June 03, 2025

101. RFJC – NAVIGATOR

We’re back with another Rapid Fire Journal Club. Luke Hedrick and Dave Furfaro discuss the NAVIGATOR trial published in NEJM in 2021 evaluating tezepelumab for adults with asthma.

Article and Reference

We are talking today about the NAVIGATOR trial evaluating the use of tezepelumab in adults with asthma.

Menzies-Gow A, Corren J, Bourdin A, Chupp G, Israel E, Wechsler ME, Brightling CE, Griffiths JM, Hellqvist Å, Bowen K, Kaur P, Almqvist G, Ponnarambil S, Colice G. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med. 2021 May 13;384(19):1800-1809. doi: 10.1056/NEJMoa2034975. PMID: 33979488.

https://www.nejm.org/doi/full/10.1056/NEJMoa2034975

Key Learning Points

Background & Rationale

Asthma biologics already exist, targeting IgE and type 2 cytokines (IL-4, IL-5, IL-13), but there’s an unmet need for patients with non-allergic or non-eosinophilic phenotypes.

Tezepelumab is a monoclonal antibody targeting TSLP (thymic stromal lymphopoietin), an upstream mediator of both T2 and non-T2 inflammation, offering a potentially broader therapeutic effect.

Study Design (Navigator Trial)

Phase 3, double-blind, placebo-controlled RCT

Conducted in 18 countries from 2017-2020

N = 1,061 patients, aged 12-80 with moderate to severe asthma

All were on medium/high-dose ICS + controller med

Required ≥2 exacerbations in prior year

Outcomes

Primary Outcome: Annualized rate of asthma exacerbations (events per patient-year)

Secondary Outcomes:

Change in pre-bronchodilator FEV₁

Symptoms & quality of life (with predefined MCIDs)

Subgroup analyses by eosinophil count, FeNO, and perennial allergen sensitivity

Key Inclusion/Exclusion

Inclusion: 12-80 years, guideline-based therapy, ≥2 exacerbations

Exclusion: recent biologic use, mild/asymptomatic asthma, no reversibility on spirometry

Patient Population (Table 1 Summary)

Middle-aged, predominantly white, female

Poorly controlled severe asthma despite high-intensity therapy

~75% on high-dose ICS, ~10% on oral steroids

~40% had normal FeNO

~60% had eosinophils <300

Median IgE ~195

Results

Efficacy:

Annualized exacerbation rate:

0.93 (tezepelumab) vs. 2.1 (placebo)

Rate ratio: 0.44, p<0.001 (very positive)

In eosinophils <300 group: rate ratio 0.59, still effective

FEV₁ improved by ~+0.25 L (vs. +0.09 L placebo), significant & sustained from week 2 onward

Quality of life: statistically improved but did not meet MCID, so unclear clinical impact

Severity of exacerbations reduced: fewer hospitalizations & ED visits in the treatment arm

~40% of treated patients still had some exacerbations → not a cure, but improves severity

Safety:

Very well tolerated

77% reported adverse events (more common in placebo)

No anaphylaxis, no GBS, no cancer signal

Most common AEs: URTI, headache, nasopharyngitis

Injection site reactions: 3.6%

Serious AEs were lower in drug arm than placebo

Overall Takeaway

Tezepelumab significantly reduces asthma exacerbations (including in patients with low eosinophils), improves lung function, and is safe and well tolerated.

Provides a broad-acting biologic option even for patients who may not be eligible for existing T2-high biologics.

Now widely used as part of the asthma biologic armamentarium for poorly controlled asthma despite maximal inhaled therapy.

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