Chronic Rhinosinusitis: Future Treatments and Unmet Needs

Background and Classification

Chronic rhinosinusitis (CRS) is an inflammatory disease of the nasal cavity and paranasal sinuses that affects 10% of the United States population and presents with two major phenotypes: with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP). Classification of CRS based on specific pathobiologic mechanisms, also termed “endotyping,” finds that the type 2 endotype (characterized by cytokines such as IL-4, IL-5, and IL-13, tissue eosinophilia, and local IgE production) comprises 80–90% of CRSwNP and 30–50% of CRSsNP patients with severe disease requiring endoscopic sinus surgery (ESS) in Western countries. CRSwNP in Asia and CRSsNP have more endotypic heterogeneity with significant subpopulations that have combinations of type 1 (IFN-y, IL-12), type 2, and type 3 (IL-17, IL-22) inflammation (1).

Current Treatment Options

Treatment options for CRS have historically centered around antibiotics, topical/systemic glucocorticoids, and ESS reserved for cases refractory to medical management (Table 1). Topical drug delivery has also been developed in the form of steroid infused stents implanted during ESS (i.e. SINUVA, PROPEL). Patients may also be evaluated for atopic sensitization to determine who may benefit from allergen immunotherapy. Recently, treatment options have expanded with FDA approval of three biologics: dupilumab (anti-IL-4Rα) in 2019, omalizumab (anti-IgE) in 2020, and mepolizumab (anti-IL-5) in 2021 (2). These drugs demonstrate the impact that suppression of the type 2 inflammatory pathway can have on endpoints such as patient-reported outcome measures (PROMs) and radiographic/endoscopic findings.

Table 1 – Comparison of the Existing and Potential New Treatment Options for Chronic Rhinosinusitis.

Existing treatment options for chronic rhinosinusitis including systemic/topical glucocorticoids, antibiotics, endoscopic sinus surgery and biologic drugs. Bottom: Potential new treatment options for chronic rhinosinusitis including other biologics, small molecular drugs, anticalins, and anti-biofilm agents. Advantages, limitations, and estimated cost of each of these treatment options are listed.

Treatments		Limitations	Advantages	Cost Estimate
Existing options	Systemic glucocorticoids	Systemic side effects Symptomatic improvements fade rapidly with cessation	Cost-effective Oral route of administration Efficacious	$10–50 per course
	Topical glucocorticoids	Patient nonadherence Inability to reach affected sinus mucosa Gradual and smaller magnitude of symptomatic improvement	Cost-effective Topical route of administration Safety Can be efficacious	$10–500 per bottle
	Antibiotics	Lack of data to support efficacy GI side effects Antibiotic resistance	Cost-effective Oral route of administration	$10–50 per course
	Endoscopic sinus surgery	Operative complications (general anesthesia, bleeding, anosmia, CSF leak, orbital injury, etc) Cost	Frequently a one-time treatment Efficacious across phenotypes and endotypes	$5,000–$15,000 per surgery
	Biologics (Dupilumab, omalizumab, mepolizumab)	Adverse effects (conjunctivitis, anaphylaxis, etc) Continued use required to maintain efficacy Parenteral delivery Cost	Bi-monthly or monthly treatment Efficacious in specific CRS populations	$10,000–40,000 per year
Potential new options	Other biologics (tezepelumab, fevipirant)	Cost Identification of responders (limited efficacy) Parenteral delivery Efficacy in CRS not established or ongoing trials	Does not require daily treatment May be efficacious in targeted populations	N/A
	Small molecule drugs (baricitinib, ruxolitinib, SB010)	Under investigation, efficacy in CRS not determined. Diarrhea, chest pain/tightness, dyspnea, nausea.	Topical or oral route of administration Less costly to manufacture than biologics May be efficacious in specific populations	N/A
	Anticalins (AZD 1402/PRS-060)	Under investigation	May be efficacious in specific populations	N/A
	Anti-biofilm agents (topical antibiotics, low frequency ultrasound, antimicrobial photodynamic therapy)	Antibiotic resistance	May be efficacious in specific populations	N/A

Type 2 Inflammatory Pathway Targeted Therapeutics

Given the success of type 2-targeted therapeutics, efforts are underway to target other components of this pathway (Figure 1). Many of these drugs were first developed for other type 2 inflammatory diseases [i.e. asthma, atopic dermatitis (AD)], providing important evidence for safety as well as efficacy against mechanistically similar diseases. Published ongoing trials in CRS include monoclonal antibodies targeting cytokines or their receptors [lebrikizumab (anti-IL-13), reslizumab (anti-IL-5), benralizumab (anti-IL-5r)] and activators of type 2 innate lymphoid cells (ILC-2s), the cellular source of considerable type 2 cytokines [e.g. tezepelumab (anti-TSLP), etokimab (anti-IL-33), fevipirant, GB001 (anti-CRTh2/DP2)] (3) (Figure 1). Despite being compelling targets and their efficacy in other type 2 diseases, these drugs have had varying success in Phase 2/3 studies in CRSwNP: benralizumab had relatively modest reductions of nasal polyp scores (NPS) and nasal congestion scores whereas fevipirant and etokimab failed to improve polyp size or symptoms. Other drugs such as Tezepelumab and GB001 remain under active investigation. These studies may yield evidence for future therapeutics, fill gaps in our understanding of the most critical aspects of type 2 inflammation to CRS pathogenesis, improve our understanding of the relationship of individual symptoms (e.g. hyposmia) to specific aspects of type 2 inflammation, and may guide trials in type 2 CRSsNP.

Figure 1 – Potentially Targetable Pathways in Chronic Rhinosinusitis: the Type 2 Inflammatory Cascade and Other Pathogenic Mechanisms.

Potentially targetable mechanisms in CRS. Left column: Drugs that target components of the type 2 inflammatory pathway (green: FDA-approved for CRSwNP, yellow: under active investigation in CRS, red: drugs without proven efficacy in CRS). Middle column: type 2 inflammation cascade is depicted including mediators of the pathway that are potential therapeutic targets. These include interleukins 4, 5, 13, 33, ILC2 cells, and IgE. Right hand: other pathogenic mechanisms that have been implicated in CRS pathogenesis including extravascular fibrin deposition (coagulation cascade), B-cell dysregulation, and the arachidonic acid pathway.

Abbreviations: Sialic acid-binding Ig-like lectin 8 (Siglec-8); Thymic stromal lymphopoietin (TSLP); myeloid dendritic cells (mDC); Tissue plasminogen activator (tPA); 5-lipoxygenase (5-LO)

Other Potentially Targetable Pathways

In addition to the type 2 inflammatory pathway, there remain other aspects of inflammation in CRS that have not yet been targeted (Figure 1). These include the type 1/3 inflammatory pathways, coagulation cascade/fibrinolysis, B-cell activation/autoantibodies (4), the arachidonic acid pathway, and microbes particularly when organized into biofilms (5). Fibrin deposition and dysregulation of the coagulation cascade may be important in CRSwNP pathogenesis, as eosinophilic and non-eosinophilic nasal polyps demonstrate an abundance of extravascular fibrin deposition (6). Additionally, nasal polyps accumulate highly activated plasma cells producing autoreactive antibodies and IgE (4). Mediators of the arachidonic acid pathway are found at elevated levels in nasal polyp tissue especially in patients with aspirin-exacerbated respiratory disease (AERD). Drugs that target these alternative mechanisms include anticoagulants/fibrinolytics, belimumab (anti-B cell-activating factor), 15-lipoxygenase inhibitors, brodalumab and secukinumab (IL-17Rα and IL-17α inhibitors, respectively). These drugs may play an important role in treatment of CRS subpopulations.

Treatment Barriers and Limitations

Although current biologics are generally well-tolerated and efficacious, real-world barriers include a substantial cost burden ($10,000–40,000 annually), parenteral administration, evidence of residual inflammation in clinical trials lasting greater than one year, and symptom worsening after cessation of treatment indicating likely need for long-term treatment. Also, unlike other type 2 diseases, CRS uniquely has ESS in its care algorithm (Table 1). Nasal polyp scores (NPS) are lower in patients treated with ESS compared to dupilumab (−5.18 vs −4.27, p<0.02) (7). These ESS benefits have to be weighed against improved olfaction and SNOT-22 scores in dupilumab patients compared to ESS at greater than one year follow-up (7). Nonetheless, post-operative recurrence rates reported by several centers may be quite variable with rates between 20–60% in 4-year follow-up and up to 79% over a 12-year period (8). Considering these factors, a recent Markov decision tree economic model found that ESS is still more cost-effective than dupilumab regardless of the need for or frequency of revision surgery so long as the cost of dupilumab is >$855/year (9). Recurrence rates may be improved, however, when surgery is followed by targeted therapy; this remains an area necessitating more research. Resultantly ESS remains a mainstay in treatment, but biologics do play an important role in treatment of patients who have contraindications, failed ESS, or other comorbidities that may benefit from biologic therapy.

Emerging Areas for Research

Given the availability of several medications and multi-modal treatments, an important emerging area of research is identification and validation of clinical features/biomarkers to guide choice and sequencing of treatments. As further biologics become approved, studies are also needed to identify specific subpopulations that best respond to each drug. While no biologics are yet approved for treatment of CRSsNP, a subset of patients may respond to these drugs and better methods to identify this group of patients is needed. No single clinical phenotype or biomarker has yet been found to strongly predict successful disease control, although emerging evidence suggests endotypic biomarkers can augment clinical predictors of outcomes after surgery (4). Further validation of the most predictive features of disease is needed.

Other promising avenues for CRS therapeutics include development of small-molecule drugs (SMDs) in tandem with mechanisms to deliver these in a sustained topical manner. Compared to biologics, SMDs are less costly to manufacture, can target intracellular signaling, and may be administered topically or orally. An inhaled SMD (SB010, DNAzyme) that targets GATA-3, a molecule that controls the differentiation of ILC-2s and Th2 cells, has performed well in patients with allergic asthma though not studied in CRS (3). Another promising class of SMDs are those that inhibit the JAK-STAT pathway and are approved or in late stage approval for AD but have not been studied in CRS (3). Additionally, anticalins are a new class of bio-engineered molecules based on endogenously occurring lipocalins that have antibody-like specificity and allow for topical administration. An inhaled anti-IL-4Rα anti-calin (AZD 1402/PRS-060) has shown a similar degree of IL-4 and IL-13 attenuation as dupilumab in mouse models in phase 1 trials for asthma (10). Given its similar mechanism and comparable efficacy to dupilumab with potential for topical administration, this drug may represent a promising future CRS therapeutic.

Recent advancements in the understanding of CRS pathogenesis have identified multiple aspects of the disease that are targetable. While appropriately focused on developing type 2 targeted therapeutics, there remain limitations to existing anti-type 2 therapeutics and multiple alternate pathologic mechanisms remain. Future clinical research needs include improved testing to identify targetable endotypes, validation of endotype-driven care pathways, and development of novel therapeutics for non-type 2 aspects of CRS.