Background
Chronic spontaneous urticaria (CSU) severely impacts quality of life (QoL), especially in patients with wheals and angioedema. Omalizumab is approved as add‐on therapy for CSU patients; ...however, its effect on patients who are double‐positive for wheals and angioedema has not been systematically studied.
Objective
The primary objective was to evaluate the efficacy of omalizumab vs placebo at week 28 using the Chronic Urticaria Quality of Life (CU‐Q2oL) questionnaire. Number of angioedema‐burdened days, time interval between successive angioedema episodes, disease activity, angioedema‐specific and overall QoL impairment were secondary objectives.
Methods
X‐ACT was a phase III, randomized, double‐blind study conducted in 24 centres (Germany), which selectively included CSU patients with angioedema and wheals. Patients were randomized (1 : 1) to omalizumab 300 mg or placebo (every 4 weeks up to week 24) (ClinicalTrials.gov number: NCT01723072).
Results
Of the 91 patients randomized to omalizumab (n = 44) or placebo (n = 47) at baseline, 68 completed the 28‐week treatment phase (omalizumab, 35; placebo, 33). Omalizumab was superior to placebo in improving CU‐Q2oL scores at week 28 (P < 0.001). There was a threefold improvement in angioedema‐burdened days/week with omalizumab (0.3) vs placebo (1.1). The median time to first recurrence of angioedema was 57–63 days with omalizumab and <5 days with placebo. Omalizumab significantly improved angioedema‐specific QoL (P < 0.001). The adverse events reported are in line with the established safety profile of omalizumab.
Conclusion
Omalizumab was an effective treatment option for patients with moderate‐to‐severe CSU symptoms and angioedema unresponsive to high doses of antihistamine treatment.
Background
The X‐ACT study aimed to examine the effect of omalizumab treatment on quality of life (QoL) in chronic spontaneous urticaria (CSU) patients with angioedema refractory to high doses of ...H1‐antihistamines.
Methods
In X‐ACT, a phase III, double‐blind, placebo‐controlled study, CSU patients (18‐75 years) with ≥4 angioedema episodes during the 6 months before inclusion were randomized (1:1) to receive omalizumab 300 mg or placebo every 4 weeks for 28 weeks. Angioedema‐related QoL, skin‐related QoL impairment, and psychological well‐being were assessed.
Results
Ninety‐one patients were randomized and 68 (omalizumab, n = 35; placebo, n = 33) completed the 28‐week treatment period. At baseline, the mean (SD) total Angioedema QoL (AE‐QoL; 56.2 18.7 and 59.9 19.2) and Dermatology Life Quality Index (DLQI; 14.6 5.7 and 16.6 7.3) score were high in the omalizumab and placebo group, respectively. At Week 4 (after the first treatment), the least squares mean difference in the AE‐QoL and DLQI score between groups was −17.6 (P < .001) and −7.2 (P < .001), respectively. Significant QoL improvements in the omalizumab vs placebo groups continued until Week 28, but returned to placebo levels at the follow‐up visit. The mean (SD) baseline 5‐item World Health Organization Well‐being Index was 10.0 (5.5, omalizumab) and 7.7 (5.3, placebo), which increased above the depression threshold (<13) from Week 4 and throughout with omalizumab but not placebo treatment. Compared to placebo, omalizumab was also associated with decreased fear of suffocation due to angioedema.
Conclusions
Our findings support omalizumab treatment in patients with severe H1‐antihistamine‐refractory CSU with angioedema.
Summary
Background
Secukinumab is a fully human monoclonal antibody that selectively binds to and neutralizes interleukin‐17A.
Objectives
To assess the efficacy and safety of different maintenance ...dosing regimens of secukinumab 300 mg based on Psoriasis Area and Severity Index (PASI) response at week 24 in patients with moderate‐to‐severe plaque psoriasis.
Methods
OPTIMISE was a randomized, open‐label, rater‐blinded phase IIIb study. Patients (n = 1647) received secukinumab 300 mg at baseline; weeks 1, 2, 3 and 4; and every 4 weeks (q4w) to week 24. At week 24, PASI 90 responders (≥ 90% improvement in PASI; n = 1306) were randomized to secukinumab 300 mg q4w (n = 644) or q6w (n = 662) to week 52, and PASI ≥ 75 to < 90 responders (n = 206) were randomized to secukinumab 300 mg q4w (n = 114) or q2w (n = 92) to week 52.
Results
PASI 90 response was maintained at week 52 by 85·7% of patients with q4w dosing vs. 74·9% with q6w dosing (odds ratio 1·91, 95% confidence interval 1·44–2·55). The primary end point, noninferiority of q6w vs. q4w dosing, was not met. In PASI ≥ 75 to < 90 responders, the proportion of patients with PASI 90 response at week 52 was numerically higher in the q2w vs. the q4w group (57% vs. 46·5%, respectively, P = 0·10). Heavier patients (≥ 90 kg) demonstrated numerically higher PASI 90 response with the q2w (57·1%) vs. the q4w regimen (40%, P = 0·11).
Conclusions
Standard q4w dosing of secukinumab 300 mg is the optimal dosing regimen to achieve and maintain clear or almost clear skin. Patients with body weight ≥ 90 kg not achieving PASI 90 at week 24 may benefit from the q2w dosing regimen.
What's already known about this topic?
Individual responses to biologics in patients with psoriasis vary considerably and there may be a need to individualize treatment.
Dose optimization strategies of currently available biologic drugs have been investigated mainly in rheumatic disorders.
Secukinumab has shown long‐term PASI 90/100 responses (percentage improvement in Psoriasis Area and Severity Index) to year 5 in patients with moderate‐to‐severe plaque psoriasis when used at the dose of 300 mg every 4 weeks.
What does this study add?
Standard every 4 week (q4w) dosing of secukinumab 300 mg is the optimal regimen to achieve and maintain clear or almost clear skin at week 52; the majority of the patients (85·7%) maintain PASI 90 at week 52.
Superiority of intensified (q2w) dosing over the q4w regimen could not be claimed.
However, patients with a higher body weight (≥ 90 kg) not achieving PASI 90 response at week 24 may benefit from q2w dosing.
Linked Comment: Morita and Ikumi. Br J Dermatol 2020; 182:264–266.
Background
Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin‐17A and shows long‐lasting efficacy and safety in plaque psoriasis. More evidence is required to ...optimize secukinumab dosing according to clinical response.
Objectives
GAIN compared the efficacy and safety of secukinumab 300 mg every 2 weeks (q2w) with 300 mg every 4 weeks (q4w) in patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) but not PASI 90 after 16 weeks.
Methods
In total, 772 patients with moderate‐to‐severe plaque psoriasis received secukinumab 300 mg subcutaneously at baseline and weeks 1, 2, 3 and 4, then q4w until week 16. At week 16, patients with PASI ≥ 75 to PASI < 90 were randomized 1: 1 to continue q4w dosing (n = 162) or switch to q2w (n = 163) to week 32. The primary endpoint was superiority of q2w to q4w dosing for PASI 90 response at week 32.
Results
PASI 90 response at week 32 was numerically greater with secukinumab 300 mg q2w than with secukinumab 300 mg q4w in suboptimal responders, but this did not reach statistical significance (64·4% vs. 57·4%; odds ratio 0·64, 95% confidence interval 0·39–1·07; P = 0·087). Although the primary endpoint was not met, absolute PASI was significantly lower at week 32 in q2w vs. q4w patients (2·11 vs. 2·84, P = 0·024). Significantly more patients with q2w vs. q4w dosing showed minimal disease activity (Investigator’s Global Assessment score 0 or 1: 73·0% vs. 64·1%, P < 0·05) and improved quality of life (Dermatology Life Quality Index score 0 or 1: 58·9% vs. 50·6%, P < 0·05) at week 32. No new or unexpected safety signals arose.
Conclusions
Most patients achieved PASI 90 response with secukinumab q4w. There was potential benefit of q2w dosing in some suboptimal responders. Continued q4w treatment can improve response even after 16 weeks.
What is already known about this topic?
Dose adjustments of biologic treatments for psoriasis according to response may occur in clinical practice, but systematic evidence for increased or individualized dosing in suboptimal responders is lacking.
Secukinumab has shown long‐lasting efficacy in psoriasis, and the GAIN study compared shortened dose intervals of every 2 weeks (q2w) with the standard dose of 300 mg every 4 weeks (q4w) in suboptimal responders (≥ 75% to < 90% improvement in Psoriasis Area and Severity Index).
What does this study add?
GAIN shows potential benefit of q2w dosing in some patients who do not respond optimally to q4w secukinumab treatment.
Although there was no statistically significant difference in PASI 90 response between patients dosed q2w and q4w, benefits were seen with the shortened treatment interval in absolute PASI, Investigator’s Global Assessment and Dermatology Life Quality Index.
Continued treatment with the approved q4w dose also improved response after 16 weeks in over half of suboptimal responders.
Linked Comment: Tsai. Br J Dermatol 2021; 184:791–792.
Summary
Background
Secukinumab is a fully human antibody that neutralizes interleukin‐17A. It has significant efficacy and a favourable safety profile in moderate‐to‐severe plaque psoriasis and ...psoriatic arthritis.
Objectives
To compare secukinumab with fumaric acid esters (FAEs) in a randomized controlled trial.
Methods
In this 24‐week, randomized, open‐label, multicentre study with blinded assessment, patients with moderate‐to‐severe plaque psoriasis, naive to systemic treatments, were randomized to receive secukinumab 300 mg subcutaneously or oral FAEs. The primary end point was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75 response) at week 24, and missing patients were considered responders if they were responders at the time of dropout.
Results
In total 202 patients were randomized and 200 were treated with at least one dose. Outcomes at week 24 were available for 147 and imputed for 53 patients. Discontinuations were mostly due to adverse events, which occurred more frequently in the FAE group (1·9% vs. 33·0%). At week 24, significantly more patients receiving secukinumab compared with FAEs achieved PASI 75 response (89·5% vs. 33·7%, P < 0·001), PASI 90 response (81·0% vs. 28·4%, P < 0·001) and Dermatology Life Quality Index 0 or 1 response (71·4% vs. 25·3%, P < 0·001).
Conclusions
Secukinumab demonstrated superior efficacy to FAEs in patients with psoriasis over a 24‐week period.
What's already known about this topic?
In Europe, secukinumab was the first biological therapy to be approved as a first‐line treatment.
Secukinumab demonstrated superiority to etanercept and ustekinumab in the clearing of skin symptoms, but has not yet been compared with first‐line systemic treatments.
Fumaric acid esters (FAEs) are recommended as a first‐line treatment by the European S3‐Guidelines.
What does this study add?
This head‐to‐head study showed that secukinumab has significantly greater efficacy in patients with psoriasis in terms of achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) response at week 24.
PASI 50, 90 and 100 responses were all higher for secukinumab vs. FAEs at week 24.
Secukinumab showed a favourable safety profile, and fewer patients discontinued secukinumab due to adverse events compared with patients on FAEs.
Linked Comment: Balak. Br J Dermatol 2017; 177:897–898.
Respond to this article
Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. ...Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC.
In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment.
Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval CI 31%–60%), the disease control rate 74% (CI 59%–85%), the median progression-free survival 4.4 (CI 3.2–6) months and the median overall survival 9.9 (CI 6.9–11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%–88%) according to Kaplan–Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1–2.
Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC.
EudraCT number 2010-022273-34, NCT01317615.
Introduction
Psoriatic disease is associated with considerable impairment of quality of life (QoL). The PROSE study (NCT02752776) investigated the impact of secukinumab treatment on patient‐reported ...outcomes (PRO) in patients with moderate to severe psoriasis stratified by their treatment history.
Methods
PROSE was a prospective, non‐randomised, multicentre study. Patients were categorized at baseline according to treatment history as naïve naïve to any systemic therapy (N = 663), conventional systemic previously exposed to ≥1 conventional systemic (CS) therapy (N = 673) and biologics previously exposed to ≥1 biologic therapy (N = 324). QoL PROs, efficacy and safety of secukinumab 300 mg were assessed for a period of 52 weeks.
Results
The primary objective was met with 70.8% patients achieving a Dermatology Life Quality Index (DLQI) 0/1 response at Week 16 (naϊve, 74.7%; CS, 71.3%; biologic, 61.7%), with effects sustained up to Week 52. Mean Family DLQI (FDLQI) score decreased from 11.5 at baseline (naϊve, 11.3; CS, 11.4; biologic, 12.1) to 2.5 at Week 16 (naϊve, 2.5; CS, 2.3; biologic: 3.5). Substantial improvements in EuroQoL 5‐Dimension Health Questionnaire, Numeric Rating Scale for pain, itching and scaling, Health Assessment Questionnaire‐Disability Index, Treatment Satisfaction Questionnaire for Medication, and Patient Benefit Index were also observed at Week 16. The QoL gains were associated with substantial improvements in Psoriasis Area and Severity Index and Investigator Global Assessment mod 2011 0/1 response. No meaningful difference was observed in the efficacy or QoL improvements across patient subpopulations. All QoL and efficacy parameter improvements were sustained up to Week 52. Secukinumab treatment was well‐tolerated, and no new safety signals were observed.
Conclusion
Secukinumab treatment resulted in complete normalization of QoL in a substantial proportion of psoriasis patients, and their families, regardless of their prior treatment history.
Summary
Background
The treatment of allergic asthma by specific immunotherapy (SIT) is hampered by potential side‐effects.
Objective
The aim of this study was to study the effect of omalizumab, a ...monoclonal anti‐IgE antibody, in combination with SIT in patients with seasonal allergic rhinoconjunctivitis (SAR) and co‐morbid seasonal allergic asthma (SAA) incompletely controlled by conventional pharmacotherapy.
Methods
A randomized, double‐blind, placebo‐controlled, multi‐centre trial was performed to assess the efficacy and safety of omalizumab (Xolair®) vs. placebo in combination with depigmented SIT (Depigoid®) during the grass pollen season. Omalizumab or placebo was started 2 weeks before SIT; the whole treatment lasted 18 weeks. Primary endpoint was daily ‘symptom load’, the sum of daily scores for symptom severity and rescue medication use.
Results
A total of 140 patients (age 11–46 years) were randomized; and a total of 130 finished the study. Combination therapy reduced the symptom load by 39% (P=0.0464, Wilcoxon test) over SIT monotherapy. This difference was mainly due to reduced symptom severity (P=0.0044), while rescue medication use did not change significantly. Combination therapy also improved asthma control (Asthma Control Questionnaire, P=0.0295) and quality of life in the case of asthma (Asthma Quality of Life Questionnaire, P=0.0293) and rhinoconjunctivitis (Rhinoconjunctivitis Quality of Life Questionnaire, P=0.0537). Numbers of patients with ‘excellent or good’ treatment efficacy according to ratings of investigators (75.0% vs. 36.9%) or patients (78.5% vs. 46.1%) were markedly higher in the combination group than under SIT alone.
Conclusion
Combination of omalizumab with SIT for treatment of patients with SAR and co‐morbid SAA was safe and reduced the symptom load in a statistically significant and clinically meaningful manner.
Summary
Background
Conventional analyses present aggregate data, masking late responders and efficacy reductions. Secukinumab, a fully human monoclonal antibody that selectively neutralizes ...interleukin (IL)‐17A, shows sustained efficacy in moderate‐to‐severe psoriasis.
Objectives
To determine stability of response to secukinumab, changes in efficacy were assessed in individual patients.
Methods
This is a post hoc analysis of two phase III randomized controlled trials, FIXTURE (trial registration: NCT01358578) and CLEAR (trial registration: NCT02074982). Patients received secukinumab 300 mg (FIXTURE and CLEAR), etanercept 50 mg (FIXTURE) or ustekinumab 45 or 90 mg (CLEAR) over 52 weeks. Mutually exclusive response categories were defined: ≥ 90% improvement in the Psoriasis Area and Severity Index (PASI 90) (‘excellent’), ≥ 75% improvement in PASI (PASI 75) and < PASI 90 (‘good’) and < PASI 75 (‘insufficient’). Reductions in efficacy were defined as shifts from higher to lower response categories between two consecutive visits maintained for a third consecutive visit. Loss of efficacy was defined as a reduction of efficacy resulting in ‘insufficient’ response. All comparisons are descriptive.
Results
At 52 weeks, in CLEAR, 90·2% (303/336) of patients on secukinumab achieved stable efficacy without loss and 77·7% (261/336) showed stable efficacy without any reduction of response 74·3% (252/339) and 59·9% (203/339) of patients for ustekinumab. In FIXTURE, 83·5% (273/327) and 66·4% (217/327) of patients on secukinumab had stable efficacy without loss or reduction of response 58·3% (190/326) and 42·6% (139/326) for etanercept. Response was regained by continuing secukinumab treatment in 50% (8/16) of patients in CLEAR and 26% (9/34) in FIXTURE. Similar patterns were observed for other response definitions.
Conclusions
Efficacy with secukinumab was stable over 52 weeks of treatment in most patients. Continued treatment with secukinumab resulted in regain of efficacy in some patients. Persistent loss of response was uncommon.
What's already known about this topic?
Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)‐17A, shows significant and sustained efficacy in the treatment of moderate‐to‐severe psoriasis.
Secondary loss of response may be experienced by a minority of patients treated with secukinumab, as with other biologics, but the extent of this and the potential for regain of efficacy with continued treatment is not well understood.
What does this study add?
To determine stability of response to secukinumab and inform clinical practice, changes in efficacy were assessed at individual patient level using response categories.
Efficacy with secukinumab was stable over 52 weeks of treatment in most patients, and continued treatment with secukinumab resulted in efficacy regain after loss in some patients. Persistent loss of response was uncommon.
Patient factors such as body weight may affect the likelihood of loss of efficacy.
Plain language summary available online
Respond to this article
Introduction
Psoriatic disease is associated with considerable impairment of Quality of Life (QoL). The PROSE study (NCT02752776) examined the impact of secukinumab on patient‐reported outcomes in ...patients with moderate‐to‐severe psoriasis (PsO) stratified by previous exposure to systemic treatment.
Methods
In this prospective, non‐randomized, multicentre study, patients were categorized at baseline according to previous exposure to systemic treatment: naïve naïve to any systemic treatment (N = 663), conventional systemic previously exposed to ≥1 conventional systemic therapy (N = 673) and biologics previously exposed to ≥1 biologic (N = 324). Baseline demographics including age, gender, race, body weight and body mass index, disease characteristics and patient‐reported QoL outcomes Dermatology Life Quality Index (DLQI), Family DLQI (F‐DLQI) of patients enrolled in the study are reported here.
Results
Baseline demographic characteristics were well balanced across the three subpopulations. Naïve patients had a shorter time since diagnosis (15.5 ± 12.1 years) compared with the conventional systemic (19.1 ± 12.5 years) and biologic patients (23.0 ± 12.5 years), and lower rates of psoriatic arthritis (6.6% vs. 17.4% and 27.8%, respectively). Metabolic syndrome (37.6‒43.5%), obesity (16.9‒19.1%), hyperlipidaemia (15.3‒21.9%) and diabetes mellitus (6.8‒14.2%) were reported at numerically higher rate in the biologic group. The mean PASI (19.7 ± 7.9), affected Body Surface Area (28.2 ± 15.3%) as well as the Investigator Global Assessment score (patients with score 4: 33.7%) indicated severe disease at baseline and were comparable for the three groups. QoL impairment was evident from mean DLQI (14.1 ± 7.1: naïve = 13.5 ± 6.8; conventional systemic = 14.3 ± 7.0; biologic = 14.8 ± 7.7) and mean F‐DLQI (11.5 ± 7.0: naïve = 11.3 ± 7.1; conventional systemic = 11.4 ± 6.7; biologic = 12.1 ± 7.7) also indicated derangement of QoL of patients and their families.
Conclusion
Patients naïve to systemic treatment had shorter disease journey compared with patients previously exposed to systemic treatments; despite this, the severe impact of disease on patient and family QoL outcomes can be as apparent in naïve patients as in systemically treated patients at baseline.
Linked Commentary: I.Y.K. Iskandar. J Eur Acad Dermatol Venereol 2020; 34: 2454–2455. https://doi.org/10.1111/jdv.16971.
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