Continued Tezepelumab Treatment Benefits Patients With Severe, Uncontrolled Asthma

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The continuation of tezepelumab showed stronger benefits after stopping treatment for 2 years and compared with placebo.

The biologics currently available for the treatment of severe asthma show varying results depending on the condition’s phenotype. Although the effect of treatment cessation on asthma symptoms and disease control following long-term biologic use was studied, tezepelumab (Tezspire; Amgen and AstraZeneca) has yet to be evaluated. Results from the DESTINATION trial (NCT03706079) published in Annals of Allergy, Asthma, & Immunology explored the changes in clinical measures of asthma and inflammatory biomarkers following the cessation of tezepelumab after 2 years of treatment in patients who have severe, uncontrolled asthma. Additionally, the off-treatment effects of prior tezepelumab were assessed during a 40-week period after the last dose (week 100).

Inhaler and wooden blocks spelling asthma -- Image credit: MarekPhotoDesign.com | stock.adobe.com

Image credit: MarekPhotoDesign.com | stock.adobe.com

DESTINATION is a multicenter, randomized, placebo-controlled, double-blind phase 3 long-term extension (LTE) study following the 52-week NAVIGATOR or 48-week SOURCE (NCT03406078) phase 3 studies. DESTINATION enrolled patients who were 12 to 80 years of age with severe, uncontrolled asthma who completed 1 of the 2 prior trials. Patients were subcutaneously treated with 210 mg of tezepelumab every 4 weeks, with the last dose administered on week 100.

For patients in the NAVIGATOR trial, DESTINATION evaluated the effects of tezepelumab cessation during a 36-week extended follow-up (EFU) period (weeks 104-140), with the duration of the EFU period based on pharmacokinetic (PK) and pharmacodynamic (PD) modeling. This indicated serum concentrations of tezepelumab, which were expected to decrease below those required for a minimal PD effect over 36 weeks. The final dose of tezepelumab or placebo was administered at week 100 and the end points were assessed during the 40-week period after the final treatment dose and consisted of 6 follow-up visits, which were optional and not required for patients to attend. Further, patients from the SOURCE study—who were required to be oral corticosteroid (OCS)-dependent at enrollment—were not eligible for the 36-week EFU period and were not included in the analysis.

About the Trial

Trial Name: Extension Study to Evaluate the Safety and Tolerability of Tezepelumab in Adults and Adolescents With Severe, Uncontrolled Asthma (DESTINATION)

ClinicalTrials.gov ID: NCT03706079

Sponsor: AstraZeneca

Completion Date: May 18, 2022

Of the total 827 participants enrolled in the NAVIGATOR trial, a total of 426 were included in the analysis, with 289 treated with tezepelumab and the remaining 137 receiving placebo. According to the investigators, baseline measures indicated that there was a greater proportion of patients in the tezepelumab group receiving inhaled corticosteroids (ICS) at baseline (80.3%) than in the placebo group (75.2%). Additionally, patients who were in the tezepelumab group had a higher fractional exhaled nitric oxide (FeNO) level (31.0; range: 5.0, 213 ppb) than those in the placebo group (27.0; range: 5.0, 258 ppb).

Compared with the biomarkers observed during the 2-year treatment period, both blood eosinophil count (BEC) and FeNO levels in the tezepelumab group increased gradually following treatment cessation, as early as 4 to 10 weeks after the final dose. Additionally, after the end of the 40-week period after the last dose, FeNO levels began to approach baseline levels, however, BECs—which were similar to placebo—remained below the levels recorded at baseline. Reductions in serum total immunoglobulin E (IgE) levels were also observed in the treatment group, which were achieved during the treatment period from the start of NAVIGATOR and to the end of the LTE period after tezepelumab cessation. Further, the investigators observed unchanging BEC, FeNO level, and serum total IgE level during the 40-week period after the last treatment dose in patients who received placebo.

Following the final dose of tezepelumab at week 100, the decreases in serum tezepelumab concentrations were consistent with the known PK properties for tezepelumab. In addition, approximately 32.9% of patients who received tezepelumab (n = 95) experienced at least 1 exacerbation during the 40 weeks after the last dose, and the placebo group demonstrated a smaller proportion of patients experiencing an exacerbation (27%; n = 37). The time to first exacerbation following the final dose was 29 weeks (203 days) and 30 weeks (211 days) for tezepelumab and placebo, respectively. Further, among the 33.5% of patients who received tezepelumab (n =127) who achieved clinical remission at the end of the LTE period (week 104), 25.6% (n = 32) did not continue into the EFU period, and of the 94 patients that continued to this period, approximately 22.0% that remained in remission (n = 21) during the 40-week period following the last dose.

Key Takeaways

  1. Early Intervention with Tezepelumab in Severe Asthma: The DESTINATION study assessed the effects of discontinuing tezepelumab treatment after 2 years in patients with severe, uncontrolled asthma. Results showed that following treatment cessation, blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) levels gradually increased, indicating potential worsening of asthma inflammation. However, reductions in serum total immunoglobulin E (IgE) levels achieved during treatment were maintained post-cessation, suggesting a sustained effect of tezepelumab on allergic responses.
  2. Long-Term Impact of Tezepelumab Cessation: Although none of the biomarkers returned to baseline levels during the 40-week follow-up period following treatment cessation, patients who stopped tezepelumab showed better asthma control and lower biomarker levels compared to baseline. This suggests a prolonged therapeutic effect of tezepelumab even after discontinuation, which could be clinically significant for patients who may need to pause or discontinue treatment temporarily.
  3. Considerations for Clinical Practice: The study findings show the importance of continued tezepelumab treatment in patients with severe, uncontrolled asthma to maintain optimal disease control and minimize exacerbations. The authors recommend that health care providers should weigh the benefits of ongoing treatment against potential exacerbation risk when considering whether discontinuation interruption of tezepelumab therapy.

A limitation of the analysis, according to the investigators, was the timeline of the DESTINATION trial overlapping with the beginning of the COVID-19 pandemic, potentially influencing up to 70% of patients who were not experiencing any exacerbations. This was observed even at 40 weeks post-treatment, which was lower than the investigators hypothesized. In addition, participation in the EFU period was optional and could have led to minor differences in the baseline characteristics between treatment groups, particularly the size.

According to the authors, although none of the outcomes assessed returned to baseline levels during a 40-week follow-up period after treatment cessation, the persistence of better asthma control and lower biomarker levels in comparison to baseline may indicate a prolonged effect post-cessation. The investigators emphasize that this may be significant in clinical practice for patients who may need to pause or discontinue treatment, but the overall results demonstrate benefits of continuing tezepelumab treatment in patients with severe, uncontrolled asthma.

Reference

Brightling CE, Caminati M, Llanos J, et al. Biomarkers and clinical outcomes after tezepelumab cessation: extended follow-up from the 2-year DESTINATION study. Annals of Allergy, Asthma & Immunology. 2024. doi:10.1016/j.anai.2024.04.031

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