Novel Therapeutic Option Striking Multiple Downstream Inflammatory Pathways Associated with Uncontrollable Asthma

JoAnn Filipov, Mercer University College of Pharmacy

Despite established standard of care therapies, literature suggests that patients diagnosed with moderate-to-severe asthma experience frequent exacerbations and significant lung function limitations due to uncontrolled asthma. [1] A proposed molecular mechanism in asthma is the type 2 (T2) inflammatory pathway, characterized by elevated levels of blood eosinophils, serum IgE, and fractional exhaled nitric oxide (FENO). [2] Thymic stromal lymphopoietin (TSLP) is an epithelial cytokine central for regulation of T2 immunity.  It has been identified as a potential therapeutic target for its ability to activate various cell types, such as basophils, mast cells, innate lymphoid cells, natural killer T cells, and neutrophils, across a broad patient population. [3]

Tezepelumab is an investigational human IgG2 monoclonal antibody. It binds to TSLP to prevent TSLP-receptor interaction. [4] This mechanism prevents the release of cytokines via immune cells targeted by TSLP early in the inflammation cascade. [5] It has been suggested that tezepelumab could be an adjunct therapy for patients with a history of asthma exacerbations and uncontrolled asthma who have failed previous therapies. [6]

Tezepelumab in adults with uncontrollable asthma
Design Multicenter, placebo-controlled, parallel-group, double-blind, phase 2b trial; N=436
Objective To evaluate the safety and efficacy of tezepelumab in patients whose asthma remained uncontrolled despite previous treatment with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids
Study Groups Low-dose tezepelumab 70 mg subcutaneously every four weeks group (n=145), medium-dose tezepelumab 210 mg subcutaneously every four weeks group (n=145), high-dose tezepelumab 280 mg subcutaneously every two weeks group (n=146), and placebo controlled group (n=148)
Methods Inclusion criteria:

–        18-75 years of age

–        current nonsmokers (≥6 months and with a lifetime history of < 10 pack-years)

–        diagnosed with asthma that was not well controlled despite treatment with long-acting beta-agonists (LABAs) and a medium-dose (250 to 500 mcg/day of fluticasone) or high-dose (greater than 500 mcg/day of fluticasone) inhaled glucocorticoids for at least six months prior to enrollment

–        history of at least two exacerbations which led to treatment with systemic glucocorticoid or a severe exacerbation which led to hospitalization within the 12 months prior to entering the trial

–        prebronchodilator forced expiratory volume in 1 second (FEV1) of minimum 40% and maximum of 80% of the predicted normal value

–        post-bronchodilator reversibility of at least 12% and minimum 200 mL

–        score on the six-item Asthma Control Questionnaire (ACQ-6) of at least 1.5 during screening which ranges from 0 (lower scores meaning better disease control) to 6

 

Exclusion criteria:

–        any clinically important pulmonary disease other than asthma

–        evidence of liver disease

–        history of cancer within the past 5 years

–        positive hepatitis B surface antigen, or hepatitis C virus antibody serology at screening, or a positive medical history for hepatitis B or C

–        positive human immunodeficiency virus test at screening or taking antiviral medication

–        pregnant, lactating, or breastfeeding females

–        use of any immunosuppressive medication within three months prior to visit one

 

Patients were randomized in a 1:1:1 ratio to receive one of the study treatment groups. They were stratified based on their location, blood eosinophil count (greater than or equal to 250 cells per microliter or less then 250 cell per microliter), and the dose level of inhaled glucocorticoids (medium or high based on GINA 2012 guidelines). Those receiving oral glucocorticoids as part of their maintenance regimen were assigned to the high-dose inhaled glucocorticoid section.

 

Baseline measurements were obtained at the 5-week screening period. At week 52, the annualized rate of asthma exacerbations was evaluated with each group compared to the placebo group. Asthma exacerbations were defined as a worsening of asthma symptoms that led any: use of systemic glucocorticoids, doubling of dose for three or more days, a visit to the emergency room (ER) that required systemic glucocorticoid treatment, or an in-patient hospitalization due to asthma. At week 52, the same measurements taken at baseline were repeated to notate any changes from baseline.

 

The calculated sample size was 138 to detect a 40% difference in the primary endpoint with 80% power. Expected drop out was 10% and two-sided alpha was set to 0.1. A two-sided alpha level of 0.1 was established, and 10% loss of information was expected due to drop outs.   The order of hierarchy was placebo versus high-dose tezepelumab, placebo versus medium-dose tezepelumab, and placebo versus low-dose tezepelumab.

 

Duration 52 weeks
Primary Outcome Measure The 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

 

Low-Dose Medium-Dose High-Dose Total
Placebo Tezepelumab Tezepelumab Tezepelumab 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. (%)† 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 28.1±5.0)
FEV1 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 score§ 2.66±0.67 2.76±0.80 2.71±0.81 2.63±0.75 2.70±0.78
AQLQ(S)+12 score¶ 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 glucocorticoids — 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/ μl
Mean 366±323 345±284 359±347 378±423 361±356
Median (range) 270

(0–1870)

270

(10–1600)

275

(0–3180)

255

(0–3990)

270

(0–3990)

Total serum IgE — IU/ml
Mean 447±1232 314±870 464±1366 344±579 374±992
Median (range) 135

(4–11,860)

109

(2–7423)

135

(2–11,430)

138

(2–3814)

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)

* Plus–values are means ±SD. 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 FEV1 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[S]+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

 

Placebo

(n = 148)

Low-Dose

Tezepelumab

(n = 145)

Medium-Dose

Tezepelumab

(n = 145)

High-Dose

Tezepelumab

(n = 146)

Variable
Annualized rate of asthma exacerbations

through week 52 — events per patient-year (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
FEV1 before bronchodilation
No. of patients evaluated 141 137 128 125
Least-squares mean change from base line at week 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 base line at week 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 base line at week 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 base line at week 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.

 

Table 3: Summary of type of asthma exacerbations

  Placebo (n = 148) Low-Dose

Tezepelumab

(n = 145)

Medium-Dose

Tezepelumab

(n = 145)

High-Dose

Tezepelumab

(n = 146)

Total Number of Asthma Exacerbations Used for Final Analysis 98 37 26 30
Hospital admission OR greater than 24 hours in ER* (serious adverse events) 19 5 3 4
ER visit less than 24 hours due to asthma that led to systemic

glucocorticoids (adverse events)

6 1 1 2
Use of systemic glucocorticoids (no hospitalization or ER) (adverse events) 72 30 22 23
Adjudicated event as an exacerbation (adverse events) 1 1 0 1

*ER – Emergency room

 

Table 4: Annualized asthma exacerbation rate reduction stratified by patients on a medium or high-dose of inhaled glucocorticoid and by patients on maintenance oral glucocorticoids through week 52

Placebo (n = 148) Low-Dose

Tezepelumab

(n = 145)

Medium-Dose

Tezepelumab

(n = 145)

High-Dose

Tezepelumab

(n = 146)

Inhaled glucocorticoid dose Medium High Medium High Medium High Medium High
Annualized AER n 73 75 71 74 70 75 72 74
AER 0.38 0.96 0.19 0.33 0.15 0.23 0.20 0.24
(95% CI) (0.26, 0.55) (0.75,1.22) (0.10, 0.32) (0.21,

0.49)

(0.07, 0.28) (0.13,

0.37)

(0.10,

0.34)

(0.14,

0.39)

AER reduction vs placebo (95%CI) 51%

(-8%,

78%)

66%

(33%,

83%)

60%

(5%,

83%)

76%

(49%,

89%)

49%

(-13%,

77%)

75%

(47%,

88%)

p-value* 0.076 0.002 0.038 <0.001 0.096 <0.001
Maintenance oral glucocorticoid use Yes No Yes No Yes No Yes No
Annualized AER n 14 134 15 130 9 136 13 133
AER 2.08 0.54 0.61 0.22 0.51 0.17 0.24 0.22
(95% CI) (1.37,

3.03)

(0.42,

0.68)

(0.28,

1.16)

(0.15,

1.32)

(0.14,

1.32)

(0.11,

0.26)

(0.05,

0.70)

(0.14,

0.32)

AER reduction vs placebo (95%CI) 72%

(31%,

89%)

59%

(25%,

77%)

75%

(11%,

93%)

68%

(40%,

83%)

88%

(49%,

97%)

59%

(27%,

77%)

p-value* 0.006 0.003 0.033 ,0.001 0.004 0.003

*p-values are nominal and without multiplicity adjustment.

AER = asthma exacerbation rate; CI = confidence interval

Adverse Events Table 5: Summary of adverse events, with and without inclusion of asthma-related events*

 

 

Placebo (n=148) Low-Dose Tezepelumab (n=145) Medium-Dose Tezepelumab (n=145) High-Dose Tezepelumab (n=146) Total Tezepelumab
All Events Asthma-Related

Events Excluded

All

Events

Asthma-Related

Events Excluded

All

Events

Asthma-Related

Events Excluded

All

Events

Asthma-Related

Events Excluded

All Events Asthma-Related

Events Excluded

≥1 Event 92 (62.2) 83 (56.1) 96 (66.2) 86 (59.3) 94 (64.8) 90 (62.1) 90 (61.6) 83 (56.8) 280 (64.2) 259 (59.4)
≥1 Event of grade 3–5

severity †

28 (18.9) 16 (10.8) 26 (17.9) 20 (13.8) 29 (20.0) 23 (15.9) 21 (14.4) 13 (8.9) 76 (17.4) 56 (12.8)
Death† 0 0 1 (0.7) 1 (0.7) 0 0 0 0 1 (0.2) 1 (0.2)
≥1 Serious event‡ 18 (12.2) 11 (7.4) 17 (11.7) 13 (9.0) 13 (9.0) 12 (8.3) 18 (12.3) 15 (10.3) 48 (11.0) 40 (9.2)
≥1 Serious event or event of grade

3–5 severity†‡

34 (23.0) 21 (14.2) 32 (22.1) 24 (16.6) 31 (21.4) 26 (17.9) 29 (19.9) 20 (13.7) 92 (21.1) 70 (16.1)
≥1 Event leading to discontinuation of trial agent 1 (0.7) 1 (0.7) 0 0 2 (1.4) 2 (1.4) 3 (2.1) 3 (2.1) 5 (1.1) 5 (1.1)
Most common events of any grade §
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)

 

 

* Patients were counted once for each category regardless of the number of events.

† Grade 3 indicates a severe adverse event, grade 4 a life-threatening event, and grade 5 a fatal event.

 

‡ A serious adverse event was defined as an event that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or clinically significant disability or incapacity, was an important medical event, or resulted in a congenital anomaly or birth defect (in the offspring of the patient).

§ Shown are events that occurred in at least 5% of the total group of patients who received tezepelumab.

 

Study Author Conclusions Among patients whose asthma remained uncontrolled despite previous treatment with LABAs and medium-to-high doses of inhaled glucocorticoids, those who received tezepelumab had lower rates of asthma exacerbations than those who received placebo, independent of base eosinophil count or other Th2 biomarkers.

 

The FEV1, ACQ-6, AQLQ, and the asthma symptom scores were utilized to evaluate the safety and efficacy of tezepelumab to produce reliable and reproducible assessment outcomes. It is stated that the possible benefits of tezepelumab’s upstream therapeutic drug targeting mechanism were demonstrated through the reductions in annual asthma exacerbations rate that were independent of baseline eosinophil count or other Th2 biomarkers. [7] The study is limited by its failure to assess multiple factors that may affect patient compliance, including self-administration of an injection, complicated dosing schedule, and financial cost associated with human monoclonal antibody injections. Additionally, the duration of study may be inadequate to assess the long-term safety and infection risks associated with tezepelumab. Despite these limitations, tezepelumab demonstrated benefit in patients suggesting it may be a viable adjunct therapy for uncontrolled asthma.

 

Reference:

[1] Peters SP, Ferguson G, Deniz Y, Reisner C. Uncontrolled asthma: a review of the 
prevalence, disease burden and options for treatment. Respir Med. 2006; 100:1139–51.

[2] Fahy JV. Type 2 inflammation in asthma–present in most, absent in many. Nat Rev Immunol. 2015; 15:57–65.

[3] 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; 370:2102–10.

[4] Zhong J, Sharma J, Raju R, et al. TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling. Database (Oxford) 2014: bau007.

[5] West EE, Kashyap M, Leonard WJ. TSLP: a key regulator of asthma pathogenesis. Drug Discov Today Dis Mech. 2012;9: e38–e88.

[6] Global Initiative for Asthma. Global strategy for asthma management and prevention, 2017. http://ginasthma.org/2017 -gina-report-global-strategy-for-asthma -management-and-prevention/. Accessed January 22, 2018.

[7] Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. New Engl J Med. 2017; 377:936-46.

 

 

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