Consider blood eosinophil counts when selecting biologic in COPD

Key takeaways:

• Dupilumab received FDA approval for treating adults with poorly controlled COPD with type 2 inflammation in September.
• Tezepelumab received an FDA breakthrough therapy designation for COPD in August.

PHILADELPHIA — The current biologics for patients with COPD include anti-IL-5 therapies, dupilumab, tezepelumab and anti-IL-33 therapies, according to a presentation at the 2024 GOLD COPD International Conference.

Dave Singh

“From a background of dysregulation of innate immunity [in patients with COPD], in the last few years, we’ve had tremendous progress with biologics that target related or different pathways,” Dave Singh, MD, professor of clinical pharmacology and respiratory medicine at University of Manchester, said.

During his presentation, Singh highlighted various studies focused on the four types of biologics for COPD with consideration to patient blood eosinophil counts.

Anti-IL-5 therapies

One anti-IL-5 therapy for this patient population is mepolizumab (Nucala, GSK). Based on pooled results from the METREX and METREO trials in patients with eosinophilic COPD, Singh shared that mepolizumab was favored over placebo in those with higher blood eosinophil counts.

Notably, the largest response was found in patients with a count less than 150 cells/mm³ plus a historical count of 300 cells/mm³ or higher, according to a presentation slide.

“That higher eosinophil pattern could have been historical,” Singh said. “I think that’s an important point because we argue back and forth that blood eosinophil counts, because they go lower, they are not a reliable biomarker. But my feeling on this is that the natural variation in blood eosinophil counts over time is irrelevant because this is a biomarker of inflammation.

“Human inflammation is dynamic,” Singh continued. “You would never get an inflammatory biomarker in any other disease that is absolutely static.”

Another anti-IL-5 therapy for patients with COPD is benralizumab (Fasenra, AstraZeneca), and Singh noted that the GALATHEA and TERRANOVA trials investigating this drug came to a similar conclusion when pooled.

“Those with higher eosinophil counts had a slightly greater response,” Singh said.

According to Singh, eosinophils in those with COPD can act as either a target or biomarker.

“For some patients, eosinophils will be the target itself,” he said. “For other patients, it’s a biomarker that’s telling you there’s a type 2 protocol present, and that’s the target.”

Dupilumab

The second biologic type Singh discussed was dupilumab (Dupixent; Sanofi, Regeneron), which received FDA approval for treating adults with poorly controlled COPD with type 2 inflammation in September.

During his presentation, Singh shared results from the multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 BOREAS and NOTUS studies. Patients included in these trials were current/former smokers with moderate to severe COPD and type 2 inflammation (blood eosinophil count ≥ 300 cells/μL) primarily receiving background and stable triple therapy.

Compared with patients on placebo, patients on 300 mg dupilumab every 2 weeks showed a 31% decrease in the annualized moderate/severe exacerbation rate at week 52 (0.794 vs. 1.156; nominal P < .0001), according to pooled analysis results.

Between baseline and week 12 in the pooled analysis, researchers also observed a larger positive change in prebronchodilator FEV₁ in the dupilumab vs. the placebo group (least squares mean difference, 83 mL; nominal P < .0001).

The same was true when analyzing changes between baseline and week 52, with a larger change observed among those receiving dupilumab (least squares mean difference, 73 mL; nominal P < .0001), according to the pooled analysis.

Tezepelumab

Moving onto tezepelumab (Tezspire; Amgen, AstraZeneca) and anti-IL-33 therapies, Singh made note of an important difference between TSLP and IL-33. Notably, tezepelumab blocks TSLP.

“One of the big differences, in my view, is that TSLP shapes the interaction between dendritic cells and T helper cells, shaping the type 2 response,” Singh said. “IL-33 also has effects on type 2 response, but more directly and not predominantly through the interaction with dendritic cells.”

When discussing tezepelumab, Singh shared results from the NAVIGATOR trial assessing the treatment in patients with asthma because it could “give us a clue of what might happen in COPD.”

Notably, the NAVIGATOR trial included patients aged 12 to 80 years with severe and uncontrolled asthma.

“This monoclonal works across the spectrum of blood eosinophil counts, but those with the highest counts above 450 had a huge effect, almost 80% reduction in exacerbations, and that floats down as the eosinophil counts get lower,” Singh said.

Switching to the use of tezepelumab in COPD, Singh was part of the research team behind the multicenter, randomized, double-blind, placebo-controlled phase 2a COURSE study and previously presented findings from the study at the 2024 American Thoracic Society International Conference.

According to the study, among patients with moderate to very severe COPD receiving 420 mg tezepelumab every 4 weeks vs. placebo, the annualized rate of exacerbations dropped by 17%.

Dividing the cohort based on blood eosinophil counts revealed an even greater drop in exacerbation rate with tezepelumab, with decreases of 37% (rate ratio = 0.63; 95% CI, 0.43-0.93) in the 150 cells/μL or more count group, 34% (rate ratio = 0.66; 95% CI, 0.42-1.04) in the at least 150 cells/μL to less than 300 cells/μL count group and 46% (rate ratio = 0.54; 95% CI, 0.25-1.15) in the 300 cells/μL or more count group.

“It looks like above 150 eosinophils is the responder population,” Singh said.

Notably, this study supported the FDA’s breakthrough therapy designation to tezepelumab as a maintenance treatment for patients with moderate to very severe COPD characterized by an eosinophilic phenotype.

Anti-IL-33 therapies

In terms of anti-IL-33 therapies, Singh said astegolimab (Genentech, Roche) is an anti-ST2 monoclonal antibody targeting IL-33 and has been studied in patients with moderate to very severe COPD in the COPD-ST2OP trial.

As Healio previously reported, astegolimab improved health status but did not significantly reduce exacerbation rates over 48 weeks of treatment compared with placebo in this patient population.

The number of exacerbations was smaller in the group with a blood eosinophil count of 170 cells/µL or less vs. more than 170 cells/µL (0.69 vs. 0.83 COPD exacerbations), according to the study.

Itepekimab (Sanofi, Regeneron) is another monoclonal antibody that targets IL-33 and has been found to be most impactful in patients with moderate to severe COPD who are ex-smokers, Singh said.

“Those patients who are ex-smokers have a benefit, whereas those who are current smokers did not,” Singh said. “[Ex-smokers had a] 42% reduction in exacerbations.”

Additionally, a recent poster presented at the European Respiratory Society International Congress showed that receiving itepekimab led to a 51% lower adjusted annualized exacerbation rate in former smokers with moderate/severe COPD and exacerbation history.

Circling back to the question his presentation sought to answer (“which biologic for which type of patient?”), Singh charted each of the four biologics by blood eosinophil count based on current evidence.

“I put [anti-IL-5] at the highest eosinophil count, so I want to stress that type 2 inflammation may not be the same for all patients,” Singh said. “There’s probably a soft limitation for very high eosinophilic activity where you would want to wipe out the eosinophils.”

Dupilumab came after anti-IL-5 therapies, and tezepelumab came after dupilumab, according to Singh’s presentation.

“Tezepelumab probably has a broad profile that doesn’t seem to work in the group who have no evidence of type 2 inflammation, eosinophils less than 150,” Singh said.

“Perhaps the broadest biomarker profile will be anti-IL-33 treatments, but maybe they’ll be restricted to explore this,” Singh continued.

Moving forward, Singh said it is still unclear if eosinophils are a main disease driver, a T2 biomarker or both.

Additionally, he stressed the importance of capturing outcomes in addition to exacerbations, such as lung function, CT scans, mucus and gas trapping.

References:

• Bhatt SP, et al. Dupilumab efficacy and safety in patients with moderate to severe COPD with type 2 inflammation: Pooled analysis of BOREAS and NOTUS Trials. Presented at: European Respiratory Society International Congress; Sept. 7-11, 2024; Vienna.
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• Menzies-Gow A, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2034975.
• Pavord ID, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1708208.
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