Severe chronic rhinosinusitis is a debilitating disease with a significant impact on quality of life. Treatment options are limited, and until recently, little progress had been made in developing new treatments. As of 18th March 2021, Xolair (omalizumab) is TGA-approved for the treatment of severe chronic rhinosinusitis with nasal polyps. We review data from the POLYP1 and POLYP2 trial which formed the basis of the approval, and speak with clinical immunologist Dr Daman Langguth, Clinical immunologist at the Wesley Hospital, Brisbane and Director of Immunology at Sullivan Nicolaides Pathology, to learn more about how this new treatment option will impact clinical practice.
Treatment challenges in CRSwNP
Chronic rhinosinusitis is estimated to affect approximately 8.4% of Australians – an incidence similar to depression and higher than diabetes.1 About 25–30% of patients with chronic sinusitis also develop nasal polyps – inflammatory outgrowths of sinonasal tissue into the nasal cavity.2 This subset of chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps (CRSwNP), is associated with high symptom burden and a substantial impact on quality of life.2
Treatment options for CRSwNP remain limited. Saline-based irrigation and intranasal corticosteroids (INCS) remain the cornerstone of medical treatment.3 While many patients experience improvement in symptoms and general quality of life with INCS, polyp-related quality of life may not improve noticeably and many patients will still require repeated courses of oral corticosteroids (OCS).3,4 Sinus surgery can be beneficial in severe CRS, but about 40% of patients relapse 18 months after surgery, despite ongoing medical management.4
The clear need for new treatment options for severe CRSwNP was echoed by Dr Daman Langguth. “It’s quite a depressing disease in that there are so few treatments, with limited effectiveness, and you very quickly run out of options for patients. There haven’t been any new treatments in more than a decade. Many patients will stop coming back because they know you can’t offer them any lasting relief.”
Rationale for anti-IgE therapy in CRSwNP
Prominent local production of immunoglobulin-E (IgE) is thought to play a central role in CRSwNP pathogenesis, by continuous activation of type 2 inflammatory cells including mast cells, basophils, and eosinophils.3,4
Xolair (omalizumab), a recombinant humanised monoclonal antibody, selectively binds to IgE, thereby reducing free circulating IgE available to bind to inflammatory cells.5 Xolair also decreases the expression of IgE receptors on type 2 inflammatory cells, further interfering with their activation and reducing inflammation.3,5
Early studies of Xolair in patients with CRSwNP showed significant improvement in symptoms, endoscopic reduction in nasal polyps and reduced need for INCS.4 Similar results were observed in patients with CRSwNP and comorbid asthma.
The major role of IgE in the disease and promising results from proof-of-concept studies warranted further investigation into the efficacy and safety of Xolair as a new treatment for patients with CRSwNP.
Xolair efficacy and safety demonstrated in severe CRSwNP in phase 3 trials
The approval of Xolair for CRSwNP was based on data from two replicate phase 3 randomised, double-blind, placebo-controlled trials – POLYP1 (NCT03280550) and POLYP2 (NCT03280537). These studies evaluated the efficacy and safety of Xolair in adult patients (≥18 years) with CRSwNP that was inadequately controlled despite daily INCS therapy.4
To be eligible for the study, patients were required to have severe CRSwNP with substantial impact on quality of life at screening visit 1 (day -35), despite receiving at least 4 weeks of INCS therapy, and at screening visit 2 (day -7), following a 4-week run-in period of 200μg twice daily INCS (or 200μg daily if unable to tolerate twice daily).4
Eligible patients (N=138, POLYP1 ; N=127, POLYP2) were randomised 1:1 to receive Xolair or placebo for 24 weeks. Dosage of Xolair was 75 to 600 mg every 2 or 4 weeks, depending on the patient’s baseline body weight and serum IgE.4 All patients received daily INCS (mometasone nasal spray) as background therapy.
The primary endpoints for both trials were change from baseline in endoscopic Nasal Polyp Score (NPS) and mean daily Nasal Congestion Score (NCS). Secondary endpoints included change from baseline in Sino-Nasal Outcome Test-22 (SNOT-22) score, Total Nasal Symptom Score (TNSS), individual daily symptoms and adverse events.4
At 24 weeks, Xolair-treated patients experienced statistically significant improvements in mean NPS and NCS versus patients treated with placebo in both trials (Figure 1a and 1b). Xolair-treated patients also showed significantly greater improvements from baseline compared with placebo in disease-related quality of life, as measured by SNOT-22, TNSS and individual nasal symptoms. Significant improvement was also seen in the smell test scores (University of Pennsylvania Smell Identification Test; UPSIT).4
Figure 1a. Mean change from baseline to week 24 in NPS in POLYP 1 and POLYP 2.4
Figure 1b. Mean change from baseline to week 24 in NCS in POLYP 1 and POLYP 2.4
Dr Langguth commented on the importance of considering disease-related quality of life as part of an effective treatment. “Quality of life can be quite poor for many patients with severe CRSwNP, even while on INCS therapy. We sometimes underestimate the burden of symptoms but it can be significant. Sense of smell, for example, is a significant thing and impacts patients’ experience of taste and enjoyment of food.”
Improvements above placebo were seen as early as week 4 for most assessed metrics. These improvements were maintained over the 24-week treatment period, suggesting a sustained treatment effect.4
Analysis of pooled data from POLYP1 and POLYP2 showed Xolair was well tolerated, with no new or unexpected safety concerns.4
The most commonly observed adverse events in Xolair-treated patients were headache, nasopharyngitis and injection site reactions, and most adverse events were mild to moderate in severity.4
Xolair improves asthma symptoms in patients with comorbid asthma
“Comorbid asthma doesn’t bias for or against Xolair working for CRSwNP in these patients”, notes Dr Langguth. “As an added benefit, it appears to improve asthma symptoms too, which makes sense as Xolair is already proven in asthma.” Asthma-related quality of life was significantly improved in Xolair-treated patients with comorbid asthma versus placebo-treated patients.4 Patients with comorbid asthma were four times more likely to achieve a minimal clinically important difference in asthma-related quality of life score (by ≥0.5 points) with Xolair than with placebo.4
Patients with CRSwNP and comorbid asthma are an important group as they are more likely to have severe disease, relapse and are more likely to need more OCS and multiple surgeries.4 “Xolair is a good treatment option for patients with comorbid asthma because it’s double bang for their buck. But clinicians need also keep in mind to check and encourage compliance with asthma therapies in these patients, as there is the risk of the patient stopping or reducing their asthma therapies if their asthma symptoms improve on Xolair.”
Continued efficacy, safety and durability of response in an open-label extension study
All patients who completed POLYP1 and POLYP2 trials without experiencing severe treatment-related adverse events (N=249) were included in an open-label extension study designed to evaluate long-term efficacy, safety and response to Xolair.6
The extension study consisted of 28 weeks of open-label treatment with Xolair, followed by a 24-week off-drug observation period. The primary endpoints were change in NCS and NPS from POLYP 1 and POLYP 2 baseline to the end of the open label extension at week 76, and adverse events during the open label extension from weeks 24 to 76. NPS and NCS were reviewed at several time-points, the most important being at the end of the open label treatment period at week 52.6
Patients who had received Xolair during POLYP1 and POLYP2 continued to experience improvements in nasal polyp score, nasal symptoms and nasal polyp-related quality of life throughout the extension treatment period. Patients who had received placebo during the original trials began the extension treatment with poorer scores compared to the Xolair treated patients, but showed similar improvements after starting treatment with Xolair and through to week 52 of the extension.6
Efficacy scores slowly declined from week 52 following discontinuation of Xolair. “Much like other chronic inflammatory diseases, CRSwNP requires long-term suppression in most people”, explains Dr Langguth. “When the medication is stopped, we see patients generally start to rebound.”
Rate and severity of adverse events from the extension study were similar to the parent studies and no new safety concerns were identified.6
Xolair is a new treatment option for Australian patients with severe CRSwNP
Dr Langguth commented on the significance of the new Australian approval for Xolair as an add-on treatment for severe CRSwNP in adults with inadequate response to INCS.5 “Considering the lack of treatment options for these patients, a new drug that seems to work is like a breath of fresh air. For patients in whom Xolair is effective, it could be life changing.
While we see the greatest improvement in results after several months of continuous treatment, we see it starts working quite quickly, with the treatment group and placebo group diverging in scores early on. Long-term treatment was shown to provide continuous improvement and discontinuation saw a rebound in symptoms – as is to be expected in chronic inflammatory conditions.”
Regarding the use of Xolair in the clinic, Dr Langguth advised alignment with current guideline recommendations.3 “In patients with current CRSwNP who have relapsed after one sinus surgery and are considering another surgery, I would interrupt and consider Xolair. That’s regardless of whether or not the patient has comorbid asthma or aspirin-exacerbated respiratory disease. You may also want to consider Xolair in patients with severe CRSwNP for whom surgery is unlikely to be effective, as deemed by an ENT surgeon experienced in nasal polyps.”
- Australian Bureau of Statistics. National Health Survey: First Results, 2014-15. Long-term health conditions – Australia. https://www.abs.gov.au/AUSSTATS/[email protected]/DetailsPage/4364.0.55.0012014-15?OpenDocument, accessed 3rd May 2021
- Stevens W et al. Allergy Clin Immunol Pract 2016;4(4):565–572.
- Fokkens W et al. Rhinology 2020;58(Suppl S29):1-464.
- Gevaert P et al. J Allergy Clin Immunol 2020;146:595-605.
- Xolair Australian Approved Product Information (2021).
- Gevaert P, et al. Presented virtually at the American College of Asthma, Allergy and Immunology Annual Meeting. November 13–15, 2020.