOURCE, the ratio over 104 weeks was 0·61 (0·38 to 0·96). INTERPRETATION: Tezepelumab treatment was well tolerated for up to 2 years and resulted in sustained, clinically meaningful reductions in asthma exacerbations in individuals with severe, uncontrolled asthma. These findings are consistent with previous randomised, placebo-controlled studies and show the long-term safety and sustained efficacy of tezepelumab in individuals with severe, uncontrolled asthma. FUNDING: AstraZeneca and Amgen.

Effect of Age on Efficacy and Safety of Fluticasone Furoate/Vilanterol (FF/VI), Umeclidinium (UMEC), and UMEC + FF/VI in Patients with Chronic Obstructive Pulmonary Disease: Analyses of Five Randomized Clinical Trials.

Introduction: Concerns have been raised about the practical use and clinical benefits of medications and inhalers in older patients with chronic obstructive pulmonary disease (COPD). Here, we report analyses according to age from five clinical trials evaluating medications administered using the ELLIPTA dry-powder inhaler (DPI). Methods: Efficacy and safety according to age groups (<65 and ≥65 years) were assessed using data from five clinical trials in patients ≥40 years of age with symptomatic COPD. There was a mix of pre-specified and post hoc analyses of two 24-week trials with fluticasone furoate (FF)/vilanterol (VI) 100/25 µg; one 24-week trial with umeclidinium (UMEC) 62.5 µg; and two 12-week trials with UMEC 62.5 µg + FF/VI 100/25 µg. The primary endpoint was trough forced expiratory volume in 1 second (FEV1) obtained 23 and 24 hours after dosing on the last day of the study. Results: A total of 2876 patients <65 years of age and 2148 patients ≥65 years of age were enrolled across all studies of whom 1333 and 1111 patients, respectively, received treatment at the doses presented. Statistically significant and clinically meaningful treatment differences in improvement from baseline in mean trough FEV1 were reported for active comparators versus placebo at study end for both <65 and ≥65 years subgroups (FF/VI vs placebo: 143 mL and 111 mL; UMEC vs placebo: 110 mL and 123 mL; UMEC + FF/VI vs placebo + FF/VI: 136 mL and 105 mL; p<0.001 for all comparisons). The incidence of adverse events reported for active treatments was similar between age groups. Conclusion: These data provide evidence to support the use of FF/VI, UMEC, or UMEC + FF/VI, all delivered via the ELLIPTA DPI, to treat older (≥65 years) and younger (<65 years) patients with COPD.

Effectiveness and safety of once-daily doxycycline capsules as monotherapy in patients with rosacea: an analysis by Fitzpatrick skin type.

Rosacea is often under-recognized or misdiagnosed in patients with skin of color (Fitzpatrick Skin Types [FST] IV-VI). Subtle clinical features and a low index of suspicion likely contribute to less frequent diagnosis in this population. Clinical trials of therapeutic agents for rosacea generally include few patients from nonwhite racial/ethnic groups and therefore, potential differences in treatment outcomes have not been previously studied. The objective of this prospective analysis was to fill the gap in knowledge of the effectiveness and safety of treatment for rosacea in patients with skin of color. We analyzed data from 826 adults aged ≥ 18 years with papulopustular (subtype 2) rosacea (663 FST I-III; 163 FST IV-VI). All patients received doxycycline 40 mg capsules (30 mg immediate release and 10 mg delayed release beads) once daily as monotherapy for 12 weeks in this open-label, multicenter, community-based study. Investigators assessed disease severity with the Investigator's Global Assessment (IGA) and erythema with the Clinician's Erythema Assessment (CEA). Significant improvement in disease severity and erythema was obtained in patients with FST I-III and IV-VI at week 12 (P<.001). Treatment success, defined as an IGA score of 0 or 1 was achieved in 74.6% and 74.3% of patients with FST I-III and IV-VI, respectively. Approximately 12% of patients experienced adverse events with no difference between the two skin type groups. The results of this prospective subgroup analysis of data from a large community-based trial suggest that doxycycline produced similar effectiveness and safety profiles in patients with FST I-III and IV-VI.

Impact of clobetasol propionate 0.05% spray on health-related quality of life in patients with plaque psoriasis.

Psoriasis causes significant distress and impairment in health-related quality of life (QOL) in afflicted patients. For this reason, QOL is an essential and important measure of treatment outcome in patients with the disease. Clobetasol propionate is a super-highpotent class I topical corticosteroid. The spray formulation is approved for twice-daily use for up to 4 weeks by patients 18 years and older with moderate to severe plaque psoriasis. Data collected from 2,236 patients enrolled in 5 clinical trials demonstrate consistent improvement in QOL measures using multiple instruments. In a randomized, double-blind trial in patients with scalp psoriasis, treatment with clobetasol propionate 0.05% spray produced significantly greater improvement in QOL compared with vehicle, as measured by the Scalpdex QOL instrument. In another randomized trial in patients with moderate to severe plaque psoriasis, clobetasol propionate 0.05% spray produced significantly greater reductions in mean affected body surface area and significantly greater improvements in QOL, as measured by the Dermatology Life Quality Index (DLQI), compared with a 0.05% foam formulation. When compared with calcipotriene/betamethasone dipropionate ointment, clobetasol propionate 0.05% spray produced greater rates of lesion clearance and similar improvement in QOL scores after 2 or 4 weeks of treatment. When clobetasol propionate 0.05% spray was used as monotherapy or as an add-on therapy for 4 weeks in a large, observational trial, approximately 80% of patients experienced consistent and significant improvement in QOL on 2 separate, validated QOL instruments (DLQI and the Koo-Menter Psoriasis Index). In conclusion, clobetasol propionate 0.05% spray is an efficacious and safe treatment for plaque psoriasis and produces significant improvement in QOL for affected patients.

Digital videography assessment of patients' experiences using adapalene-benzoyl peroxide gel in the treatment of acne vulgaris.

BACKGROUND: Acne profoundly affects patients' lives, but the effect of treatment is not fully characterized. OBJECTIVE: The purpose of this study was to explore patients' experiences and viewpoints regarding treatment for mild to moderate acne vulgaris. METHODS: This was an open-label, single-center study of 30 patients with mild to moderate acne vulgaris, treated with adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-BPO gel) once daily for 12 weeks. An acne-specific quality of life questionnaire (Acne-QoL©) was conducted. Each subject's global assessment (SGA) was recorded at baseline and weeks 4, 8, and 12. Photographs were taken and video interviews were recorded. Local tolerability assessments and incidence of adverse events were documented. RESULTS: A statistically significant number of patients were clear/almost clear (treatment success) at week 12 (P<.001). At week 12, patients experienced a 44.1% and 57.1% mean reduction in inflammatory and noninflammatory lesions, respectively. By week 12, 67% of the patients in the video population (n=27) believed they had achieved treatment success (P<.001). Patients reported higher Acne-QoL© scores at week 12 compared to baseline, indicating better quality of life after treatment with adapalene-BPO gel (P<.001 for all domains). No unexpected adverse or serious adverse events were reported. LIMITATIONS: This was an open-label study of 12 weeks duration. CONCLUSION: Overall, patients with mild to moderate acne treated with adapalene-BPO gel showed significant improvement in disease severity and quality of life. The video recordings chronicled the patients' experiences throughout the treatment process.

A comparison of the tolerability of adapalene 0.1% cream and adapalene 0.1% lotion in healthy individuals.

Two separate single-center, randomized, evaluator-blinded, bilateral (split-face) comparison studies compared the tolerability of adapalene 0.1% cream with adapalene 0.1% lotion in individuals with healthy skin treated once per day for 3 weeks. At each visit, the participants were graded on erythema, scaling, dryness, and stinging/burning (scale: 0 = none to 3 = severe). On the final study visit, the participants completed a Cosmetic Acceptability Questionnaire. Adverse events were recorded at each study visit. A total of 144 participants were enrolled and 130 completed the studies (study 1, n = 66; study 2, n = 64). The lotion formulation was non-inferior to the cream for the success rates and tolerability assessments in both studies. The frequency distributions of worst scores of either 0 (none) or 1 (mild) (study 1; study 2) for adapalene lotion were erythema (98.5%; 40.7%), scaling (100%; 73.5%), dryness (100%; 68.8%), and stinging/burning (98.5%; 100%). The most common treatment-related adverse event was dryness (study 1, cream 2.7% [2 of 75] and lotion 4.0% [3/75]); study 2, cream 2.9% [2 of 69] and lotion 4.3% [3 of 69]. Both the adapalene 0.1% cream and 0.1% lotion formulations were well tolerated and acceptable to the study participants. The adapalene 0.1% lotion provides clinicians with a retinoid for the treatment of acne in a lotion formulation.

Effectiveness and safety of modified-release doxycycline capsules once daily for papulopustular rosacea monotherapy results from a large community-based trial in subgroups based on gender.

This article is a prospective planned analysis of data evaluating the effectiveness and safety of modified-release doxycycline capsules (30 mg immediate-release and 10 mg delayed-release beads) used once daily for up to 12 weeks in subgroups of males and females with papulopustular (subtype 2) rosacea from a large, open-label, multicenter, community-based study. A total of 1421 patients participated in the study. The per-protocol population comprised 826 patients on monotherapy, with 28.5% male participants (n=235) and 71.5% female participants (n=591). Rosacea was assessed on a 5-point investigator's global assessment (IGA) scale (0=clear, 1=near clear, 2=mild, 3=moderate, 4=severe). Erythema was also assessed on a 5-point clinician's erythema assessment (CEA) scale (0=none, 1=mild, 2=moderate, 3=significant, 4=severe). At baseline, males had a higher percentage of IGA scores of 3 (116 per 235; 49.4% versus 273 per 591; 46.2% in females) and 4 (32 per 235; 13.6% versus 35 per 591; 5.9% in females). Significant improvements in severity rating and erythema were observed in males and females as demonstrated by shifts in the distribution of IGA and CEA scores between baseline and week 12 (P<.001). Treatment success (IGA score of 0 or 1) at week 12 was achieved in 172 per 235 (73.2%) of males and in 444 per 591 (75.2%) of females. Adverse events (primarily mild or moderate gastrointestinal events) were reported in 9.9% of males and 12.8% of females. Anti-inflammatory dose doxycycline, which is administered as a 40 mg modified-release capsule once daily was effective and safe as monotherapy for papulopustular rosacea in both the female (n=591) and male (n=235) study groups. This specific 40 mg capsule delivers 30 mg immediate-release and 10 mg as delayed release using specially designed beads, and is subantimicrobial with both single and repeated dosing.

Clobetasol propionate 0.05% spray for the management of moderate-to-severe plaque psoriasis of the scalp: results from a randomized controlled trial.

BACKGROUND: Clobetasol propionate 0.05% spray is available for treating moderate-to-severe plaque psoriasis; however, there is limited information with plaque psoriasis of the scalp. OBJECTIVE: Evaluate the efficacy, safety, and quality-of-life impact of clobetasol propionate 0.05% spray in patients with moderate to severe plaque psoriasis of the scalp. METHODS: Multicenter, randomized, double-blind, vehicle-controlled study involving 81 men and women with moderate-to-severe (Global Severity Score [GSS] = 3 or 4) plaque psoriasis of the scalp. Eligible patients were treated with clobetasol propionate 0.05% spray or vehicle spray, which was applied twice daily for up to four weeks. The primary efficacy end point was the GSS of psoriasis of the scalp after four weeks. Safety assessments included local tolerability, presence of Cushing's syndrome, and adverse events. RESULTS: At the end of treatment, 85 percent (35/41) of patients in the clobetasol propionate 0.05% spray group achieved success (GSS clear or almost clear), compared with 13 percent (5/40) in the vehicle spray group (P is less than .001). The proportion of patients treated with clobetasol propionate 0.05% spray who achieved a rating of clear (GSS = 0) after two weeks and at the end of treatment was 12 percent and 51 percent, respectively. Clobetasol propionate 0.05% spray was well tolerated, and there were no serious adverse events or reported cases of folliculitis or Cushing's syndrome. CONCLUSION: Treatment with clobetasol propionate 0.05% spray for up to four weeks is effective and well tolerated for moderate-to-severe plaque psoriasis of the scalp.