乌鸦传媒

SAN DIEGO -- Tezepelumab (Tezspire) may hold potential as an add-on treatment for patients with chronic obstructive pulmonary disease (COPD) at high-risk for exacerbations, despite missing its primary goal in a randomized mid-stage trial.

In the phase IIa study of COPD patients on triple therapy, subcutaneous treatment with the recently approved asthma drug was associated with a non-significant 17% reduction in the annualized rate of moderate or severe exacerbations (1.75 vs 2.11 per year with placebo; incidence rate ratio [IRR] 0.83, 95% CI 0.61-1.11, P=0.10), according to David Singh, MD, of the University of Manchester in England.

Secondary endpoints, however, showed improvements in forced expiratory volume in 1 second (FEV₁) and symptom burden with the monoclonal antibody, and subgroup analyses suggested that "the benefit of tezepelumab increased with higher blood eosinophil counts [BECs]," Singh said during a presentation here at the American Thoracic Society (ATS) annual meeting.

While a post-hoc analysis of the exacerbation endpoint showed no benefit with tezepelumab for the subset of patients with lower BECs, a marker for type 2 inflammation, Singh suggested that those with BECs of at least 150 cells/μl appeared to represent a responder population:

• BEC <150 cells/μl: IRR 1.19 (95% CI 0.75-1.90)
• BEC ≥150 cells/μl: IRR 0.63 (95% CI 0.43-0.93)

A phase III program for tezepelumab in COPD is now being .

Despite the availability of triple therapy -- i.e., inhaled corticosteroids, long-acting beta-agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) -- "we still have many patients who continue to , and these exacerbations are drivers of poor quality of life, more rapid decline in lung function, and ultimately mortality," Singh noted in his introductory remarks.

"For pharmacological therapy, 'one size fits all' does not work, and we know that from our clinical practice," he continued. "The future of new treatments is highly likely to be targeted therapy, based on identifying clinical and biological characteristics of responder populations."

Tezepelumab targets thymic stromal lymphopoietin (TSLP), an epithelial-cell-derived cytokine thought to be implicated in the heterogenous disease pathology and clinical manifestations of COPD, said Singh. The biologic is currently approved as an add-on treatment for asthma in adults and kids ages 12 and up.

While no biologic is currently approved for COPD, a decision from the FDA on dupilumab (Dupixent) is expected in June. That biologic has a head start over tezepelumab, however, having already demonstrated significant reductions in moderate or severe exacerbations along with improvements in lung function in both the BOREAS and NOTUS trials. Those two phase III studies restricted enrollment to COPD patients with type 2 inflammation, as indicated by BECs of 300 cells/μl or higher.

At ATS, Singh presented data on , a double-blind randomized trial that featured a total of 333 COPD patients who were randomized 1:1 to 52 weeks of either tezepelumab (420 mg every 4 weeks subcutaneously) or placebo on top of their background triple therapy.

To be eligible for inclusion, patients needed to be between the ages of 40 and 80 years and have two or more moderate or severe COPD exacerbations within the year prior to enrollment (41% had three or more). Patients with asthma or other notable respiratory diseases were excluded.

Participants had a mean age of 67 years, a mean BMI of 27, and 44% were women. A majority had chronic bronchitis (56%) and emphysema (58%), and all participants were either current (32%) or former (68%) smokers.

Average pre-bronchodilator FEV₁ was 0.987 L, while the average fractional exhaled nitric oxide (FENO) level was 18.3 ppb and 59% of the patients had BECs of 150 cells/µL or higher.

The study's primary endpoint was the annualized rate of moderate or severe exacerbations. Tezepelumab also demonstrated no significant reduction in the annualized rate of severe COPD exacerbations only (0.13 vs 0.25 per year with placebo; IRR 0.52, 95% CI 0.24-1.11), a secondary endpoint.

Other secondary endpoints included changes from baseline to 52 weeks in pre-bronchodilator FEV₁, quality-of-life scores on the St. George's Respiratory Questionnaire (SGRQ, a 0-100 scale where lower scores indicate better quality of life), and symptom burden on the COPD Assessment Test (CAT, a 0-40 scale where higher scores indicate a greater impact of COPD on patient health).

At 52 weeks, the least-squares (LS) mean change in pre-bronchodilator FEV₁ was 0.026 L among the tezepelumab-treated patients and -0.029 L among patients assigned placebo (0.055 L difference, 95% CI 0.014-0.096). Scores on the SGRQ decreased for both groups (LS mean change of -4.80 with tezepelumab and -1.8 with placebo), though the between-group difference was not significant. Mean CAT scores decreased in both groups (LS mean change of -3.04 and -1.18 points, respectively), for a significant -1.86 difference (95% CI -3.31 to -0.40) that favored the tezepelumab-treated patients.

The safety profile with tezepelumab was similar to what has been previously reported in patients with asthma, said Singh.

Adverse events (AEs) occurred in 81% of patients on tezepelumab versus 75% of those on placebo, most frequently COVID infections (15% vs 8%, respectively) and worsening of COPD (12% vs 17%). AEs leading to treatment discontinuation occurred in 2.4% of patients on tezepelumab and 3.6% of those on placebo.

Serious AEs were reported in 30% of both groups, with worsening of COPD responsible for 10% of events in the tezepelumab arm and 14% of events in the placebo arm. AEs leading to death occurred in 1.2% and 1.8%, respectively.

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