The argument against the use of dupilumab in patients with limited polyp burden in chronic rhinosinusitis with nasal polyposis (CRSwNP)

Current regulations

On June 16, 2019, the United States Food and Drug Administration (FDA) approved dupilumab for use in patients 18 years and older with CRSwNP [6]. This approval took the form of an amendment to the list of indications for this drug. The FDA's indication for CRSwNP specifies that the drug may be used “as an add-on maintenance treatment in adult patients with inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP) [7]”. Following the approval of dupilumab, two other biologics have been approved by the FDA for recalcitrant CRSwNP; omalizumab and mepolizumab.

In the European Union (EU), pharmaceuticals are regulated by the European Commission (EC). On October 29, 2019, the EC approved dupilumab for use in adults with severe CRSwNP. The European Commission's indication closely mirrors that published by the US FDA, stating that dupilumab is indicated “as an add-on therapy with intranasal corticosteroids for the treatment of adults with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate disease control [8]”. This language is more explicit than that offered by the US FDA, essentially outlining the expected treatment algorithm for patients with CRSwNP and making it clear that dupilumab is to be offered to truly recalcitrant patients.

In summary, review of regulations in both the Unites States and European Union indicates that dupilumab is indicated for recalcitrant disease and is considered an “add-on” therapy. Therefore, use of dupilumab as first-line therapy without concomitant use of intranasal steroids would be considered off-label use. The inherent legal, practical and ethical considerations of off-label use of dupilumab must be weighed against aggressive use of this drug.

Comparable efficacy of surgery

While the efficacy of dupilumab and other biologics has been well-established for patients with CRSwNP who have persistent symptoms after failure of initial surgical management and steroids [3, 4], the central question is whether biologics offer equal treatment efficacy to endoscopic sinus surgery (ESS). This is an especially important topic to understand, as non-surgical healthcare professionals may inherently seek to offer biologics in place of surgical management. All physicians (including otolaryngologists) tend to offer therapeutic options based on both their training background and the treatments that they themselves are able to provide [9].

The topic of the efficacy of ESS versus biologics was recently studied in a multi-center prospective cohort, conducted by Miglani et al. at the Medical University of South Carolina and Oregon Health Sciences University [10]. A total of 111 patients were divided into cohorts of patients receiving ESS, dupilumab, mepolizumab or omalizumab [10]. A variety of objective and subjective outcome measures were assessed at 24 and 52 weeks [10].

At 24 weeks, patients undergoing ESS displayed significantly greater improvements in the Sino Nasal Outcome Test (SNOT-22) and significantly lower nasal polyp scores (NPS) compared to dupilumab (p < 0.05, p < 0.001 respectively) and omalizumab (p < 0.001 and p < 0.001 respectively) [10]. The study found comparable improvements in smell identification between those receiving ESS and all biologics (p > 0.05) [10].

At 52 weeks, improvement in SNOT-22 scores were comparable between ESS and dupilumab (p = 0.21), but NPSs were once again significantly lower in the ESS group compared to dupilumab (p < 0.001) and mepolizumab groups (p < 0.001) [10].

It is important to consider the results of the study from Campion et al. contained in this current publication in the context of the above study from Miglani et al. Though the investigators in Campion et al. have shown that NPS improvement is comparable in dupilumab patients with both limited and heavy polyp burdens, we should remember that ESS was ultimately shown by Miglani et al. to offer significantly lower NPS compared to dupilumab.

Complete endoscopic sinus surgery offers some distinct advantages over biologics in terms of long-term polyp control. Perhaps the greatest advantage, in our experience, is the creation of favorable anatomy to decrease inflammation and improve access of topic nasal steroids to the sinus mucosa. This creation of favorable anatomy is often able to dramatically decrease the impact of polyps on the functioning of the paranasal sinuses, thus decreasing symptoms for the patient. Likewise, we must consider patient adherence to treatment. It has unfortunately been our experience that long-term compliance with topical steroid irrigations in patients with CRSwNP is poor. In patients who have undergone complete ESS, their optimized anatomy decreases the impact of recurrent polyps and allows for in-office intervention in symptomatic cases of recurrence (ie polypectomy, placement of drug-eluting stents). Non-compliant patients with biologics could expect to see a rapid recurrence of symptoms, given their unaltered anatomy.

Cost

With current evidence demonstrating that ESS offers the same or better performance as biologics, including dupilumab, we should now consider the relative costs of these two treatment modalities.

As of the date of this publication, the cost per course of dupilumab is $31,154 for the first year of therapy, followed by $30,000 per year for each subsequent year [11]. It is too early to be certain, but all current evidence indicates that dupilumab and other biologics would need to be continued indefinitely for the beneficial effects to continue. Indeed, the major clinical trials investigating the efficacy of omalizumab on CRSwNP found that, when treatment was stopped at 52 weeks, patients experienced a gradual worsening of symptoms [12]. The financial implications of such an expensive and long-term therapy are staggering. According to the Centers for Disease Control (CDC), life expectancy for an American man in 2023 is 76.4 years. If we consider a 26 year-old male with CRSwNP, dupilumab administered over the ensuing 50 years would currently be estimated to cost $1.5 million, assuming no change in cost over time (a significant assumption).

In 2021, Scangas et al. performed a cost utility analysis of dupilumab versus endoscopic sinus surgery for CRSwNP [13]. They utilized Quality Adjusted Life Years (QALY) which equate to one year of perfect health. For example, if a drug improves a patient's quality of life to the point of perfect health for 6 months of a year, this equals 0.5 QALY. Likewise, if a drug improves their quality of life by 50% for one year, this also equates to 0.5 QALY. Generally speaking, in the United States, health economists accept $150,000 to $200,000 per QALY as the cutoff for a reasonable treatment. This cost per QALY is also referred to as the incremental cost effectiveness ratio (ICER).

In their well-designed cohort study, Scangas et al. [13] matched 197 patients who underwent ESS to 293 patients from the prior Sinus 24 and Sinus 52 studies of dupilumab. SNOT-22 scores were compared in both cohorts. The investigators utilized a decision-tree analysis and a 10-state Markov model to assess event probabilities over a 36-year time horizon [13]. The primary outcome was ICER [13].

The results were remarkable, if not completely surprising. The ESS strategy yielded a cost of $50,436.99 and produced 9.80 QALYs (ICER = $5145.63 per QALY) [13]. The dupilumab strategy, on the other hand, yielded a much higher expected cost of $536,420.22 and offered a lower 8.95 QALYs (ICER = $59,935.22 per QALY) [13]. Though the dupilumab ICER still falls within the acceptable limits outlined by health economists, there is clearly a tremendous difference in cost between ESS and dupilumab with a superior yield of QALYs with ESS. Indeed, when examining the results of this study, the investigators determined that the annual cost of dupilumab would have to decrease to $855 to match the ICER of ESS [13]. With a current annual price of $30,000, the cost of dupilumab would therefore have to decrease by 97.15% to become an economical alternative to ESS.

Naturally, patients are not bearing the direct burden of the cost of dupilumab. Insurance coverage of dupilumab, in our experience, has been steadily improving. Such costly medications, however, drive up healthcare costs indirectly for all patients in the US. In universal healthcare systems, the economic burden of biologics may be substantial enough to dramatically limit their availability. In developing nations, it is incomprehensible that biologics would be used when a superior and more economical surgical alternative exists.

Adverse effects

Initial safety and efficacy data for dupilumab in regard to CRSwNP was published in The Lancet in 2019, following completion of a pair of phase 3 clinical trials [3]. This initial data highlighted nasopharyngitis, worsening of nasal polyps/asthma, headache, epistaxis, and injection-site reactions as the most frequent adverse events [3]. Interestingly, reports of conjunctivitis did not feature prominently in the results of these CRSwNP trials, though trials performed for atopic dermatitis noted a higher incidence of mild-to-moderate conjunctivitis [14]. This discrepancy is thought to be due to the higher rate of conjunctivitis in patients with severe atopic dermatitis [14]. Regardless, this does raise questions about other comorbid conditions which could eventually provoke unexpected responses to biologics. Long-term data is essentially limited to omalizumab, and we must be prepared for the possibility of encountering unexpected adverse events related to biologics in the future. Who among us would have expected ranitidine to lead to elevated cancer risk or montelukast to receive a black box warning for suicidal ideation? While this should not necessarily deter us from utilizing biologics, we must consider that we are starting a patient on a relatively new drug with powerful anti-inflammatory effects which they could be using for decades. Accordingly, we feel that it is important to discuss the potential for unforeseen adverse effects with patients.

Current practice guidelines

Based on the above considerations and the considerable experience and expertise of their authors, Han et al. have released a multidisciplinary consensus treatment algorithm for management of CRSwNP [15]. This study incorporates input from both otolaryngologists and allergists from across the United States. Their algorithm offers biologics in patients whose symptoms recur after complete ESS, those with contraindications for surgery, patients with poorly-controlled asthma despite standard therapy / oral steroid-dependent asthma, or patients who decline surgery as part of a shared decision-making process [15]. They specifically advise against the use of biologics in patients with light polyp burden or minimal symptoms [15]. The most recent International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR: Rhinosinusitis 2021) from The American Rhinologic Society and the American Academy of Otolaryngic Allergy lists dupilumab as a “Recommendation,” stating that it “May be considered for patients with severe CRSwNP who have not improved despite other medical and surgical treatment options [16]”.

The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) released their consensus statement on the use of biologics in CRSwNP in 2019, around the same time that the drug was being approved for use in the same patient population in the US [17]. EUFOREA took a slightly different approach to their treatment guidelines, setting forth a list of criteria for biologics. These criteria include evidence of type 2 inflammation, systemic corticosteroids ≥ twice per year, significantly impaired quality of life, significant loss of smell, and diagnosis of comorbid asthma [17]. Patients who undergo surgery need three of these criteria to qualify for biologics [17]. Patients without prior surgery need four of the above criteria [17]. The authors of those guidelines stipulate that biologics should only be considered in non-surgical patients with severe asthma ¹⁷ .