Dupilumab is a fully human monoclonal antibody targeting the interleukin (IL)-4 receptor alpha, inhibiting IL-4 and IL-13 downstream signaling. Approved for multiple atopic diseases,1 dupilumab use for asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP) is of particular interest given they are common comorbid conditions. In asthma and CRSwNP clinical trials, discontinuation rates of dupilumab were low, at 2 to 12 percent.2,3 Real-world data on compliance and factors impacting compliance are limited. Compliance is an inherently difficult metric to measure; therefore, persistence is employed as a surrogate. Persistence, defined as the time from initiation to discontinuation of therapy, ceases when the patient experiences a gap in therapy. Little is known about persistent use of dupilumab when prescribed for asthma or CRSwNP. The current study seeks to evaluate the influence of type 2 (T2) comorbidities on the rates of therapy persistence in a tertiary care center. We hypothesized that the presence of T2 inflammatory comorbidities in individuals prescribed dupilumab for asthma and/or CRSwNP would increase persistence on dupilumab therapy.
Patients aged 18 and older prescribed dupilumab between July 1, 2019 and September 30, 2021 for an indication of asthma and/or CRSwNP were identified; patients were excluded if they did not fill with the institution's integrated specialty pharmacy. A retrospective cohort study was performed, and all patients had a minimum of 6 months of data. A new dupilumab prescription was defined as no prior dupilumab prescription or a 12-month or greater lapse between prescriptions.
Prescription records from the electronic health record identified new dupilumab prescriptions. Pharmacy claims identified patients who were non-persistent, defined as greater than a 60-day gap between last fill or lack of a fill based on fill quantity and days’ supply. Demographics, body mass index, prescription date, prescription diagnosis, concomitant allergic/immunologic medical therapies, and physician-diagnosed allergic/immunologic comorbidities [asthma, allergic rhinitis, CRSwNP, CRSsNP, food allergy, eosinophilic esophagitis, atopic dermatitis (AD), chronic spontaneous urticaria, and aspirin sensitivity/aspirin-exacerbated respiratory disease (AERD)] were extracted. Clinical measures included absolute eosinophil count (AEC), serum total immunoglobulin (Ig)E level, spirometry data, and Asthma Control Test (ACT) score obtained during routine care. This study was approved by the institutional review board, and all data was stored on REDCap.
Data were summarized using medians and interquartile ranges (IQR) for continuous variables and frequencies and proportions for categorical variables. Wilcoxon rank sum tests and Pearson’s chi-squared tests compared persistent vs. non-persistent patient groups for continuous variables and categorical variables, respectively. A log-rank test was used to compare the time to non-persistence between patient groups. Analyses were conducted with the R programming language, version 4.2.1.
Pharmacy records identified 99 adult patients with a new dupilumab prescription during the study period for asthma or CRSwNP. Eighty-one patients met inclusion criteria. Median age was 51 (38.0-61.0) years; 60% of patients were female; 72% were Caucasian. Thirty-eight percent were prescribed dupilumab for asthma; 35% for CRSwNP; 27% for both indications. Most patients were diagnosed with moderate-to-severe asthma (71%) by the prescriber. Persistence did not differ by age, sex, race, disease indication, or disease severity. Patients with commercial insurance were more likely to be persistent on therapy when compared to those with Medicare (p=0.010, data not shown).
Twenty patients (25%) were non-persistent during the study period; fourteen patients (17%) discontinued dupilumab. The median time to non-persistence was 66 days (24.75-95). Non-persistence was 19% at 3 months and 22% at 6 months. Patients with AERD were more likely to be persistent on dupilumab therapy (p = 0.042) than those without AERD (Figure 1). A similar trend was observed among patients with CRSwNP independent of aspirin sensitivity (p=0.06).
Figure 1. Dupilumab persistence in AERD.
Kaplan-Meier curves describe the time to non-persistence from prescription index date for those with and without AERD. A log-rank test was used to compare persistence between patients with and without AERD. Subjects were censored at the last date of follow up at which time they were reported to be continued on medication. Vertical tick marks indicate censoring. Persistence did not differ between comorbidities other than AERD, though there was a similar trend toward persistence in those with CRSwNP (p=0.06).
Baseline spirometry metrics, AEC, IgE level, ACT score, number of non-biologic therapies at the time of dupilumab prescription, or previous use of T2 biologics did not differ between groups (data not shown). Twelve patients (15%) had one allergic/immunologic comorbidity; 69 (85%) had two or more comorbidities. Individuals who persisted on dupilumab had more comorbidities than those who were non-persistent [3 (2-4) versus 2 (2-3), p=0.023].
In our cohort of patients prescribed dupilumab for asthma or CRSwNP at an academic medical center, non-persistence was infrequent and occurred early. Among patients who were non-persistent, the median time to non-persistence was less than 3 months from the index date. This rate of persistence is consistent with the 78-96% persistence report in AD.4,5
As indications for dupilumab expand, it is important to understand the impact of comorbidities on persistence with dupilumab therapy. In this cohort, it is notable that the median number of allergic/immunologic comorbidities is greater for those who were persistent on dupilumab during the study period. Dupilumab has known efficacy across multiple comorbidities, independent of the prescribed indication.6 Improvement of multiple comorbidities may promote continued use.
The proportion of patients with AERD in this cohort (27%) is higher than the reported prevalence of AERD in severe asthma (15%) and CRSwNP (9.7%).7 This reflects our study site: an academic medical center with a dedicated AERD clinic. Previous studies have demonstrated dupilumab improves clinical outcomes in patients with AERD8 within 1 month of initiation.9 Our persistence data additionally supports that patients with AERD are a good target population for dupilumab therapy.
This study does have limitations. To accurately capture persistence using pharmacy claims, our study population was restricted to individuals who filled dupilumab through our institution’s specialty pharmacy. Over 50% of our cohort with asthma were diagnosed with moderate-to-severe asthma. Severe and difficult-to-control disease may influence persistence, positively or negatively. We observed similar rates of prior T2 biologic use between the persistent and non-persistent groups suggesting refractory disease was not a major driver of non-persistence.
Dupilumab non-persistence in patients with asthma or CRSwNP is infrequent, occurs early in therapy, and is less likely to occur with a higher number of allergic/immunologic comorbidities. Among allergic/immunologic comorbidities, AERD and CRswNP, are associated with high rates of persistence. Understanding factors that promote biologic therapy persistence may help providers minimize non-persistence and the associated adverse health outcomes and cost. Further studies are needed to identify predictors of therapeutic response and to eliminate barriers to persistence.
Acknowledgements:
The authors thank and acknowledge the contribution of Leena Choi, PhD for guidance on statistical methods and for research student Madeline Wurst for data visualization assistance, and research assistant Courtney Lehman for clinical data extraction.
Funding:
K.N.C reports funding from U01 AI155299 and institutional funds.
Abbreviations:
- ACT
Asthma Control Test
- AEC
Absolute eosinophil count
- AERD
aspirin-exacerbated respiratory disease
- AD
atopic dermatitis
- CRSwNP
chronic rhinosinusitis with nasal polyposis
- Ig
Immunoglobulin
- IL
interleukin
Footnotes
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Conflict of Interest: K.B.C. and R.M. have no conflicts to report. A.Z. reports research funding support from AstraZeneca, Pfizer, Sanofi, and Beigene unrelated to the current study. M.L. reports research funding support from Sanofi and personal fees from AstraZeneca. K.N.C. reported personal fees from Novartis, GSK, AstraZeneca, Regeneron, Third Harmonic Bio, and Sanofi and research support from NovoNordisk outside the submitted work.
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