Tezepelumab in Adults with Uncontrolled Asthma

Christopher Ling, Mercer University College of Pharmacy

Asthma is a prevalent disorder that affects approximately 300 million people worldwide and is projected to increase to 400 million by 2025. [1] While most patients can be managed on current recommended therapies (e.g. long-acting and short-acting beta agonists [LABAs/ SABAs], inhaled glucocorticoids, long-acting and short-acting muscarinic antagonists), some patients remain uncontrolled. [2] Thymic stromal lymphopoietin (TSLP) is a cytokine produced in response to environmental and proinflammatory stimuli with the ability to promote B cell and dendritic cell activation. [3]  Its expression is increased in patients with severe asthma and is suggested to be correlated with Th2 cytokine and chemokine expression. [4]

Tezepelumab is a human IgG2 monoclonal antibody that inhibits TSLP interactions with TSLP receptor complexes. One study showed that in mild, atopic asthmatic patients, tezepelumab inhibited both early and late asthmatic response and suppressed biomarkers of type 2 inflammation after inhaled allergen challenge. [5] To further explore the effectiveness of tezepelumab, the following study evaluated the effects of tezepelumab in patients with moderate-to-severe asthma who were uncontrolled with LABAs combined with medium-to-high doses of inhaled glucocorticoids. [6]

 

Tezepelumab in Adults with Uncontrolled Asthma
Design Multicenter, placebo-controlled, parallel-group, double-blind, phase 2 trial; N= 584
Objective To better define the biologic and clinical importance of TSLP in patients with moderate-to-severe asthma
Study Groups Placebo (n= 148)

Low-dose tezepelumab (n= 145)

Medium-dose tezepelumab (n= 145)

High-dose tezepelumab (n= 146)

Methods Patients were randomly assigned to tezepelumab doses of 70 mg every 4 weeks (low dose), 210 mg every 4 weeks (medium dose), or 280 mg every 2 weeks (high dose) or of placebo every 2 weeks for the duration of the trial.
Baseline prebronchodilator and post bronchodilator spirometric assessments, measurements of the fraction of exhaled nitric oxide (Feno), blood eosinophil counts, the ACQ-6 score, and the score on the Asthma Quality of Life Questionnaire (standardized) for persons 12 years of age or older were obtained throughout the 5-week screening period.
Duration 64 weeks
Primary Outcome Measure Annualized rate of asthma exacerbations (events per patient-year) at week 52
Baseline Characteristics
Table 1. Baseline Demographic and Clinical Characteristics in the Intention.to-Treat Population.*
Placebo Low-Dose

Tezepelumab

Medium-Dose

Tezepelumab

High-Dose

Tezepelumab

Total

Tezepelumab

Characteristic (n= 148) (n= 145) (n= 145) (n= 146) (n= 436)
Age – yr 52.2±11.5 50.6±12.4 52.6±12.5 50.1±12.2 51.1±12.4
Male sex – no. (%) 48 (32.4) 50 (34.5) 54 (37.2) 53 (36.3) 157 (36.0)
White race – no. (%)t 133 (89.9) 138 (95.2) 136 (93.8) 129 (88.4) 403 (92.4)
Body-mass index* 28.5±5.5 28.3±5.1 28.4±4.9 27.7±5.0 28.1t5.0)
FEVI before bronchodilation– liters 1.83±0.58 1.91±0.66 1.83±0.58 1.87±0.60 1.87±0.61
ACQ-6 scores 2.66±0.67 2.76±0.80 2.71±0.81 2.63±0.75 2.70±0.78
AQLQ(S)+12 scorel 4.06±0.86 4.14±0.94 4.19±0.90 4.09±0.90 4.14±0.91
Asthma symptom score) 1.72±0.58 1.70±0.63 1.76±0.57 1.68±0.61 1.72±0.60
Dose level of inhaled gluco-corticoids – no. (%)
Medium 73 (49.3) 71 (49.0) 70 (48.3) 72 (49.3) 213 (48.9)
High 75 (50.7) 74 (51.0) 75 (51.7) 74 (50.7) 223 (51.1)
Blood eosinophil count – cells/microliter
Mean 366±323 345±284 359±347 378±423 361±356
Median (range) 270 (0-1,870) 270 (10-1,600) 275 (0-3,180) 255 (0-3,990) 270 (0-3,990)
Total serum IgE – IU/mL
Mean 447±1,232 314±870 464±1,366 344±579 374±992
Median (range) 135 (4-11,860) 109 (2-7,423) 135 (2-11,430) 138 (2-3,814) 127 (2-11,430)
FENO
No. of patients evaluated 146 144 143 141 428
Mean – ppb 36.3±38.9 34.5±46.9 30.4±29.4 32.6±33.9 32.5±37.5
Median (range) – ppb 21.5 (3.5-276.3) 22.0 (2.5-349.0) 20.5 (4.0-152.5) 19.7 (2.0-217.5) 21.0 (2.0-349.0)

±: standard deviation. The low dose of tezepelumab was 70 mg every 4 weeks, the medium dose 210 mg every 4 weeks, and the high dose 280 mg every 2 weeks. FENO denotes fraction of exhaled nitric oxide, and FEVI forced expiratory volume in 1 second. Race was reported by the patient.The body-mass index is the weight in kilograms divided by the square of the height in meters. Scores on the six-item Asthma Control Questionnaire (ACQ-6) range from 0 to 6, with lower scores indicating better disease control. A score of 1.5 or more indicates uncontrolled asthma. Scores on the Asthma Quality of Life Questionnaire (standardized) for persons 12 years of age or older (AQLQ[SI+12) range from 1 to 7, with higher scores indicating better asthma-related quality of life. Asthma symptom scores (reflecting daytime severity, daytime frequency, and nighttime severity) range from 0 (no symptoms) to 4 (worst possible symptoms).

Results
Table 2. Annualized Rate of Asthma Exacerbations and Change from Baseline in FEV1, ACQ-6 Score, and AQLQ(S)+12 Score in the Intention-to-treat population
Variable Placebo (n= 148) Low-Dose Tezepelumab (n= 145) Medium-Dose Tezepelumab (n= 145) High-dose Tezepelumab (n= 146)
Annualized rate of asthma exacerbations through wk 52 – events per patient-yr (90% CI) 0.67 (0.57 to 0.80) 0.26 (0.19 to 0.34) 0.19 (0.13 to 0.27) 0.22 (0.16 to 0.30)
Relative reduction vs. placebo – % (90% CI) 61 (39 to 75) 71 (53 to 82) 66 (47 to 79)
p value <0.001 <0.001 <0.001
FEVI before bronchodilation
No. of patients evaluated 141 137 128 125
Least-squares mean change from baseline at wk 52 – %of predicted value -0.99 7.11 7.27 9.37
Difference vs. placebo (95% CI) 8.11 (2.39 to 13.82) 8.26 (2.50 to 14.03) 10.36 (4.60 to 16.13)
p value* 0.006 0.005 <0.001
Least-squares mean change from baseline at wk 52 – liters -0.05 0.07 0.06 0.11
Difference vs. placebo (95% CI) 0.12 (0.02 to 0.21) 0.11 (0.02 to 0.20) 0.15 (0.06 to 0.25)
p value* 0.01 0.02 0.002
ACQ-6 score
No. of patients evaluated 53 53 44 49
Least-squares mean change from baseline at wk 52 -0.89 -1.13 -1.16 -1.22
Difference vs. placebo (95% CI) -0.24 (-0.50 to 0.02) -0.27 (-0.54 to 0.00) -0.33 (-0.60 to -0.07)
p value* 0.07 0.046 0.01
AQLQ(S)+12 score*
No. of patients evaluated 47 52 41 49
Least-squares mean change from baseline at wk 52 0.95 1.07 1.13 1.33
Difference vs. placebo (95% CI) 0.12 (-0.15 to 0.39) 0.18 (-0.10 to 0.47) 0.38 (0.10 to 0.65)
p value* 0.39 0.21 0.008

*p values are nominal and were not adjusted for multiplicity.

ACQ-6 scores range from 0 to 6, with lower scores indicating better disease control. The minimal clinically important difference is 0.5 points.

AQLQ(S)+12 scores range from 1 to 7, with higher scores indicating better asthma-related quality of life. The minimal clinically important difference is 0.5 points.

Adverse Events Common Adverse Events:

Placebo (n= 148) Low Dose Tezepelumab (n= 145) Medium Dose Tezepelumab (n= 145) High Dose Tezepelumab (n= 146) Total Tezepelumab (n=436)
Bronchitis 7 (4.7) 8 (5.5) 5 (3.4) 9 (6.2) 22 (5.0)
Nasopharyngitis 17 (11.5) 21 (14.5) 19 (13.1) 15 (10.3) 55 (12.6)
Headache 7 (4.7) 8 (5.5) 11 (7.6) 5 (3.4) 24 (5.5)
Asthma 50 (33.8) 35 (24.1) 27 (18.6) 38 (26.0 100 (22.9)
Serious Adverse Events:

Pneumonia (3 in low dose/ 2 in high dose) and Stroke (1 in low dose) , Guillian-Barre syndrome (1 in medium dose)

Percentage that Discontinued due to Adverse Events:

Placebo (n= 148) Low Dose Tezepelumab (n= 145) Medium Dose Tezepelumab (n= 145) High Dose Tezepelumab (n= 146) Total Tezepelumab (n=436)
≥1 event leading to discontinuation of trial agent 1 (0.7) 0 2 (1.4) 3 (2.1) 5 (1.1)
Study Author Conclusions Inhibition of an upstream cytokine, Thymic stromal lymphopoietin (TSLP), with tezepelumab led to a lower annualized rate of asthma exacerbations than placebo in patients with uncontrolled asthma who are receiving long-acting beta agonists (LABAs) and medium-to-high doses of inhaled glucocorticoids.

The results of this study shows tezepelumab as a possible therapeutic option for patients that have uncontrolled asthma despite being on LABA and medium-to-high doses of inhaled glucocorticoids. However, several limiting factors exists in this study including the age and race of the patients. Most of the patients included are in their early 50s, but asthma is a disorder that is also prevalent in young adults and children. A majority of the patients included are also white ranging from 88.4% to 95.2% of each treatment groups. Based on a 2015 Center of Disease Control and Prevention (CDC) surveillance data, asthma appears to be more prevalent in black population than white population (10.3% vs 7.8%). [7] Another possible limitation is the lack of  the long term safety and efficacy data of tezepelumab. While tezepelumab had no significant differences in its safety profile within 62 weeks and had a reduction in annualized exacerbations within 52 weeks, the long term benefits and effects were not measured. Further studies with longer follow-up periods with more diverse population may be able to further demonstrate the clinical significance of tezepelumab and targeting an upstream cytokine such as TSLP for asthma control.  

 

 

References

[1] To T, Stanojevic S, Moores G, et. al. Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC Public Health. 2012 Mar 19;12:204.

[2] Bateman ED, Bousquet J, Busse WW, et. al. Stability of asthma control with regular treatment: an analysis of the Gaining Optimal Asthma controL (GOAL) study. Allergy. 2008 Jul;63(7):932-8.

[3] Steven F Ziegler and David Artis. Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol. 2010 Apr; 11(4): 289–293

[4] Aarti Shikotra, David F.Choy, Chandra M.Ohri, et. al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. Journal of Allergy and Clinical Immunology. 2012 January; 129(1):104-111.

[5] Gauvreau GM, O’Byrne PM, Boulet LP, et. al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014 May 29;370(22):2102-10.

[6] Corren J, Parnes JR, Wang L, et. al. Tezepelumab in Adults with Uncontrolled Asthma. N Engl J Med. 2017 Sep 7;377(10):936-946.

[7] Center of Disease Control and Prevention. Data, Statistics, and Surveillance: Asthma Surveillance Data. Atlanta, GA: U.S. Department of Health & Human Services; Updated 2016.

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