Tezepelumab promising for persistent, uncontrolled asthma
The human IgG2 monoclonal antibody tezepelumab reduces asthma exacerbations in patients whose disease remained uncontrolled despite treatment with long-acting beta-agonists and inhaled glucocorticoids, a phase II trial has shown.
At week 52, significant and clinically meaningful reductions in exacerbation rates were observed with the tezepelumab groups relevant to placebo (p<0.001 for all comparisons). “The [primary endpoint of] annual asthma exacerbation rate was also lower in the tezepelumab vs the placebo group, independent of baseline blood eosinophil count or other indicators of Th2 [type 2 helper T cytokine] status,” said principal investigator of the trial, Dr Jonathan Corren from the David Geffen School of Medicine at the University of California, Los Angeles, US. [N Engl J Med 2017;377:936-946]
“Tezepelumab appears to be the broadest and most promising biologic for the treatment of persistent, uncontrolled asthma to date,” said Dr Elisabeth Bel from the Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, the Netherlands, who is unaffiliated with the study, in an editorial. However, she cautioned that the potential negative effects of targeting upstream cytokines must be considered, adding that the possibility of infections arising as a result of thymic stromal lymphopoietin (TSLP) inhibition should not be dismissed. [N Engl J Med 2017;377:989-991]
Subcutaneous tezepelumab vs placebo
Corren and his team sought to evaluate the efficacy and safety of three different doses of tezepelumab vs placebo over a 52-week treatment period in 584 patients (age 18–75 years) with moderate-to-severe uncontrolled asthma. Patients were randomly assigned to subcutaneous injections of tezepelumab 70 mg every 4 weeks (n=145), 210 mg (n=145) every 4 weeks, 280 mg every 2 weeks (n=146), or placebo every 2 weeks (n=148). Patients receiving 4-week dosing regimens received placebo at the intermediate visits.
Secondary endpoints included changes from baseline in the prebronchodilator and postbronchodilator forced expiratory volume in 1 second (FEV1), symptom and quality-of-life questionnaire scores, forced vital capacity, annual rate of severe asthma exacerbations (leading to hospital admissions of 24 hours or longer) at week 52, time to first asthma exacerbation, time to first severe asthma exacerbation, the percentage of patients with at least one asthma exacerbation, and the percentage of patients with at least one severe asthma exacerbation.
Longer time to first asthma exacerbation with tezepelumab
At the end of the study period, tezepelumab was associated with a longer time to the first asthma exacerbation at all doses studied. The risk for any exacerbation was lower with tezepelumab vs placebo by 34 percent (hazard ratio [HR], 0.66; p=0.08), 54 percent (HR, 0.46; p=0.003), and 45 percent (HR, 0.55; p=0.02) in the low-, medium-, and high-dose groups, respectively.
To add to that, the change from baseline in the prebronchodilator FEV1 at 52 weeks was higher in all tezepelumab groups than in the placebo group (difference of 0.12 L with the low dose [p= 0.01], 0.11 L with the medium dose [p=0.02], and 0.15 L with the high dose [p=0.002]). “The differences were comparable when the prebronchodilator FEV1 was measured as the percent of the predicted value,” the researchers said.
As early as week 4, there were substantial and persistent decreases in blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels. There were also progressive decreases in total serum immunoglobulin E (IgE) in all tezepelumab groups, the researchers noted. The overall incidence of adverse events was comparable between the tezepelumab and the placebo groups and so was the discontinuation rate. The most common adverse events in the tezepelumab-treated patients were asthma, nasopharyngitis, headaches, and bronchitis.
First-in-class treatment that blocks TSLP
Tezepelumab targets the TSLP cytokine, an upstream driver of inflammation in asthma. As TSLP acts upstream of the main allergic immune cascade, tezepelumab may be effective in a broader population of patients compared with therapies that inhibit a single downstream pathway, said Corren.
“Due to its activity early in the inflammatory cascade, tezepelumab may be suitable for patients with both T2 [type 2] and non-T2 driven asthma, including those ineligible for current biologic therapies which only target the T2 pathway.”
The significant reductions in blood eosinophil counts, IgE, and FeNO levels shown in the study indicate that tezepelumab may impact interleukin-4, -5, and -13 pathways, and may have broader physiological impact than just targeting individual Th2 cytokines, said the researchers.
Confirming tezepelumab’s safety, as well as the mode of delivery, in future trials is warranted, said Dr Christopher Caroll from the Connecticut Children’s Medical Center, Hartford, Connecticut, US. While the results are promising, “the fact that tezepelumab is given subcutaneously once every 4 weeks could limit its use in clinical practice.”