Severe Asthma Management: Exploring the Mechanism of Action in Tezepelumab and Omalizumab

Chris Ambrose, MD

Credit: AstraZeneca

In a recent post-hoc exploratory analysis, tezepelumab, an FDA-approved biologic targeting thymic stromal lymphopoietin (TSLP), demonstrated a significant reduction in exacerbations compared with placebo, irrespective of prior omalizumab use, highlighting its effectiveness as a treatment option for patients with severe, uncontrolled asthma.

Jean-Pierre Llanos Ackert, MD

Credit: Amgen

While the post-hoc analysis presented promising results, the investigators explained further studies will delve into the sustained benefits of tezepelumab treatment in this population. The emergence of biologics targeting different pathways in severe asthma management has revolutionized the approach to treatment.

With its novel mechanism of action (MOA), tezepelumab addresses an unmet need for patients who do not fit the traditional phenotypic classifications or have biomarker limitations allowing for a more personalized and tailored approach to asthma management.

Study investigators Jean-Pierre Llanos Ackert, MD, executive medical director, Global Medical Affairs, Amgen, and Chris Ambrose, MD, franchise head, US Medical, Respiratory, AstraZeneca provided explained the therapy’s unique mechanism of action (MOA) and how it’s distinct from omalizumab's anti-immunoglobulin E approach.

Llanos Ackert and Ambrose Stated:

Tezepelumab Efficacy and the Role of Omalizumab

This post-hoc exploratory analysis demonstrated that tezepelumab reduced exacerbations compared with placebo in patients with severe, uncontrolled asthma, to similar degrees (51% to 57%) in those with and without prior omalizumab use. Additionally, frequencies of adverse events were similar in tezepelumab recipients compared with placebo recipients, regardless of prior omalizumab use.

These results, in combination with previously published analyses describing tezepelumab’s efficacy in patients with allergic asthma, inform specialists that tezepelumab can be considered an effective biologic option with an established safety profile for patients with severe, uncontrolled asthma including those with allergic phenotype.

The Mechanism of Action

Tezepelumab is the first and only biologic approved by the FDA to target TSLP, a key epithelial cytokine that has multiple effects within the asthma inflammatory cascade. By blocking TSLP, tezepelumab has been demonstrated to reduce the activity of IL-4, IL-5, and IL-13, with reductions in IgE, blood and airway eosinophils, as well as FeNO, mucus production, and airway mucus plugging.

Tezepelumab has also been shown to reduce airway hyperresponsiveness, likely via effects on mast cells and airway smooth muscle. However, the mechanism of action of TEZSPIRE in severe asthma has not been definitively established.

Expanding Efficacy Exploration of Tezepelumab

Looking ahead, we plan to further examine the clinical efficacy and real-world effectiveness of tezepelumab across clinically-relevant subgroups of patients with severe, uncontrolled asthma, including those eligible for or switching from other biologics.

We have a particular focus on patients with both allergic and eosinophilic asthma, as these patients may particularly benefit from the multiple beneficial effects of blocking TSLP with tezepelumab.

The Future of Biologics for Asthma Treatment

The findings from the NAVIGATOR phase 3 trial and subsequent exploratory analyses highlight the continuous advancements in the field of asthma therapeutics. Tezepelumab represents a promising addition to the armamentarium of biologic therapies available for severe, uncontrolled asthma.

The treatment especially stands out because of its efficacy regardless of prior omalizumab use. These findings offered healthcare providers the potential to expand their range of treatment options in addressing the complex needs of these patients.

For more expert insight on the NAVIGATOR phase 3 trial data presented at the American Thoracic Society (ATS) 2023 International Conference in Washington DC, check out the rest of Llanos Ackert's and Ambrose's email interview with HCPLive.