Asthma biologic reduces exacerbations but questions remain

Tezepelumab (Tezspire) achieves substantial and sustained reductions in severe asthma exacerbations but more data are needed in two areas before it can be considered the ‘ubiquitous’ biologic for severe asthma, experts say.

The Phase III DESTINATION trial held across 182 sites and 18 countries [link here] assessed the safety and efficacy of tezepelumab over two years in patients aged 12-80 years with severe, uncontrolled asthma who had previously completed the 52-week NAVIGATOR or 48-week SOURCE trials.

Patients who were previously randomised to receive tezepelumab in either the NAVIGATOR or SOURCE trials continued treatment of subcutaneous tezepelumab (210mg every 4 weeks), while those previously in placebo arms were re-randomised 1:1 to receive either subcutaneous tezepelumab (210mg every 4 weeks) or placebo (every 4 weeks).

​​The trial, led by Professor Andrew Menzies Gow, Consultant in Respiratory Medicine at the Royal Brompton Hospital, London, is the first long-term extension study of a biologic for severe asthma to include a placebo group.

Clinically meaningful reductions in exacerbations

Results showed that treatment with tezepelumab resulted in “clinically meaningful” reductions in asthma exacerbations compared with placebo over two years.

In patients originating from NAVIGATOR, the annualised asthma exacerbation rate ratio over two years was 0.42 (95% CI 0·35 to 0·51), while in those originating from SOURCE it was 0.61 (CI 0·38 to 0·96).

Although clinically meaningful reductions in exacerbations were observed in adolescents, greater reductions were seen in adults.

The magnitude of reductions in exacerbations compared to placebo was also greater among those with high levels of type 2 inflammatory biomarkers or with nasal polyps, the research team noted.

“This difference confirms findings from PATHWAY and NAVIGATOR that tezepelumab consistently shows clinically meaningful reductions in exacerbations in users across the spectrum of type 2 inflammation, with an enhanced effect in individuals with high type 2 biomarker levels,” the study authors wrote in the paper published in The Lancet Respiratory Medicine.

Drilling down on adverse events 

For individuals who initially received tezepelumab (n=528) in NAVIGATOR, incidence of adverse events over 104 weeks was 49·62 (95% CI 45·16 to 54·39) per 100 patient-years, compared with 62 ·66 (56·93 to 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 to 9·89) per 100 patient-years for individuals who initially received tezepelumab and 12·45 (9·97 to 15·35) for those who received placebo (difference −4·59, −7·69 to −1 ·65).

For patients originating from SOURCE  the incidence of adverse events was 47 ·15 (36·06 to 60·56) per 100 patient-years for those who initially received tezepelumab (n=74) and 69·97 (54·54 to 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).

Imbalance in cardiac events “not understood”

However, delving deeper into the data, cardiac-related serious adverse events were found to be significantly higher in patients receiving tezepelumab than those taking placebo (incidence 1.30 vs 0.23 per 100 patient years for tezepelumab and placebo respectively, with an estimated incidence difference of 1·07 per 100 patient-years (95% CI 0·35–1·86)).

“The reason for this imbalance in cardiac serious adverse events is not understood,” the study authors said.

“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 signalling via the TSLP receptor pathway in these tissues is unlikely,” they wrote.

“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,” they stressed.

They further noted that all participants who had a cardiac related serious adverse event had at least two risk factors at baseline and 44% had a cardiac disorder at baseline.

“The incidence of cardiac serious adverse events in tezepelumab-treated participants in DESTINATION is similar to those estimated from publicly available data of other biologics for severe asthma,” they added.

Is tezepelumab the ubiquitous biologic for severe asthma?

Writing in a linked editorial [link here], New Zealand based respiratory physician Professor Richard Beasley and paediatric respiratory physician Professor Anne B Chang from Brisbane, Australia, said further investigation into a potential cardiac risk with tezepelumab and related biologics was a priority.

“Review of pre-clinical data and meta-analyses of randomised controlled trials of tezepelumab and dupilumab might represent initial lines of enquiry,” they suggested.

According to the editorialists there were also two further points to consider when implementing DESTINATION’s findings into clinical practice.

For example, there was a limited systematic assessment and treatment of treatable traits, patients were also not required to take optimal inhaled therapy before initiation of tezepelumab.

“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,” they concluded.

The study was funded by AstraZeneca and Amgen. 

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