Clinical and out-of-pocket cost outcomes after switching to biosimilar adalimumab-atto in patients with rheumatoid arthritis

Click here to view the Original article by Goll et al.

To better inform clinicians about the use of etanercept biosimilar (SB4) in patients with rheumatoid arthritis (RA), COMPANION-B, a prospective real-world observational study, evaluated the effectiveness of the voluntary switch from originator (etanercept, ETN) to SB4 in patients with stable RA (low-disease activity/remission). The study recruited adult patients (18years or older) with RA (2010 American College of Rheumatology criteria) prescribed ETN as their first or second biologic for at least 6months across 14 sites in Canada and five in Australia. Patients had stable disease (Disease Activity Score-28 using erythrocyte sedimentation rate [DAS28-ESR] less than 3.2) at enrollment with no evidence of flare within the previous 3months. Concomitant disease-modifying antirheumatic drugs (DMARDs) were permitted. Patients could elect to continue ETN or voluntarily switch to SB4 in consultation with their doctors. The primary effectiveness measure was the proportion of patients with disease worsening (defined as a DAS28-ESR increase of at least 1.2 from baseline and minimum score of at least 3.2 or a defined modification in RA treatment) during 12months of follow-up. The secondary effectiveness measure was the proportion of patients with disease worsening at month6. Serious adverse events (SAEs) and non-serious adverse reactions (NSARs) were recorded. Of 163 patients enrolled, 109 elected to continue on ETN and 54 switched to SB4; 65.8% of patients received non-biologic DMARD(s), 52.6% methotrexate, and 10.5% oral corticosteroid(s). At month12, the proportion of patients with disease worsening was comparable in the ETN group (22.8% [95%CI 15.0-32.2]) and SB4 group (17.6% [95%CI 8.4-30.9]). Similarly, the proportions of patients with disease worsening were also comparable at month6 (ETN: 7.9% [95%CI 3.5-15.0]; SB4: 7.8% [95%CI 2.2-18.9]). SAEs were low and similar across both groups (ETN: 8.7%; SB4: 5.7%). NSARs were slightly higher in the SB4 vs. ETN group (13.2% vs. 2.9%). SB4 demonstrated comparable effectiveness to ETN over 12months in patients with stable RA who voluntarily switched to the biosimilar in a real-world setting.

Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial

Background/ObjectiveThe effect of treatment withdrawal on patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) whose disease is in sustained remission has not been well described. This analysis aimed to compare PRO changes in patients with RA following medication withdrawal and disease worsening.MethodsSEAM-RA (Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With Rheumatoid Arthritis) was a phase 3, multicenter, randomized withdrawal, double-blind controlled study in patients with RA taking methotrexate plus etanercept and in remission (Simple Disease Activity Index ≤3.3). Patient's Global Assessment of Disease Activity, Patient's Assessment of Joint Pain, Health Assessment Questionnaire–Disability Index, and 36-Item Short-Form Health Survey were evaluated for 48 weeks following methotrexate or etanercept withdrawal. Treatment differences for patients with versus without disease worsening were evaluated using a 2-sample t test for continuous end points and log-rank test for time-to-event end points.ResultsOf 253 patients, 121 experienced disease worsening and 132 did not. All PRO scores were similar to those of a general population at baseline and deteriorated over time across the study population. The PtGA and Patient's Assessment of Joint Pain values deteriorated less in those on etanercept monotherapy compared with methotrexate monotherapy. More patients with versus without disease worsening experienced deterioration that was greater than the minimal clinically important difference (MCID) for all PROs tested. In patients with disease worsening, PtGA deterioration more than the MCID preceded Simple Disease Activity Index disease worsening.ConclusionsEtanercept monotherapy showed benefit over methotrexate in maintaining PRO scores. Patients with disease worsening experienced a more rapid worsening of PtGA beyond the MCID versus patients without disease worsening.Categories: autoinflammatory disease, biological therapy, DMARDs, rheumatoid arthritis

OP0118 EFFECT OF WITHDRAWING ETANERCEPT OR METHOTREXATE ON PATIENT-REPORTED OUTCOMES IN RHEUMATOID ARTHRITIS PATIENTS IN REMISSION ON COMBINATION THERAPY: RESULTS FROM THE SEAM-RA TRIAL

Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. ClinicalTrials.gov Identifier: NCT03074656.

Introduction: Linezolid is an oxazolidinone antibiotic that is active against drug-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis. Real-world studies on the safety of linezolid in large populations are lacking. This study aimed to determine the adverse events associated with linezolid in real-world settings by analyzing data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: We retrospectively extracted reports on adverse drug events (ADEs) from the FAERS database from the first quarter of 2004 to that of 2023. By using disproportionality analysis including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), along with the multi-item gamma Poisson shrinker (MGPS), we evaluated whether there was a significant association between linezolid and ADE. The time to onset of ADE was further analyzed in the general population and within each age, weight, reporting population, and weight subgroups. Results: A total of 11,176 reports of linezolid as the "primary suspected" drug and 263 significant adverse events of linezolid were identified, including some common adverse events such as thrombocytopenia (n = 1,139, ROR 21.98), anaemia (n = 704, ROR 7.39), and unexpected signals that were not listed on the drug label such as rhabdomyolysis (n = 90, ROR 4.33), and electrocardiogram QT prolonged (n = 73, ROR 4.07). Linezolid-induced adverse reactions involved 27 System Organ Class (SOC). Gender differences existed in ADE signals related to linezolid. The median onset time of all ADEs was 6 days, and most ADEs (n = 3,778) occurred within the first month of linezolid use but some may continue to occur even after a year of treatment (n = 46). Conclusion: This study reports the time to onset of adverse effects in detail at the levels of SOC and specific preferred term (PT). The results of our study provide valuable insights for optimizing the use of linezolid and reducing potential side effects, expected to facilitate the safe use of linezolid in clinical settings.

BackgroundThe NOR-SWITCH study was a 52-week randomized, double-blind, non-inferiority, phase IV switch trial in patients with Crohn's disease (CD), ulcerative colitis (UC), spondyloarthritis (SpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA)...

Studies have shown conflicting results when using thrombopoietin-related drugs (TPORD) for thromboembolic events (TEEs). Our study aimed to explore the correlation between TPORDs and TEEs. Drug-targeted Mendelian randomization (MR) and multivariate MR (MVMR) analysis were used to explore the causal relationship between TPORDs and TEEs such as venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) and ischemic stroke (STR). At the same time, a real-world study was conducted by extracting adverse events (AEs) from the FDA Adverse Event Reporting System database included in AERSMine to further validate our findings. In drug-target MR, TPORDs were associated with VTE (OR = 1.193, 95% confidence interval (CI): 1.001-1.423, p = 0.049], DVT (OR = 1.321, 95% CI: 1.027-1.700, p = 0.030), MI (OR = 1.216, 95% CI: 1.010-1.464, p = 0.039), STR (OR = 1.224, 95% CI: 1.021-1.468, p = 0.029). VTE/DVT/STR remained stable in MVMR (VTE: OR = 1.3, 95% CI: 1.187-1.422, p < 0.001; DVT: OR = 1.465,95% CI:1.285-1.671, p < 0.001; STR: OR = 1.119, 95% CI: 1.018-1.229, p = 0.019) and real-world studies [lower bound of proportional reporting ratio (ROR) greater than 1]. The significance of myocardial infarction disappeared in MVMR (OR = 0.996, 95% CI: 0.894-1.109, p = 0.942) and in real-world studies (lower ROR lower than 1). There was no evidence of a causal relationship between TPORD and PE (OR = 1.244, 95% CI: 0.969-1.597, p = 0.087), but it generated a signal from a real-world study (lower bound of ROR greater than 1). This study suggests that TPORDs may be associated with an increased risk of TEEs, particularly AEs leading to VTE/DVT/STR. In addition, the relationship between TPORDs and PE/MI is debatable and requires more research.

Background:Eligible subjects with moderate-to-severely active rheumatoid arthritis (RA) who completed a phase 3 double-blind comparative efficacy and safety study (Study No. YLB113-002; Yamanaka et al, 2019) of 50 mg etanercept...

ObjectiveEvaluate tolerability and effectiveness of golimumab-IV versus infliximab in patients with rheumatoid arthritis (RA) in a real-world setting.MethodsAWARE, a prospective, real-world, pragmatic, observational, multicenter, phase 4 study, enrolled RA patients when initiating golimumab-IV or infliximab. Treatment decisions were made by the treating rheumatologist. The approved doses for RA are 2 mg/kg at weeks 0, 4, then Q8W for golimumab-IV and 3 mg/kg at weeks 0, 2, 6, then Q8W (dose escalation permitted) for infliximab. A prespecified formal interim analysis was conducted. The primary endpoint was the incidence of infusion reactions (any adverse event that occurred during or within 1 h of infusion) through week 52. Major secondary endpoints were mean change from baseline in CDAI at months 6 and 12 in biologic-naïve patients (non-inferiority margin in the CDAI = 6). Baseline characteristics were adjusted using propensity scores with inverse probability of treatment weights (IPTW).ResultsIn the formal interim analysis (golimumab-IV, n = 479; infliximab, n = 354), the incidence of infusion reactions was significantly lower with golimumab-IV vs. infliximab (3.6 vs. 17.6%, p < 0.001, IPTW-adjusted). Among biologic-naïve patients, mean changes from baseline in CDAI at month 6 (– 9.5 golimumab-IV vs. − 10.1 infliximab) and at month 12 (− 9.4 golimumab-IV vs. − 10.1 infliximab) demonstrated non-inferiority.ConclusionsThe proportion of patients with an infusion reaction was significantly lower with golimumab-IV vs. infliximab. Among biologic-naïve patients, mean change from baseline in CDAI at months 6 and 12 was non-inferior for golimumab-IV vs. infliximab. Compared with fixed-dose golimumab-IV, infliximab dose escalation did not provide any greater improvements in CDAI for patients with RA.Trial RegistrationClinicalTrials.gov identifier, NCT02728934.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00354-4.

Poorer Outcomes in Real-World Studies of Anti–Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration

Confounding factors are inevitable in real-world study. In order to obtain effective research conclusions, it is essential to reasonably consider the influence of the confounding factors and eliminate the bias. The propensity score (PS) and Mendelian randomization (MR) methods are widely used to control for the confounding effects in real-world studies. PS utilizes methodologies such as matching, stratification, weighting, and regression adjustment to improve the comparability of the distributions of the potential confounders between groups, thereby weakening or balancing the influence of measurable confounding factors on effect estimation and expecting to achieve a mimic-randomization; MR relies on the natural, random assortment of genetic variants during meiosis and uses genetic variants as instrumental variables to simulate the randomization in a population, thereby controlling for the confounding effects, especially for the unknown and unmeasurable confounding factors in the effect estimation. These two methods are distinctive in research design, model assumptions, analysis procedures, and the interpretation of the estimation results, and they each have their statistical advantages and limitations in obtaining valid effect estimates. In this chapter, the authors briefly introduce the recent research progress and findings of the methodology aspects in terms of the PS and MR models in China. The main content includes formulating the theoretical background of the two methods on basic principles and model construction, methodological research progress, limitations and issues that should be aware of, and illustrating the application of the two methods in real-world study through some examples.

Biologic therapy for treatment of rheumatoid arthritis (RA) has evolved considerably over the past 20 years. Biosimilar development continues to accelerate at a frenetic pace worldwide. Initial regulatory efforts were developed within the EU and subsequent guidelines have now evolved in over 20 countries. Biosimilars by definition are highly similar, with ‘comparable quality, safety, and efficacy’ (EMA) and ‘no clinically meaningful differences in safety, purity, and potency’ (FDA) to the reference product. Development and manufacturing are based on reverse engineering of the reference product as only the primary amino acid sequence is known. Testing of primary, secondary, tertiary, and quaternary structure, binding pharmacokinetics, and stability is required. Characterization of post-translational modifications and biologic function, pharmacokinetics, evaluation of immunogenicity, and at least one comparative efficacy clinical trial are major requirements for regulatory approval. Clinical trials to assess biosimilarity are required in only one clinical indication and may be extrapolated to other indications for which the reference product is approved. Both single and multiple switching trials (between biosimilar and reference product) have yielded consistent results across numerous patient populations and diseases, with no evidence of detrimental outcomes. Two prospective large observational series (Danbio and Nor-Switch) have similarly assessed non-medical switching. Several open-label switching studies have revealed equivalent efficacy, safety, and discontinuation rates but real-world studies have raised concerns about potential nocebo responses.

A MULTICENTER REAL-WORLD COHORT TO VALIDATE THE EFFICACY AND SAFETY OF DIRECT ANTIVIRAL AGENTS FOR HEPATITIS C, AND RELATED RISK FACTORS FOR NON-SVR IN DECOMPENSATED CIRRHOSIS