Tezepelumab in Adults with Uncontrolled Asthma

Reviewed by Dr. Jennifer Wagner
Corren J, et al. N Engl J Med. 2017 Sept 7;377(10):936-46

SUMMARY
Asthma is common world-wide, and many have difficult to control disease despite high dose steroids. This study evaluates the use of Tezepelumab, an investigational monoclonal antibody that binds to thymic stromal lymphopoietin (TSLP), which is a cytokine produced by pro-inflammatory stimuli and is more highly expressed in the airways of asthmatics. This paper describes a randomized, double-blind, multicenter phase two study across 12 countries. Participants were adults with moderate-severe asthma that was not well controlled despite LABA and moderate to high dose inhaled steroids. Participants were randomized to receive subcutaneous Tezepelumab at low dose of 70 mg every 4 weeks (145 patients), medium dose of 210 mg every 4 weeks (145 patients), or high dose of 280 mg every 2 weeks (146 patients), or placebo every 2 weeks (148 patients) for 52 weeks. Asthma control medications were continued during the trial. The primary efficacy end point was the annual rate of asthma exacerbations at week 52, which resulted at 0.26, 0.19, and 0.22 in the low-dose, medium dose, and high-dose Tezepelumab, respectively, versus 0.67 in the placebo group. Rates were not affected by the pre-study blood eosinophil levels. The prebronchodilator FEV1 was significantly improved in all doses of Tezepelumab as compared to placebo. Tezepelumab treatment decreased eosinophil counts and IgE levels. Treatment effects were noted by week 4 and persisted. Adverse events had similar rates among Tezepelumab doses and placebo. Three serious events felt to be due to Tezepelumab were pneumonia, stroke, and Guillain-Barre syndrome.

COMMENTARY
Tezepelumab is a promising new therapy for poorly controlled asthma. It is effective in lowering the rate of asthma exacerbations at all doses compared to placebo while being well tolerated without increased rates of adverse side effects. The study does not discuss which dose of Tezepelumab provided the best outcomes overall, however it appears that the rates of asthma exacerbation did not vary significantly regardless of the dose. Of note, patient questionnaires on asthma control symptoms, while showing a statistical improvement with Tezepelumab treatment, does not meet the minimal clinically important difference in scores between treatment and placebo, questioning whether the significance is clinically relevant. Thus, this medication might impact exacerbation rates without affecting their daily control symptoms. Furthermore, while the relative risk reduction for exacerbations with Tezepelumab was striking, the absolute risk reduction was small because participants had <1 exacerbation in the year. Cost-benefit analysis should be performed to see whether the savings from prevented hospitalizations/treatment for exacerbations outweigh the cost of the drug.

Interestingly, positive antidrug antibodies were highest in the placebo group when compared to all doses of the investigational drug, which is curious as these were the only patients not exposed to the drug. Also, Tezepelumab had equal results regardless of eosinophil level or Th2 status, therefore indicating that the drug is not limited to treating type 2 asthma. However, the markers used to assess Th2 status were not all the same as the markers used in other studies. One limitation of the study was that the vast majority of participants were white, so future studies would need to include other ethnicities to evaluate efficacy in these populations. In summary, Tezepelumab appears to have high potential as an effective new asthma medication to prevent exacerbations in patients not already controlled on LABA and steroid and is not limited to type 2 asthma.

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