DESTINATION: Tezepelumab Proves Safe, Tolerable for Severe Asthma

Tezepelumab, a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), was well tolerated for up to 2 years and led to sustained, clinically meaningful reductions in asthma exacerbations among patients with severe, uncontrolled asthma, according to findings from the phase III DESTINATION trial.

Their findings were reported in The Lancet Respiratory Medicine.

They found that "tezepelumab was well tolerated in individuals with severe, uncontrolled asthma over 104 weeks of treatment. The exposure-adjusted incidence of adverse events and serious adverse events was lower with tezepelumab than with placebo. These findings following long-term exposure to tezepelumab are consistent with the favorable safety profile found in previous studies. DESTINATION also further confirmed the long-term benefits of tezepelumab in reducing exacerbations and improving lung function, asthma control, and health-related quality of life."

For this trial, Menzies-Gow and colleagues recruited patients ages 12-80 years old with severe uncontrolled asthma who had completed treatment in the 52-week NAVIGATOR study or the 48-week SOURCE trial. Patients had received medium- to high-dose inhaled corticosteroids, with at least one additional asthma controller medication with or without oral corticosteroids. Patients were excluded if they had any clinically important pulmonary disease aside from asthma; pulmonary or systemic diseases other than asthma linked to elevated peripheral eosinophil counts; any clinically meaningful abnormal finding or protocol deviations during the SOURCE/NAVIGATOR studies; and any disorders that were not stable and could impact participant safety.

Patients were stratified according to parent study. Those who were previously randomized to receive tezepelumab continued treatment at the same dosage (210 mg subcutaneously every four weeks); patients who previously received placebo were re-randomized 1:1 to either tezepelumab or placebo.

Patients received either tezepelumab 210 mg or placebo every four weeks for 52 weeks (NAVIGATOR participants) or 56 weeks (SOURCE participants), resulting in a total of 104 weeks of treatment.

The study’s primary outcomes were exposure-adjusted incidence of adverse events and serious adverse events over the 104 week treatment period; the secondary outcome was annualized asthma exacerbation rates over 104 weeks.

DESTINATION’s primary dataset included a total of 1,059 participants from NAVIGATOR trial (tezepelumab, n=528; placebo, n=531) and 150 from the SOURCE tril (tezepelumab, n=74; placebo, n=76). Of these, 951 (827 from NAVIGATOR and 124 from SOURCE) were randomized into DESTINATION.

Among the findings:

• "For individuals who initially received tezepelumab (n=528) in NAVIGATOR, incidence of adverse events over 104 weeks was 49.62 (95% CI 45.16-54.39) per 100 patient-years, compared with 62.66 (56.93-68.81) for those receiving placebo (n=531; difference −13.04, 95% CI −17.83 to −8.18). For serious adverse events, incidence was 7.85 (6.14-9.89) per 100 patient-years for individuals who initially received tezepelumab and 12.45 (9.97-15.35) for those who received placebo (difference −4.59, −7.69 to −1.65).
• "In SOURCE, incidence of adverse events was 47.15 (36.06-60.56) per 100 patient-years for those who initially received tezepelumab (n=74) and 69.97 (54.54-88.40) for those who received placebo (n=76; difference −22.82, −34.77 to −10.01). For serious adverse events, incidence was 13.14 (7.65 to 21.04) per 100 patient-years for those who initially received tezepelumab and 17.99 (10.66 to 28.44) for those who received placebo (difference −4.85, −14.88 to 4.53).
• "Tezepelumab reduced the annualized asthma exacerbation rate over 104 weeks compared with placebo. In participants initially from NAVIGATOR, the annualized asthma exacerbation rate ratio over 104 weeks was 0.42 (95% CI 0.35-0.51); in those initially from SOURCE, the ratio over 104 weeks was 0.61 (0.38-0.96)."

Menzies-Gow and colleagues pointed out that there was a lower incidence of respiratory, thoracic, and mediastinal disorder system organ class serious adverse events among patients randomized to tezepelumab versus placebo; however, there was also a higher incidence of cardiac disorder system organ class serious adverse events in the tezepelumab group.

"There is no known biological mechanism by which blocking TSLP with tezepelumab would lead to cardiac pathophysiology, and the very low expression of TSLP and TSLP receptor mRNA in cardiac tissue suggests that signaling via the TSLP receptor pathway in these tissues is unlikely," they noted. "The incidence of cardiac disorder adverse events was similar between tezepelumab and placebo recipients, with very few events independently adjudicated as major adverse cardiovascular events or cardiovascular deaths observed. No patterns were identified in the causes of cardiac serious adverse events among tezepelumab-treated individuals or in the timing of the cardiac serious adverse events in relation to tezepelumab dosing. Additionally, no cardiac serious adverse event was causally attributed to tezepelumab by either the investigator or a masked independent adjudication committee. All participants who had a cardiac disorder serious adverse event had at least two risk factors at baseline and 44% had a cardiac disorder at baseline. Imbalances in cardiac serious adverse events have not been observed in previous multidose studies of tezepelumab of up to 1 year of treatment. No causal relationship between tezepelumab and these events has been established, nor has a patient population at risk of these events been identified."

In an editorial accompanying the study, Richard Beasley, DSc, of the Medical Research Institute of New Zealand and Te Whatu Ora: Capital Coast and Hutt Valley, both in Wellington, New Zealand, and Anne B. Chung, PhD, of Queensland University of Technology and Queensland Children’s Hospital in Brisbane and Menzies School of Health Research in Darwin, Australia, noted that there are two additional caveats to consider when applying the DESTINATION findings in clinical practice.

First, they noted that prior to initiating biologic therapy, there was limited systematic assessment and treatment of "treatable traits" that might contribute to poor respiratory health in severe asthma. "This limitation means that common and important overlapping disorders, comorbidities, environmental or occupational exposures, and behavioral factors might not have been identified and treated," they explained. "The clinical implications of this scenario are that a proportion of patients (of unknown size) could have benefited from alternative treatments and might not have needed tezepelumab, and that the benefit of tezepelumab could have been greater if such patients were not included in the trial. Systematic assessment and management of treatable traits should become standard clinical practice in all individuals with severe asthma, especially before the initiation of biologic therapy."

Second, patients in the DESTINATION trial were not required to take optimal inhaled therapy, which could reduce severe asthma exacerbations, prior to initiating tezepelumab treatment; they argued that patients should receive inhaled corticosteroid–formoterol maintenance and reliever therapy prior to starting biologic therapies.

"To conclude, we propose that in considering whether tezepelumab is the ubiquitous biologic for severe asthma, further consideration needs to be given to efficacy for children and adolescents and to cardiac-related safety for all," Beasley and Chung wrote. "Furthermore, a comprehensive systematic assessment and management of treatable traits, together with a therapeutic trial of ICS-formoterol maintenance and reliever therapy, should be undertaken before tezepelumab, or indeed any biologic therapy, is initiated, in case these measures result in sufficient clinical improvement that mean tezepelumab therapy would not be required."

Study limitations cited by the researchers included an imbalance in exposure between tezepelumab and placebo during the long-term extension period. Also, the overall environment for the study—including "non-confirmed Covid-19 illness, societal and healthcare disruptions, and participant stress during the pandemic"—was inconsistent between study years 1 and 2.

The study was funded by AstraZeneca and Amgen.

Menzies Gow has attended advisory board meetings for AstraZeneca, GlaxoSmithKline, Novartis, Regeneron, Sanofi, and Teva Pharmaceuticals; has received speaker fees from AstraZeneca, Novartis, Sanofi, and Teva Pharmaceuticals; has participated in research with AstraZeneca, for which his institution has been remunerated; has attended international conferences with Teva Pharmaceuticals; and has consultancy agreements with AstraZeneca and Sanofi. Coauthors reported relevant relationships with AstraZeneca, Genentech, GlaxoSmithKline, Novartis, Regeneron, Roche, Sanofi, Teva Pharmaceuticals, Cown, Merck, Gossamer Bio, and Amgen.

Beasley reported grant funding to the Medical Research Institute of New Zealand from AstraZeneca, Genentech, and the New Zealand Health Research Council and personal consulting fees from AstraZeneca, Cipla, Avillion, Health Research Council (New Zealand), CSL Seqirus, and Teva Pharmaceuticals. Chang had no relevant relationships to disclose.

Menzies-Gow A, et al "Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): A randomised, placebo-controlled extension study" Lancet Respir Med 2023; DOI: 10.1016/S2213-2600(22)00492-1.

Beasley R, Chang AB "Is tezepelumab the ubiquitous biologic for severe asthma?" Lancet Respir Med 2023; DOI: 10.1016/S2213-2600(22)00530-6.