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Omalizumab is recommended as an add-on therapy in patients aged ≥6 years with inadequately controlled, moderate-to-severe persistent allergic asthma. The efficacy and safety of omalizumab treatment in allergic asthma clinical trials and its effectiveness in the real world have been reported in numerous studies. In this review, we examine clinical evidence in pediatric and adult patients with allergic asthma who received omalizumab treatment for at least 2 years, to assess its effectiveness, durability, and trajectory of response over time as well as safety. We performed a literature search from inception until March 2022 in PubMed using the keywords “omalizumab” and “allergic asthma” to retrieve articles examining the effects of omalizumab in patients with allergic asthma, aged ≥6 years. Only articles that evaluated the effectiveness of omalizumab for at least 2 years were included. Data from case reports were excluded. Our review confirmed the long-term effectiveness and safety of omalizumab, demonstrating reduced rate of exacerbations, improved lung function, asthma control, and quality of life, decreased health care resource utilization, and use of corticosteroids (oral/inhaled) with a favorable safety and tolerability profile for up to 9 years in adult patients with moderate-to-severe allergic asthma. Similar results were also observed in the pediatric population with up to 7.5 years of omalizumab treatment. This review highlights and confirms the sustained clinical benefits of omalizumab over long periods of treatment in pediatric and adult populations with allergic asthma.
Patients with moderate or severe asthma require treatment with medium-to high-dose inhaled corticosteroids (ICS) ± long-acting β2-agonists (LABAs) or other add-on controllers. However, some patients with severe asthma remain uncontrolled despite treatment with high-dose ICS/LABA ± other add-on agents such as leukotriene receptor antagonists and/or long-acting muscarinic antagonists.
While assessing severe asthma, attention to possible comorbidities, differential diagnoses, and accurate phenotyping are needed prior to consideration of complex therapies, such as biologics. Failure to do so may result in non-response to all biologics.
Omalizumab, an anti-IgE monoclonal antibody, was the first biologic approved for patients aged ≥6 years with moderate-to-severe persistent asthma (USA) or severe persistent allergic asthma (Europe), uncontrolled despite appropriate high-dose ICS treatment.
Randomized clinical studies and real-world evidence have demonstrated the efficacy and effectiveness of omalizumab in reducing asthma exacerbations and hospitalization rates, improving quality of life (QoL) and asthma daily symptoms. In addition, omalizumab has a very satisfactory short- and long-term safety profile in children aged 6–12 years, teenagers, and adults.
Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): innovate.
In this review, we comprehensively examine the existing clinical evidence from real-world studies, including pediatric and adult patients with allergic asthma who have received omalizumab treatment for ≥2 years, to evaluate its effectiveness and safety and help clinicians assess the durability and trajectory of its response over time.
Methodology
We performed a literature search in PubMed published from inception until March 2022, using the keywords “omalizumab” and “allergic asthma” to retrieve articles evaluating the effects of omalizumab in allergic asthma in patients aged ≥6 years. Studies that evaluated the effectiveness of omalizumab for ≥2 years, with real-life experiences, registry-based or observational designs, and published in the English language, were deemed eligible for inclusion. Case reports were excluded. The included articles were further categorized into 2 sections based on treatment duration: omalizumab use for 2–5 years and >5 years (Table 1).
Table 1Publications that evaluated omalizumab use in asthma patients receiving the drug for >2 years.
Czech eXpeRience Study Group Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
Cardiovascular and cerebrovascular events among patients receiving omalizumab: pooled analysis of patient-level data from 25 randomized, double-blind, placebo-controlled clinical trials.
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
Data on exacerbation rate, lung function, asthma control, QoL, systemic corticosteroid (SCS) or ICS use, and healthcare resource utilization (HCRU) were reported as measures of effectiveness of omalizumab. Although the criterion set for defining exacerbations differed for each study, making between-study comparisons difficult, certain criteria such as exacerbations requiring oral corticosteroids (EROCS), worsening of asthma, increased need for ICS or SCS, hospitalizations, and emergency room (ER) visits are common in many of the studies for definitions of exacerbations (Supplementary Table 1).
Other parameters assessed were lung function in terms of forced expiratory volume in 1 second (FEV1), asthma control measured by Asthma Control Test (ACT) or Asthma Control Questionnaire (ACQ), QoL assessed using different questionnaires including Asthma Quality of Life Questionnaire (AQLQ), and Asthma Life Questionnaire (ALQ).
, In some studies, early clinical response to omalizumab treatment was evaluated using the validated “global evaluation of treatment effectiveness (GETE)” tool.
We identified 42 publications meeting the inclusion criteria, 30 of which included a treatment duration/follow-up of 2–5 years and 12 were of >5 years. The eligible literature data with demographic details of the patients are shown in Table 1.
Long-term effectiveness
Asthma exacerbations
Omalizumab treatment showed ≥72% reduction in exacerbation rates in patients with moderate-to-severe allergic asthma.
The proportion of patients experiencing exacerbations decreased over time, and notably, fewer or no episodes of exacerbations requiring ER visits or hospitalizations were observed.
In addition, a higher proportion of patients who were free from exacerbations requiring emergency visits or hospital admissions were observed with ∼2 years of omalizumab treatment compared with the pretreatment period (88.6% vs 41.9%).
Similar results were observed for exacerbations requiring oral steroids with 79% patients reported to be exacerbation free after ∼2 years of omalizumab treatment compared with 16.3% patients during the pretreatment period.
Evaluation of data from studies with a longer treatment duration of ∼3–4 years also demonstrated reductions in the rate of exacerbations by 54.4%–95% in omalizumab-treated patients, indicating sustained effectiveness.
From pretreatment to the end of the 5-year omalizumab treatment period (follow-up: 5.5–7.0 years) the mean annualized exacerbation rate significantly decreased by 77.1% in 17 allergic patients.
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
In the XPORT study (Xolair Persistency Of Response After Long-Term Therapy), patients who continued omalizumab beyond 5 years were significantly less likely to experience a protocol-defined exacerbation compared with those who withdrew from treatment (odds ratio: 0.45 [95% CI: 0.24–0.83]). In addition, treatment continuation (1 year) prolonged the time-to-first exacerbation (hazard ratio [HR], 0.49 [95% CI: 0.28–0.86]).
In a cohort of 78 severe allergic asthmatic children aged 6–18 years, Deschildre et al observed a continuous decrease in severe exacerbation rates after 2 years of omalizumab treatment, with a trend to zero exacerbations at the end of 2 years, since the rate reached a mean (95% CI) of 0.22 (0.03–0.41) per year in the second year. A significant decrease of –72% and –83% in rate of exacerbation requiring emergency visits or hospitalization was observed during the first and second year (P = 0.0001) with no hospitalization for exacerbation during the second year.
Folqué et al in a 6-year follow-up study showed a significant decrease in the rate of hospital admissions and visits to the ER for asthma exacerbations during the third and fourth years of follow-up, respectively.
In another 6-year follow-up study of 426 patients (ANCHORS), the mean number of moderate-to-severe exacerbations decreased significantly from 7.9 at baseline to 1.1 during the first year [−80.2%, P < 0.001]), and these improvements were sustained during the 6 year follow-up period with exacerbation numbers trending to zero after 2 years of omalizumab treatment.
It is important to highlight the improvements observed in terms of rate of exacerbations requiring systemic corticosteroids, reaching nearly zero in pediatric patients after 2 years of omalizumab treatment,
which indeed is an important treatment goal in asthma management.
Asthma control and GETE score
Overall, omalizumab improved ACT scores in patients across all age groups, with greater improvements in the younger patients compared with the older patients. Patients who continued omalizumab treatment were more likely to have controlled asthma compared with those who discontinued and never reinitiated. The proportion of patients with good or excellent omalizumab response on global evaluation of treatment effectiveness (GETE) scale increased over years of treatment.
Omalizumab use for 2–5 years in adult with asthma
In a retrospective study, 44% of patients who received consistent omalizumab treatment for 24 months had uncontrolled asthma during the follow-up period (13–24 months) compared with 55% of patients who discontinued omalizumab at 12 months (and never reinitiated).
Sposato et al showed that although ACT scores increased in all age groups of patients treated with omalizumab for ∼3 years, the level of improvement was greater in patients aged 18–39 years (by ∼9 points) compared with 40–64 years (by ∼7 points) and ≥65 years (by ∼5 points).
In contrast, Tat et al reported significant improvements in ACT scores by 11.4 points from baseline in elderly patients for the same treatment duration.
Fig. 2Effect of omalizumab on asthma control, as demonstrated by Asthma Control Test (ACT) score, in allergic asthma. Bars indicate the ACT score changes in individual studies. ACT, Asthma Control Test
In another real-world study, as compared to 24.1% of patients at baseline, 92.1% and 87.1% patients reported controlled/partially controlled asthma with omalizumab after 12 and 24 months of treatment, respectively.
Czech eXpeRience Study Group Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
Omalizumab treatment for a median duration of 32 months resulted in good asthma control in 25.2%, partial control in 47.1%, and poor control in 24.5% of patients, according to GINA.
Additionally, in the EXCELS study (Epidemiologic Study of Xolair [Omalizumab]: Evaluating Clinical Effectiveness and Long-term Safety in Patients With Moderate to Severe Asthma), more patients were well-controlled (ACT score of >20) after 5 years of omalizumab treatment compared with prior to treatment (66.7% vs 48.6% for omalizumab-naïve cohort, 60.3% vs 25% for new starters, and 61.3% vs 47.8% for established users).
Studies that evaluated response to omalizumab treatment on the GETE scale showed that the proportion of patients with good or excellent response increased from 74.6% at 4 months to 81.6% after 2 years of treatment
In a real-life, observational surveillance study, Al-Ahmad et al evaluated treatment response of omalizumab using modified physician GETE (mGETE) scale, which demonstrated an excellent response in 53.8% of patients at 16 weeks that increased to 73.8% after 4 years of treatment.
Significant improvements in asthma control from baseline have been reported in most studies that assessed omalizumab treatment for >5 years. This was demonstrated by a 5.1-point increase in mean ACT score
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
A recent study with ∼10 years of omalizumab treatment demonstrated nearly 6-point increase in ACT score at 3 years which remained high up to 8 years of treatment.
The XPORT study showed benefits of continuation of omalizumab treatment after long-term treatment results, supported by improved symptom control and reduced exacerbation risk.
In a French cohort of uncontrolled severe allergic asthmatic children, 80% of 73 children were well-controlled (Global Initiative for Asthma – GINA criteria) after 2 years of omalizumab treatment.
In severe allergic asthmatic children who had received omalizumab for 24 months, 76.7% of 30 children were controlled who were still on omalizumab maintenance therapy after a mean treatment duration of 46.2 months.
In the ANCHORS study (Asthma iN CHildren: Omalizumab in Real-life in Spain), 8.4% of 334 patients were controlled at baseline which improved significantly to 45.0% (148/329; [P < 0.001]) during the first year of omalizumab treatment and increased to 89.3% (75/84) at year 6.
Czech eXpeRience Study Group Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
In the only study that evaluated the effect of omalizumab on QoL beyond 5 years, a significant increase in median AQLQ score by 3.4 points was observed over 9 years from baseline.
The Pediatric Asthma Quality of Life Questionnaire (PAQLQ) scores improved after 16, 24, and 104 weeks of omalizumab treatment compared with baseline, although the difference between time points was not significant. Significant improvements in total PAQLQ scores >1.5 points were achieved by 41.5% and 39.6% of children after 52 and 104 weeks of treatment, respectively. Of the total population, only 5% of children did not respond (improvement of PAQLQ <0.5 points) to omalizumab therapy.
Omalizumab use for 2–5 years in adults with asthma
Treatment with omalizumab for 2 years resulted in decrease in the rate of OCS use as well as proportion of patients receiving OCS compared with baseline.
Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): innovate.
Cardiovascular and cerebrovascular events among patients receiving omalizumab: pooled analysis of patient-level data from 25 randomized, double-blind, placebo-controlled clinical trials.
Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): innovate.
Additionally, patients consistent (patient with ≥1 dispensing of omalizumab, ≥6 months of continuous eligibility before their first omalizumab dispensing [washout period], and had ≥1 diagnosis for asthma during the baseline period) with omalizumab treatment at 2 years showed a greater decrease in OCS use compared with those who were not consistent.
During a mean follow-up of >5 years in patients receiving omalizumab, mean daily maintenance OCS dose significantly decreased by >75%, along with a decrease in mean annualized number of steroid courses per patient.
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
Omalizumab decreased the number of OCS cycles after 4 and 7 years of treatment. The improvements observed at 4 years were more evident after 7 years of treatment.
During a 9-year follow-up study, 7 of 8 patients were using OCS at baseline, whereas after omalizumab treatment, only 1 patient used OCS. The mean daily OCS dose was decreased to 1.6 mg/day after 8 years of omalizumab treatment as compared to 7.8 mg of prednisolone or the equivalent per day.
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
In pediatric patients with asthma, at the end of first year of omalizumab treatment, in a cohort of 92 severe allergic asthmatic children aged 6–18 years, no patient remained under daily OCS treatment (6 at baseline).
Omalizumab use for 2–5 years in adults with asthma
Omalizumab treatment resulted in a decrease in the mean daily dose of beclomethasone-equivalent ICS and budesonide-equivalent ICS from baseline to 2 years.
In the EXCELS study, following 2 years of omalizumab therapy, the mean total ICS daily dose was reduced by 57.7%, 44.7%, and 42.4% in new starters, established users, and omalizumab-naïve patients, respectively. Similarly, ICS monotherapy dose was also reduced by 60%–68% in all groups.
Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study of moderate-to-severe asthma.
Omalizumab use for >5 years in adult patients with asthma
Omalizumab treatment for 7 years decreased the need for nebulized corticosteroid/bronchodilator and reduced the dose of ICS/LABA in 4 of 7 patients, with 2 patients discontinuing ICS/LABA.
In addition, of all patients receiving high-dose ICS at baseline, only 1 patient remained on high dose after 9 years of treatment. Other patients reported a 65% decrease in ICS dose.
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
In a pediatric study, a decrease of 30% of mean ICS dose (703 μg at initiation and 488 μg fluticasone equivalent per day after 1 year) was noted during the first year. No further significant decrease was observed at 2 years (mean = 429 μg/day); however, 63% of patients benefited from ≥50% decrease in initial dose of ICS.
In a long-term study by Deschildre et al the median daily ICS dose (range, μg/d) decreased significantly from 1000 (250–1250) to 375 (0–1000) in a subgroup of 30 children still treated after a mean of 46.2 months (31.5–90.3).
Sztafińska et al showed that 63.33% of pediatric patients achieved a reduction in ICS dose (median reduction of 300 μg/day after 52-weeks of omalizumab treatment). No further reduction in ICS use was observed between 52 and 104 weeks of treatment.
A 6-year follow-up study in 48 children with allergic asthma reported a significant decrease in the use of maintenance therapy (fluticasone) in patients after six months (329.89 μg/day) of omalizumab therapy compared to baseline (452 μg/day). The difference was maintained throughout the follow-up period.
In the ANCHORS study, the mean daily ICS dose decreased significantly after 1 year (867.3 vs 663.4 μg budesonide equivalent) of omalizumab treatment that continued over 6 years (350.2 μg budesonide equivalent compared with baseline).
Of the 19 studies evaluating the effect of omalizumab on lung function in patients with allergic asthma for ∼2–5 years, omalizumab improved lung function in 16 studies.
Czech eXpeRience Study Group Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
In pediatric patients, Deschildre et al showed improvement in lung function (FEV1) during the first year of omalizumab treatment with no significant additional improvement in the second year.
Omalizumab use for 2–5 years in adults with asthma
Omalizumab treatment for 2 years significantly increased mean FEV1 (% predicted) by 7.5%–16.75% and mean peak expiratory flow (PEF) by 21.8–45.4 L/min.
Czech eXpeRience Study Group Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
Further improvement in lung function was observed with longer periods of omalizumab treatment (∼3–4 years), with an increase in mean FEV1 (% predicted) ranging from 16.8% to 24.5%.
A study by Vennera et al showed that omalizumab treatment for 2 years significantly increased FEV1 (% predicted) in patients aged <50 years (14.2%) compared with those aged ≥50 years (3.2%).
A non-significant increase in FEV1 (% predicted) of 12.2% was observed in elderly patients aged ≥65 years who received omalizumab for a mean duration of ∼3 years.
In contrast, omalizumab treatment for a mean of 35 months resulted in comparable improvements in lung function (overall increase in FEV1 [% predicted] of 12%–14%) in 3 subgroups of patients categorized by age (18–39, 40–64, and ≥65 years).
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
Sztafińska et al reported no significant improvement in FEV1 in children and adolescents with severe persistent allergic asthma after 2 years of omalizumab treatment.
In children aged 6–18 years, compared with baseline (FEV1, 88% [% predicted value] [95% CI: 83.8; 92.2]), mean FEV1% predicted increased by 4.9% during 1 year of follow-up with no significant modification during the second year. Indeed, FEV1 was maintained at a high level, 89.9% predicted (95% CI: 86.7%–93.0%) at the end of 2-year treatment.
These results were confirmed by Deschildre et al showing an pre-β2 agonist FEV1 (% predictive value) of 97 (50–119) after 31.5–90.3 months of omalizumab treatment.
In the ANCHORS study, FEV1% predicted increased significantly from 84.6% at baseline to 92.3% after one year of treatment (P < 0.001), and these improvements remained consistent during 6 years of follow-up (92.8%).
Omalizumab use for 2–5 years in adults with asthma
Omalizumab treatment for 2 years reduced the mean number of annualized healthcare visits per patient (6.4 vs 0.5) and increased the proportion of patients with no annualized healthcare visit (12.3% vs 75.4%).
Czech eXpeRience Study Group Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
Patients who received consistent omalizumab treatment for 24 months showed a 70% reduction in asthma-related ER visits and 39% reduction in hospitalizations compared with patients who discontinued omalizumab at 12 months and did not reinitiate. Furthermore, consistent omalizumab treatment for 2 years demonstrated ∼94% reduction in HCRU and significantly prolonged time-to-first asthma-related ER visit/hospitalization (HR: 0.70; 95% CI: 0.58–0.84; P < 0.01).
Czech eXpeRience Study Group Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
Other studies also reported improvement in HCRU in terms of decreased hospitalizations and ER/intensive care unit visits with omalizumab for 2–4 years.
Of note, in one study, omalizumab treatment for 4 years resulted in no hospitalizations during the treatment period compared with almost two-thirds of patients who reported ≥1 annualized hospitalization prior to treatment.
Omalizumab treatment from the pre-treatment period to ≥5 years resulted in reduction in number of hospitalizations and ER visits by 80.7% and 48.5%, respectively. A reduction in mean annual per-patient hospitalization and ER visit was also observed.
Improvement in HCRU with omalizumab has also been reported in pediatric patients. In children, the rate of hospitalizations and ER visits/patient-year significantly decreased from baseline during omalizumab treatment.
In the French cohort, there was a huge improvement with 88.5% decrease in hospitalizations during the first year and no patients hospitalized for exacerbations in the second year of treatment, compared to 44% in the year preceding the initiation.
In the 6-year ANCHORS study, the number of healthcare visits decreased significantly after 1 year of omalizumab treatment (P < 0.001), with no ICU admissions from the second year onward.
Proportion of patients experiencing ≥ 2 severe exacerbations remained low and stable: First year: 12.42%, Second year: 7.87% Third year: 11.97%
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Reduction in mean ± SD ACQ-6 total score vs baseline: 1.7 ± 1.23 vs 2.0 ± 1.22 at 3 years change from baseline: −0.18 ± 1.07 (P = 0.340) Improvement in Mini-AQLQ total score vs baseline (4.5 ± 1.26): Month 6: 5.0 ± 1.35; P = 0.002 1 year: 4.9 ± 1.36; P = 0.001 1.5 years: 4.8 ± 1.40; P = 0.009 2 years: 4.9 ± 1.48; P = 0.011 3 years: 4.7 ± 1.48; P = 0.186 Increase in Mini AQLQ score at 3 years vs baseline: 0.26 ± 1.35, P = 0.186
Czech eXpeRience Study Group Real-world effectiveness and safety of omalizumab in patients with uncontrolled severe allergic asthma from the Czech Republic.
Reduction in clinically significant exacerbations vs baseline: 0.7 vs 5.7 at months 24 Proportion of patients with no clinically significant exacerbations: Month 12: 56.2% Month 24: 63.0% Reduction in severe exacerbations vs baseline: 2.2 vs 0.1 at months 24 Proportion of patients with no severe exacerbations: Month 12: 89.9% Month 24: 95.1%
Improvement in mean FEV1(mL): Change from baseline: Week 16:205 Month 8: 215 Month 12: 273 Month 18: 200 Month 24: 137 Improvement in PEF (L/min); Mean change from baseline: Week 16: 11.01 Month 8: 18.38 Month 12: 32.82 Month 18: 25.18 Month 24: 21.85
Improvement in ACT scores vs baseline: 17.3 vs 12.4 at months 24 Proportion of patients with controlled/partly controlled asthma vs baseline: Month 12: 92.1% Month 24: 87.7% Mean change in mini-AQLQ vs baseline: Month 12: 0.8 points Month 24: 0.94 points
Reduction in mean number of asthma-related hospitalizations vs pre-treatment period: 0.0 ± 0.2 vs 0.5 ± 1.2 at month 24 Reduction in mean ± SD number of days stayed in hospital vs pre-treatment period: 0.2 ± 2.2 vs 3.3 ± 9.8 at month 12 Patients free from asthma-related hospitalizations at months 12 and 24: 100% and 98.8%
Reduction in OCS use vs baseline: Month 12: 50% vs 33.9% Month 24: 52.6% vs 33.9% Reduction in mean total daily dose (in prednisolone equivalent mg) of OCS vs baseline: 6.4 vs 11.6 at months 24
Reduction in severe asthma exacerbations vs pre-treatment: 1.5% vs 47.7% patients after 4 years; P < 0.001
Improvement in %FEV1predicted vs baseline: 76.6% vs 55.6% at 4 years; P = 0.003
Increase in ACT score vs baseline: 23 ± 3 vs 15 ± 3 at 4 years; P < 0.001
Decrease in HCRU: No. of ER visits decreased by 90.8% after 4 years (P < 0.001) Patients with ≥1 hospitalizations due to severe asthma exacerbation decreased from 47.7% at baseline to by 1.5% after 4 years (P < 0.001)
Reduction in OCS use: Proportion of patients who did not use OCS Week 16: 55.4% 1 year: 78.0% 4 years: 83.1 Proportion of patients with reduction in ICS/LABA use at different time points: Week 16: 35.4% 1 year: 44.6%; P < 0.014 4 years: 56.9%; P < 0.001
Baseline of the core study vs end of treatment period of the extension study: Mean FEV1% predicted: 90.3% vs 89.2% Mean FEF25%-75%predicted: 76.3% vs 75.1%
Mean change in JPAC score from start of the extension study to end of the treatment period: 3.0 (P < 0.001) % of patients with well controlled asthma at start of extension study vs end of treatment period: 23.7% vs 76.3% Median QoL scores at baseline of the core study vs end of treatment period: 39 vs 48 (P < 0.001)
Rate per patient-year at baseline of the core study vs overall treatment period of the extension study: Hospitalizations: 1.33 vs 0.16 (P < 0.001) ER visits: 0.68 vs 0.15 (P = 0.002)
ICS dose decreased by 13.2% from baseline of the core study to end of treatment period
% of patients with asthma control vs baseline: Omalizumab-naïve cohort: Well-controlled asthma: 66.7% vs 48.6% Poorly controlled asthma: 14.8% vs 26.6% Omalizumab cohort: Well-controlled asthma: 61.2% vs 45.2% Poorly controlled asthma: 19.0% vs 31.6%
% of patients with HCRU vs baseline with: ≥1 hospitalization: 2.1% vs 38.2% (P < 0.0001) ≥1 ER visits: 19.1% vs 95.7% (P < 0.0001) ≥1 intensive care admission: 0% vs 4.2%
Mean ICS dose vs baseline: 765 μg/day (n = 42) vs 1750 μg/day (n = 47) After 3 years: 5 patients discontinued ICS
(eXpeRience study –Portuguese subgroup) Treatment duration: 2 years
% of patients free from clinically significant exacerbations vs baseline: 60% vs 6.5%
Increase from baseline in Mean FEV1% predicted: 9.6% Mean PEF: 45.4 L/min
Increase from baseline in mean ACT score: 7.0 mean mini-AQLQ score: 2.7 Increase in ACT score by ≥ 2 points and mini-AQLQ scores by ≥ 0.5 points is considered minimal clinically important difference
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Corticosteroids use vs baseline: Patients on OCS: 8.2% vs 17.7% Patients on ICS: 88.9% vs 96.8% Mean total daily OCS dose (prednisolone equivalent): 13.1 mg vs 16.7 mg Mean total daily ICS dose (beclomethasone equivalent): 1351.1 μg vs 1497.5 μg
Exacerbation rate decreased from baseline to 1st year by 70.1% (P = 0.002) and from 1st year to 2nd year by 75.9% (P = 0.05)
Mean FEV1% predicted vs baseline: 65% vs 51.7% P = 0.007
Mean ACT score vs baseline: 18.9 vs 12.3 P = 0.008 Mean ALQ score vs baseline: 11.8 vs 15.3 P = 0.024
Unscheduled health care visits decreased from baseline to 1st year by 86.1% (P = 0.002) and from 1st year to 2nd year by 69% (P = 0.12)
Corticosteroid use vs baseline: Mean daily ICS dose (budesonide equivalent): 1111.1 μg vs 1653.3 μg P = 0.028 Percentage of patients with daily OCS use: 10% vs 53%
At 2 years vs baseline, % of patients free from clinically significant exacerbations: 67.3% vs 6.8% severe clinically significant exacerbations: 89.9% vs 30.2% Mean annualized no. of clinically significant and severe clinically significant exacerbations vs baseline: 0.6 and 0.1 vs 4.9 and 2.2 respectively
Increase from baseline in mean FEV1% predicted: 8.7% mean PEF: 34.0 L/min
Mean change from baseline in ACT score: +6.2 ACQ score: −0.80 AQLQ score: 0.75 Mini-AQLQ: 1.62 Increase in ACT score by ≥ 3 points, AQLQ/mini-AQLQ scores by ≥ 0.5 points and decrease in ACQ score by ≥ 0.5 points is considered minimal clinically important difference
Mean annualized no. of health-care visits/patient vs baseline: 0.5 vs 6.2 % of patients vs baseline with: No annualized asthma-related medical healthcare use: 75.4% vs 12.3% No hospitalization: 93.8% vs 62.3% No ER visit: 91.9% vs 49.3% No unscheduled doctor visit: 78.4% vs 19.3%
Corticosteroids use vs baseline: Maintenance OCS therapy: 14.2% vs 28.6% Mean total daily OCS dose (prednisolone equivalent): 5.8 mg vs 15.5 mg Mean total daily ICS dose (beclomethasone equivalent): 1381 μg vs 1675 μg
% of patients with uncontrolled asthma who were consistent with omalizumab at 24 months vs non-consistent at 12 months and never re-initiated omalizumab: 44% vs 55%
Mean number of asthma-related ER visits and hospitalizations in patients consistent with omalizumab at 24 months vs non-consistent at 12 months and never re-initiated omalizumab: 0.038 vs 0.126 and 0.106 vs 0.173, respectively
Mean number of OCS claims in patients consistent with omalizumab at 24 months vs non-consistent at 12 months and never re-initiated omalizumab: 1.648 vs 2.446
% reduction in dose from baseline in new starters, established users, and omalizumab-naïve patients respectively, by: total ICS dose: 57.7%, 44.7%, and 42.4% ICS monotherapy dose: 67.8%, 67.9%, and 60.1%
Number of exacerbations decreased by 90% from baseline to 12 months and improvement sustained until end of treatment (P < 0.05)
Increase in FEV1% predicted from baseline: Month 24: 21.5 Month 36: 23 End of visit: 20.4 (All P < 0.05)
Increase in mean ACT score from baseline: Month 24: 10.3 Month 36: 11.6 End of visit: 11 (P = 0.001, all) Mean AQLQ total score vs baseline: 5.34 vs 1.98 Increase in AQLQ scores by ≥ 0.5 points is considered minimal clinically important difference
Decrease in HCRU vs baseline: No. of exacerbations by 90% No. of ER visits by 93.3% No. of hospitalizations by 71.3% Improvement was maintained until end of treatment (P < 0.05)
Number of patients with systemic steroid use vs baseline: 0 vs 6
Reduction in exacerbations vs pretreatment: 1.1 vs 4.1 per year after 1 year of treatment and remained low during all the years up to the 8th year of treatment (P < 0.001)
Improvement in FEV1% predicted vs baseline: 73.6% vs 61.5% after 12 years of treatment (P < 0.001) Improvement in FEV1 (ml) vs baseline: 239.8 vs. 160.8 after 12 years of treatment (P < 0.001)
Improvement in asthma control expressed as ACT vs pre-treatment: 22.1 vs 16.2 after 3 years and remained as high up to the 8th year of treatment (P < 0.001)
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Discontinuation of OCS use: 21.1% patients discontinue at 6 months; 47.4% and 31.6% of patients were on OCS after 4 years and 8 years, respectively Proportion of patients with ≥50% OCS reduction: Month 6: 36.8% 2 years: 68.4%
Mean FEV1% predicted vs baseline: 75.7% vs 59.2% (P = 0.0013)
Mean ACQ7 score vs baseline: 2.3 vs 4.0 (P < 0.0001)
Treatment vs baseline: Number of hospitalizations: 40 vs 207 Mean annual per patient hospitalizations: 0.89 vs 4.8 (P < 0.00001) Number of emergency visits: 42 vs 80 Mean annual per patient emergency attendance: 3.0 vs 4.4 (P = 0.17) Mean annual per patient ICU admissions: 0.19 vs 0.48 (P = 0.13)
Treatment vs baseline: % of patients with maintenance OCS use: 44.2% vs 82% Mean daily maintenance OCS dose (prednisolone equivalent): 6.0 mg vs 25.8 mg (P < 0.0001) Mean annual number of steroid courses per patient: 3.1 vs 6.1 (P < 0.001)
Time-to-first exacerbation was longer in the omalizumab-continuation group versus the omalizumab-discontinuation group (HR, 0.49 [95% CI: 0.28, 0.86])
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Mean change in score from baseline to Week 52 in omalizumab-continuation group vs omalizumab-discontinuation group: ACT score: −1.16 vs −2.88; P = 0.0188 ACQ score: 0.22 vs 0.63; P = 0.0039
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
Mean number of exacerbations vs baseline: 1.1 vs 7.9 per year, after 1 year of treatment and remained low during all the years up to the 6th year of treatment (P < 0.001)
Mean FEV1% predicted vs baseline: 92.8% vs 84.6% (P < 0.001)
% of patients with controlled asthma vs baseline: 89.3% vs 8.4%
Mean annualized hospitalizations rate vs baseline: 0.1 vs 1.0 (P < 0.001) Mean annualized pediatric ICU admissions rate: 0.0 vs 0.1 (P < 0.001)
ICS dose vs baseline (budesonide equivalent): 350.2 μg vs 867.3 μg (P < 0.001)
ACQ, asthma control questionnaire; ACT, asthma control test; ALQ, asthma life quality; AQLQ, asthma quality of life questionnaire; ER, emergency room; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HCRU, healthcare resource utilization; HR, hazards ratio; ICS, inhaled corticosteroids; JPAC, Japanese pediatric asthma control; LABA, long-acting β2 agonist; OCS, oral corticosteroids; PEF, peak expiratory flow; QoL, quality of life
Data from studies that evaluated the short-term use of omalizumab (<2 years) in asthma patients have reported that omalizumab has a favorable safety and tolerability profile.
Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): innovate.
Overall, the incidences of adverse events (AEs) and serious adverse events (SAEs) were similar between long- and short-term use, reassuring the safety profile of omalizumab after prolonged use. These results are supported by at ≥1.75 million patient-years of omalizumab exposure in the post-marketing setting.
Comparison of allergic asthma patients treated with omalizumab and non-allergic patients treated with continuous oral corticosteroids: results of five year follow-up therapies.
12 patients reported mild adverse reactions: headache 5 (6.3%); tiredness/fatigue 2 (2.5%); hair loss 1 (1.3%); local reactions (mild pain and swelling at the site of injection) 4 (6.1%)
2 patients developed serious comorbidities: Malignancy and Liver cirrhosis
Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study of moderate-to-severe asthma.
Rate (per 1000 person-years) of cardiovascular or cerebrovascular SAEs and arterial thromboembolic events in the omalizumab vs omalizumab-naïve group: 13.4 and 6.66 vs 8.1 and 4.64, respectively
Rate of AEs/100 patient-year in omalizumab-continuation vs omalizumab-discontinuation groups: 413.2 vs 425.9 Most common AEs: asthma, sinusitis, upper respiratory tract infection, acute sinusitis
Rate of SAEs/100 patient-year in omalizumab-continuation vs omalizumab-discontinuation groups: 8.3 vs 9.1 Most common SAE: asthma Malignancy SAEs: adenocarcinoma of colon (omalizumab-continuation group) and Müllerian tumor (omalizumab-discontinuation group Deaths: 1 (omalizumab-discontinuation group)
295 malignancy AEs in 220 patients in omalizumab group and 190 malignancy AEs in 126 patients in omalizumab-naïve group. Most common malignancy AEs: non-melanoma, breast cancer, prostate cancer, colorectal cancer, melanoma, lung cancer
At least 1 non-malignant SAE in 1263 patients (25.2%) in omalizumab group and 571 patients (20.2%) in the omalizumab-naïve group
SAEs: 150 SAEs No of patients who reported SAEs: 64 patients (6.9%) Most common SAEs: asthma, dyspnea, and pneumonia Drug-related SAEs: 25 Deaths: 9 (not related to omalizumab) Discontinued omalizumab due to SAEs: 38
Long-term omalizumab treatment for 2–5 years was well-tolerated in most studies. As anticipated with most subcutaneous biological agents, local injection-site reaction with omalizumab was reported in a few studies.
In another study, headache and nausea (26.7%) and fatigue and paresthesia (13.3%) were the most frequent AEs reported during 2 years of omalizumab treatment; however, most of these events did not lead to treatment discontinuation.
Repeat acute asthma episodes, myalgia and paresthesia, and breast neoplasm (causal relationship with omalizumab not established) reported in 1 patient each led to treatment discontinuation.
In a 3-year real-life study, osteo-articular pain and vasovagal syncope were reported in 1 patient each, and mild headache was reported in 2 of 49 patients. Two cases, one of severe headache and another of mild anaphylaxis, were reported after initiating omalizumab; hence, treatment was discontinued in these patients.
Similar to the AE profile observed with 2–3 years of omalizumab treatment, 11.6% of patients treated with omalizumab for 4 years reported AEs (of mild to moderate severity), with headache, local injection-site reaction, and arthralgia being the most frequent; none of these events led to treatment discontinuation.
Omalizumab use for 2–5 years in adults with asthma
In the 2-year eXpeRience study, 150 SAEs were reported in 64 (6.9%) patients; asthma (3.5%), dyspnea (0.8%), and pneumonia (0.8%) were the most common SAEs. Of 25 SAEs suspected of being drug-related, dyspnea, sudden chest tightness, and headache were the most common (3 events each); 14 SAEs led to treatment discontinuation. Nine deaths were reported during the study, none of which was omalizumab-related.
are reported in different studies after 3 and 3.5 years of omalizumab treatment, respectively, no association between tumor and omalizumab treatment is reported. Further evidence on the correlation of omalizumab treatment with malignancy was evaluated in the dedicated 5-year EXCELS study, which demonstrated that crude malignancy rates for all malignancies, and all malignancies excluding non-melanoma skin cancer were similar in omalizumab and non-omalizumab users, with a rate ratio of 0.84 (95% CI, 0.62–1.13) and 0.98 (95% CI, 0.71–1.36).
(Table 4). After control for measured confounders, the estimated increase in risk was reduced considerably. In addition, rates of ischemic stroke (0.5 [95% CI: 0.2–1.0] vs 0.7 [95% CI: 0.3–1.4]) and cardiovascular death (2.4 [95% CI: 1.6–3.3] vs 2.0 [95% CI: 1.2–3.1]) were similar in both groups.
Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study of moderate-to-severe asthma.
Cardiovascular and cerebrovascular events among patients receiving omalizumab: pooled analysis of patient-level data from 25 randomized, double-blind, placebo-controlled clinical trials.
As the primary endpoint in the EXCELS study was to assess malignancy risk, patients were not randomized or balanced based on their cardiovascular risk at baseline, and this constitutes one of the confounders for cardiovascular risk assessment. After considering confounding imbalances between the cohorts, crude associations between omalizumab and cardiovascular/cerebrovascular SAEs were substantially reduced.
Cardiovascular and cerebrovascular events among patients receiving omalizumab: results from EXCELS, a prospective cohort study of moderate-to-severe asthma.
In the XPORT study, the rate (per 100 patient-years) of SAEs was similar in omalizumab-continuation and omalizumab-discontinuation groups (8.3 vs 9.1).
Asthma exacerbation was the most common SAE (5.9 vs 6.8 per 100 patient-years) reported in omalizumab continuation versus discontinuation groups. Among 176 patients, 2 patients reported malignant SAEs: (i) adenocarcinoma of the colon (omalizumab-continuation group) and (ii) a mixed Müllerian tumor (omalizumab-discontinuation group); one death due to an SAE of a mixed Müllerian tumor was reported (placebo group) 7 months after withdrawal from the study.
In a study conducted in 38 children, ≥1 SAE was reported in 10 patients treated with omalizumab for ∼2 years; 7 patients reported asthma exacerbations. Peri-tonsillar abscess reported in one patient was suspected of being drug-related.
In such patients, once asthma has been confirmed as the cause despite adherence to therapy, omalizumab treatment is recommended to achieve daily symptom control and decrease exacerbation rates.
Even though substantial evidence exists regarding the efficacy and effectiveness of omalizumab, understanding its effectiveness and safety in long-term/chronic use is of utmost importance.
In this review, we examined data from various studies to evaluate the long-term effectiveness of omalizumab in different patient populations. Overall, omalizumab demonstrated up to 9 years of continuous treatment effectiveness in reducing the rate of (severe) exacerbations, improving lung function, asthma control, and QoL, and decreasing HCRU and use of corticosteroids (oral/inhaled) in patients with moderate-to-severe allergic asthma.
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