- Email: [email protected]
Comparison of real-world treatment patterns among patients with psoriasis prescribed ixekizumab or secukinumab
Journal Pre-proof Comparison of Real-World Treatment Patterns among Psoriasis Patients Prescribed Ixekizumab or Secukinumab Andrew Blauvelt, MD, MBA, Nianwen Shi, PhD, Russel Burge, PhD, William N. Malatestinic, PharmD, MBA, Chen-Yen Lin, PhD, Carolyn R. Lew, PhD, Nicole M. Zimmerman, MS, Orin M. Goldblum, MD, Baojin Zhu, PhD, Mwangi J. Murage, PhD, MPH PII:
S0190-9622(19)33021-X
DOI:
https://doi.org/10.1016/j.jaad.2019.11.015
Reference:
YMJD 13997
To appear in:
Journal of the American Academy of Dermatology
Received Date: 18 June 2019 Revised Date:
5 November 2019
Accepted Date: 5 November 2019
Please cite this article as: Blauvelt A, Shi N, Burge R, Malatestinic WN, Lin C-Y, Lew CR, Zimmerman NM, Goldblum OM, Zhu B, Murage MJ, Comparison of Real-World Treatment Patterns among Psoriasis Patients Prescribed Ixekizumab or Secukinumab, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/j.jaad.2019.11.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
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Article type: Original article
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Title: Comparison of Real-World Treatment Patterns among Psoriasis Patients Prescribed
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Ixekizumab or Secukinumab
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Andrew Blauvelt, MD, MBA1, Nianwen Shi, PhD2, Russel Burge, PhD3,4, William N. Malatestinic,
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PharmD, MBA3, Chen-Yen Lin, PhD3, Carolyn R. Lew, PhD2, Nicole M. Zimmerman, MS2, Orin
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M. Goldblum, MD3, Baojin Zhu, PhD3, Mwangi J. Murage, PhD, MPH3 1
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Oregon Medical Research Center, Portland, Oregon; 2IBM Watson Health, Cambridge,
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Massachusetts; 3Eli Lilly and Company, Indianapolis, Indiana; 4University of Cincinnati,
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Cincinnati, Ohio, USA
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Corresponding author:
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Mwangi J. Murage, PhD, MPH
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Global Patient Outcomes and Real World Evidence (GPORWE)
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Eli Lilly and Company, USA
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LCT – South Building 171-2, Drop Code 5221
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1555 Harding St., Indianapolis, IN 46221
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Email: [email protected]
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Funding sources: Eli Lilly and Company.
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Conflicts of interest: Dr. Andrew Blauvelt had received honoraria as a scientific adviser/clinical
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study investigator from AbbVie, Aclaris, Akros, Allergan, Almirall, Amgen, Arena, Athenex,
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Boehringer Ingelheim, Celgene, Dermavant, Dermira, Inc., Eli Lilly and Company, Galderma,
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Genentech/Roche, GlaxoSmithKline, Janssen, Leo, Meiji, Merck Sharp & Dohme, Novartis,
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Pfizer, Purdue Pharma, Regeneron, Revance, Sandoz, Sanofi Genzyme, Sienna
2
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Pharmaceuticals, Sun Pharma, UCB Pharma, Valeant, Vidac, and as a paid speaker from
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Abbvie, Regeneron, Sanofi Genzyme, but none related to this work. Dr. Nianwen Shi, Dr.
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Carolyn R. Lew, and Nicole M. Zimmerman, are employees of IBM Watson Health that was
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compensated by Eli Lilly and Company for conducting this research. Dr. Russel Burge, Dr.
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William N. Malatestinic, Dr. Chen Yen Lin, Dr. Orin M. Goldblum, Dr. Baojin Zhu, and Dr. Mwangi
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J. Murage are employees of Eli Lilly and Company and hold stock in Eli Lilly and Company.
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Editorial support was provided by Dr. Jessamine P. Winer-Jones, Ph.D. of IBM Watson Health.
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These services were paid for by Eli Lilly and Company.
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IRB approval status: Not applicable. All study data were accessed with protocols compliant with
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US patient confidentiality requirements, including the Health Insurance Portability and
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Accountability Act of 1996 regulations (HIPAA). As all database used in the study are fully de-
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identified and compliant with the HIPPA, this study was exempted from Institutional Review
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Board approval.
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Part of the data on this manuscript has been planned to be presented as a poster at the 2019
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Annual Meeting of the American Academy of Dermatology, March 1-5, Washington, DC.
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Reprint requests: Mwangi J. Murage
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Manuscript word count: 2,499 words
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Abstract word count: 200
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Capsule summary word count: 51
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References: 31
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Figures: 3
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Tables: 2
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Key words: psoriasis, ixekizumab, secukinumab, treatment persistence, treatment adherence,
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treatment discontinuation, treatment switching
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Abstract
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Background: Real-world data on treatment patterns associated with use of IL-17A inhibitors in
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psoriasis are lacking.
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Objective: To compare treatment patterns between ixekizumab or secukinumab users in
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clinical practice.
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Methods: Psoriasis patients ≥18 years old with ixekizumab or secukinumab between March 1,
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2016, and May 31, 2018 in IBM MarketScan® databases. Inverse probability of treatment
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weighting and multivariable models were used to address cohort imbalances and estimate the
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risks of non-persistence (60-day gap), discontinuation (≥90-day gap), switching, and the odds
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of adherence.
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Results: 645 ixekizumab and 1,152 secukinumab users were followed for 13.7 and 16.3
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months, respectively. Ixekizumab users showed higher persistence rate (54.8% vs. 45.1%,
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P<0.001) and lower discontinuation rate (37.8% vs. 47.5%, P<0.001) than SEC. After
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multivariable adjustment, Ixekizumab users had lower risks of non-persistence (HR 0.82,
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95%CI 0.71-0.95) and discontinuation (HR 0.82, 95%CI 0.70-0.96), and higher odds of high
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adherence to treatment measured by medication possession ratio≥80% (HR 1.31, 95%CI 1.07-
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1.60). The risk of switching was similar between cohorts.
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Limitations: Disease severity and clinical outcomes were unavailable.
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Conclusion: Ixekizumab users demonstrated longer drug persistence, lower discontinuation
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rate and risk of discontinuation, higher likelihood of adherence, and similar risk of switching
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compared to secukinumab users in clinical practices.
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Capsule summary
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•
The article provides real-world data on ixekizumab and secukinumab use patterns in daily
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practice, and shows that ixekizumab users, when compared to secukinumab users, remain
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on drug longer.
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These data provide practicing clinicians with real-world evidence regarding drug persistence
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aiding their decision-making process when considering an IL-17A blocker for psoriasis
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patients.
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Introduction
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For moderate-to-severe psoriasis, systemic therapies are indicated, but 77%-80% of patients on
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conventional oral agents and 40-70% of patients on biologics switch therapies within 5 years
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due to lack or loss of efficacy or adverse events.1-3 Effective treatment with biologics requires
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continuous therapy; symptoms often recur within 2-4 months of discontinuation regardless of the
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original treatment response.4,5 Among biologic users, 11%-51% discontinue therapy within the
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first year, and treatment failure is associated with increased utilization of healthcare services.6-9
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Two newer biologics for psoriasis, ixekizumab (IXE) and secukinumab (SEC), are IL-17A
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inhibitors that were FDA-approved in 2016 and 2015, respectively.10,11 Both IXE and SEC have
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demonstrated clinical superiority to placebo, etanercept, and ustekinumab in the treatment of
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moderate-to-severe psoriasis.12-16 Few analyses on treatment patterns associated with these
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medications in clinical practice have been reported in psoriasis patients. Here, we performed a
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retrospective cohort study using real-world data to compare treatment adherence, persistence,
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switching, discontinuation, and reinitiation between psoriasis patients prescribed IXE or SEC.
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Methods
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Data source
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This analysis used administrative claims data from three IBM Watson Health MarketScan®
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Databases: The Commercial Claims and Encounters Database (CCAE), the Medicare
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Supplemental and Coordination of Benefits Database (MDCR), and the Early View Database
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(EV) (July 1, 2014, to May 31, 2018). CCAE contains inpatient, outpatient, and outpatient
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prescription drug claims of approximately 147.9 million employees and their dependents
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covered under fee-for-service and managed care health plans between 1995 and 2017. MDCR
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contains the same information of approximately 10.6 million retirees with Medicare
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supplemental insurance paid for by employers between 1995 and 2017. EV includes the same
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components as the CCAE and MDCR for the period of January-May 2018.
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Data were obtained using International Classification of Diseases, 9th and 10th Revision,
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Clinical Modification (ICD-9-CM and ICD-10-CM) codes, Current Procedural Terminology 4th
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edition codes, Healthcare Common Procedure Coding System codes, and National Drug
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Codes.
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Patient cohorts
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Patients with ≥1 inpatient or ≥2 outpatient claims ≥30 days apart for psoriasis (ICD-9-CM
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diagnoses: 696.1x or ICD-10-CM diagnoses: L40.0-L40.4, L40.8) between July 1, 2015, and
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May 31, 2018, were identified, excluding claims for diagnostic procedures. Patients were
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required to have ≥1 claim for IXE or SEC between March 1, 2016, and May 31, 2018, on or after
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the first psoriasis diagnosis. The first drug claim set the index date, and patients were classified
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as IXE and SEC users accordingly. Patients were ≥18 years old on the index date and had
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continuous enrollment with medical and pharmacy benefits for 12 months before (baseline
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period) and ≥6 months after the index date (follow-up period). Patients were excluded if they
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had the index drug within 90 days before the index date or other approved indications for the
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index medication during the pre-index period (ankylosing spondylitis for SEC; psoriatic arthritis
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for IXE and SEC). Patients were followed for ≥6 months until inpatient death, end of database
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enrollment, or study end (May 31, 2018), whichever came first.
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Treatment pattern characteristics
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Treatment persistence, adherence, switching, discontinuation, and re-initiation were assessed
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during the variable follow-up period. Index treatment was considered persistent if treatment
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gaps were <60 days. Persistence ended at the last days’ supply before the first 60-day gap. If a
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patient's last days’ supply occurred <60 days from the end of their follow-up period, the
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persistence end date was the last days’ supply, and no assumption about treatment was made
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beyond that date. Allowable gaps of 45, 60, and 90 days have been used in treatment
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persistence analyses for autoimmune disease biologics.17-19 In this study, 45- and 90-day gaps
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were used as sensitivity analysis. Percentages of patients who were persistent during the
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follow-up period and time on persistent treatment were reported.
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The primary measure of adherence was medication possession ratio (MPR), and the secondary
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measure was proportion of days covered (PDC). MPR and PDC were defined as the sum of
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days’ supply during the follow-up period divided by the length of the follow-up. Overlapping
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days’ supply between consecutive fills were appended for MPR and truncated for PDC. Mean
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MPR and PDC and the percentage of highly adherent patients, defined as MPR or PDC ≥80%,
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were reported.19
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Discontinuation has been used as a measure for drug survival in prior studies.20,21 In this study,
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discontinuation was defined as a gap in treatment of ≥90 days. A 90-day gap is commonly used
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in claims-based studies of biologic discontinuation.22-24 The date of the last day supply before
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the first 90-day gap was the discontinuation date. Restart was defined as having a new claim for
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the index drug after discontinuation. Percentages of patients who discontinued and restarted
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and the time from the index date to discontinuation and from discontinuation to restart were
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reported.
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Switching was defined as having a different systemic psoriasis drug as monotherapy for ≥30
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days. Eligible agents included adalimumab, brodalumab, certolizumab, etanercept, guselkumab,
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infliximab, IXE (for SEC users), SEC (for IXE users), ustekinumab, apremilast, acitretin,
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cyclosporine, and methotrexate. If the new agent had <30 days overlapping with the index drug,
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the switching date was set as the date of the first claim of the new therapy. If the overlapping
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period was ≥30 days, the switching date was the first day supply date after the overlapping
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period. For example, a patient who had drug A on days 1-60 and filled a 90-day prescription for
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drug B on day 54 would be recorded as switching to drug B on day 54. By contrast, a patient
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who had drug A on days 1-90 and filled a 90-day prescription for drug B on day 50 would be
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recorded as switching to drug B on day 91. Gaps <90 days between the days’ supply of two
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consecutive scripts were included in the determination of the length of overlapping period and
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the initiation of new monotherapy. Percentages of patients who switched, the new agents, and
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time from the index to switching were captured.
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Covariates
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Age, gender, geographic region, payer, and health plan type were measured on the index date.
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Baseline clinical characteristics included Deyo-Charlson Comorbidity Index (DCCI), comorbid
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conditions (anxiety, coronary heart disease, depression, diabetes, hyperlipidemia, hypertension,
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multiple sclerosis, obesity, osteoarthritis, other autoimmune disorders, peripheral vascular
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disease, and sleep apnea), and all-cause and psoriasis-related healthcare costs. Baseline
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psoriasis-related medication usage was reported, i.e., use of biologic (adalimumab, brodalumab,
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certolizumab, etanercept, guselkumab, infliximab, IXE, SEC, or ustekinumab) and the number of
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unique biologics, non-biologic systemic therapy (apremilast, acitretin, systemic steroids,
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cyclosporine, methotrexate, azathioprine, hydroxyurea, isotretinoin, leflunomide, methoxsalen,
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mycophenolate mofetil, sulfasalazine, or thioguanine), topical treatment, and phototherapy.
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Statistical analysis
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Bivariate analyses were conducted for all treatment pattern variables. Continuous measures
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were reported as means and standard deviations. Categorical measures were presented as
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percentages. To address cohort imbalances, inverse probability of treatment weighting (IPTW)
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was employed via a logistic regression model, using IXE vs. SEC as the dependent variable.
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Covariates included demographic and clinical variables (excepting multiple sclerosis, which
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occurred in only 0.2-0.3% of patients) listed in the covariate section and pre-index psoriasis-
10
178
related costs. Cohort balances were evaluated by standardized difference (StdDiff), and a
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StdDiff of ≤0.1 indicated good balance. For outcome variables, weighted data were reported,
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and statistical significance was assessed using Chi-square tests for categorical variables and
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two-sample t-tests for continuous variables.
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Kaplan-Meier curves estimated the probability of persistent treatment for IXE and SEC users
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using weighted data. Cox proportional hazard regression models were employed to estimate the
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risks of treatment non-persistence, discontinuation, and switching. Logistic regression was used
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to estimate the odds of being highly adherent to treatment based on MPR and PDC, adjusting
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for baseline differences. The same covariates in the IPTW model were included in all
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multivariable models with the inclusion of multiple sclerosis. All models were weighted by IPTW
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and used a robust “sandwich” covariance approach to estimate standard error.25 Results were
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reported with 95% confidence intervals (CI). A p-value of <0.05 was set a priori as the threshold
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for statistical significance. Descriptive analyses were conducted using SAS version 9.4 (SAS
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Institute Inc., Cary, NC). Weighted descriptive analyses, Kaplan-Meier curves, and multivariable
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analyses were generated with R version 3.5.1 (R Foundation for Statistical Computing, Vienna,
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Austria).
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Results
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In total, 645 and 1,152 IXE and SEC users were selected (Fig 1). Before weighting, the IXE and
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SEC cohorts had similar baseline demographic and clinical profiles (Table I). Both cohorts had a
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mean age of 49-50±12 years, and roughly half were male. Baseline DCCI and total all-cause
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and psoriasis-related healthcare costs were comparable between the cohorts. The most
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common comorbidities were hypertension (39.1%–39.8%), hyperlipidemia (29.0%–34.1%), and
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obesity (24.6%–24.8%). Prior biologic use was similar between IXE (66%) and SEC (68%)
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users. All baseline characteristics were well-balanced after weighting. IXE and SEC users had a
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mean follow-up of 13.7±5.1 and 16.1±6.3 months, respectively.
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Bivariate analysis
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A significantly higher proportion of IXE users, versus SEC users, remained persistent on
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treatment throughout the variable follow-up period (54.8% vs. 45.1%, P<0.001) using a 60-day
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gap (Table II). IXE users were also on persistent treatment for a larger proportion of the variable
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follow-up period (71.5%±34.1% vs. 64.2%±36.1%, P<0.001) than SEC users. Kaplan-Meier
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curves show that the rate of persistent treatment was consistently and significantly higher for
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IXE than SEC over the whole follow-up period (P=0.007; Fig 2). The differences in the rate of
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persistent treatment increased as follow-up time lengthened: 2% (71%/IXE and 69%/SEC) at 6
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months, 7% (57%/IXE and 50%/SEC) at 12 months, and 10% (39%/IXE and 29%/SEC) at 24
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months. This pattern was confirmed by sensitivity analyses using 45-day (P=0.029) and 90-day
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gaps (P=0.011).
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IXE users had a higher mean MPR (0.66±0.29 vs. 0.63±0.30, P=0.011) and adherence rate
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(46.4% vs. 40.2%, P=0.014) than SEC users over an average follow-up of 13.7 and 16.1
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months, respectively. Differences in mean PDC were directionally consistent with MPR but
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statistically insignificant. Like MPR, the percentage of IXE users with PDC ≥80% was higher
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than SEC users (38.3% vs. 32.4%, P=0.015).
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Compared to SEC, IXE users had a lower discontinuation rate (37.8% vs. 47.5%, P<0.001).
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Kaplan-Meier estimation showed one-year probability of survival from discontinuation was 0.63
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and 0.56 for IXE and SEC respectively (P=0.009). IXE users also had lower restart rate after
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discontinuation (5.0% vs. 10.0%, P<0.001). Among restarters, the mean time from
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discontinuation to restart was 5.3±2.8 months for IXE and 5.8±3.3 months for SEC (P=0.312).
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IXE users had a lower switching rate (19.2% vs. 24.2%, P=0.020) than SEC users. Kaplan-
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Meier estimation showed one-year probability of remaining on index drug was 0.83 and 0.80 for
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IXE and SEC respectively (P=0.190). The top agents that IXE users switched to were SEC
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(3.4%), ustekinumab (3.4%), or guselkumab (2.6%); the most common switches for SEC users
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were to IXE (8.7%), adalimumab (3.2%), or apremilast (3.1%).
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Multivariable analyses
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After adjusting for differences in baseline characteristics, IXE use was associated with an 18%
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lower risk of non-persistence than SEC (HR=0.82, 95% CI: 0.71–0.95) when using a 60-day gap
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(Fig 3). Models using 45- and 90-day gaps showed consistent findings (HR=0.85, 95% CI: 0.75–
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0.98 and HR=0.83, 95% CI: 0.71–0.97, respectively). IXE users had 31% and 32% higher odds
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of being highly adherent to index treatment as measured by MPR (OR=1.31, 95% CI: 1.07–
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1.60) and PDC (OR=1.32, 95% CI: 1.07–1.63), respectively. Compared to SEC, IXE users had
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18% lower risk of discontinuation (HR=0.82, 95% CI: 0.70–0.96). The risk of switching was
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numerically lower but not statistically significant (HR=0.88, 95% CI: 0.70–1.11).
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Discussion
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This retrospective cohort study compared real-world treatment patterns of psoriasis patients
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treated with IXE or SEC. Compared to SEC users, IXE users had better persistence and a lower
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discontinuation rate. After multivariable adjustment, IXE users demonstrated a lower risk of non-
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persistence and discontinuation and a higher likelihood of treatment adherence than SEC users.
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The risk of switching was similar between IXE and SEC users.
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Treatment persistence of older biologics, such as adalimumab, etanercept, infliximab, and
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ustekinumab, has been reported,7,21 but real-world data on IXE and SEC are limited. Recently,
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several studies reported 24%-29% discontinuation rates within first year use of SEC.26,27 In a
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Danish registry study, SEC had the shortest time to discontinuation compared to adalimumab,
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etanercept, infliximab, and ustekinumab; however, only 21.5% of SEC users were bio-naïve,
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compared with 52.7%–73.7% of patients taking other biologics.3 Prior biologic use is associated
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with decreased future biologic drug survival.9,20 New biologics like IXE and SEC are more likely
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to be used in bio-experienced patients.3 Nevertheless, it is notable that IXE users demonstrated
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a significantly higher rate of drug survival than SEC users, as measured by discontinuation,
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despite similar rates of prior biologic use. This study did not find statistically significant
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differences in the risk of switching based on 14-16 months of follow-up. Future analysis using
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more longitudinal data to explore the long-term switching outcomes along with other treatment
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pattern outcomes would be of considerable interest.
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In the 2018 Institute for Clinical and Economic Review (ICER) evidence rating, a head-to-head
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comparison between IXE and SEC placed IXE as “C+” and SEC as “C-“ based on indirect
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evidence from meta-analyses.28 While it is not possible to measure treatment response based
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on the Psoriasis Area and Severity Index (PASI) directly from claims data, drug treatment
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patterns serves as a proxy for clinical benefits, since patient satisfaction with drug effectiveness
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correlates with adherence.29 Currently, there are a lack of accurate measures of drug
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persistence for newer biologic therapies.28 This real-world study fills the gap by providing direct
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evidence of drug survival for IXE and SEC in clinical practice settings. Findings from this study
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will benefit future cost-effectiveness models for the variety of available psoriasis therapies.
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Limitations
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This analysis relied on administrative claim data and thus was subject to data coding limitations
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and data entry errors. The EV Database may miss 1%-3% of pharmacy claims due to shorter
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adjudication period; however, this impacted both cohorts equally. Treatment pattern analysis
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assumed patients took medications as prescribed. IPTW and multivariable modeling were
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employed to address observable imbalances between patient cohorts, but not all relevant
272
covariates (e.g., psoriasis severity) are captured in claims data. Pre-index biologic use and
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psoriasis-related healthcare costs were included in the models as proxy for severity, but
274
unobservable differences may remain. This study evaluated adherence using variable length
275
follow-up. While this approach has been used in prior publications,30,31 it has inherent limitations
14
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when the length of follow-up is longer for one cohort than another, as in this study. Future
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analysis using fixed-length follow-up is necessary to confirm the adherence findings. The data
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sources used are limited to patients with commercial health coverage or private Medicare
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supplemental coverage. The results may not be generalizable to the uninsured or those with
280
other types of insurance.
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Conclusions
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In real-world treatment settings, psoriasis patients prescribed either IXE or SEC had
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comparable demographic and clinical profiles at treatment initiation. IXE users demonstrated
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longer persistence and lower drug discontinuation rates than SEC users. After multivariable
285
adjustment IXE users had lower risk of non-persistence and discontinuation and higher
286
likelihood of treatment adherence than SEC users. The risk of switching was similar between
287
the cohorts. These findings may inform future treatment decisions for moderate-to-severe
288
psoriasis patients.
15
289
Abbreviations
290
CI:
confidence interval
291
HR:
hazard ratio
292
ICD-9/10-CM: International Classification of Diseases, 9th and 10th Revision, Clinical Modification
293 294
IL:
interleukin
295
IPTW:
inverse probability of treatment weighting
296
IXE:
ixekizumab
297
MPR:
medication possession ratio
298
OR:
odds ratio
299
PDC:
proportion of days covered
300
SD:
standard deviation
301
SEC:
secukinumab
302
StdDiff:
standardized difference
16
303
Acknowledgments
304
Natalie N Boytsov, Ph.D., Meghan E Jones, MSPH, and Alan J M Brnabic, MSc, of Eli Lilly and
305
Company provided critical review of the analyses. Aswin Kalyanaraman and Arun Eswaran of
306
IBM Watson Health provided programming support for this project. Jessamine Winer-Jones,
307
Ph.D. of IBM Watson Health provided editorial support. These services were paid for by Eli Lilly
308
and Company.
17
309
References
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Dermatol. 2018;138(4):775-784.
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10.
Cosentyx® (secukinumab) BLA 125504/0 approval letter. 2015;
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https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/125504Orig1s000ltr.pdf
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11.
Taltz® (ixekizumab) BLA 125521 approval letter. 2016;
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12.
Papp KA, Leonardi CL, Blauvelt A, et al. Ixekizumab treatment for psoriasis: integrated
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2, UNCOVER-3). Br J Dermatol. 2018;178(3):674-681.
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13.
Mease PJ, van der Heijde D, Ritchlin CT, et al. Ixekizumab, an interleukin-17A specific
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monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic
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arthritis: results from the 24-week randomised, double-blind, placebo-controlled and
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active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis.
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2017;76(1):79-87.
353
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of two phase 3 trials. New Engl J Med. 2014;371(4):326-338.
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Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis — results
15.
Reich K, Pinter A, Lacour JP, et al. Comparison of ixekizumab with ustekinumab in
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moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J
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Dermatol. 2017;177(4):1014-1023.
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358
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Thaçi D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing
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skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized
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controlled trial. J Am Acad Dermatol. 2015;73(3):400-409.
361
17.
rheumatoid arthritis. Am J Pharm Benefits. 2017;9(5):e1-e7.
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Bonafede M, Johnson BH, Tan DH, et al. Compliance and cost of biologic therapies for
18.
Harnett J, Gerber R, Gruben D, et al. Evaluation of real-world experience with tofacitinib
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compared with adalimumab, etanercept, and abatacept in RA patients with 1 previous
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biologic DMARD: Data from a US administrative claims database. J Manag Care Spec
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Pharm. 2016;22(12):1457-1471.
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Murage MJ, Tongbram V, Feldman SR, et al. Medication adherence and persistence in
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patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis: a systematic literature
369
review. Patient Prefer Adherence. 2018;12:1483-1503.
370
20.
Menter A, Papp K, Gooderham M, et al. Drug survival of biologic therapy in a large,
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disease‐based registry of patients with psoriasis: results from the Psoriasis Longitudinal
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Assessment and Registry (PSOLAR). J Eur Acad Dermatol Venereol. 2016;30(7):1148-
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1158.
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systematic review. J Dermatolog Treat. 2018;29(5):460-466.
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No DJ, Inkeles MS, Amin M, et al. Drug survival of biologic treatments in psoriasis: a
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Doshi JA, Takeshita J, Pinto L, et al. Biologic therapy adherence, discontinuation,
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switching, and restarting among patients with psoriasis in the US Medicare population. J
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Li P, Blum MA, Von Feldt J, et al. Adherence, discontinuation, and switching of biologic
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Johnston SS, McMorrow D, Farr AM, et al. Comparison of biologic disease-modifying
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patients switching from another biologic. Rheumatol Ther. 2014;2(1):59-71.
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(IPTW) with survival analysis. Stat Med. 2016;35(30):5642-5655.
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Georgakopoulos JR, Ighani A, Phung M, et al. Drug survival of secukinumab in real-
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van den Reek J, van Vugt LJ, van Doorn MBA, et al. Initial results of secukinumab drug
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Venereol. 2018;98(7):648-654.
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Banken R, Foluso Agboola, Ellis A, et al. Targeted immunomodulators for the treatment
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Shin S, Song H, Oh S-K, Choi KE, Kim H, Jang S. Effect of antihypertensive medication
404
adherence on hospitalization for cardiovascular disease and mortality in hypertensive
405
patients. Hypertens. Res. 2013;36(11):1000-1005.
21
406
Table I. Baseline demographic and clinical characteristics before and after weighting. Before Weighting IXE
SEC
After Weighting StdDiff*
IXE
SEC
StdDiff*
N = 645 N = 1,152 Age, mean (SD)
49.9 (12.0)
49.1 (12.3)
0.068
49.4 (12.4)
49.4 (12.2)
0.001
Male, %
54.7%
50.0%
0.095
51.5%
51.7%
0.003
Commercial, %
91.8%
92.9%
0.041
92.2%
92.5%
0.011
Insurance Plan Type, %
0.192
0.062
Comprehensive/indemnity
4.5%
5.0%
5.3%
4.9%
HMO
5.0%
7.6%
7.0%
6.7%
POS/POS with capitation
12.2%
7.9%
9.2%
9.3%
PPO
59.2%
58.9%
58.5%
59.0%
Other (CHDP, HDHP, EPO, Unknown)
19.1%
20.6%
20.1%
20.1%
Geographic Region, %
0.151
0.059
Northeast
13.6%
16.1%
15.4%
15.3%
North Central
19.5%
18.6%
19.8%
19.0%
South
57.8%
52.9%
53.7%
54.4%
West
9.0%
12.2%
11.2%
11.1%
Unknown
0.0%
0.2%
0.0%
0.0%
Length of follow-up, mean (SD) Deyo Charlson Comorbidity Index, mean (SD)
13.7 (5.1) 16.1 (6.3)
0.418 13.7 (5.1) 16.1 (6.3)
0.413
0.5 (1.2)
0.6 (1.2)
0.070
0.6 (1.4)
0.6 (1.2)
0.009
12.6%
13.5%
0.027
13.1%
13.1%
0.001
6.5%
5.6%
0.040
6.4%
6.0%
0.016
Depression
12.1%
12.5%
0.012
12.7%
12.5%
0.007
Diabetes
17.1%
18.1%
0.029
17.0%
17.6%
0.015
Hyperlipidemia
34.1%
29.0%
0.110
30.5%
30.7%
0.004
Hypertension
39.8%
39.1%
0.016
38.5%
39.0%
0.011
0.2%
0.3%
n/a
0.1%
0.4%
n/a
Comorbid conditions, % Anxiety Coronary heart disease
Multiple sclerosis
22
Obesity
24.8%
24.6%
0.006
24.8%
24.6%
0.005
Osteoarthritis
10.2%
11.0%
0.026
11.5%
10.9%
0.018
Other autoimmune disorders
5.6%
6.3%
0.032
5.9%
6.0%
0.007
Peripheral vascular disease
0.8%
2.3%
n/a
1.8%
1.7%
n/a
12.9%
11.4%
0.046
11.8%
11.8%
0.000
65.7%
68.0%
0.047
67.9%
67.4%
0.010
Number of unique biologics, mean (SD)
0.7 (0.6)
0.8 (0.6)
0.091
0.8 (0.6)
0.8 (0.6)
0.022
Any systemic agents/targeted oral therapies, %
58.6%
58.9%
0.007
58.8%
58.9%
0.000
Any topical agents, %
73.3%
76.0%
0.062
75.4%
75.2%
0.004
6.7%
6.2%
0.021
6.8%
6.4%
0.015
$3,698 ($3,648)
$3,670 ($4,164)
0.007
$3,789 ($3,838)
$3,659 ($4,174)
0.032
Psoriasis-specific healthcare cost†, mean $2,707 $2,676 0.013 $2,697 $2,697 ($2,309) ($2,486) ($2,237) ($2,663) (SD) CDHP, consumer driven health plan; EPO, exclusive provider organization; HDHP, highdeductible health plan; HMO, health maintenance organization; IXE, ixekizumab; POS, point of service; PPO, preferred provider organization; SEC, secukinumab; SD, standard deviation; StdDiff, standardized difference.
0.000
Sleep apnea Treatments Any biologics, %
Phototherapy or laser treatments, % †
All-cause healthcare cost , mean (SD)
407 408 409 410 411 412 413
*A standardized difference of less than 0.1 is considered well balanced. † Reported per-person per-month.
23
414 415
Table II. Treatment patterns for the variable length follow-up period after weighting IXE
SEC
p-value
Persistence (60-day gap) Patients who were persistent, %
54.8%
45.1%
<0.001
Months on persistent treatment, mean (SD)
9.59 (5.92)
9.74 (6.58)
0.612
Percent of persistent days during follow-up period, mean (SD)
71.5% (34.1%)
64.2% (36.1%)
<0.001
0.66 (0.29)
0.63 (0.30)
0.011
46.4%
40.2%
0.014
0.62 (0.29)
0.59 (0.28)
0.071
38.3%
32.4%
0.015
37.8%
47.5%
<0.001
5.41 (4.13)
6.75 (5.17)
<0.001
5.0%
10.0%
<0.001
5.25 (2.82)
5.80 (3.26)
19.2%
24.2%
Adherence MPR, mean (SD) MPR ≥ 80%, % PDC, mean (SD) PDC ≥ 80%, % Discontinuation and Reinitiation Patients who discontinued, % Months to discontinuation, mean (SD) Patients who reinitiated, % Months from discontinuation to reinitiation, mean (SD)
0.312
Switching Patients who switched to another psoriasis treatment, % 416 417
0.02
Months to switching, mean (SD) 7.74 (4.59) 8.97 (5.58) 0.026 IXE, ixekizumab; MPR, medication possession ratio; PDC, proportion of days covered; SEC, secukinumab, SD, standard deviation.
24
418
Figure legends
419
Fig 1. Selection of ixekizumab and secukinumab treated psoriasis (PsO) patients.
420
Fig 2. Kaplan-Meier curve for probability of persistent treatment using a 60-day treatment gap.
421
IXE, ixekizumab; SEC, secukinumab.
422
Fig 3. Multivariable adjusted analysis of treatment patterns for the variable length follow-up
423
period. Reference group = SEC. CI, confidence interval; IXE, ixekizumab; MPR, medication
424
possession ratio; PDC, proportion of days covered; PsO, psoriasis; SEC, secukinumab.
425
Figure 1.
426 427
Figure 2.
25
428
26
429
430
Figure 3.
S0190-9622(19)33021-X
DOI:
https://doi.org/10.1016/j.jaad.2019.11.015
Reference:
YMJD 13997
To appear in:
Journal of the American Academy of Dermatology
Received Date: 18 June 2019 Revised Date:
5 November 2019
Accepted Date: 5 November 2019
Please cite this article as: Blauvelt A, Shi N, Burge R, Malatestinic WN, Lin C-Y, Lew CR, Zimmerman NM, Goldblum OM, Zhu B, Murage MJ, Comparison of Real-World Treatment Patterns among Psoriasis Patients Prescribed Ixekizumab or Secukinumab, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/j.jaad.2019.11.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1
1
Article type: Original article
2
Title: Comparison of Real-World Treatment Patterns among Psoriasis Patients Prescribed
3
Ixekizumab or Secukinumab
4
Andrew Blauvelt, MD, MBA1, Nianwen Shi, PhD2, Russel Burge, PhD3,4, William N. Malatestinic,
5
PharmD, MBA3, Chen-Yen Lin, PhD3, Carolyn R. Lew, PhD2, Nicole M. Zimmerman, MS2, Orin
6
M. Goldblum, MD3, Baojin Zhu, PhD3, Mwangi J. Murage, PhD, MPH3 1
7
Oregon Medical Research Center, Portland, Oregon; 2IBM Watson Health, Cambridge,
8
Massachusetts; 3Eli Lilly and Company, Indianapolis, Indiana; 4University of Cincinnati,
9
Cincinnati, Ohio, USA
10
Corresponding author:
11
Mwangi J. Murage, PhD, MPH
12
Global Patient Outcomes and Real World Evidence (GPORWE)
13
Eli Lilly and Company, USA
14
LCT – South Building 171-2, Drop Code 5221
15
1555 Harding St., Indianapolis, IN 46221
16
Email: [email protected]
17 18
Funding sources: Eli Lilly and Company.
19 20
Conflicts of interest: Dr. Andrew Blauvelt had received honoraria as a scientific adviser/clinical
21
study investigator from AbbVie, Aclaris, Akros, Allergan, Almirall, Amgen, Arena, Athenex,
22
Boehringer Ingelheim, Celgene, Dermavant, Dermira, Inc., Eli Lilly and Company, Galderma,
23
Genentech/Roche, GlaxoSmithKline, Janssen, Leo, Meiji, Merck Sharp & Dohme, Novartis,
24
Pfizer, Purdue Pharma, Regeneron, Revance, Sandoz, Sanofi Genzyme, Sienna
2
25
Pharmaceuticals, Sun Pharma, UCB Pharma, Valeant, Vidac, and as a paid speaker from
26
Abbvie, Regeneron, Sanofi Genzyme, but none related to this work. Dr. Nianwen Shi, Dr.
27
Carolyn R. Lew, and Nicole M. Zimmerman, are employees of IBM Watson Health that was
28
compensated by Eli Lilly and Company for conducting this research. Dr. Russel Burge, Dr.
29
William N. Malatestinic, Dr. Chen Yen Lin, Dr. Orin M. Goldblum, Dr. Baojin Zhu, and Dr. Mwangi
30
J. Murage are employees of Eli Lilly and Company and hold stock in Eli Lilly and Company.
31
Editorial support was provided by Dr. Jessamine P. Winer-Jones, Ph.D. of IBM Watson Health.
32
These services were paid for by Eli Lilly and Company.
33 34
IRB approval status: Not applicable. All study data were accessed with protocols compliant with
35
US patient confidentiality requirements, including the Health Insurance Portability and
36
Accountability Act of 1996 regulations (HIPAA). As all database used in the study are fully de-
37
identified and compliant with the HIPPA, this study was exempted from Institutional Review
38
Board approval.
39 40
Part of the data on this manuscript has been planned to be presented as a poster at the 2019
41
Annual Meeting of the American Academy of Dermatology, March 1-5, Washington, DC.
42 43
Reprint requests: Mwangi J. Murage
44 45
Manuscript word count: 2,499 words
46
Abstract word count: 200
47
Capsule summary word count: 51
48
References: 31
49
Figures: 3
50
Tables: 2
3
51 52
Key words: psoriasis, ixekizumab, secukinumab, treatment persistence, treatment adherence,
53
treatment discontinuation, treatment switching
4
54
Abstract
55
Background: Real-world data on treatment patterns associated with use of IL-17A inhibitors in
56
psoriasis are lacking.
57
Objective: To compare treatment patterns between ixekizumab or secukinumab users in
58
clinical practice.
59
Methods: Psoriasis patients ≥18 years old with ixekizumab or secukinumab between March 1,
60
2016, and May 31, 2018 in IBM MarketScan® databases. Inverse probability of treatment
61
weighting and multivariable models were used to address cohort imbalances and estimate the
62
risks of non-persistence (60-day gap), discontinuation (≥90-day gap), switching, and the odds
63
of adherence.
64
Results: 645 ixekizumab and 1,152 secukinumab users were followed for 13.7 and 16.3
65
months, respectively. Ixekizumab users showed higher persistence rate (54.8% vs. 45.1%,
66
P<0.001) and lower discontinuation rate (37.8% vs. 47.5%, P<0.001) than SEC. After
67
multivariable adjustment, Ixekizumab users had lower risks of non-persistence (HR 0.82,
68
95%CI 0.71-0.95) and discontinuation (HR 0.82, 95%CI 0.70-0.96), and higher odds of high
69
adherence to treatment measured by medication possession ratio≥80% (HR 1.31, 95%CI 1.07-
70
1.60). The risk of switching was similar between cohorts.
71
Limitations: Disease severity and clinical outcomes were unavailable.
72
Conclusion: Ixekizumab users demonstrated longer drug persistence, lower discontinuation
73
rate and risk of discontinuation, higher likelihood of adherence, and similar risk of switching
74
compared to secukinumab users in clinical practices.
5
75
Capsule summary
76
•
The article provides real-world data on ixekizumab and secukinumab use patterns in daily
77
practice, and shows that ixekizumab users, when compared to secukinumab users, remain
78
on drug longer.
79
•
These data provide practicing clinicians with real-world evidence regarding drug persistence
80
aiding their decision-making process when considering an IL-17A blocker for psoriasis
81
patients.
6
82
Introduction
83
For moderate-to-severe psoriasis, systemic therapies are indicated, but 77%-80% of patients on
84
conventional oral agents and 40-70% of patients on biologics switch therapies within 5 years
85
due to lack or loss of efficacy or adverse events.1-3 Effective treatment with biologics requires
86
continuous therapy; symptoms often recur within 2-4 months of discontinuation regardless of the
87
original treatment response.4,5 Among biologic users, 11%-51% discontinue therapy within the
88
first year, and treatment failure is associated with increased utilization of healthcare services.6-9
89
Two newer biologics for psoriasis, ixekizumab (IXE) and secukinumab (SEC), are IL-17A
90
inhibitors that were FDA-approved in 2016 and 2015, respectively.10,11 Both IXE and SEC have
91
demonstrated clinical superiority to placebo, etanercept, and ustekinumab in the treatment of
92
moderate-to-severe psoriasis.12-16 Few analyses on treatment patterns associated with these
93
medications in clinical practice have been reported in psoriasis patients. Here, we performed a
94
retrospective cohort study using real-world data to compare treatment adherence, persistence,
95
switching, discontinuation, and reinitiation between psoriasis patients prescribed IXE or SEC.
96
Methods
97
Data source
98
This analysis used administrative claims data from three IBM Watson Health MarketScan®
99
Databases: The Commercial Claims and Encounters Database (CCAE), the Medicare
100
Supplemental and Coordination of Benefits Database (MDCR), and the Early View Database
101
(EV) (July 1, 2014, to May 31, 2018). CCAE contains inpatient, outpatient, and outpatient
102
prescription drug claims of approximately 147.9 million employees and their dependents
103
covered under fee-for-service and managed care health plans between 1995 and 2017. MDCR
104
contains the same information of approximately 10.6 million retirees with Medicare
7
105
supplemental insurance paid for by employers between 1995 and 2017. EV includes the same
106
components as the CCAE and MDCR for the period of January-May 2018.
107
Data were obtained using International Classification of Diseases, 9th and 10th Revision,
108
Clinical Modification (ICD-9-CM and ICD-10-CM) codes, Current Procedural Terminology 4th
109
edition codes, Healthcare Common Procedure Coding System codes, and National Drug
110
Codes.
111
Patient cohorts
112
Patients with ≥1 inpatient or ≥2 outpatient claims ≥30 days apart for psoriasis (ICD-9-CM
113
diagnoses: 696.1x or ICD-10-CM diagnoses: L40.0-L40.4, L40.8) between July 1, 2015, and
114
May 31, 2018, were identified, excluding claims for diagnostic procedures. Patients were
115
required to have ≥1 claim for IXE or SEC between March 1, 2016, and May 31, 2018, on or after
116
the first psoriasis diagnosis. The first drug claim set the index date, and patients were classified
117
as IXE and SEC users accordingly. Patients were ≥18 years old on the index date and had
118
continuous enrollment with medical and pharmacy benefits for 12 months before (baseline
119
period) and ≥6 months after the index date (follow-up period). Patients were excluded if they
120
had the index drug within 90 days before the index date or other approved indications for the
121
index medication during the pre-index period (ankylosing spondylitis for SEC; psoriatic arthritis
122
for IXE and SEC). Patients were followed for ≥6 months until inpatient death, end of database
123
enrollment, or study end (May 31, 2018), whichever came first.
124
Treatment pattern characteristics
125
Treatment persistence, adherence, switching, discontinuation, and re-initiation were assessed
126
during the variable follow-up period. Index treatment was considered persistent if treatment
127
gaps were <60 days. Persistence ended at the last days’ supply before the first 60-day gap. If a
128
patient's last days’ supply occurred <60 days from the end of their follow-up period, the
8
129
persistence end date was the last days’ supply, and no assumption about treatment was made
130
beyond that date. Allowable gaps of 45, 60, and 90 days have been used in treatment
131
persistence analyses for autoimmune disease biologics.17-19 In this study, 45- and 90-day gaps
132
were used as sensitivity analysis. Percentages of patients who were persistent during the
133
follow-up period and time on persistent treatment were reported.
134
The primary measure of adherence was medication possession ratio (MPR), and the secondary
135
measure was proportion of days covered (PDC). MPR and PDC were defined as the sum of
136
days’ supply during the follow-up period divided by the length of the follow-up. Overlapping
137
days’ supply between consecutive fills were appended for MPR and truncated for PDC. Mean
138
MPR and PDC and the percentage of highly adherent patients, defined as MPR or PDC ≥80%,
139
were reported.19
140
Discontinuation has been used as a measure for drug survival in prior studies.20,21 In this study,
141
discontinuation was defined as a gap in treatment of ≥90 days. A 90-day gap is commonly used
142
in claims-based studies of biologic discontinuation.22-24 The date of the last day supply before
143
the first 90-day gap was the discontinuation date. Restart was defined as having a new claim for
144
the index drug after discontinuation. Percentages of patients who discontinued and restarted
145
and the time from the index date to discontinuation and from discontinuation to restart were
146
reported.
147
Switching was defined as having a different systemic psoriasis drug as monotherapy for ≥30
148
days. Eligible agents included adalimumab, brodalumab, certolizumab, etanercept, guselkumab,
149
infliximab, IXE (for SEC users), SEC (for IXE users), ustekinumab, apremilast, acitretin,
150
cyclosporine, and methotrexate. If the new agent had <30 days overlapping with the index drug,
151
the switching date was set as the date of the first claim of the new therapy. If the overlapping
152
period was ≥30 days, the switching date was the first day supply date after the overlapping
153
period. For example, a patient who had drug A on days 1-60 and filled a 90-day prescription for
9
154
drug B on day 54 would be recorded as switching to drug B on day 54. By contrast, a patient
155
who had drug A on days 1-90 and filled a 90-day prescription for drug B on day 50 would be
156
recorded as switching to drug B on day 91. Gaps <90 days between the days’ supply of two
157
consecutive scripts were included in the determination of the length of overlapping period and
158
the initiation of new monotherapy. Percentages of patients who switched, the new agents, and
159
time from the index to switching were captured.
160
Covariates
161
Age, gender, geographic region, payer, and health plan type were measured on the index date.
162
Baseline clinical characteristics included Deyo-Charlson Comorbidity Index (DCCI), comorbid
163
conditions (anxiety, coronary heart disease, depression, diabetes, hyperlipidemia, hypertension,
164
multiple sclerosis, obesity, osteoarthritis, other autoimmune disorders, peripheral vascular
165
disease, and sleep apnea), and all-cause and psoriasis-related healthcare costs. Baseline
166
psoriasis-related medication usage was reported, i.e., use of biologic (adalimumab, brodalumab,
167
certolizumab, etanercept, guselkumab, infliximab, IXE, SEC, or ustekinumab) and the number of
168
unique biologics, non-biologic systemic therapy (apremilast, acitretin, systemic steroids,
169
cyclosporine, methotrexate, azathioprine, hydroxyurea, isotretinoin, leflunomide, methoxsalen,
170
mycophenolate mofetil, sulfasalazine, or thioguanine), topical treatment, and phototherapy.
171
Statistical analysis
172
Bivariate analyses were conducted for all treatment pattern variables. Continuous measures
173
were reported as means and standard deviations. Categorical measures were presented as
174
percentages. To address cohort imbalances, inverse probability of treatment weighting (IPTW)
175
was employed via a logistic regression model, using IXE vs. SEC as the dependent variable.
176
Covariates included demographic and clinical variables (excepting multiple sclerosis, which
177
occurred in only 0.2-0.3% of patients) listed in the covariate section and pre-index psoriasis-
10
178
related costs. Cohort balances were evaluated by standardized difference (StdDiff), and a
179
StdDiff of ≤0.1 indicated good balance. For outcome variables, weighted data were reported,
180
and statistical significance was assessed using Chi-square tests for categorical variables and
181
two-sample t-tests for continuous variables.
182
Kaplan-Meier curves estimated the probability of persistent treatment for IXE and SEC users
183
using weighted data. Cox proportional hazard regression models were employed to estimate the
184
risks of treatment non-persistence, discontinuation, and switching. Logistic regression was used
185
to estimate the odds of being highly adherent to treatment based on MPR and PDC, adjusting
186
for baseline differences. The same covariates in the IPTW model were included in all
187
multivariable models with the inclusion of multiple sclerosis. All models were weighted by IPTW
188
and used a robust “sandwich” covariance approach to estimate standard error.25 Results were
189
reported with 95% confidence intervals (CI). A p-value of <0.05 was set a priori as the threshold
190
for statistical significance. Descriptive analyses were conducted using SAS version 9.4 (SAS
191
Institute Inc., Cary, NC). Weighted descriptive analyses, Kaplan-Meier curves, and multivariable
192
analyses were generated with R version 3.5.1 (R Foundation for Statistical Computing, Vienna,
193
Austria).
194
Results
195
In total, 645 and 1,152 IXE and SEC users were selected (Fig 1). Before weighting, the IXE and
196
SEC cohorts had similar baseline demographic and clinical profiles (Table I). Both cohorts had a
197
mean age of 49-50±12 years, and roughly half were male. Baseline DCCI and total all-cause
198
and psoriasis-related healthcare costs were comparable between the cohorts. The most
199
common comorbidities were hypertension (39.1%–39.8%), hyperlipidemia (29.0%–34.1%), and
200
obesity (24.6%–24.8%). Prior biologic use was similar between IXE (66%) and SEC (68%)
201
users. All baseline characteristics were well-balanced after weighting. IXE and SEC users had a
202
mean follow-up of 13.7±5.1 and 16.1±6.3 months, respectively.
11
203
Bivariate analysis
204
A significantly higher proportion of IXE users, versus SEC users, remained persistent on
205
treatment throughout the variable follow-up period (54.8% vs. 45.1%, P<0.001) using a 60-day
206
gap (Table II). IXE users were also on persistent treatment for a larger proportion of the variable
207
follow-up period (71.5%±34.1% vs. 64.2%±36.1%, P<0.001) than SEC users. Kaplan-Meier
208
curves show that the rate of persistent treatment was consistently and significantly higher for
209
IXE than SEC over the whole follow-up period (P=0.007; Fig 2). The differences in the rate of
210
persistent treatment increased as follow-up time lengthened: 2% (71%/IXE and 69%/SEC) at 6
211
months, 7% (57%/IXE and 50%/SEC) at 12 months, and 10% (39%/IXE and 29%/SEC) at 24
212
months. This pattern was confirmed by sensitivity analyses using 45-day (P=0.029) and 90-day
213
gaps (P=0.011).
214
IXE users had a higher mean MPR (0.66±0.29 vs. 0.63±0.30, P=0.011) and adherence rate
215
(46.4% vs. 40.2%, P=0.014) than SEC users over an average follow-up of 13.7 and 16.1
216
months, respectively. Differences in mean PDC were directionally consistent with MPR but
217
statistically insignificant. Like MPR, the percentage of IXE users with PDC ≥80% was higher
218
than SEC users (38.3% vs. 32.4%, P=0.015).
219
Compared to SEC, IXE users had a lower discontinuation rate (37.8% vs. 47.5%, P<0.001).
220
Kaplan-Meier estimation showed one-year probability of survival from discontinuation was 0.63
221
and 0.56 for IXE and SEC respectively (P=0.009). IXE users also had lower restart rate after
222
discontinuation (5.0% vs. 10.0%, P<0.001). Among restarters, the mean time from
223
discontinuation to restart was 5.3±2.8 months for IXE and 5.8±3.3 months for SEC (P=0.312).
224
IXE users had a lower switching rate (19.2% vs. 24.2%, P=0.020) than SEC users. Kaplan-
225
Meier estimation showed one-year probability of remaining on index drug was 0.83 and 0.80 for
226
IXE and SEC respectively (P=0.190). The top agents that IXE users switched to were SEC
12
227
(3.4%), ustekinumab (3.4%), or guselkumab (2.6%); the most common switches for SEC users
228
were to IXE (8.7%), adalimumab (3.2%), or apremilast (3.1%).
229
Multivariable analyses
230
After adjusting for differences in baseline characteristics, IXE use was associated with an 18%
231
lower risk of non-persistence than SEC (HR=0.82, 95% CI: 0.71–0.95) when using a 60-day gap
232
(Fig 3). Models using 45- and 90-day gaps showed consistent findings (HR=0.85, 95% CI: 0.75–
233
0.98 and HR=0.83, 95% CI: 0.71–0.97, respectively). IXE users had 31% and 32% higher odds
234
of being highly adherent to index treatment as measured by MPR (OR=1.31, 95% CI: 1.07–
235
1.60) and PDC (OR=1.32, 95% CI: 1.07–1.63), respectively. Compared to SEC, IXE users had
236
18% lower risk of discontinuation (HR=0.82, 95% CI: 0.70–0.96). The risk of switching was
237
numerically lower but not statistically significant (HR=0.88, 95% CI: 0.70–1.11).
238
Discussion
239
This retrospective cohort study compared real-world treatment patterns of psoriasis patients
240
treated with IXE or SEC. Compared to SEC users, IXE users had better persistence and a lower
241
discontinuation rate. After multivariable adjustment, IXE users demonstrated a lower risk of non-
242
persistence and discontinuation and a higher likelihood of treatment adherence than SEC users.
243
The risk of switching was similar between IXE and SEC users.
244
Treatment persistence of older biologics, such as adalimumab, etanercept, infliximab, and
245
ustekinumab, has been reported,7,21 but real-world data on IXE and SEC are limited. Recently,
246
several studies reported 24%-29% discontinuation rates within first year use of SEC.26,27 In a
247
Danish registry study, SEC had the shortest time to discontinuation compared to adalimumab,
248
etanercept, infliximab, and ustekinumab; however, only 21.5% of SEC users were bio-naïve,
249
compared with 52.7%–73.7% of patients taking other biologics.3 Prior biologic use is associated
250
with decreased future biologic drug survival.9,20 New biologics like IXE and SEC are more likely
13
251
to be used in bio-experienced patients.3 Nevertheless, it is notable that IXE users demonstrated
252
a significantly higher rate of drug survival than SEC users, as measured by discontinuation,
253
despite similar rates of prior biologic use. This study did not find statistically significant
254
differences in the risk of switching based on 14-16 months of follow-up. Future analysis using
255
more longitudinal data to explore the long-term switching outcomes along with other treatment
256
pattern outcomes would be of considerable interest.
257
In the 2018 Institute for Clinical and Economic Review (ICER) evidence rating, a head-to-head
258
comparison between IXE and SEC placed IXE as “C+” and SEC as “C-“ based on indirect
259
evidence from meta-analyses.28 While it is not possible to measure treatment response based
260
on the Psoriasis Area and Severity Index (PASI) directly from claims data, drug treatment
261
patterns serves as a proxy for clinical benefits, since patient satisfaction with drug effectiveness
262
correlates with adherence.29 Currently, there are a lack of accurate measures of drug
263
persistence for newer biologic therapies.28 This real-world study fills the gap by providing direct
264
evidence of drug survival for IXE and SEC in clinical practice settings. Findings from this study
265
will benefit future cost-effectiveness models for the variety of available psoriasis therapies.
266
Limitations
267
This analysis relied on administrative claim data and thus was subject to data coding limitations
268
and data entry errors. The EV Database may miss 1%-3% of pharmacy claims due to shorter
269
adjudication period; however, this impacted both cohorts equally. Treatment pattern analysis
270
assumed patients took medications as prescribed. IPTW and multivariable modeling were
271
employed to address observable imbalances between patient cohorts, but not all relevant
272
covariates (e.g., psoriasis severity) are captured in claims data. Pre-index biologic use and
273
psoriasis-related healthcare costs were included in the models as proxy for severity, but
274
unobservable differences may remain. This study evaluated adherence using variable length
275
follow-up. While this approach has been used in prior publications,30,31 it has inherent limitations
14
276
when the length of follow-up is longer for one cohort than another, as in this study. Future
277
analysis using fixed-length follow-up is necessary to confirm the adherence findings. The data
278
sources used are limited to patients with commercial health coverage or private Medicare
279
supplemental coverage. The results may not be generalizable to the uninsured or those with
280
other types of insurance.
281
Conclusions
282
In real-world treatment settings, psoriasis patients prescribed either IXE or SEC had
283
comparable demographic and clinical profiles at treatment initiation. IXE users demonstrated
284
longer persistence and lower drug discontinuation rates than SEC users. After multivariable
285
adjustment IXE users had lower risk of non-persistence and discontinuation and higher
286
likelihood of treatment adherence than SEC users. The risk of switching was similar between
287
the cohorts. These findings may inform future treatment decisions for moderate-to-severe
288
psoriasis patients.
15
289
Abbreviations
290
CI:
confidence interval
291
HR:
hazard ratio
292
ICD-9/10-CM: International Classification of Diseases, 9th and 10th Revision, Clinical Modification
293 294
IL:
interleukin
295
IPTW:
inverse probability of treatment weighting
296
IXE:
ixekizumab
297
MPR:
medication possession ratio
298
OR:
odds ratio
299
PDC:
proportion of days covered
300
SD:
standard deviation
301
SEC:
secukinumab
302
StdDiff:
standardized difference
16
303
Acknowledgments
304
Natalie N Boytsov, Ph.D., Meghan E Jones, MSPH, and Alan J M Brnabic, MSc, of Eli Lilly and
305
Company provided critical review of the analyses. Aswin Kalyanaraman and Arun Eswaran of
306
IBM Watson Health provided programming support for this project. Jessamine Winer-Jones,
307
Ph.D. of IBM Watson Health provided editorial support. These services were paid for by Eli Lilly
308
and Company.
17
309
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310
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406
Table I. Baseline demographic and clinical characteristics before and after weighting. Before Weighting IXE
SEC
After Weighting StdDiff*
IXE
SEC
StdDiff*
N = 645 N = 1,152 Age, mean (SD)
49.9 (12.0)
49.1 (12.3)
0.068
49.4 (12.4)
49.4 (12.2)
0.001
Male, %
54.7%
50.0%
0.095
51.5%
51.7%
0.003
Commercial, %
91.8%
92.9%
0.041
92.2%
92.5%
0.011
Insurance Plan Type, %
0.192
0.062
Comprehensive/indemnity
4.5%
5.0%
5.3%
4.9%
HMO
5.0%
7.6%
7.0%
6.7%
POS/POS with capitation
12.2%
7.9%
9.2%
9.3%
PPO
59.2%
58.9%
58.5%
59.0%
Other (CHDP, HDHP, EPO, Unknown)
19.1%
20.6%
20.1%
20.1%
Geographic Region, %
0.151
0.059
Northeast
13.6%
16.1%
15.4%
15.3%
North Central
19.5%
18.6%
19.8%
19.0%
South
57.8%
52.9%
53.7%
54.4%
West
9.0%
12.2%
11.2%
11.1%
Unknown
0.0%
0.2%
0.0%
0.0%
Length of follow-up, mean (SD) Deyo Charlson Comorbidity Index, mean (SD)
13.7 (5.1) 16.1 (6.3)
0.418 13.7 (5.1) 16.1 (6.3)
0.413
0.5 (1.2)
0.6 (1.2)
0.070
0.6 (1.4)
0.6 (1.2)
0.009
12.6%
13.5%
0.027
13.1%
13.1%
0.001
6.5%
5.6%
0.040
6.4%
6.0%
0.016
Depression
12.1%
12.5%
0.012
12.7%
12.5%
0.007
Diabetes
17.1%
18.1%
0.029
17.0%
17.6%
0.015
Hyperlipidemia
34.1%
29.0%
0.110
30.5%
30.7%
0.004
Hypertension
39.8%
39.1%
0.016
38.5%
39.0%
0.011
0.2%
0.3%
n/a
0.1%
0.4%
n/a
Comorbid conditions, % Anxiety Coronary heart disease
Multiple sclerosis
22
Obesity
24.8%
24.6%
0.006
24.8%
24.6%
0.005
Osteoarthritis
10.2%
11.0%
0.026
11.5%
10.9%
0.018
Other autoimmune disorders
5.6%
6.3%
0.032
5.9%
6.0%
0.007
Peripheral vascular disease
0.8%
2.3%
n/a
1.8%
1.7%
n/a
12.9%
11.4%
0.046
11.8%
11.8%
0.000
65.7%
68.0%
0.047
67.9%
67.4%
0.010
Number of unique biologics, mean (SD)
0.7 (0.6)
0.8 (0.6)
0.091
0.8 (0.6)
0.8 (0.6)
0.022
Any systemic agents/targeted oral therapies, %
58.6%
58.9%
0.007
58.8%
58.9%
0.000
Any topical agents, %
73.3%
76.0%
0.062
75.4%
75.2%
0.004
6.7%
6.2%
0.021
6.8%
6.4%
0.015
$3,698 ($3,648)
$3,670 ($4,164)
0.007
$3,789 ($3,838)
$3,659 ($4,174)
0.032
Psoriasis-specific healthcare cost†, mean $2,707 $2,676 0.013 $2,697 $2,697 ($2,309) ($2,486) ($2,237) ($2,663) (SD) CDHP, consumer driven health plan; EPO, exclusive provider organization; HDHP, highdeductible health plan; HMO, health maintenance organization; IXE, ixekizumab; POS, point of service; PPO, preferred provider organization; SEC, secukinumab; SD, standard deviation; StdDiff, standardized difference.
0.000
Sleep apnea Treatments Any biologics, %
Phototherapy or laser treatments, % †
All-cause healthcare cost , mean (SD)
407 408 409 410 411 412 413
*A standardized difference of less than 0.1 is considered well balanced. † Reported per-person per-month.
23
414 415
Table II. Treatment patterns for the variable length follow-up period after weighting IXE
SEC
p-value
Persistence (60-day gap) Patients who were persistent, %
54.8%
45.1%
<0.001
Months on persistent treatment, mean (SD)
9.59 (5.92)
9.74 (6.58)
0.612
Percent of persistent days during follow-up period, mean (SD)
71.5% (34.1%)
64.2% (36.1%)
<0.001
0.66 (0.29)
0.63 (0.30)
0.011
46.4%
40.2%
0.014
0.62 (0.29)
0.59 (0.28)
0.071
38.3%
32.4%
0.015
37.8%
47.5%
<0.001
5.41 (4.13)
6.75 (5.17)
<0.001
5.0%
10.0%
<0.001
5.25 (2.82)
5.80 (3.26)
19.2%
24.2%
Adherence MPR, mean (SD) MPR ≥ 80%, % PDC, mean (SD) PDC ≥ 80%, % Discontinuation and Reinitiation Patients who discontinued, % Months to discontinuation, mean (SD) Patients who reinitiated, % Months from discontinuation to reinitiation, mean (SD)
0.312
Switching Patients who switched to another psoriasis treatment, % 416 417
0.02
Months to switching, mean (SD) 7.74 (4.59) 8.97 (5.58) 0.026 IXE, ixekizumab; MPR, medication possession ratio; PDC, proportion of days covered; SEC, secukinumab, SD, standard deviation.
24
418
Figure legends
419
Fig 1. Selection of ixekizumab and secukinumab treated psoriasis (PsO) patients.
420
Fig 2. Kaplan-Meier curve for probability of persistent treatment using a 60-day treatment gap.
421
IXE, ixekizumab; SEC, secukinumab.
422
Fig 3. Multivariable adjusted analysis of treatment patterns for the variable length follow-up
423
period. Reference group = SEC. CI, confidence interval; IXE, ixekizumab; MPR, medication
424
possession ratio; PDC, proportion of days covered; PsO, psoriasis; SEC, secukinumab.
425
Figure 1.
426 427
Figure 2.
25
428
26
429
430
Figure 3.