Tezepelumab as an Oral Corticosteroid-Sparing Therapy in Severe, OCS-Dependent Asthma: Insights from the SUNRISE Trial

Overview of Severe Asthma and Current Management

Severe asthma represents a significant clinical challenge, often characterized by persistent symptoms and frequent exacerbations despite adherence to high-dose inhaled corticosteroids (ICS) and additional controllers like long-acting 2-agonists (LABA). For many of these patients, maintenance oral corticosteroids (OCS) have historically been the "last resort" adjunct therapy to maintain asthma control and prevent life-threatening attacks. While effective in the short term, the reliance on systemic steroids indicates a failure of standard inhaled therapies to address the underlying inflammatory pathways, necessitating more targeted biological interventions.

The Hidden Cost: Risks of Long-term OCS Use

The clinical community has become increasingly wary of the systemic "cost" associated with OCS dependency. Long-term use—typically defined as six months or more—is inextricably linked to a spectrum of serious adverse events, including cardiovascular disease, metabolic disorders like diabetes, psychiatric disturbances, and skeletal issues such as osteoporosis.

Research indicates that even cumulative exposure to relatively low doses (0.5g to 1.0g) can significantly heighten the risk of OCS-related comorbidities. Furthermore, maintenance doses as low as 5 mg per day are associated with increased mortality and decreased health-related quality of life. Consequently, a primary goal in modern asthma management is to identify "steroid-sparing" treatments that allow patients to reduce or eliminate OCS use without sacrificing symptom control.

Study Design: The SUNRISE Trial

The SUNRISE study was a Phase 3, multicenter, double-blind, placebo-controlled trial designed specifically to evaluate the OCS-sparing potential of Tezepelumab. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin (TSLP), an epithelial cytokine that plays a foundational role in initiating the inflammatory cascade in asthma.

In this trial, adults aged 18–80 with severe, OCS-dependent asthma were randomized in a 2:1 ratio to receive either Tezepelumab 210 mg or a placebo subcutaneously every four weeks for 28 weeks. The study employed a rigorous OCS optimization phase followed by a structured reduction phase, where doses were decreased every four weeks as long as asthma control was maintained. The primary endpoint was the categorized percentage reduction from baseline in the daily OCS dose at week 28.

Highlighted Clinical Results

Despite an early termination of the study due to recruitment challenges in an evolving clinical landscape, the SUNRISE trial yielded statistically significant and clinically meaningful results.

• Primary Outcome: Patients treated with Tezepelumab were nearly three times more likely (Odds Ratio: 2.93; p=0.0034) to achieve a higher category of OCS dose reduction compared to the placebo group.
• Total discontinuation: Notably, 35-36% of participants in the Tezepelumab group were able to achieve a 90–100% reduction in their maintenance OCS dose, compared to only 21% in the placebo group.
• Broad Efficacy: Approximately 69% of patients receiving Tezepelumab achieved at least a 50% reduction in their OCS dose.
• Secondary Clinical Benefits: Beyond steroid reduction, Tezepelumab demonstrated a significant improvement in lung function, with an increase in pre-bronchodilator FEV1 of 0.26 L over placebo. Furthermore, the annualized asthma exacerbation rate (AAER) was significantly lower in the Tezepelumab group (0.64) compared to placebo (2.04).
• Safety Profile: Tezepelumab was well-tolerated, with a safety profile consistent with previous studies; the most common adverse event was nasopharyngitis.

Summary and Future Directions

The SUNRISE trial confirms that Tezepelumab is a potent OCS-sparing agent for a broad population of severe asthma patients, regardless of their baseline blood eosinophil counts. By blocking TSLP at the top of the inflammatory cascade, Tezepelumab appears to enhance steroid sensitivity, allowing for significant dose reductions while simultaneously improving lung function and reducing exacerbations.

Looking forward, these findings support a paradigm shift in clinical practice away from the chronic use of systemic steroids. The ability of Tezepelumab to provide OCS-sparing benefits while maintaining efficacy highlights its role as a versatile biologic for patients who have traditionally been the most difficult to treat. Future research should continue to explore the long-term sustainability of OCS discontinuation and the potential for Tezepelumab to mitigate the cumulative burden of steroid-related morbidities in this vulnerable population.

Source:

1. https://doi.org/10.1016/ S2213-2600(26)00076-7
2. NewsMedical Life Sciences – access May 2026