Phase III Results Put Novel Asthma Biologic on Target for Approval

A first-in-class drug under development for severe asthma passed what its developers hope is the final test: achieving its primary endpoint in a phase III registration trial dubbed NAVIGATOR and now reported in a major journal.

Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), cut the annualized rate of asthma exacerbations by more than half relative to the study’s placebo group (rate ratio 0.44, 95% CI 0.37-0.53, P<0.001), according to Andrew Menzies-Gow, MD, of Royal Brompton Hospital in London, and colleagues, writing in the New England Journal of Medicine (NEJM).

Annualized exacerbation rates averaged 0.93 (95% CI 0.80-1.07) in the 528 patients assigned to tezepelumab versus 2.10 for the 532 receiving placebo (95% CI 1.84-2.39) in the 52-week trial.

The drug was superior to placebo for a host of secondary outcomes as well, including forced expiratory volume in 1 second (FEV₁), scores on patient-reported assessments of symptom severity and quality of life, and emergency visits and hospitalizations for asthma exacerbations.

If approved, tezepelumab would be the first drug for asthma, or any other condition, targeting TSLP. As Menzies-Gow and colleagues explained, this molecule is a “cytokine implicated in multiple downstream processes involved in asthma pathophysiology.” High levels of it are associated with increased asthma severity and resistance to corticosteroids. Moreover, lab studies — some going back 20 years or more — showed that TSLP plays a role in airway tissue interactions with immune cells, the researchers said.

Tezepelumab began life as a potential asthma drug about a decade ago, with phase I results reported in 2014. The drug has progressed steadily through the pipeline since then, with a phase II study called PATHWAY completed 4 years ago.

NAVIGATOR commenced in 2017, randomizing patients ages 12-80 with poorly controlled asthma 1:1 to tezepelumab or placebo, both given by subcutaneous injection every 4 weeks, both in addition to patients’ previous controller regimens.

To be eligible, participants had to be using medium- to high-dose inhaled steroids (at least 500 μg/day of fluticasone or the equivalent) for at least 1 year prior to enrollment, plus at least one other controller medication for at least 3 months, and to have experienced at least two exacerbations in the past year. Also, FEV₁ had to be less than 80% of predicted (90% for patients younger than 18) in a morning evaluation before bronchodilator administration while showing at least 12% reversal following an albuterol dose.

Patients were recruited from nearly 300 sites in the U.S., Canada, Brazil, Japan, South Korea, and 13 other countries; just over half were enrolled in North America and the Asia-Pacific region. Randomization took place after a 5- to 6-week run-in period to confirm eligibility.

Menzies-Gow and colleagues aimed to enroll a sample in which about 20% of patients were taking medium-dose steroids, 40% had experienced at least three exacerbations in the past year, and half had blood eosinophil counts of at least 300/μL. In the end, the researchers screened 2,420 patients to enroll the final sample of 1,061.

Tezepelumab might have been slightly less effective in the subgroup of patients with eosinophil counts below 300/μL. Annualized exacerbation rates for those patients were 1.02 with tezepelumab (95% CI 0.84-1.23) versus 1.73 in those assigned to placebo (95% CI 1.46-2.05), for a rate ratio of 0.59 (95% CI 0.46-0.75) — twice as high as in the subgroup with higher eosinophil counts (RR 0.30, 95% CI 0.22-0.40).

Efficacy also differed significantly according to baseline fraction of exhaled nitric oxide, with tezepelumab showing less difference from placebo in annualized exacerbations in patients with levels <25 ppb than in those with greater exhaled nitric oxide.

Allergic sensitivity, however, did not appear to affect the drug’s effectiveness, with similar differences from placebo irrespective of IgE test results for common allergens including cat dander, molds, and dust mite proteins.

Patients underwent FEV₁ measurements at various points during the study, and also completed the Asthma Control Questionnaire-6 and the Asthma Quality of Life Questionnaire at baseline and 52-week follow-up and the weekly Asthma Symptom Diary.

Pre-bronchodilator FEV₁ improved from baseline by about 0.2 L on average with tezepelumab, whereas the placebo group showed mean increases of about 0.1 L (P<0.001). Results for the patient-reported outcomes also substantially favored the active drug.

A supplementary appendix published with the study in NEJM indicated that the rates of hospitalizations or emergency department visits were cut fivefold with the drug relative to placebo; hospital admissions were reduced by 85%.

The rates of serious adverse events overall did not differ markedly between treatments, and were numerically greater in the placebo group. The only adverse event type that was more common with tezepelumab was injection-site reactions, occurring in 3.6% of patients receiving the drug versus 2.6% of those assigned to placebo. Strangely, perhaps, antidrug antibodies were found in 8.3% of the placebo group but only 4.9% of those receiving tezepelumab.

In announcing topline results from the study in February, trial co-sponsor AstraZeneca (which is developing tezepelumab in a collaboration with Amgen) said it expected results from NAVIGATOR to serve as the basis for the drug’s marketing applications, although it gave no timeline for submitting them. Amgen initially developed the drug, bringing AstraZeneca, which has an established franchise in asthma therapeutics, on board in 2012. AstraZeneca is handling clinical development, while Amgen is the manufacturer; the two firms will share profits and have divided marketing responsibilities by region, with Amgen to manage U.S. sales.

Although the NAVIGATOR results suggest a smooth approval path for tezepelumab, the drug recently hit a pothole. A supportive trial completed last year, called SOURCE, tested the drug against placebo in 150 patients with use of oral corticosteroids as the primary outcome measure. The sponsors hoped tezepelumab would allow patients to reduce use of these add-on drugs, often used when asthma isn’t controlled with inhalers, without seeing increases in symptoms. But that goal was not achieved, AstraZeneca said in December.

Some 950 participants from NAVIGATOR and SOURCE are now enrolled in a placebo-controlled extension study called DESTINATION, with adverse events as the primary outcome measure and exacerbations rates a secondary endpoint.