Persistence, adherence, healthcare resource utilization and costs for ocrelizumab in the real-world of the Campania Region of Italy

Aims We aim to provide real-world evidence on the use of ocrelizumab for treating multiple sclerosis (MS), with specific regard to prescription pattern, adherence, persistence, healthcare resource utilization and related costs, also in relation to other disease-modifying treatments (DMTs). Methods We included 2495 people with MS from the Campania Region (South Italy) who received first or switch DMT prescription from Jan 2018 to Dec 2020, and with at least 6-month follow-up. We collected hospital discharge records, drug prescriptions, and related costs, and calculated persistence (time from first prescription to discontinuation or switch to other DMT), adherence (proportion of days covered (PDC)), annualized hospitalization rate (AHR) for MS-related hospital admissions, and DMT costs. Results Ocrelizumab was the most commonly prescribed DMT (n = 399; age = 45.74 ± 10.98 years; females = 224), after dimethyl fumarate (n = 588) and fingolimod (n = 401); 26% patients treated with ocrelizumab were naïve. When compared with ocrelizumab, the risk of discontinuation was higher for other highly active DMTs (HR = 3.78; p = 0.01), and low/medium efficacy DMTs (HR = 7.59; p < 0.01). When compared with ocrelizumab, PDC was similar to other highly active DMTs (Coeff = 0.01; p = 0.31), but higher for low/medium efficacy DMTs (Coeff = 0.09; p < 0.01). When compared with ocrelizumab, AHR was similar to other highly active DMTs (Coeff = 0.01; p = 0.51), and low/medium efficacy DMTs (Coeff = 0.01; p = 0.55). When compared with ocrelizumab, DMT monthly costs were higher for other highly active DMTs (Coeff = 92.30; p < 0.01), but lower for low/medium efficacy DMTs (Coeff = − 1043.61; p < 0.01). Discussion Ocrelizumab was among the most frequently prescribed DMTs, with 26% prescriptions to treatment-naïve patients, suggesting its relevance in addressing unmet clinical needs (e.g., first approved treatment for primary progressive MS). Ocrelizumab was associated with the highest persistence, confirming its favorable benefit-risk profile. Costs for ocrelizumab were lower than those associated to similarly effective DMTs, in absence of changes in healthcare resource utilization.


Introduction
Ocrelizumab is approved for the use in both relapsing-remitting and primary progressive multiple sclerosis (MS) [1,2]. Ocrelizumab efficacy and safety have been preliminarily explored in clinical trials and their long-term extensions [3,4]. More recently, insights on ocrelizumab real-world use and related clinical efficacy have been gained through clinical registries [5,6]. However, clinical registries do not include healthcare resource utilization and, more in general, do not cover the complexity of MS management [7,8]. Also, few studies have directly compared different DMTs in terms of efficacy measures [9]. Datasets based on routinely collected healthcare data can overcome these limitations and provide detailed information on healthcare resource utilization in the long term and on fully representative populations [10]. In the Campania Region of Italy, we have developed an algorithm, specific for individuals with a diagnosis of MS, to merge healthcare data (e.g. planned and unplanned hospital admissions with related diagnoses and costs) and prescription data [11], and to derive measures of DMT utilization (e.g., adherence, persistence) and economic viability.
Hereby, we aim to provide real-world evidence on the use of ocrelizumab, with specific regard to prescription pattern, persistence, adherence, healthcare resource utilization and related costs, and also to compare ocrelizumab to other DMTs, based on administration (e.g., injectable, oral, and infusion) and activity (e.g., low/medium efficacy and highly active DMTs).

Study design
This is a population-based study, based on the retrospective analysis of routinely collected healthcare data, prospectively recorded from 2018 to 2020, on individuals with a diagnosis of MS living in the Campania Region of Italy. The original dataset has been fully described elsewhere [11]. For the purposes of the present study, we have selected this time frame to include ocrelizumab-treated patients, from the beginning of its use in the real-world (first prescription is recorded on Nov 6, 2018).
The study was approved by the Federico II Ethics Committee (355/19). All patients signed informed consent authorizing the use of anonymized data collected routinely as part of the clinical practice, in line with data protection regulation (GDPR EU2016/679). The study was performed in accordance with good clinical practice and Declaration of Helsinki.

Population
The dataset was created by merging different data sources of the Campania Region [11]. We specifically included all individuals resident in the Campania Region who had at least one MS record, from 2018 to 2020, in the Hospital Discharge Record database, the Regional Drug Prescription database, or the outpatient database with payment exemptions for MS. The case-finding algorithm has 99.0% sensitivity, with very low risk of missing individuals (2.7%) [11]. We have referred to both individual patients and individual treatment periods (ITPs), since the same patient could have been using different DMTs during the study period.
Inclusion criteria were: (1) new DMT prescriptions from Jan 1, 2018, to Dec 31, 2020 (switch from a previous DMT or DMT start in absence of previous treatment records, using data from 2015 to 2017 as characterization period); (2) DMT prescription maintained for at least 6 months (e.g., corresponding to two full infusions for ocrelizumab).
Exclusion criteria were: (1) individual treatment periods already including a DMT at baseline (Jan 1, 2018); (2) incomplete records; (3) lack of written consent to participate in the study; (4) residence outside of the Campania Region.
Based on DMT prescriptions in the previous 12 months, ITPs were classified into treatment naïve (no treatment records in the previous 12 months) and switcher patients (presence of previous treatment records).

Persistence, adherence, healthcare resource utilization and costs
DMT discontinuation was defined as a switch to another DMT or complete discontinuation (i.e., no further record of medication initiation) [8,13].
Adherence was calculated as the proportion of days covered (PDC) over 1-year time (total days covered during 1 year divided by 365 days of follow-up, using the expected refill/retreatment timing from current regulatory indications); PDC ≥ 0.8 was considered adherent [12]. Considering that some DMTs have low frequency administration that would have caused too much variability in estimating adherence in 6 months (e.g., alemtuzumab, cladribine, ocrelizumab), we have included in adherence analyses only patients with at least 12 months' follow-up.
Healthcare resource utilization included MS-related and non-MS-related hospital admissions, that were classified based on the main discharge diagnosis. The number of hospital admissions was then reported on annual basis (annualized hospitalization rates (AHR)) [13,15].
Direct healthcare costs were derived from regional datasets, referred to corresponding healthcare resource utilization, and inflated to the most recent values (2020), to avoid variations in price per unit of service through different years [13,15].
We further collected age, sex, and, for patients with Hospital Discharge Records, Charlson Comorbidity Index [15,16].

Statistics
Study variables are presented as mean (± standard deviation), number (percent) or median (range), as appropriate.
Differences between DMT groups (using ocrelizumab as reference in the statistical models) were explored using Cox regression models (i.e., persistence), and linear regression models (i.e., adherence, AHR, costs), as appropriate. Covariates were age, sex, year of treatment start (2018, 2019, or 2020), treatment duration, and adherence; statistical models were then run for the subgroup of patients with hospital discharge records, also including Charlson comorbidity index among covariates.
Results were reported as adjusted coefficient (Coeff), adjusted hazard ratio (HR), 95% confidence intervals (95%CI), and p values, as appropriate. Statistical analyses were performed using Stata 15.0. Results were considered statistically significant for p < 0.05.

Results
From the population of people with MS in the Campania Region from 2015 to 2020 (n = 7080), we included 2495 individuals who were commenced on a DMT from 2018 to 2020, corresponding to 2918 ITPs (the same individual being treated with different DMTs within the study period). Reasons for exclusion are reported in Fig. 1. Demographics, comorbidities and treatment features of included patients (and respective ITPs) are reported in Table 1.
Adherence to treatment is reported in Table 3. Healthcare resource utilization and costs are reported in Table 4. When compared with ocrelizumab, AHR was higher for other infusion DMTs

Discussion
In this population-based study, we specifically aimed to describe the use of ocrelizumab in the real-world of the Campania Region of Italy, with regards to prescription This is the first real-world study on ocrelizumab describing both utilization pattern (i.e., persistence, adherence), and related healthcare resource utilization and costs. When compared with other high-efficacy DMTs, ocrelizumab was used on much more complex populations (i.e., older age, higher comorbidity burden), as already described by some previous studies [17][18][19]. Notwithstanding this, in our cohort, only 1% patients were discontinued from ocrelizumab, suggesting optimal efficacy and safety [20,21], with higher persistence rates compared with other oral, infusion and injectable DMTs. This could be at least in part due to the use of ocrelizumab on newly diagnosed and treatment-naïve patients in our cohort, which is a known factor of optimal treatment response [5]. Ocrelizumab has already proved high persistence rates in previous studies [12,19,22,23], with efficacy and safety issues being the most common causes of discontinuation [19,23]. Of note, relapses, disability progression and MRI activity are expected to occur in a minority of patients treated with ocrelizumab [17,18,24]. Taken together, our data suggest that ocrelizumab high persistence rates might be a consequence of optimal efficacy and safety.
We also found high rates of adherence to ocrelizumab compared with lower and similar efficacy class. While we have to acknowledge that adherence analyses were run on the subset of patients with at least 12 months of follow-up, our rate of adherence is in line with previous similar studies [12,25], and overall suggests optimal safety profile (e.g., no need to delay infusions). Looking at previous real-world studies, side effects were reported by 10% of patients, mostly consisting of mild infusion-related reactions and infections [18], independently from age [17].
The main novelty of our study is the inclusion of healthcare resource utilization and costs. In particular, ocrelizumab was associated with lower direct treatment costs, but was associated with similar probability of MS-related hospital admissions and costs, when compared with other DMTs similar in administration route (e.g., natalizumab, alemtuzumab) and efficacy class (e.g., natalizumab, alemtuzumab, cladribine, fingolimod). Similarly, in a previous US claims' study including 189 patients treated with ocrelizumab, alemtuzumab or natalizumab for 1 year, authors showed reduced  costs for ocrelizumab treatment and related procedures [26]. Overall, these findings suggest that ocrelizumab is less expensive but similarly effective to other high-efficacy DMTs.
Limitations of our study include the generalizability of our results, since we only included patients from a specific Italian region. However, our cohort had similar distribution (e.g., age, DMT use), when compared to other international studies [17,18,27], and, hence, may reflect the general MS population treated with ocrelizumab. Also, rates of disability progression, relapses and related healthcare resource utilization are expected to increase over the follow-up [28]. Therefore, longer follow-up is warranted to confirm our findings. In addition, we have also included 2020 year in the analysis, with the bias of COVID19 pandemic that could have caused extended interval dosing for ocrelizumab [29]; however, based on adherence results, this was not the case for most infusions and the drop of new prescriptions in 2020 is in line with a previous English study [30]. Our study also holds limitations derived from the use of routinely collected healthcare data, including the definition of MS-related hospital admission based on the primary diagnosis that could be biased by the physician perspective. We compared ocrelizumab to other approved DMTs specifically approved for MS, while did not extend the analysis to other treatments (e.g., rituximab) due to sample size constraints and possible selection bias, deriving from their use in highly selected populations (e.g., non-responders to approved DMTs).
In conclusion, we confirmed previous results on high persistence and adherence rates of ocrelizumab, when compared with DMTs of similar efficacy and mode of administration. We also showed that ocrelizumab is less expensive than other high-efficacy DMTs, while possibly equally effective based on indirect measures on routinely collected healthcare data (i.e., AHR and related costs). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.