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Abstract

Background:

Chronic rhinosinusitis (CRS) is a common sinonasal disorder which results in significant inflammation in the nasal cavity and paranasal sinuses. Topical nasal steroids play an important role in the treatment of CRS. Exhalation delivery system with fluticasone (EDS-FLU) utilizes a patient’s forced exhalation to power the delivery of topical steroids to deeper areas of the nasal cavity and paranasal sinuses most affected by CRS. This review focuses on evidence surrounding the safety and efficacy of the EDS-FLU system.

Methods:

Literature search was conducted of articles investigating the safety and efficacy of EDS-FLU. Relevant efficacy and safety data were examined and summarized from the studies.

Results:

The efficacy and safety of EDS-FLU in CRS, both with and without polyps, has been established in open-label and placebo-controlled phase 3 trials. There was significant improvement in the cardinal symptoms of CRS and subjective patient-reported outcomes scores. Additionally, there was objective improvement in sinonasal inflammation as measured by polyp grade. Recent studies have also established significant improvement in health status and general quality of life following treatment using EDS-FLU. Emerging data have also examined patients who have previously had endoscopic sinus surgery and on appropriate medical therapy and noted improvement in polyp burden and overall Lund-Kennedy scores after using EDS-FLU.

Conclusion:

Exhalation delivery system with fluticasone demonstrates significant results in both patient-oriented outcomes and objective measures of sinonasal inflammation in patients with CRS with and without polyps. Further research is needed to investigate the long-term outcomes of EDS-FLU and to compare the effects of EDS-FLU with ESS. Exhalation delivery system with fluticasone provides an additional effective treatment modality for patients suffering from CRS.

Keywords

chronic sinusitis exhalation delivery system fluticasone topical therapies

Introduction

Chronic rhinosinusitis (CRS), a common sinonasal disorder originating from both host and environmental factors, causes chronic local inflammation within the paranasal sinuses and leads to significant impact on quality of life, which translates to additional burdens to society, healthcare system, and the economy.^1

-6 Approximately 10% to 15% of the population is affected by CRS. Chronic rhinosinusitis is generally divided into 2 phenotypes: chronic rhinosinusitis without polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP), with approximately 20% having CRSwNP. Optimal treatment of CRS includes medical, such as topical nasal corticosteroids, irrigations, antibiotics, and systemic steroids, and surgical options, specifically endoscopic sinus surgery (ESS). In most cases, ESS leads to improved disease control through removal of inflamed tissues, restoration of normal sinus drainage pathways, and reshaping sinus cavities with patent sinus ostia, which allows for more increased deposition of medication resulting in improved disease control.⁷

Intranasal topical steroid sprays are the first-line medical therapy for patients with CRS, which allow for high local concentrations of medication while minimizing systemic uptake and adverse events. However, despite adequate treatment with nasal steroids sprays, many patients continue to suffer from uncontrolled CRS. Investigations have shown that traditional intranasal sprays deliver medication to the anterior aspect of the nose and have limited deposition of medication into the ostiomeatal complex (OMC) and the paranasal sinuses, where CRS is most problematic.^8,9 In response to these findings, alternative techniques of delivering medication throughout the nasal cavity and paranasal sinuses were developed. The exhalation delivery system with fluticasone (EDS-FLU) was developed to improve topical delivery but also limit deposition in areas outside of the nasal cavity, such as the oral cavity and pharynx.⁹ While this platform was first developed in 2006, EDS-FLU was approved by the Food and Drug Administration in 2017. Since then, numerous studies have since evaluated the evidence of EDS-FLU and its use in controlling the CRS disease process.^10,11

Delivery of Topical Steroid Into the Nasal Cavity in Patients With CRS

Standard medical therapy for the long-term treatment of CRS involves inflammatory control, generally using steroids. While oral and topical steroids are both commonly used options, topical steroids are the mainstay of treatment due to limited systemic absorption and side effects. However, topical medication must reach the target site in order to be efficacious, which can be difficult in CRS with inflamed tissues and naturally restricted access into undissected sinus cavities. Two main factors determine the distribution of medication into the nasal cavity—delivery technique and underlying nasal anatomy. The distribution of medications in the nasal cavity with various delivery techniques was extensively examined by Schlosser and Harvey.^8,12 All delivery techniques had improvement in deposition after ESS when compared to controls, with the frontal and sphenoid sinuses having the least deposition in unoperated patients. Steroid sprays, which are traditionally the first-line medical treatment, utilize a low-volume, low-pressure delivery technique. Steroid sprays have the least deposition into the sinuses prior to and after ESS.¹² Nasal steroid sprays primarily deposit medication in the anterior nasal cavity and are generally intended to treat the heads of the inferior turbinates. An alternative delivery method is steroid irrigations, including budesonide and mometasone, which use a high-volume, high-pressure technique. Steroid irrigations are typically used in patients after ESS, though there is emerging evidence suggesting their use in preoperative patients.¹³ Irrigations are thought to allow for increased distribution of medications and more effective treatment of all mucosal surfaces, though it is unclear how much medications remains in the paranasal sinuses after the rinse leaves the nasal cavity.¹⁴ As well, patient compliance with irrigations may be less than sprays due to ease of utilization with the latter.¹⁵

In contrast, EDS-FLU utilizes a completely different delivery method in order to deposit steroid throughout the nasal cavity and paranasal sinuses.¹⁶ The EDS-FLU utilizes forced exhalation to power the delivery of steroids rather than by hand-operated sprays or irrigations. An added benefit of delivering medication with a patient’s exhalation is elevation of the soft palate which seals off the nasal cavity and limits deposition of medication outside of the nasal cavity. When exhalation delivery systems were compared to traditional spray systems, results demonstrated a statistically significant increase in deposition into the OMC and paranasal sinuses.

Evidence of EDS-FLU in Patients With CRSwNP

Thus far, the most robust evidence for EDS-FLU is in patients with CRSwNP. NAVIGATE I and II were prospective, double-blind, randomized controlled phase 3 trials.^17,18 These studies only enrolled patients with CRSwNP. These 2 studies had 4 treatment arms (placebo, 93, 186, and 372 µg delivered via EDS-FLU; all twice daily) lasting 16 weeks; after the double-blind portion, all patients then used 372 µg twice daily for 8 years. Subjective and objective outcomes were examined. Compared with placebo, patients using EDS-FLU demonstrated statistically significant improvements in the 4 cardinal symptoms of CRS: facial pain/pressure, rhinorrhea or postnasal drip, hyposmia/anosmia, and nasal congestion/obstruction. While there was significant improvement in the majority of symptoms across different dosages, there was not a statistically significant improvement in anosmia at 186 µg or facial pain/pressure at 93 µg. Sinonasal Outcome Test 22 (SNOT-22) scores were obtained in all treatment arms, and patients using EDS-FLU had improvement of 18 to 20 points as compared with 11 points in the placebo group. Subjective measures of efficacy were also determined using the Patient Global Impression of Change (PGIC) scale, which measures a patient’s perspective on the clinical improvement; 67% and 68% of participants noted “much” or “very much” symptomatic improvement by week 16 compared with 41% and 38% in placebo group in the NAVIGATE I and NAVIGATE II studies, respectively.

Endoscopic assessment of nasal polyp grade was used to objectively measure the impact of EDS-FLU. Nasal polyp grade improved for patients treated with EDS-FLU as compared to the placebo group in both studies. NAVIGATE I demonstrated ≥1 polyp grade improvement in 56%, 66%, and 72% of patients receiving 93, 186, and 372 µg EDS-FLU, respectively.¹⁷ In addition, NAVIGATE II demonstrated ≥1 polyp grade improvement in 68%, 63%, and 69% of patients in the 93, 186, and 372 µg EDS-FLU, respectively.¹⁸ NAVIGATE I reported polyp elimination in 25%, 17%, and 19% of patients in the 93, 186, and 372 µg EDS-FLU compared to 13% improvement in the placebo group at the end of the double-blind portion of the study. Additionally, NAVIGATE II demonstrated polyp elimination in 13%, 8%, and 14% of patients in the 93, 186, and 372 µg EDS-FLU compared to 4% improvement in the placebo group at the end of the double-blind portion of the study. Polyp elimination was not found to be statistically significant at the end of 16 weeks. However, in NAVIGATE II, there was polyp elimination in at least 1 nostril for 25% to 28% of patients receiving EDS-FLU at the end of the 24 weeks, as compared with 9% in the group who initially received placebo, which was statistically significant.

EXHANCE-3 and EXHANCE-12 were 2 open-label studies including patients with CRSwNP and CRSsNP which lasted for 3 and 12 months, respectively.^19,20 All patients were treated with 372 µg of EDS-FLU. The majority of enrolled patients in each study had CRSsNP. EXHANCE-3 enrolled 705 patients (102 with CRSwNP), and EXHANCE-12 enrolled 223 patients (34 with CRSwNP). The SNOT-22 scores improved by 20 points at month 1 and 24 points at month 3 in EXHANCE-3 and by 21 points at month 12 in EXHANCE-12. Patients noted “much” or “very much” improvement of 74% and 65% in the PGIC in EXHANCE-3 and EXHANCE-12, respectively.

Improvement of polyp grad by ≥1 point was also demonstrated in 63% and 83% of patients in EXHANCE-3 and EXHANCE-12.^19,20 Polyp elimination in at least 1 nostril was reported in 48% and 54% of patients in EXHANCE-3 and EXHANCE-12. In addition to examining the resolution of polyps, EXHANCE-3 found there was elimination of edema in 33% of patients with CRSwNP. Overall, Lund-Kennedy endoscopy scores improved in both studies, with limited improvement in crusting and scarring.

Additionally, EXHANCE-3 also compared a cohort of patients who had switched from using standard topical intranasal spray to EDS-FLU and found that there was no significant difference in subjective or objective improvements in the 2 cohorts.¹⁹ However, this statistical analysis was not further divided into subgroups of patients with CRSwNP and CRSsNP.

In the above 4 large trials, predefined surgical criteria were set at the beginning of the trials. The predefined surgical criteria for patients with CRSwNP included moderate to severe nasal congestion for at least 3 months, at least grade 2 nasal polyps in at least 1 nostril, and being unresponsive to appropriate doses of topical steroids and saline irrigations for 6 weeks. There was noted a decrease in patients meeting surgical criteria from 42% to 19.1% and 47% to 15% in EXHANCE-3 and EXHANCE-12, respectively.^19,20 NAVIGATE I and NAVIGATE II reported a reduction of patients meeting surgical criteria by 37% and 39%.^17,18

Recently, data from the participants of the NAVIGATE I and II trials were examined to determine the effects on quality of life and overall health impact.²¹ Quality of life was measured using the Short Form-36 Health Survey version 2 test and was calculated at the end of double-blind and open-label portions of the trials. Participants’ health status was measured using the Short-Form 6 Dimension, which measures quality of life from 0 (worst) to 1 (best). At the end of the double-blind portion of the study, there was a statistically significant improvement in quality of life scores in the EDS-FLU group as compare to the placebo group. The magnitude of improvement in the component scores ranged from 1.8 to 4 times than that of the placebo group.²¹ Overall, both the placebo and EDS-FLU groups were noted to have baseline health status scores below general population norms. The improvement in health status was significantly higher in the EDS-FLU group. While improvement in overall health status did not return to population norms at the end of the 16-week double-blind portion of the study, the improvement in the EDS-FLU group was 1.9 times the minimal clinically important difference (MCID, defined as 0.03) and 2.5 times the improvement as compared to the placebo group. Health status was measured again at 24 weeks after all groups transitioned to the 372 µg dose, and the overall health status returned to levels comparable to that of the general population.²¹

Another recently published study examined the effect of EDS-FLU in patients with prior sinus surgery and previously using standard topical steroid therapy. VISUALIZE is an open-label, 24-week study with patients receiving twice-daily 186 µg EDS-FLU.²² All 11 patients enrolled had CRSwNP, and all had previously used intranasal steroids and had ESS. There was an improvement in SNOT-22 scores by 21 points, which is consistent with results from the 4 larger trials discussed above. As well, 8 of the 11 patients reported “much” or “very much” improvement in their symptoms on the PGIC.²² There was an improvement of ≥1 polyp grade in 5 of the 11 patients, as well as a statistically significant improvement in the overall polyp grade. While there was noted to be improvement in the patient’s olfactory sense by 39.8% as measured by Sniffin’ Sticks Test, Determination, Identification (TDI) score, patients still noted continued olfactory impairment as measured by the TDI.²²

While EDS-FLU has not been directly compared to oral steroids, prior data have been reported on the effect of oral steroids on CRSwNP. Oral steroids were found to significantly decrease hyposmia, congestion, and postnasal drip up to 4 weeks after treatment with return to baseline by week 7 to 8.²³ The EDS-FLU was found to statistically improve all 4 cardinal symptoms of CRS at 4 weeks compared to placebo with continued improvement to the end of the double-blind period at week 16.^17,18 Similarly, oral steroids were found to significantly decrease the polyp burden with a maximum decrease in polyp grade of 2.5, graded 0 o 4 on each side, by week 2, with a return to baseline by week 11 to 12.²³ Navigate I had improvement in polyp grade throughout the study period and reached significance by week 12 and had continued improvement through week 16.¹⁷ Navigate II demonstrated improvement in polyp grade throughout the study and reached significant values by week 8 with continued improvement through week 16.¹⁸

Evidence for EDS-FLU in Patients With CRSsNP

The evidence of the efficacy and safety of EDS-FLU in patients with CRSsNP was examined in EXHANCE-3 and EXHANCE-12.^19,20 Patients received 372 µg twice daily. EXHANCE-3 enrolled 705 patients (603 with CRSsNP) and EXHANCE-12 enrolled 223 patients (189 with CRSsNP). Improvements in CRSsNP SNOT-22 scores were similar to the improvement in patients with CRSwNP. The SNOT-22 scores improved by 21 points at 4 weeks and 24 points at month 3 in EXHANCE-3 and by 21 points at month 12 in EXHANCE-12. Each of these improvements exceeded the MCID; 68% and 74% of CRSsNP patients in EXHANCE-3 and EXHANCE-12 patients indicated “much” or “very much” improvement in their subjective symptoms on the PGIC.^19,20 The nonpolyp domains of Lund-Kennedy scores were examined in patients with CRSsNP and were noted to have similar improvement as patients with CRSwNP. At the end of EXHANCE-3, there was complete resolution of edema in 55% of patients with CRSsNP.¹⁹

The number of CRSsNP patients who met the predefined surgical criteria was also examined. The surgical criteria for patients with CRSsNP included moderate severity of at least 2 core symptoms (congestion, nasal discharge, facial pain/pressure, hyposmia) for at least 3 months, purulent mucus or obstructive edema or mucus in the middle meatus or ethmoid region on endoscopic examination, and at least moderate symptoms despite use of standard intranasal steroids and saline for at least 6 weeks. There was a reduction in patients meeting surgical criteria from 6% to 2.2% in EXHANCE-3¹⁹ and from 6% to 3% in EXHANCE-12.²⁰

Exhalation Delivery System With Fluticasone Safety and Side Effect Profile

The side effect profile of EDS-FLU was examined in each of the 4 large studies. The majority of the described adverse events were reactions to fluticasone, which typically improved even with continued use of the medication.^17

-20 Due to the possibility of topical steroids having an impact on intraocular pressure, patients’ data from EXHANCE-3 and EXHANCE-12 were examined by a group of ophthalmologists, and ocular complications related to chronic steroid use (eg, glaucoma) were not identified in any of the patients.^19,20 Epistaxis, acute sinusitis, upper respiratory infections, headache, and septal ulceration were the most common adverse events and were classified as minor and occurred in less than 5% of participants.

Further evidence of the safety and bioavailability of EDS-FLU has recently been published. Messina et al examined the systemic uptake of EDS-FLU compared to traditional fluticasone nasal sprays and inhaled fluticasone.²⁴ The EDS-FLU was found to have higher bioavailability and systemic uptake than comparable doses of fluticasone nasal sprays. However, it was also found to have half the peak plasma concentration compared to the inhaled fluticasone.²⁴ Previous studies have found no significant effects on bone mineral density and minimal effects on the hypothalamic–pituitary–axis with inhaled fluticasone.²⁴ Given the substantial decrease in the plasma concentrations in relation to inhaled fluticasone, EDS-FLU is likely to have a comparable to improved safety profile as inhaled fluticasone, which is commonly used for lower airway inflammation.

Areas for Future Research

While the current evidence demonstrates the efficacy and safety of EDS-FLU, there are additional areas where future research is needed. To date, there has not been a direct comparison between EDS-FLU and topical nasal steroids, which remain the gold standard first-line treatment. In addition, long-term outcomes of EDS-FLU will need to be examined beyond the 12-month follow-up EXHANCE period in prior studies. While the recent VISUALIZE study examined the effect of EDS-FLU on patients who previously had ESS, further studies will need to be conducted with larger statistical power to determine how EDS-FLU is comparable to ESS in patients who have failed standard intranasal steroids or who previously had ESS. The role of EDS-FLU in postoperative inflammatory control, especially as compared to steroid irrigations, is also unknown. The effects of EDS-FLU on computed tomography findings of CRS has not yet been investigated. No data have yet been reported for the patient compliance for EDS-FLU. To date, all studies have been industry funded, and further nonindustry studies are needed.

Conclusion

In multiple studies, EDS-FLU has been found to be effective in improving patient symptoms for both CRSwNP and CRSsNP as measured by SNOT-22 and PGIC. As well, EDS-FLU has been found to improve, and potentially resolve, the objective findings of sinonasal inflammation, especially polyps and edema. The safety profile of EDS-FLU has been found similar to traditionally delivered fluticasone nasal sprays, while having less systemic uptake as compared to inhaled fluticasone. In summary, EDS-FLU provides an additional treatment modality to improve patients’ quality of life and further disease control in CRS.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.D.A. is a consultant for Optinose (Yardley, PA). E.C.K. is a consultant for Stryker (Kalamazoo, MI).

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Nithin D. Adappa

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Exhalation Delivery Systems for Application of Intranasal Corticosteroids

Abstract

Background:

Methods:

Results:

Conclusion:

Keywords

Introduction

Delivery of Topical Steroid Into the Nasal Cavity in Patients With CRS

Evidence of EDS-FLU in Patients With CRSwNP

Evidence for EDS-FLU in Patients With CRSsNP

Exhalation Delivery System With Fluticasone Safety and Side Effect Profile

Areas for Future Research

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References