Tezepelumab Promising in Adults With Poorly Controlled Asthma

Diana Phillips                         

September 08, 2017

The biologic drug tezepelumab reduced asthma exacerbations in patients with moderate to severe, uncontrolled disease independent of baseline blood eosinophil counts in a phase 2 trial. Tezepelumab may be a promising option for patients with uncontrolled asthma despite treatment with long-acting β-agonists and medium to high doses of inhaled glucocorticoids.

Jonathan Corren, MD, from the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues report their findings online September 6 in the New England Journal of Medicine.

The researchers randomly assigned 584 patients to receive subcutaneous injections of tezepelumab 70 mg every 4 weeks mg (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.

At week 52, exacerbation rates were lower in the low-, medium-, and high-dose tezepelumab groups than in the placebo group by 61% (90% confidence interval [CI], 39% - 75%; P < .001), 71% (90% CI, 53% - 82%; P < .001), and 66% (90% CI, 47% - 79%; P < .001), respectively. "The annualized asthma exacerbation rate was lower in the tezepelumab groups than in the placebo group, irrespective of baseline blood eosinophil count or other assessed indicators of  Th2 [type 2 helper T cytokine] status," the researchers write.

"This is a groundbreaking study," Christopher Carroll, MD, associate professor at the University of Connecticut, pediatric intensivist at Connecticut Children's Medical Center, Hartford, and member of the American College of Chest Physicians, told Medscape Medical News. "Uncontrolled moderate and severe asthma is a significant problem, affecting more than 300 million people worldwide, and tezepelumab will definitely serve a role in the treatment of a subset of these patients." Dr Carroll was not involved in the trial.

Tezepelumab was associated with some but not all secondary outcomes compared with placebo. For example, at all doses, tezepelumab was associated with a longer time to the first asthma exacerbation, and the risk for any exacerbation was lower with treatment compared with placebo by 34% (hazard ratio, 0.66; 95% CI, 0.41 - 1.05; P = .08), 54% (hazard ratio, 0.46; 95% CI, 0.27 - 0.78; P = .003), and 45% (hazard ratio, 0.55; 95% CI, 0.34 - 0.90; P = .02) in the low-, medium-, and high-dose groups, respectively.

Further, the change from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) was greater in the low-, medium-, and high-dose tezepelumab groups than in the placebo group by 0.12 L (95% CI, 0.02 - 0.21 L; P = .01), 0.11 L (95% CI, 0.02 - 0.20 L; P = .02), and 0.15 L (95% CI, 0.06 - 0.25 L; P = .002). "Similar differences were observed when the prebronchodilator FEV1 was measured as the percent of the predicted value," the researchers note.

From week 4, the first time point assessed, the investigators observed substantial and persistent decreases in blood eosinophil counts and fractional exhaled nitric oxide (F ENO ) levels, as well as progressive decreases in total serum IgE in all tezepelumab groups.

"[T]he incidence of adverse events was similar in the tezepelumab and placebo groups, with similar levels of discontinuations, regardless of asthma-related adverse events," the authors write.

At least one adverse event was reported by 62.2% of the placebo group, 66.2% of the low-dose tezepelumab group, 64.8% of the medium-dose group, and 61.6% of the high-dose group. In the respective groups, a serious adverse event was reported by 12.2%, 11.7%, 9.0%, and 12.3% of patients.

"When asthma-related adverse events were removed from the above analysis, the overall incidence of adverse events was similar across the trial groups," the authors report.

Thymic Stromal Lymphopoietin Cytokine Plays Key Role

Tezepelumab is a human IgG2 monoclonal antibody that targets the thymic stromal lymphopoietin (TSLP) cytokine, an upstream molecule that activates multiple pathways involved in asthma induction, persistence, and flares.

Because TSLP acts upstream of the main allergic immune cascade, tezepelumab may have efficacy in a broader patient population than drugs that inhibit a single downstream pathway, the authors write. Additional investigations involving large, ethnically diverse patients are warranted, they say.

The findings "are consistent with those of a previous allergen-challenge study involving patients with mild asthma, in which tezepelumab inhibited post–allergen challenge increases in sputum and blood eosinophil counts and FENO levels," the researchers write. "These changes in biomarker levels indicate that tezepelumab has important effects on interleukin-4, interleukin-5, and interleukin-13 pathways and support the concept that inhibition of TSLP may have broader physiological effects than the targeting of individual Th2 cytokines."

The treatment-related improvements point to the potential pathogenic role of TSLP in different asthma phenotypes, the authors state. "Nonallergic factors, including tobacco smoke, diesel particles, and viruses, have been shown to trigger TSLP release and lead to activation of inflammatory responses in asthma," they write, noting that many cell types that are activated by or respond to TSLP may play a role in inflammation in asthma beyond type 2 inflammation.

In an accompanying editorial, Elisabeth H. Bel, MD, PhD, from the Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, the Netherlands, contends that "tezepelumab appears to be the broadest and most promising biologic for the treatment of persistent uncontrolled asthma to date" but warns that the potential negative effects of targeting upstream cytokines must also be considered.

Although the safety profile of tezepelumab is "reassuring," the limited pool of at-risk patients and the fact that the study period was only 1 year suggest the possibility of infections arising as a result of TSLP inhibition should not be dismissed, Dr Bel states. "[A] role for this cytokine in host defense against infection has been suggested in atopic dermatitis, a related chronic inflammatory disorder," she writes. "Confirming the safety of tezepelumab should therefore be a priority in future trials."

Additional research should also be directed toward mode of drug delivery, according to Dr Carroll. "Although the drug is groundbreaking, for many patients, the fact that it is delivered by subcutaneous injection once every 4 weeks will limit its use in clinical practice."

The current investigation — a randomized, placebo-controlled, dose-ranging trial conducted at 108 sites across 12 countries — was designed to better define the biologic and clinical importance of TSLP in uncontrolled moderate to severe asthma.

The primary endpoint was annualized rates of asthma exacerbations at 1 year. Secondary endpoints included changes from baseline in the prebronchodilator and postbronchodilator FEV1, symptom and quality-of-life questionnaire scores, forced vital capacity, the annualized rate of severe asthma exacerbations (those leading to hospital admissions lasting 24 hours or more) 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.

The study included current nonsmokers aged 18 to 75 years with poorly controlled asthma despite treatment with long-acting β-agonists combined with a medium to high dose of inhaled glucocorticoids for at least 6 months before enrollment. Additional inclusion criteria included a history of at least two asthma exacerbations that led to systemic glucocorticoid treatment, or one severe exacerbation that led to hospitalization, in the 12 months before trial entry; a prebronchodilator FEV1 of at least 40% and no more than 80% of the predicted normal value; postbronchodilator reversibility of at least 12% and at least 200 mL; and a score on the 6-item Asthma Control Questionnaire of at least 1.5.

"Given the potentially broad effects of TSLP in asthma, we included patients with a wide range of blood eosinophil counts," the authors explain.

Funding for this study was provided by MedImmune and Amgen. The study authors report financial relationships with multiple companies, including Medimmune, AstraZeneca, Genentech, Sanofi, and Vectura Group. Dr Bel reports financial relationships with Sanofi-Regeneron, Novartis, AstraZeneca, Teva, GlaxoSmithKline, Vectura, Boehringer, and Roche. Dr Carroll has disclosed no relevant financial relationships.

N Engl J Med. 2017;377:936-946. Abstract, Editorial

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