Introduction
Moderate-to-severe psoriasis generally requires lifelong treatment, and continuous therapy is needed to maintain disease control. Lack of adherence, resulting in decreased frequency of administration or interruption of therapy, is associated with the recurrence of symptoms, commonly within 2–5 months [
1‐
4]. In addition, up to 50% of patients starting tumor necrosis factor inhibitors may discontinue within 12 months [
5‐
8]. Notably, the rate of treatment discontinuation and switching for all biologics is substantially higher in patients previously treated with biologics vs. biologic-naïve subjects [
5,
7,
8], and treatment persistence appears to decline with additional prior biologic therapies [
9]. Finally, treatment failure and switching are reported to be associated with increased use of health care services [
10‐
13].
Ixekizumab, an interleukin (IL)-17A inhibitor approved for use in adult patients with moderate-to-severe psoriasis, has demonstrated long-term efficacy and safety up to 5 years [
14,
15], and has generally shown drug persistence equal to or greater than that of other biologics for psoriasis [
7,
9,
16‐
18]. Guselkumab, an IL-23p19 inhibitor also approved for psoriasis, has demonstrated efficacy and safety through 4 years [
19]. Of note, the efficacy and safety of ixekizumab and guselkumab were compared in a head-to-head trial that demonstrated a faster initial response to ixekizumab through 12–16 weeks but generally comparable levels of response at 24 weeks [
20,
21]. However, to date, long-term adherence to and persistence with ixekizumab have not been compared in clinical practice settings to any of the 3 currently approved IL-23 inhibitors, including guselkumab. Here, using real-world administrative claims data, we compared ixekizumab and guselkumab in terms of adherence to and persistence with therapy, days on monotherapy, days on concomitant therapy, and rates of discontinuation and switching.
Methods
Data Source
This analysis assessed data from the IBM Watson Health MarketScan® Commercial Encounters, Medicare Supplemental, and Monthly Early View Databases. The Commercial Encounters database contained records for inpatient, outpatient, and outpatient prescription drug claims for employees and their dependents covered under fee-for-service and managed care health plans; the Medicare Supplemental database contained similar data for retirees with employer-paid Medicare supplemental insurance. Early View included similar data to both databases for the period from May 1, 2019 to July 31, 2020. Data were identified using enrollment records, service dates, International Classification of Diseases, 9th and 10th Revision, Clinical Modification (ICD-9-CM and ICD-10-CM) diagnosis codes, Current Procedural Technology 4th edition (CPT-4®) codes, Healthcare Common Procedure Coding System (HCPCS) codes, and National Drug Codes (NDCs), as needed. As all data were anonymized, no ethics committee approval was needed for these analyses.
Patients
Eligible patients had at least 1 inpatient or 2 outpatient claims (at least 30 days apart) with a diagnosis of psoriasis (ICD-9-CM diagnosis code 696.1x or ICD-10-CM diagnosis codes L40.0–L40.4 or L40.8) between July 1, 2017 and December 31, 2018 (the indexing period). The study sample includes patients with ≥ 1 claim for ixekizumab or for guselkumab after the first psoriasis diagnosis.
The date of the first prescription for ixekizumab or guselkumab during the indexing period was the index date. Patients were required to have medical and benefit enrollment data for a minimum of 6 months pre-index and, for the primary analysis, a minimum 1-year follow-up (≥ 6-months follow-up for the secondary analysis). Patients could have no diagnosis for other conditions indicated for ixekizumab (psoriatic arthritis, ankylosing spondylitis) or guselkumab (psoriatic arthritis) or a prescription for the index drug during the pre-index period. Study follow-up was censored at the first among study end, health insurance plan enrollment end, and death. Patients were classified as receiving prior biologics if they received biologics with an indication for psoriasis in the 6-month pre-index period. For patients who received both drugs during the study period, the first drug was considered to be the only index drug, and they were then considered to have either discontinued or switched, depending upon the gap between receiving the drugs.
Treatment Patterns
Treatment pattern outcomes, including treatment persistence, discontinuation, switching, reinitiation, and adherence, were assessed during the follow-up period based on filled prescriptions. Treatment adherence based on actual use of the index medication without counting treatment gaps and treatment persistence based on a < 60-day or < 90-day allowable gap through the 1-year follow-up were analyzed. Treatment adherence was measured by proportion of days covered (PDC) and medication possession ratio (MPR) during follow-up. PDC and MPR were each defined as the number of days’ supply divided by the total number of days during the follow-up period; when the periods covered by consecutive fills overlapped, PDC counted the actual or concurrently covered days while MPR counted all days supplied. High adherence was defined as MPR or PDC ≥ 80%.
Treatment persistence was defined as a prescription refill within < 60 or < 90 days of the last day of supply [
22]. For example, for a 60-day gap (assuming no overlap with the last prescription), counting for the treatment gap for ixekizumab would start the first day after the 4-week dosing period (day 29) that started with the prescription fill. The patient would be considered nonpersistent if no refill was recorded between day 29 and day 89 (29 plus 60 days). For guselkumab, counting for the gap would start at the first day after the 8-week dosing period (day 57), and the patient would be considered nonpersistent with no refill by day 117. For a 90-day gap, these would correspond to no prescription fills between day 29 and day 119 for ixekizumab and day 57 and day 147 for guselkumab. The end date of persistence was defined as the last day’s supply of the prescription before the permissible gap. A gap of 45 days has also been considered in previous assessments of treatment persistence [
23,
24], and was assessed in this study as a sensitivity analysis.
Drug discontinuation was defined as a treatment gap of ≥ 90 days based on prior claims-based studies of biologic discontinuation [
24‐
26]. Reinitiation was defined as a new claim for the index drug after meeting the criteria for discontinuation and not switching to other therapies. Switching from the index therapy was defined as when a new medication was prescribed, and the days’ supply of the new therapy (other biologics, systemic therapy, phototherapy) extended beyond the last day supplied by the index medication. The percentages of patients who discontinued, reinitiated, or switched from the index drug were reported.
Statistical Analysis
Patient demographics included age, sex, geographic location, and primary payer and health plan type, and were assessed at the index date. The Deyo–Charlson Comorbidity Index, comorbid conditions (anxiety, cerebrovascular disease, coronary heart disease, depression, diabetes, hyperlipidemia, hypersensitivity, hypertension, lymphoma, multiple sclerosis, obesity, osteoarthritis, other autoimmune disorders, peripheral vascular disease, reactive arthritis, skin cancer, and sleep apnea), and all-cause health care costs were assessed for the 6-month pre-index period. Psoriasis-related medication and treatment usage was also reported for the pre-index period. This included the use of biologic(s) (adalimumab, brodalumab, certolizumab, etanercept, guselkumab, infliximab, ixekizumab, secukinumab, or ustekinumab) and the number of unique biologics, nonbiologic systemic (apremilast, acitretin, systemic steroids, cyclosporine, methotrexate, azathioprine, hydroxyurea, isotretinoin, leflunomide, methoxsalen, mycophenolate mofetil, sulfasalazine, or thioguanine) or topical therapy, and phototherapy. All of these factors were included as covariates in weighting/models as described below.
In order to minimize bias in the comparison between ixekizumab and guselkumab, inverse probability of treatment weighting (IPTW) was employed for the adjustment of baseline heterogeneity between treatment groups. The number of unique biologics during the pre-index period and the covariates (listed above) were included in the IPTW. The balance of cohorts was evaluated using the standardized difference, with a standardized difference of < 0.1 indicating good balance. Unless otherwise specified, weighted data were reported for outcomes.
High adherence (PDC or MPR ≥ 80%) was assessed using logistic regression to calculate odds ratios with confidence intervals and p-values. Persistence was assessed using Kaplan–Meier curves for time to nonpersistence and by Cox proportional hazards regression analysis, reported as the hazard ratio with the 95% confidence interval and the p-value. All variables included in the IPTW model were also included in the models for treatment comparisons. R 3.5.1 software (R Foundation for Statistical Computing, Vienna, Austria) and SAS EG 7.15 software (SAS Institute Inc, Cary, NC) were used for the data analysis in this study.
Discussion
Drug adherence and persistence are considered important real-world measures of treatment effectiveness, combining efficacy, safety/tolerability, and convenience [
27,
28]. Here, utilizing administrative claims databases, ixekizumab demonstrated greater adherence and similar-to-greater persistence through 1 year of follow-up when compared to guselkumab. These adherence and persistence findings were confirmed in a secondary analysis assessing patients over a variable follow-up period of ≥ 6 months and up to 30 months. Patients receiving ixekizumab had a significantly higher proportion of days covered on monotherapy, with similar rates of concomitant therapies. Switching therapies was more common among patients receiving ixekizumab vs. guselkumab, while the discontinuation rate was similar for ixekizumab and guselkumab.
Adherence to and persistence with treatment in patients with psoriasis have been suggested to correspond roughly to overall treatment success and patient satisfaction, respectively [
27,
28]. Adherence to medication assesses the proportion of the study period covered by the index drugs, irrespective of differences in dosing intervals or the specific lengths of gaps in treatment. The likelihood of high adherence, defined either as PDC or MPR ≥ 80%, was significantly greater for ixekizumab vs. guselkumab. This is consistent with the finding of a significantly greater proportion of days covered by the drug overall and as monotherapy for ixekizumab. The proportion of the study period during which patients used concomitant medications was similar for the index drugs.
Overall, patients with psoriasis in clinical practice settings who were treated with ixekizumab had significantly greater persistence with therapy vs. guselkumab when assessed using 45-day and 60-day allowable gaps, but no difference in persistence was observed between groups in the analysis when using a more generous 90-day allowable gap. Previous studies on persistence in psoriasis have used a range of allowable gaps from 45 to 150 days [
16,
23,
24], and we have previously reported results for comparisons of ixekizumab and adalimumab or secukinumab based on a 60-day gap [
17,
18]. However, a recent analysis of multiple drugs for psoriasis found that persistence estimates for ustekinumab, which has a 12-week dosing interval, varied more widely depending on the allowable treatment gap than other drugs with shorter dosing and refill intervals [
16]. Our results are consistent with this finding in that the significance of differences in persistence between ixekizumab, with typical maintenance dosing every 4 weeks, and guselkumab, with typical maintenance dosing every 8 weeks, varied depending upon the length of the allowable gap.
These data add to the body of evidence showing higher treatment adherence to and similar-to-longer treatment persistence with ixekizumab vs. other biologics from previous real-world studies using administrative claims data, where ixekizumab demonstrated better adherence vs. secukinumab [
17] and better persistence vs. adalimumab [
18] and secukinumab [
9,
17]. A longer drug survival vs. other IL-17 inhibitors and other biologics was also shown with ixekizumab using the Corrona (CorEvitas) Psoriasis Registry [
8]. Earlier registry studies performed prior to the significant use of ixekizumab have shown mean 1-year persistence rates (based on a 90-day gap) for both first- and second-line biologics of 77% in a British cohort [
11,
12], 62% overall in a study assessing the French National Health Insurance database [
29], and from 47% (adalimumab) to 79% (ustekinumab) in a Japanese claims study (based on a 60-day gap) [
30]. Results from the current study (approximately 64%) using a 90-day gap were generally comparable to or slightly lower than those in the earlier registry studies. Differences in medical coverage/usage in nationalized health systems vs. under commercial insurance in the United States (US), as well as the effect of the availability of additional biologics (which has been shown to increase rates of switching) [
31] in the present, more recent study, likely contributed to this finding. In a recent assessment of US insurance claims for a period immediately prior to that assessed in the present report, the 1-year persistence based on a 90-day gap was 59.4% and 60.5% for secukinumab and ustekinumab, respectively [
32], which is comparable to the ~ 64% seen for ixekizumab and guselkumab herein. A recent study based on patients in the large North American Corrona Psoriasis Registry compared persistence (based on a 60-day allowable gap) between ixekizumab, non-ixekizumab IL-17 inhibitors, and TNF inhibitors [
8]. For ixekizumab, persistence at 1 year was 81% in biologic-naive patients and 65% in biologic experienced patients [
8]—rates that, when combined, would be higher than that observed in the present claims-based analysis.
Strengths of the current study include the large sample size, use of multiple measures of treatment adherence, evaluation of key subgroups, and sensitivity analyses using multiple persistence windows. Common to all US claims database analyses, some key patient variables—including psoriasis severity, patient weight, and full treatment history—are not available and therefore could not be used for IPTW adjustment; however, data were adjusted by biologic experience (along with other variables) in the 6-month pre-index period. Limitations include the retrospective nature of the study and the lack of available clinical information such as reason for discontinuation, which are common to all US claims database analyses, and the 1-year follow-up period, which was due to the limited amount of longer-term data available for these 2 relatively new biologics. Adherence and persistence were based on the dispensed date of prescription; it was not known with certainty when or if the patient administered the drug. In addition, we could not address the possibility that a patient could have received a free drug sample, as our analysis was restricted to insurance claims for prescription medication. As the present analyses are based on a US claims database, these results are generalizable to a commercially insured population in the US, but not necessarily to other regions or countries. Finally, although administrative data can help assess adherence and persistence of a treatment, additional studies would be needed to help understand the factors contributing to these outcomes.
Acknowledgements
Disclosures
Andrew Blauvelt have received honoraria as a scientific adviser/clinical study investigator from AbbVie, Aligos, Almirall, Amgen, Arcutis, Arena, Athenex, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, EcoR1, Eli Lilly and Company, Evommune, Forte, Galderma, Incyte, Janssen, Leo, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma and Vibliome, but none related to this work. Russel Burge, Gaia Gallo, Bridget Charbonneau, William Malatestinic, Baojin Zhu, and Fangyu Wang were employees and held stock in Eli Lilly and Company. Benjamin Lockshin has served as a speaker and/or investigator for AbbVie, Amgen, Celgene Corporation, Eli Lilly and Company, Janssen, Galderma, Incyte, Leo, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB Pharma, but none related to this work.