Authors Cheng WY, Sarda SP, Mody-Patel N, Krishnan S, Yenikomshian M, Kunzweiler C, Vu JD, Cheung HC , Duh MS
Received 6 November 2021
Accepted for publication 12 April 2022
Published 3 May 2022 Volume 2022:14 Pages 357—369
DOI https://doi.org/10.2147/CEOR.S346816
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Dean SmithDownload Article [PDF]
Wendy Y Cheng,1 Sujata P Sarda,2 Nikita Mody-Patel,2 Sangeeta Krishnan,2 Mihran Yenikomshian,1 Colin Kunzweiler,1 Jensen Duy Vu,1 Hoi Ching Cheung,1 Mei Sheng Duh1
1Analysis Group, Inc., Boston, MA, USA; 2Apellis Pharmaceuticals, Inc., Waltham, MA, USA
Correspondence: Wendy Y Cheng, Analysis Group, Inc., 111 Huntington Ave, 14th Floor, Boston, MA, 02199, USA, Tel +1 617 425 8219, Fax +1 617 425 8000, Email Wendy.Cheng@analysisgroup.com
Purpose: Current pharmacologic management of paroxysmal nocturnal hemoglobinuria (PNH) consists of C5 inhibitors, eculizumab and ravulizumab; however, because patients experience incomplete symptom control, off-label doses may be utilized. We conducted a retrospective, longitudinal cohort study of provider-based claims data to assess the real-world eculizumab dosing patterns in PNH patients.
Patients and Methods: Patients were ≥ 12 years, received ≥ 2 eculizumab infusions between January 1, 2015 and September 30, 2019, and had ≥ 3 months of continuous clinical activity prior to index. The index date was the first claim for eculizumab. Patients with ≥ 1 diagnosis of another indication for eculizumab were excluded. Treatment patterns including the proportion with high, label-recommended, and low dosages during induction (first 28 days) and maintenance (beginning day 29) phases were described. The proportion and time-to-first dose escalation, defined as an increase in dose or frequency of infusion, were assessed among a subset of patients (ie, escalation analysis cohort).
Results: A total of 707 patients were examined. Mean (standard deviation [SD]) starting dose was 862mg (412mg) and was higher than label-recommended 600mg for 64% of the patients. Mean (SD) dose per infusion was 859mg (391mg) during the induction phase; average dose was higher than label-recommended 600mg for 68%. Mean (SD) dose per infusion during the maintenance phase was 1005mg (335mg); average dose was higher than label-recommended 900mg for 43%. Dose escalation occurred in 40/121 escalation analysis cohort patients. Median time-to-first dose escalation was ∼ 12 months.
Conclusion: Results suggest that deviations from label-recommended dosing patterns were common. Future budget impact assessments of eculizumab should account for real-world dosing patterns to comprehensively assess costs and benefits.
Keywords: complement inhibitors, dose escalation, dosing patterns, eculizumab, paroxysmal nocturnal hemoglobinuria
Introduction
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, chronic, rare, and potentially life-threatening disorder that results from the destruction of blood cells by the complement system due to the absence of complement inhibiting proteins on the cell’s surface.1 In the United States (US), the prevalence of PNH has been estimated to be 12–13 cases per 1,000,000 individuals.2 Although PNH is an acquired disease that can affect any age group, patients are commonly diagnosed in their early 30s.3 Clinical manifestations of PNH include hemolytic anemia, thrombosis, bone marrow failure, abdominal pain, and hemoglobinuria.4
Currently, the C5 inhibitors eculizumab and ravulizumab, both humanized monoclonal antibodies that interfere with C5 thus blocking complement-activated hemolysis, have received approval by the US Food and Drug Administration (FDA) to treat PNH.4,5 Due to the limited real-world data currently available for ravulizumab (approval was in December 2018), our analysis sought to evaluate eculizumab, the first-to-market treatment for PNH, given its broader long term use among patients with PNH. Available as an intravenous infusion, eculizumab is administered in two phases: an induction phase (standard dosage: 600 mg/week for the first 4 weeks) and a maintenance phase (900 mg for the fifth dose 1 week later, and 900 mg every 2 weeks thereafter).5 The standard two-phase dosing regimen is aimed to maintain eculizumab serum concentration >35 μg/mL, which has been shown in clinical trials to be sufficient to ensure complete and consistent blockade of complement-mediated intravascular hemolysis in most patients with PNH.6 Yet despite significant reductions in complement-mediated hemolysis and associated symptoms observed in clinical trials,7–12 many patients do not experience sustained symptom control with the label-recommended eculizumab dosage.7,13–15
To address PNH symptoms related to breakthrough hemolysis (BTH) and reestablish complete complement blockade, clinicians may modify the dosing schedule of eculizumab via an increase in dosage, frequency of infusions, or both (referred to as “dose escalation” in the present study).16–20 For example, in an analysis of 195 clinical trial patients receiving eculizumab, 21 (10.8%) patients had a median of 22 reductions (range: 3–124) in dose interval (ie, reducing time between infusions to <14 days) following inadequate symptom control.11 Additionally, in response to BTH among a small number of clinical trial patients, clinicians examined alternative eculizumab dosing schedules, including modifications to frequency (ie, reducing the number of days between infusions) and dosage (ie, increasing dosage per infusion to 1200 mg) during the induction and maintenance phases.14 Other events that may prompt clinicians to escalate the dose of eculizumab include variations in patient’s body weight,21 transfusion dependence,12 breakthrough thrombosis,22 and recurrence of PNH symptoms prior to the administration of the new dose.20 However, there is limited evidence regarding eculizumab dosing patterns, particularly dose escalation, in the real-world settings. A retrospective, single-center study of 30 patients with PNH who were treated with eculizumab found that 2 (6.7%) of 30 patients required repeated dose escalations in order to adequately manage symptoms related to intravascular hemolysis.13 Despite dose escalation to 1200 mg every 12 days, followed by 1500 mg every 12–14 days, both patients reported a return of BTH symptoms by day 10 or 11 of the dosing schedule.13 As these studies demonstrate that dose escalation occurs for patients with PNH, additional doses may result in increased costs, which can be better understood by examining real-world dosing patterns.
Given the lack of information on the treatment for PNH with eculizumab in the real world, a comprehensive assessment of the dosing patterns of eculizumab in a large, nationally representative real-world patient population is needed to understand the clinical unmet needs among patients with PNH. The present study evaluated dosing patterns among patients with PNH who were treated with eculizumab using a health insurance claims database in the US.
Materials and Methods
Data Source
This study used data from Symphony Health IDV® (Integrated Dataverse; October 1, 2014 to September 30, 2019). Symphony Health IDV is a large nationally representative claims database covering approximately 280 million US beneficiaries each year and represents over 73% of specialty prescriptions, 58% of medical claims, and 30% of hospital claims volume in the US. Symphony Health IDV aggregates data from physician practices, outpatient (OP) and specialty pharmacies, and hospitals to provide a longitudinal view of patient treatment patterns across all payer types. Thus, the Symphony database provides relevant information about IV medications ordered which were of particular interest to this study. All data contained in the database are de-identified and compliant with the patient confidentiality requirements of the Health Insurance Portability and Accountability Act. Institutional review board approval was not required for this study.
Study Design
This retrospective, longitudinal, cohort study was conducted using data from medical and pharmacy claims. The date of the first eculizumab infusion occurring on or after January 1, 2015, was used to define the index date. Patients had ≥3 months of continuous clinical activity prior to the index date, which was used to define the baseline period. The observation period for each patient spanned from the index date to the end of continuous clinical activity or end of data availability, whichever occurred first.
Eculizumab dosing patterns were examined during each patient’s treatment period, which was defined as the period from the index date to the date of the last infusion of eculizumab prior to treatment discontinuation, end of continuous clinical activity, or end of data availability, whichever was earlier. The induction phase was the first 28 days following the index date, which corresponds with weekly infusions for the first 4 weeks per the approved labeling. The maintenance phase started on day 29 after the index date. Similar to a previous real-world study of insurance claims data, treatment discontinuation was defined as a gap of >42 days between eculizumab infusions (which reflects a 14-day exposure period plus 28-day grace period between infusions, and is equivalent to missing two infusions based on the biweekly schedule of eculizumab), or between the last infusion and the end of the observation period.2
Sample Selection
To be included in this study, patients were required to meet the following criteria: have ≥2 or more medical claims for infusion of eculizumab (identified using Healthcare Common Procedure Coding System [HCPCS] code J1300) between January 1, 2015 and September 30, 2019; have data available for a minimum of 3 months of continuous clinical activity prior to the index date (ie, baseline period); and be ≥12 years of age on the index date. Patients were excluded if they had (a) ≥1 medical claim for infusion of eculizumab prior to January 1, 2015 or (b) ≥1 diagnosis of another indication for eculizumab during the baseline period or on the index date as identified based on diagnosis codes from the International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification (ICD-9/10-CM) that included atypical hemolytic uremic syndrome (ICD-9-CM: 283.11; ICD-10-CM: D59.3), generalized myasthenia gravis (ICD-9-CM: 358.0; ICD-10-CM: G70.0x), and/or neuromyelitis optica spectrum disorder (ICD-9-CM: 341.0; ICD-10-CM: G36.0). This constituted the overall cohort. Because the ICD-9 diagnosis code for PNH is an imprecise, broad code that encompasses other related diagnoses, this inclusion by exclusion principle as shown in exclusion criterion (b), in which patients were excluded if they had ≥1 diagnosis of another indication of eculizumab, rather than a conventional approach of including patients with ≥1 diagnosis of PNH, helps to improve specificity of the treated population and ensure that eculizumab was given for the indication of PNH. Patients who received ravulizumab were not assessed in this study given that the current data were available through September 2019 and the HCPCS J-code was not effective until October 2019.
Per FDA prescribing information, patients with PNH initiating treatment with eculizumab, a C5 inhibitor, receive four weekly infusions during the induction phase. Dose escalation was assessed during the maintenance phase and was restricted to a subset of patients from the overall cohort (referred to as the “escalation analysis cohort”) with a label-recommended induction phase (ie, received exactly four infusions of 600 mg eculizumab, each 7 days ± 2 days apart) and ≥1 infusion of eculizumab during the maintenance phase.
Baseline Characteristics
Patient demographics assessed at index date included age, sex, year of first eculizumab infusion, geographic region of residence, and insurance plan type. Clinical characteristics assessed during the 3-month baseline period prior to the index date included the Quan-Charlson Comorbidity Index (Quan-CCI),23 Elixhauser comorbidities (Supplemental Table 1),23 PNH-related comorbidities (ie, aplastic anemia and myelodysplastic syndrome), PNH-related symptoms (ie, anemia other than aplastic anemia, viral and bacterial infections, chronic kidney disease, fatigue, abdominal pain, dyspnea, thrombosis, pulmonary hypertension, dysphagia, and erectile dysfunction), use of PNH-related treatments (ie, corticosteroid therapy, blood transfusions, anticoagulants, immunosuppressants, iron therapy, iron-chelation therapy, and androgen therapy), as well as all-cause and PNH-related healthcare resource utilization (HRU). Specific diagnosis codes, drug codes, and procedure codes used to identify these characteristics are provided in the online electronic Supplemental Tables 2–10.
Study Outcomes
Dosing Patterns
All eculizumab infusions received during the first 4 days beginning on the index date were summed and considered the starting dose. The number and proportion of patients with a high (>600 mg), label-recommended (600 mg), or low (<600 mg) starting dose were assessed. The number of infusions received, average number of days between infusions by patient, average dose per infusion by patient, and the number and proportion of patients with a high (>600 mg during the induction phase, >900 mg during the maintenance phase), label-recommended (600 mg during the induction phase, 900 mg during the maintenance phase), or low (<600 mg during the induction phase, <900 mg during the maintenance phase) average dose per infusion were assessed during the induction phase and maintenance phase.
Dose Escalation
For patients in the escalation analysis cohort, additional outcomes that were assessed included the proportions of patients with ≥1 and ≥2 episodes of dose escalation, time-to-first dose escalation, and probability of dose escalation by the end of 3, 6, 9, and 12 months following the index date. Dose escalation during the maintenance phase was defined as either an increase in dose (ie, receiving >900 mg on a single infusion day) or an increase in frequency of infusion (ie, receiving >900 mg of eculizumab within 12 days); consecutive escalated doses were considered part of the same dose escalation episode. Given that the FDA prescribing information allows for the administration of eculizumab within 2 days of the recommended dosage regimen time points,5 infusions administered 12–16 days apart during the maintenance phase were considered to be consistent with the label recommendation.
Statistical Analyses
Descriptive summary statistics (eg, mean, median, standard deviation [SD], interquartile range [IQR]) were generated for baseline characteristics, eculizumab dosing patterns, and dose escalation outcomes, as applicable. For patients in the escalation analysis cohort, the time-to-first dose escalation was evaluated using Kaplan–Meier methodology, which censored patients at the end of continuous eculizumab treatment, continuous clinical activity, or end of data availability. All analyses were conducted using SAS Enterprise Guide v7.1 (Cary, NC).