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ABP 959 is a biosimilar to the eculizumab reference product (RP), which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This multicenter, randomized, double-blind, active-controlled, two-period crossover study randomized eculizumab RP-treated patients with PNH to one of two treatment sequences (ABP 959/eculizumab RP or eculizumab RP/ABP 959) to evaluate the clinical similarity of ABP 959 when compared with eculizumab RP. This study evaluated the efficacy of ABP 959 when compared with eculizumab RP based on control of intravascular hemolysis as measured by lactate dehydrogenase (LDH) and by the time-adjusted area under the effect curve of LDH. Secondary outcomes included safety, pharmacokinetics, and immunogenicity. Forty-two patients were randomized (20 in the ABP 959/eculizumab RP group and 22 in the eculizumab RP/ABP 959 group) across 25 centers. Similarity of efficacy was established by a ratio of geometric least squares means of LDH (ABP 959/eculizumab RP) of 1.0628, with a one-sided 97.5% upper CI of 1.1576 at week 27, and a geometric means ratio of time-adjusted area under the effect curve (ABP 959 vs. eculizumab RP) of LDH of 0.981, with a 90% CI of 0.9403-1.0239 from week 13 to 27, week 39 to 53, and week 65 to 79. All secondary efficacy endpoints were comparable between treatment groups. No new safety concerns were identified. The results of this study in patients with PNH, along with previously demonstrated similarity of analytical, nonclinical, and clinical pharmacokinetics and pharmacodynamics in healthy volunteers support a demonstration of no clinically meaningful differences between ABP 959 and eculizumab RP. Clinical Trial Registration: NCT03818607., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Rituximab is a monoclonal antibody that targets CD20 antigen in B cells. For pemphigus, rituximab has been highly effective in steroid-sparing therapy for moderate to severe cases. Originator rituximab has demonstrated favorable treatment effects in patients with pemphigus, but its high cost remains a challenge. Biosimilar rituximab is expected to offer a potential solution. However, it is required for the comparative study of efficacy and safety between biosimilar and originator because all biosimilars may not be identical to the originator. In this study, we compared the treatment effects and safety of biosimilar (Truxima) and originator (MabThera) rituximab in patients with pemphigus. A final cohort of 52 patients in the MabThera group and 72 patients in the Truxima group was enrolled. Except for the intravenous immunoglobulin administration rate, there were no differences in baseline characteristics between the two groups, and for the purpose of comparing efficacy, investigations into time to complete remission, total steroid intake to complete remission, and total steroid intake for 6 months following rituximab treatment revealed no significant differences between the two groups. Truxima can be considered a relatively affordable alternative treatment option for pemphigus, offering cost-effectiveness to patients who are indicated for the treatment with MabThera., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Aim: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus., Methods: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins., Results: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups., Conclusions: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study., (© 2024 John Wiley & Sons Ltd.)

Background: Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed., Aim: To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease., Methods: We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks., Results: We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036)., Conclusions: First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease., Trial Registration Number: NCT02517684., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: The long-term risk of relapse after switching from intravenous (IV) to subcutaneous (SC) infliximab remains unknown in inflammatory bowel disease (IBD)., Aims: To assess the long-term effectiveness and acceptability of switching from IV to SC infliximab in patients with IBD treated with or without an intensified IV regimen., Methods: We extended the follow-up of the REMSWITCH study including patients with IBD in clinical remission who were switched from IV to SC infliximab (120 mg/2 weeks). Relapse was defined as clinical relapse or faecal calprotectin increase ≥150 μg/g compared to baseline., Results: After median follow-up of 18 [15-20] months, among 128 patients, rates of relapse were 13.8% (8/58), 18.4% (7/38), 35.3% (6/17) and 86.7% (13/15) at last follow-up (p < 0.001), in those receiving 5 mg/kg/8 weeks, 10 mg/kg/8 weeks, 10 mg/kg/6 weeks and 10 mg/kg/4 weeks at baseline, respectively. Among relapsing patients, dose escalation led to clinical remission in 82.1% (23/28). In multivariable analyses, factors associated with higher risk of relapse were IV infliximab 10 mg/kg/4 weeks (OR = 61.0 [6.1-607.0], p < 0.001) or 10 mg/kg/6 weeks (OR = 4.7 [1.1-20.2], p = 0.017), and decreased (OR = 5.6 [1.5-20.3], p = 0.004) or stable (OR = 5.0 [1.6-15.0], p = 0.009) serum levels of infliximab between baseline and first post-switch visit. Acceptability was improved at 6 months and did not decrease over time (6.9 ± 1.6 before the switch vs. 8.8 ± 1.3 at 6 months and 8.8 ± 1.3 at last follow-up; p < 0.001). No severe adverse events were reported., Conclusions: Switching from IV to SC infliximab 120 mg every other week is safe and well accepted leading to low long-term risk of relapse. Tight monitoring and dose escalation should be recommended for patients receiving 10 mg/kg/6 weeks and 4 weeks, respectively., (© 2023 John Wiley & Sons Ltd.)

Aim: For the successful approval and clinical prescription of insulin biosimilars, it is essential to show pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence to the respective reference products sourced from the European Union and the United States., Methods: Three phase 1, randomized, double-blind, three-period crossover trials compared single doses of the proposed biosimilar insulin analogues aspart (GL-Asp, n = 36), lispro (GL-Lis, n = 38) and glargine (GL-Gla, n = 113), all manufactured by Gan & Lee pharmaceuticals, to the respective EU- and US-reference products in healthy male participants (GL-Asp and GL-Lis) or people with type 1 diabetes (GL-Gla). Study participants received 0.2 U/kg (aspart and lispro) or 0.5 U/kg (glargine) of each treatment under automated euglycaemic clamp conditions. The clamp duration was 12 h (aspart and lispro) or 30 h (glargine). Primary PK endpoints were the total area under the PK curves (AUC ins.total ) and maximum insulin concentrations (C ins.max ). Primary PD endpoints were the total area under the glucose infusion rate curve (AUC GIR.total ) and maximum glucose infusion rate (GIR max )., Results: Bioequivalence to both EU- and US-reference products were shown for all three GL insulins. Least squares mean ratios for the primary PK/PD endpoints were close to 100%, and both 90% and 95% confidence intervals were within 80%-125% in all three studies. There were no noticeable differences in the safety profiles between test and reference insulins, and no serious adverse events were reported for the GL insulins., Conclusion: GL-Asp, GL-Lis and GL-Gla are bioequivalent to their EU- and US-reference products., (© 2023 John Wiley & Sons Ltd.)

Health systems encourage switching from originators to biosimilars as biosimilars are more cost-effective. The speed and completeness of biosimilar adoption is a measure of efficiency. We describe the approach to biosimilar adoption at a single hospital Trust and compare its efficiency against the English average. We additionally follow up patients who reverted to a previously used biologic, having switched to a biosimilar, to establish whether they benefitted from re-establishing prior treatment. The approach we describe resulted in a faster and more complete switch to biosimilars, which saved an additional £380 000 on drug costs in 2021/2022. Of patients who reverted to their original biologic, 87% improved short-term, and a time on treatment analysis showed the benefit was retained long term. Our approach to biosimilar adoption outperformed the English average and permits patients to revert to their original biosimilar post-switch if appropriate., (© 2023 British Pharmacological Society.)

Background and Aims: Data on the outcomes after switching from adalimumab (ADA) originator to ADA biosimilar are limited. The aim was to compare the treatment persistence, clinical efficacy, and safety outcomes in inflammatory bowel disease patients who maintained ADA originator vs. those who switched to ADA biosimilar., Methods: Patients receiving ADA originator who were in clinical remission at standard dose of ADA originator were included. Patients who maintained ADA originator formed the non-switch cohort (NSC), and those who switched to different ADA biosimilars constituted the switch cohort (SC). Clinical remission was defined as a Harvey-Bradshaw index ≤4 in Crohn's disease and a partial Mayo score ≤2 in ulcerative colitis. To control possible confounding effects on treatment discontinuation, an inverse probability treatment weighted proportional hazard Cox regression was performed., Results: Five hundred and twenty-four patients were included: 211 in the SC and 313 in the NSC. The median follow-up was 13 months in the SC and 24 months in the NSC (p < 0.001). The incidence rate of ADA discontinuation was 8% and 7% per patient-year in the SC and in the NSC, respectively (p > 0.05). In the multivariate analysis, switching from ADA originator to ADA biosimilar was not associated with therapy discontinuation. The incidence rate of relapse was 8% per patient-year in the SC and 6% per patient-year in the NSC (p > 0.05). Six percent of the patients had adverse events in the SC vs. 5% in the NSC (p > 0.05)., Conclusion: Switching to ADA biosimilar did not impair patients' outcomes in comparison with maintaining on the originator., (© 2023 John Wiley & Sons Ltd.)

Aim: To establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar Insulin N (Biocon's Insulin-N; Biocon Biologics Ltd., Bangalore, India) and US-licensed Humulin® N (Humulin-N; Eli Lilly and Company, Indianapolis, IN, USA) in healthy subjects., Materials and Methods: This was a phase-1, single-centre, double-blind, randomized, three-period, six-sequence, partially replicated, crossover, 24-h euglycaemic clamp study. Overall, 90 healthy subjects were randomized, of whom 85 completed the study. The subjects received either two single doses of Biocon's Insulin-N and a single dose of Humulin-N or two single doses of Humulin-N and a single dose of Biocon's Insulin-N subcutaneously at a dose of 0.4 IU/kg. The primary PK endpoints were the area under the insulin concentration-time curve from 0 to 24 h (AUC ins.0-24h ) and the maximum insulin concentration (C ins.max ). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 h (AUC GIR.0-24h ) and the maximum GIR (GIR max )., Results: Biocon's Insulin-N was found to be equivalent to Humulin-N for the primary PK (geometric 90% confidence interval for the least squares mean ratio: AUC ins.0-24h , 100.98%-115.66% and C ins.max , 95.91%-110.16%) and PD endpoints (intra-subject variability ≥0.294; 95% upper confidence interval [(μT - μR) 2  - θσ 2 WR] <0; point estimates of geometric least squares mean ratio: AUC GIR.0-24h , 104.61% and GIR max , 100.81%). The safety profile of Biocon's Insulin-N was similar to that of Humulin-N, and no serious adverse events were reported., Conclusion: PK and PD equivalence was shown between Biocon's Insulin-N and Humulin-N in healthy subjects, and both treatments were well tolerated and considered safe., (© 2023 John Wiley & Sons Ltd.)

Background: Chronic spontaneous urticaria (CSU) is a mast cell-mediated disease, which is sometimes associated with various inflammatory disorders. Omalizumab is a commonly used biological agent, which is a recombinant, humanized, monoclonal antibody against human immunoglobulin E. However, there are only few reports about the combination of omalizumab for CSU with any other biologics for accompanying inflammatory diseases in the literature. The aim of this study was to evaluate the patients whose treatment of omalizumab for CSU were combined with any other biologics for associated inflammatory disorders and to describe whether these combinations might have any safety concerns., Methods: We conducted a retrospective cohort study of adult patients with CSU treated with omalizumab concurrently using another biological agent for their other dermatological conditions., Results: Thirty-one patients, 19 women and 12 men, were evaluated. The mean age was 45.13 years. The median duration of omalizumab was 11 months. Biological agents which patients were treated other than omalizumab were as follows: adalimumab biosimilar (n = 3), ustekinumab (n = 4), secukinumab (n = 17) and ixekizumab (n = 7). The median duration of concurrent use of omalizumab and other biologics was 8 months. None of the drug combinations was stopped because of side effects., Conclusion: This observational study demonstrated that omalizumab treatment for CSU in combination with any other biological agents for dermatological disorders appeared to be well tolerated without any major safety concerns., (© 2023 Australasian College of Dermatologists.)

The new subcutaneous (sc) formulation of the infliximab (IFX) biosimilar CT-P13 results in homogeneous serum trough concentrations of IFX at steady state. The present study aimed to investigate in Crohn's disease (CD) patients the intra-individual variations of IFX drug levels at multiple time-points during 2 consecutive cycles of maintenance therapy with CT-P13 sc., Patients and Methods: CD patients in clinico-biological remission under maintenance therapy with intravenous (iv) IFX/CT-P13 were switched to CT-P13 sc 8 weeks (W) after the last infusion. They were treated with CT-P13 sc, 120 mg every 2 W. Assessments were performed from 8 W after starting CT-P13 sc and patients had to attend 6 visits on 2 consecutive cycles of treatment (cycles A and B). Visits were scheduled on days 4-6 (visit 1), days 7-9 (visit 2) and day 14 (visit 3) of each cycle, where days 1 and 14 were the days of sc injection of CT-P13. At each visit, peripheral blood was collected to measure serum IFX levels and anti-drug antibodies., Results: Twenty patients underwent 120 evaluations. Large intra-individual variations of serum drug levels of IFX were observed. When pooling the 120 evaluations, the mean drug level was 11.3 ± 4.9 μg/ml, and the median drug level was 10.9 μg/ml (IQR 7.5-15.5). During each cycle, the median drug levels were similar between visits 1 and 2 as well as between visits 1 and 3 and between visits 2 and 3. In cycle A, median drug levels were 11.1 μg/ml (7.8-14.5), 12.0 μg/ml (7.2-16.1) and 11.0 μg/ml (7.5-15.1) at V1, V2 and V3, respectively. Similar results were obtained in cycle B, where median drug levels were 11.6 μg/ml (7.9-14.9), 11.4 μg/ml (8.1-15.2) and 10.9 μg/ml (7.9-15.6) at V1, V2 and V3, respectively. In univariate analysis, we failed to identify factors predictive of low drug levels., Conclusions: IFX drug levels are quite stable within 14-day treatment cycle, without trough levels in CD patients in remission during the maintenance therapy with CT-P13 sc. In patients with inactive CD under maintenance therapy with CT-P13 sc, therapeutic drug monitoring of IFX can be performed at any time between two CT-P13 sc injections., (© 2022 John Wiley & Sons Ltd.)

Aim: To establish equivalence in the pharmacokinetic (PK) and pharmacodynamic (PD) endpoints between proposed biosimilar Insulin-R (Biocon's Insulin-R) and Humulin® R using the euglycaemic clamp technique in healthy subjects., Materials and Methods: In this phase-1 automated euglycaemic glucose clamp study, 42 healthy subjects were randomized (1:1) to receive a single dose of 0.3 IU/kg of Biocon's Insulin-R and Humulin-R. Plasma insulin concentrations and glucose infusion rates (GIRs) were assessed over 12 hours. Primary PK endpoints were area under the insulin concentration-time curve from 0 to 12 hours (AUC ins.0-12h ) and maximum insulin concentration (C ins.max ). Primary PD endpoints were area under the GIR time curve from 0 to 12 hours (AUC GIR.0-12h ) and maximum GIR (GIR max )., Results: Equivalence was demonstrated between Biocon's Insulin-R and Humulin-R for the primary PK and PD endpoints. The 90% confidence intervals were within 80.00% to 125.00% limits. The PK and PD profiles were comparable. There were no significant differences in the safety profiles of the two treatments, and no serious adverse events were reported., Conclusion: PK and PD equivalence was demonstrated between Biocon's Insulin-R and Humulin-R in healthy subjects. Treatment with Biocon's Insulin-R and Humulin-R was well tolerated., (© 2022 Biocon Biologics Limited. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: The objective of this retrospective cohort study was to provide an overview of the utilization of originator and biosimilar infliximab in the Netherlands., Methods: All infliximab dispensings were selected from the PHARMO In-patient Pharmacy Database from 2002-2018. Descriptive analyses were performed in order to characterise initiators and to describe switching patterns over time., Results: Overall, 3840 patients with 61 274 infliximab dispensings were identified. 2496 patients initiated an originator infliximab and 777 patients initiated a biosimilar infliximab. Overall, 57% of the patients was female and mean age was 43.2 years. Both originators and biosimilars were mostly prescribed by gastroenterologists, followed by internists and rheumatologists. After market authorisation of the first biosimilar, the proportion of new patients initiating the biosimilar increased from 39% in 2015 to 91% in 2018. Out of 704 patients eligible for switching 34% switched. Among switchers, the proportion of females was 60% and mean age at index was 45.1 years. Among nonswitchers, 55% were female and mean age was 39.8 years. The median time to switch was 1.7 years and switchers were most frequently initiated on infliximab by a rheumatologist (42%), while nonswitchers were most frequently initiated by a gastroenterologist (42%)., Conclusion: The results of this large population-based cohort show an increase in biosimilar initiation in daily clinical practice. The number of switchers remains relatively low as nonmedical switch is not encouraged in the Netherlands., (© 2021 British Pharmacological Society.)

Aims: Adalimumab-adbm is a monoclonal antibody developed as a biosimilar to adalimumab (Humira, AbbVie Inc.). The key objectives of this study were using a population pharmacokinetic (PPK) approach to assess pharmacokinetic (PK) similarity between adalimumab-adbm and Humira in patients with active rheumatoid arthritis (RA), to quantify the effects of potential covariates on adalimumab PK and to assess the impact of switching treatment from Humira to adalimumab-adbm on PK., Methods: A PPK model was firstly developed using intensive PK data from the phase-1 study in healthy subjects (NCT02045979). PPK models were developed separately for phase-3 base study (NCT02137226) and its extension study (NCT02640612) in patients with active RA., Results: PPK models were developed for adalimumab from adalimumab-adbm and Humira treatment in healthy subjects and RA patients. Weight and anti-drug antibodies were found to be important predictors of adalimumab clearance. Adalimumab PK was similar between adalimumab-adbm and Humira. The estimated effect of Humira on clearance, relative to the adalimumab-adbm, was 1.02 (i.e., Humira has 0.02 greater clearance). Similarly, the effect of treatment arms (switching) on clearance was estimated to be 1.00 and 0.997 for Humira:Humira:BI and Humira:BI:BI arms, respectively, relative to the BI:BI:BI arm (BI refers to adalimumab-adbm) in the phase-3 extension study., Conclusion: PK similarity between adalimumab-adbm and Humira in patients with active RA was demonstrated using PPK approach. Adalimumab PK was also similar when switching treatment from Humira to adalimumab-adbm at either week 24 or 48., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: Tumour necrosis factor α inhibitors (anti-TNFα) are the main therapy for moderate to severe inflammatory bowel disease (IBD) in children. Biosimilars to the original drug infliximab are now available, but there are few reports on their real-life use. We compared the outcomes of patients treated with infliximab and its biosimilar, CT-P13., Methods: We collected outcome data on anti-TNFα-naive patients who started infliximab in the Children's Hospital, University of Helsinki, Finland, in 2015-2016. We studied 51 paediatric patients with IBD at a median age of 12 (range 4-16): 65% had Crohn disease, 23 received the original infliximab drug and 28 received the biosimilar. During 2015, infliximab was introduced to all treatment-naïve patients, and during 2016, all treatment-naïve patients received the biosimilar., Results: We found no statistically significant differences between the two drug products related to the outcome of the therapy during the first year. There were no significant differences in the trough levels between the treatment groups. Likewise, the proportion of patients with therapy enhancement was comparable between the two treatment groups., Conclusion: The first-year therapy outcomes of infliximab and its biosimilar were comparable. There were no alarming signs of differences in safety., (© 2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo. International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied. Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m 2 for 4 weeks. Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was -20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity. One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (-12.62%-18.24%) showing equivalent efficacy. Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported. Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold. Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages. In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile, pharmacodynamics, and immunogenicity of BCD-020 were also comparable with those of reference rituximab., (© 2019 John Wiley & Sons, Ltd.)

Background: CT-P13, a biosimilar of the reference product infliximab, has been approved for the treatment of ulcerative colitis on the basis of the results of trials conducted in patients with spondyloarthritis and rheumatoid arthritis., Aim: To compare the effectiveness and safety of CT-P13 and the reference product in infliximab-naive patients with ulcerative colitis METHODS: A comparative real-life equivalence cohort study was conducted using the French nationwide health administrative database. Infliximab-naive patients with ulcerative colitis over 15 years of age who started infliximab with no other indications for infliximab were included. The primary outcome was a composite endpoint (death, ulcerative colitis-related surgery, all-cause hospitalisation and reimbursement for other biologics). Equivalence was defined as a 95% CI of the hazard ratio (HR) of CT-P13 vs the reference product, in a multivariable marginal Cox model situated within prespecified margins of (0.80-1.25)., Results: A total of 3112 patients were included between 1 January 2015 and 30 June 2017: 1434 received the reference product, 1678 received CT-P13. Overall, 710 patients in the reference product group and 743 patients in the CT-P13 group met the composite endpoint. In multivariable analysis of the primary outcome, CT-P13 was equivalent to the reference product (HR 1.04; 95% CI: 0.94-1.15). The number of serious infections was lower in the CT-P13 group (HR 0.65; 95% CI: 0.48-0.88). There was no difference in the incidence of solid or haematologic malignancy (HR 0.81; 95% CI: 0.41-1.60)., Conclusions: The effectiveness of CT-P13 is equivalent and the risk of serious infections could be lower than that of the reference product for infliximab-naive patients with ulcerative colitis., (© 2019 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Immune thrombotic thrombocytopenic purpura (iTTP) is an acute, multisystem thrombotic microangiopathy mediated by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) autoantibodies. Immunosuppression with anti-CD20 therapy is the mainstay of treatment. MabThera's patent has now expired and biosimilars have been approved. Eighty-four consecutive patient episodes over 2 years, prior to and following our switch to Truxima are presented. Day 1 (D1), Day 28 (D28) and 3-month platelet counts, ADAMTS13 activity, and CD19 levels, adverse reactions and infective complications were recorded. Platelet counts were not significantly different between acute MabThera and Truxima treatment (D1 P = 0.085, D28 P = 0.77, 3 months P = 0.71) and electively (D1 P = 0.79, D28 P = 0.68, 3 months P = 0.99). ADAMTS13 recovery also was not significantly different acutely (D1 P = 0.99, D28 P = 0.27, 3 months P = 0.26) and electively (D1 P = 0.59, D28 P = 0.61, 3 months P = 0.34). CD19% depletion at D1 and 3 months was not significantly different acutely (D1 P = 0.52, 3 months P = 0.56) and electively (D1 P = 0.22, 3 months P = 0.19). Infusion reactions and infective complications were comparable with both therapies. This is the first series of the Rituximab biosimilar Truxima to be reported in iTTP, demonstrating equivalence to MabThera in terms of ADAMTS13 recovery, CD19 depletion, and platelet count at D28 and 3 months post-administration, with comparable infusion and infective complications. The financial benefit of the biosimilar anti-CD20 is considerable., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Regulation of medicines involves complex scientific and public health policies which are reflected in the regulatory approaches used by the European Medicines Agency and the United States Food and Drug Administration for the approval of products developed for metabolic bone diseases. For osteoporosis therapies, utilized by many patients, the approaches and existing guidance for product development of both agencies are similar; confirmatory studies for the approval of osteoporosis products can rely on well-defined efficacy outcome parameters. Therapeutics for rare bone diseases, a rapidly expanding area, often require an individualized regulatory approach. This review outlines key aspects of these regulatory approaches applied by the two agencies for products for metabolic bone diseases., (© 2018 The British Pharmacological Society.)

Background: The nocebo effect is a negative effect of a pharmacological or nonpharmacological medical treatment that is induced by patients' expectations, and that is unrelated to the physiological action of the treatment. The nocebo effect can negatively affect treatment outcomes., Aim: To develop evidence-based consensus recommendations for the prevention and management of the nocebo effect in biosimilar-treated patients with IBD., Methods: The "NOCE-BIO Consensus Group" was composed of 19 members from five European countries, and with different fields of expertise. A literature review on the nocebo effect, with specific focus on information about its prevention and management in biosimilar-treated IBD patients, was performed. Preliminary statements were formulated and voted on during a consensus group meeting held in Milan, Italy, in July 2018. A statement was accepted if >75% of participants voted 4 ("agree") or 5 ("strongly agree") on a scale of 1-5., Results: Consensus was reached on 11 recommendation statements. Seven statements reached consensus after one voting round and four statements reached consensus after two voting rounds. All statements were supported by very low-quality level of evidence. The panel agreed that patient-health-care provider relationship is a key driver of acceptance of biosimilars, which limits the risk of negative bias and the nocebo effect. Lack of knowledge among patients and health-care providers about the effectiveness and safety of biosimilars should be minimized. Education about biosimilars needs to be tailored to the individual patient, and positive framing is recommended., Conclusions: The nocebo effect is under-recognised in the era of biosimilars, although it may negatively impact on the cost-savings of biosimilars. Future research should focus on the magnitude, the risk factors, the impact, and the management of the nocebo effect in biosimilars-treated IBD patients., (© 2019 John Wiley & Sons Ltd.)

Aims: To assess the non-inferiority of MYL-1501D, a proposed biosimilar or follow-on biological agent to marketed insulin glargine, to reference insulin glargine (Lantus®; Sanofi-Aventis US LLC, Bridgewater, New Jersey) based on change in glycated hemoglobin (HbA1c)., Materials and Methods: INSTRIDE 2 was a multicentre, open-label, randomized, parallel-group, phase III non-inferiority study comparing the efficacy and safety of MYL-1501D with those of reference insulin glargine in insulin-naive and insulin-non-naive patients with type 2 diabetes mellitus receiving oral antidiabetic drugs (OADs). The primary efficacy endpoint was change in HbA1c from baseline to week 24. Secondary endpoints included metabolic readouts (eg, changes in fasting plasma glucose, insulin dosage, self-monitored blood glucose), immunogenicity and adverse events, including hypoglycaemia and nocturnal hypoglycaemic events., Results: In all, 560 patients were randomized to MYL-1501D or insulin glargine in combination with OADs for 24 weeks. The mean change in HbA1c from baseline to week 24 was -0.60% (95% CI -0.78, -0.41) and - 0.66% (95% CI -0.84, -0.48) for MYL-1501D and reference insulin glargine, respectively. MYL-1501D was well tolerated and had a safety profile similar to that of reference insulin glargine., Conclusions: Demonstration of non-inferiority between MYL-1501D and reference insulin glargine for reduction of HbA1c during 24 weeks of treatment was achieved. The two treatment groups were similar in terms of secondary endpoints, including hypoglycaemia and nocturnal hypoglycaemia, local and systemic reactions, other safety variables, and immunogenicity., (© 2018 John Wiley & Sons Ltd.)

Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their biosimilars are used to treat anaemia in MDS and, currently, epoetin alfa and darbepoetin alfa are commonly used and recommended by clinical guidelines. To better understand the evidence available on the use of ESAs for anaemia in lower-risk MDS, we conducted a systematic literature review to identify randomized and nonrandomized prospective studies reporting on clinical efficacy/effectiveness, patient-reported quality of life (QoL), and safety. We extended our review to include retrospective studies for darbepoetin alfa specifically and to ascertain the feasibility of completing an indirect network meta-analysis comparing epoetin and darbepoetin alfa. Overall, 53 articles reporting on 35 studies were included. The studies indicated a clinical benefit of ESAs, with benefits observed across key clinical outcomes. ESAs showed consistent improvement in erythroid response rates (ESA-naïve, 45-73%; previous ESA exposure, 25-75%) and duration of response. Comparative studies demonstrated similar progression to acute myeloid leukaemia and several showed improved overall survival and QoL. Limited safety concerns were identified. This analysis confirmed ESA therapy should be the foremost first-line treatment of anaemia in most patients with lower-risk MDS who lack the 5q deletion., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Aim: To test the cross-immunogenicity of anti-CT-P13 IBD patients' sera to CT-P13/infliximab originator and the comparative antigenicity evoked by CT-P13/infliximab originator sera., Methods: Sera of patients with IBD with measurable anti-CT-P13 antibodies were tested for their cross-reactivity to 5 batches of infliximab originator and CT-P13. Anti-drug antibody positive sera from treated patients were used to compare antigenic epitopes., Results: All 42 anti-CT-P13 and 37 anti-infliximab originator IBD sera were cross-reactive with infliximab originator and CT-P13 respectively. Concentration of anti-drug antibodies against infliximab originator or CT-P13 were strongly correlated both for IgG1 and IgG4 (P < 0.001). Anti-CT-P13 sera of patients with IBD (n = 32) exerted similar functional inhibition on CT-P13 or infliximab originator TNF binding capacity and showed reduced binding to CT-P13 in the presence of five different batches of CT-P13 and infliximab originator. Anti-CT-P13 and anti-infliximab originator IBD sera selectively enriched phage-peptides from the VH (CDR1 and CDR3) and VL domains (CDR2 and CDR3) of infliximab. Sera reactivity detected major infliximab epitopes in these regions of infliximab in 60%-79% of patients, and no significant differences were identified between CT-P13 and infliximab originator immunogenic sera. Minor epitopes were localised in framework regions of infliximab with reduced antibody reactivity shown, in 30%-50% of patients. Monoclonal antibodies derived from naïve individuals and ADA-positive IBD patients treated with CT-P13 provided comparable epitope specificity to five different batches of CT-P13 and infliximab originator., Conclusions: These results strongly support a similar antigenic profile for infliximab originator and CT-P13, and point toward a safe switching between the two drugs in anti-drug antibody negative patients., (© 2018 John Wiley & Sons Ltd.)

Aim: To test the safety and efficacy of MYL-1501D, a proposed insulin glargine biosimilar, in patients with type 1 diabetes mellitus (T1DM)., Methods: The safety and efficacy of MYL-1501D and reference insulin glargine were evaluated in INSTRIDE 1, a 52-week, open-label, randomized, phase III study in patients with T1DM. The primary objective was to determine whether once-daily MYL-1501D was non-inferior to once-daily insulin glargine when administered in combination with mealtime insulin lispro based on change in glycated haemoglobin (HbA1c) from baseline to week 24. Secondary endpoints were changes in fasting plasma glucose, insulin dose, self-monitored blood glucose and immunogenicity from baseline, and occurrences of hypoglycaemic, nocturnal hypoglycaemic and adverse events up to week 52., Results: Overall, 558 patients were randomized 1:1 to MYL-1501D or reference insulin glargine in combination with thrice-daily mealtime insulin lispro for 52 weeks. The mean change in HbA1c from baseline to week 24 was 0.14% (standard error [SE] 0.054; 95% confidence interval [CI] 0.033, 0.244) for MYL-1501D and 0.11% (SE 0.054; 95% CI 0.007, 0.220) for reference insulin glargine. MYL-1501D had a safety profile similar to that of reference insulin glargine and was well tolerated in patients with T1DM up to week 52., Conclusions: The upper 95% CI limit for mean change in HbA1c at week 24 indicated that MYL-1501D was non-inferior to reference insulin glargine. There were no clinically meaningful differences between groups in incidence of overall and nocturnal hypoglycaemia, local or systemic reactions, safety or immunogenicity., (© 2018 John Wiley & Sons Ltd.)

Biosimilars are highly similar versions of approved branded biologics. In contrast to generics, which are identical copies of the originator medicines, biosimilars are considered unique but related molecules that differ from the originator reference product as well as from each other. Owing to the complexity of biologic medicines, such as therapeutic monoclonal antibodies, minor differences between biosimilars and the reference products are acceptable provided these differences do not result in any clinically meaningful differences in safety or efficacy. In addition, minor changes in structure and function may occur over time in originator biologic products as a result of alterations in production materials (e.g. cell lines), processes or conditions. The developmental process for biosimilars focuses on a 'totality of evidence' approach that emphasizes a stepwise investigational process, including comprehensive structural, functional, pharmacologic and clinical assessment for similarity. The goal of the phase 3 clinical development programme for a biosimilar is not to establish efficacy, per se, but to demonstrate that there are no clinically meaningful differences between the proposed biosimilar and the reference product. The requirement to show clinical similarity informs biosimilar study design, including the selection of the patient population, disease state (indication), study endpoints and statistical methods. Based on the clinical trial results in a representative patient population, results may be extrapolated to other indications provided scientific justification is demonstrated based on, among other things, similar mechanism of action in the extrapolated indications. This review presents the current state of knowledge with respect to biosimilars. We aim to provide the practising clinician with a working knowledge of biosimilars as well as provide some practical guidance on their use and potential benefits in treating dermatologic diseases., (© 2018 European Academy of Dermatology and Venereology.)

Biosimilar insulins have expanded the treatment options for diabetes. We compared the clinical efficacy and safety of biosimilar insulins with those of originator insulins by conducting a meta-analysis. A random-effects meta-analysis was performed on randomized controlled trials comparing biosimilar and originator insulins in adults with diabetes. Studies were obtained by searching electronic databases up to December 2017. Ten trials, in a total of 4935 patients, were assessed (2 trials each on LY2963016, MK-1293, Mylan's insulin glargine and SAR342434, and 1 trial each on FFP-112 and Basalog). The meta-analysis found no differences between long-acting biosimilar and originator insulins with regard to reduction in glycated haemoglobin at 24 weeks (0.04%, 95% confidence interval [CI] -0.01, 0.08; P for efficacy = .14, I 2 = 0%) or at 52 weeks (0.03%, 95% CI -0.04, 0.1), or reduction in fasting plasma glucose (0.08 mmol/L, 95% CI 0.36, 0.53), hypoglycaemia (odds ratio 0.99, 95% CI 0.96, 1.03), mortality, injection site reactions, insulin antibodies and allergic reactions. Analyses stratified by type of diabetes and prior insulin use yielded similar findings. Similarly, no significant differences were found between short-acting biosimilar and originator insulins. In summary, our meta-analysis showed no significant differences in clinical efficacy and safety, including immune reactions, between biosimilar and originator insulins. Biosimilar insulins can increase access to modern insulin therapy and reduce medical costs., (© 2018 John Wiley & Sons Ltd.)

Background: EGALITY was a phase III confirmatory efficacy and safety study conducted in patients with plaque-type psoriasis as a part of totality of evidence gathered during the development of GP2015, an etanercept biosimilar., Objective: To demonstrate equivalent efficacy and comparable safety and immunogenicity of GP2015 and the etanercept originator product (ETN, Enbrel ® ) and evaluate effects of repeated switching between GP2015 and ETN. Results for efficacy, safety and immunogenicity during treatment period (TP) 2 (TP2) are presented pooling the two continued treatment arms (pooled continued) versus the two treatment arms with repeated switches (pooled switched)., Methods: Patients (n = 531) were randomized 1:1 to self-administer GP2015 or ETN twice-weekly subcutaneously during TP1. Patients with a ≥50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 12 were re-randomized for TP2 to continue the same treatment at once-weekly dosing or to undergo three consecutive treatment switches between GP2015 and ETN until week 30. Patients continued the last-assigned treatment during TP2, until week 52., Results: Mean (standard deviation [SD]) PASI scores at baseline were similar in patients who underwent multiple switches compared to those with continued treatments during TP2. During TP2, PASI 50, PASI 75 and PASI 90 response rates, percent change from baseline in PASI scores and all other efficacy parameters were similar between the pooled switched and pooled continued treatment groups at all time points. The incidence of treatment-emergent adverse events including injection site reactions was comparable between the pooled switched (36.7%) and pooled continued (34.9%) groups. None of the patients in either treatment group were positive for binding anti-drug antibodies in TP2., Conclusion: Treatment efficacy, safety and immunogenicity were similar between the pooled continued and pooled switched treatments during TP2, indicating that there are no effects in the short term on clinical data of multiple switches between GP2015 and ETN., (© 2017 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Infliximab biosimilars have become available for treatment of inflammatory bowel disease (IBD). However, data showing long-term safety and effectiveness of biosimilars in IBD patients are limited., Aim: To study prospectively the switch from infliximab innovator to biosimilar in an IBD cohort with 12 months follow-up to evaluate safety and effectiveness., Methods: Adult IBD patients from two hospitals treated with infliximab innovator (Remicade; Janssen Biotech,  Horsham ,  Pennsylvania, USA) were switched to infliximab biosimilar (Inflectra; Hospira, Lake Forest, Illinois, USA) as part of routine care, but in a controlled setting. Blood samples were taken just before the first, second, fourth and seventh infusion of biosimilar. Infliximab trough levels, antibodies-to-infliximab (ATI), CRP and ESR were measured and disease activity scores were calculated., Results: Our cohort consisted of 133 IBD patients (64% CD, 36% UC). Before switching we found widely varying infliximab levels (median 3.5 μg/mL). ATI were detected in eight patients (6%). Most patients were in remission or had mild disease (CD: 82% UC: 90%). After switching to biosimilar, 35 patients (26%) discontinued therapy within 12 months, mostly due to subjective higher disease activity (9%) and adverse events (AE, 9.8%). AE included general malaise/fatigue (n = 7), arthralgia (n = 2), skin problems (n = 2) and infusion reactions (n = 2). No differences in IFX levels, CRP, and disease activity scores were found between the four time points (P ≥ .0917)., Conclusions: We found no differences in drug levels and disease activity between infliximab innovator and biosimilar in our IBD cohort, indicating that biosimilars are safe and effective. The high proportions of discontinuers were mostly due to elective withdrawal or subjective disease worsening., (© 2017 John Wiley & Sons Ltd.)

Aims: MK-1293 is an insulin glargine that has an amino acid sequence identical to that of Lantus, the originator insulin glargine. Two euglycaemic clamp studies, 1 in subjects with type 1 diabetes (T1D) and 1 in healthy subjects, were conducted to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK-1293 and Lantus commercially procured in both the European Union (EU-Lantus) and the USA (US-Lantus)., Materials and Methods: Both studies were single-dose, randomized, double-blind, single-centre, crossover studies with ≥7 days between dosing periods. A 2-treatment, 4-period replicate crossover study in T1D subjects (N = 76) compared the PK and PD of MK-1293 to EU-Lantus for 30 hours after dosing. A 3-period crossover study in healthy subjects (N = 109) compared the PK and PD of MK-1293, EU-Lantus and US-Lantus for 24 hours after dosing. In both studies, all subjects received single 0.4 units/kg subcutaneous doses of MK-1293 or Lantus in all dosing periods. Pharmacokinetic assessment was based on LC-MS/MS-based measurement of the major insulin glargine metabolite (M1) and PD was characterized using the euglycaemic clamp platform., Results: In both studies, pre-specified similarity criteria were met between MK-1293 and Lantus for comparison of PK (AUC 0-24 and C max of M1) and PD (GIR-AUC 0-24 , GIR-AUC 0-12 , GIR-AUC 12-24 , and GIR max ) primary endpoints. All treatments were well tolerated., Conclusion: Based on comparative assessment in both T1D and healthy subjects, it can be concluded that the PK and PD properties of MK-1293 are highly similar to those of Lantus. (ClinicalTrials.gov: NCT02059174)., (© 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 rapid-acting insulin lispro products: SAR342434 solution, United States (US)-approved Humalog and European Union (EU)-approved Humalog., Methods: In a single-centre, randomized, double-blind, 3-treatment, 3-period, 6-sequence, crossover, euglycaemic clamp study (NCT02273258), adult male subjects with type 1 diabetes were randomized to receive 0.3 U/kg of SAR342434 solution, US-approved and EU-approved Humalog under fasted conditions. PK and PD (glucose infusion rate [GIR]) were assessed up to 12 hours., Results: Of the 30 subjects randomized, 28 completed all 3 treatment periods. Mean concentration and GIR vs time profiles were similar for all 3 products. Exposure (INS-C max , INS-AUC last and INS-AUC) and activity (GIR max and GIR-AUC 0-12h ) of SAR342434, US-approved and EU-approved Humalog were similar in all comparisons (point estimates of treatment ratios, 0.95-1.03 for PK parameters and 1.00-1.07 for PD parameters), with 90% confidence intervals for the ratios of geometric least squares means within the pre-specified bioequivalence limit (0.80-1.25) and no significant differences in time-related parameters. Within-subject variability of exposure and activity was low across the 3 clamps, indicating high day-to-day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for all 3 products. No safety concerns were noted in vital signs or in laboratory and electrocardiogram data., Conclusions: The results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US- and EU-approved Humalog, and between both US- and EU-approved Humalog, supporting the use of SAR342434 solution for injection as a follow-on product., (© 2016 John Wiley & Sons Ltd.)

Background: Biosimilars of anti-tumour necrosis factor (TNF)-α agents have now become clinically available for the treatment of inflammatory bowel diseases (IBD)., Aim: To perform a systematic review and meta-analysis to evaluate the efficacy and safety of biosimilars of anti-TNF-α agents in patients with IBD., Methods: Electronic databases were searched. The outcomes were the pooled rates of clinical response or remission, sustained clinical response or remission, and adverse events in patients with IBD induced with or switched to biosimilars of anti-TNF-α agents., Results: Eleven observational studies reporting outcomes in 829 patients treated with biosimilar of infliximab (CT-P13) were identified. The pooled rates of clinical response among Crohn's disease (CD) and ulcerative colitis (UC) at 8-14 weeks were 0.79 (95% confidence interval (CI) = 0.65-0.88) and 0.74 (95% CI = 0.65-0.82), respectively, and at 24-30 weeks were 0.77 (95% CI = 0.63-0.86) and 0.77 (95% CI = 0.67-0.85) respectively. Adverse events were rare (CD, 0.08 (95% CI = 0.02-0.26); UC, 0.08 (95% CI = 0.03-0.17)). The pooled rates of sustained clinical response among CD and UC after switching from infliximab to CT-P13 at 30-32 weeks were 0.85 (95% CI = 0.71-0.93) and 0.96 (95% CI = 0.58-1.00), respectively, and at 48-63 weeks were 0.75 (95% CI = 0.44-0.92) and 0.83 (95% CI = 0.19-0.99) respectively. Adverse events were rare (CD, 0.10, 95% CI = 0.02-0.31; UC, 0.22, 95% CI = 0.04-0.63)., Conclusions: CT-P13 was associated with excellent clinical efficacy and safety profile, supporting its use in the treatment of IBD., (© 2017 John Wiley & Sons Ltd.)

Latin American countries view biosimilar agents as an effective approach to curtail health-care expenditures while maintaining the safety and efficacy profile of their branded innovator comparators. To understand the complexities of the regulatory landscape and key therapeutic issues for use of biosimilars to treat moderate to severe psoriasis in Latin America, the International Psoriasis Council convened dermatology experts from Argentina, Brazil, Chile, Colombia and Mexico in October 2015 to review the definition, approval, marketing and future of biosimilars in each country and develop a consensus statement. The regulatory framework for marketing approval of biosimilars in Latin America is currently a mosaic of disparate, country-specific, regulatory review processes, rules and standards, with considerable heterogeneity in clarity and specificity. Regulations in Argentina, Brazil, Chile and Mexico have undergone multiple refinements whereas Colombia is finalizing draft guidelines. Verification of the similarity in quality, safety and efficacy of biosimilars to the innovator biologic remains a key challenge for policy makers and regulatory authorities. Other key regulatory challenges include: naming of agents and traceability, pharmacovigilance, extrapolation of indications, and interchangeability and substitution. An urgent need exists for more Latin American countries to establish national psoriasis registries and to integrate their common components into a multinational psoriasis network, thereby enhancing their interpretative power and impact. A Latin American psoriasis network similar to PSONET in Europe would assist health-care providers, pharmaceutical companies, regulators and patients to fully comprehend specific products being prescribed and dispensed and to identify potential regional trends or differences in safety or outcomes., (© 2016 Japanese Dermatological Association.)

Aim: In 2006, Omnitrope (by Sandoz) was the first approved biosimilar in Europe. To date, 21 biosimilars for seven different biologics are on the market. The present study compared the clinical trials undertaken to obtain market authorization., Methods: We summarized the findings of a comprehensive review of all clinical trials up to market authorization of approved biosimilars, using the European public assessment reports (EPARs) published by the European Medicines Agency (EMA). The features compared were, among others, the number of patients enrolled, the number of trials, the types of trial design, choice of endpoints and equivalence margins for pharmacokinetic (PK)/pharmacodynamic (PD) and phase III trials., Results: The variability between the clinical development strategies is high. Some differences are explainable by the characteristics of the product; if, for example, the PD marker can be assumed to predict the clinical outcome, no efficacy trials might be necessary. However, even for products with the same reference product, the sample size, endpoints and statistical models are not always the same., Conclusions: There seems to be flexibility for sponsors regarding the decision as to how best to prove biosimilarity., (© 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: To evaluate potential differences between PF-05280586 and rituximab sourced from the European Union (rituximab-EU) and USA (rituximab-US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF-05280586., Methods: A randomised, double-blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti-tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF-05280586, rituximab-EU or rituximab-US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab-EU and rituximab-US responses using longitudinal nonlinear mixed effects models., Results: The analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group-to-group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF-05280586 vs. rituximab-EU or rituximab-US lie outside the reference ranges were low., Conclusions: No clinically meaningful differences were detected in DAS28 or ACR response between PF-05280586 and rituximab-EU or rituximab-US as the differences were within the pre-specified reference ranges., Trial Registration Number: NCT01526057., (© 2016 Pfizer Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The safety and efficacy of LY2963016 insulin glargine (LY IGlar) and Lantus insulin glargine (IGlar), products with identical primary amino acid sequences, were assessed in subgroups of patients with type 1 (T1D, n = 452) or type 2 diabetes (T2D, n = 299) reporting prestudy IGlar treatment in 52-week open-label (ELEMENT-1) and 24-week double-blind (ELEMENT-2) studies. At randomization, patients transitioned from their prestudy IGlar to equivalent doses of LY IGlar or IGlar. Primary efficacy (change in glycated haemoglobin from baseline to 24 weeks), other efficacy and select safety outcomes of LY IGlar were compared with those of IGlar. Continuous data were analysed using analysis of covariance, categorical data by Fisher's exact test, and treatment comparisons for hypoglycaemia by Wilcoxon test. No statistically significant treatment differences were identified for efficacy and safety outcomes except for weight change (T1D), overall incidence of detectable insulin antibodies (T2D), and serious adverse events (T2D). These differences were neither consistently observed across both studies nor observed in the total study populations, and their magnitude suggests they were not clinically meaningful. LY IGlar and IGlar show similar efficacy and safety profiles in patients reporting prestudy IGlar treatment., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM)., Methods: To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response (TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test., Results: No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward (LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naïve subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint (LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (<5%) in both treatment groups. Insulin antibody levels or developing TEAR was not associated with clinical outcomes., Conclusions: LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes., (© 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Anti-tumour necrosis factor (anti-TNF) monoclonal antibodies have shown efficacy in inflammatory bowel diseases (IBD). As these therapies lose patent protection, biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13; however, some uncertainty exists regarding their pharmacology in IBD., Aim: To review the literature on anti-TNF biosimilars focusing on pharmacokinetics, pharmacodynamic properties and comparative effectiveness, related to their use in IBD., Methods: A PubMed literature search was performed using the following terms individually or in combination: 'biosimilars,' 'CT-P13,' 'Crohn's disease,' 'inflammatory bowel disease,' 'ulcerative colitis,' 'anti-TNFα therapy,' 'infliximab,' 'adalimumab,' 'pharmacokinetics,' 'immunogenicity.', Results: Bioequivalence of CT-P13 and infliximab was shown in ankylosing spondylitis (AS) and therapeutic equivalence in rheumatoid arthritis (RA). Preliminary results of CT-P13 in IBD come from small post-marketing registries and case series with a relatively short-term follow-up period and suggest comparable efficacy and safety to infliximab. Inter- and intra-individual differences in exposure and response are well known for the original molecules but dosing regimens and concomitant medications are different for RA compared to IBD, limiting the ability to translate some of the pharmacology data in RA to IBD. Uncertainty exists about cross-reactivity of anti-drug antibodies and whether similar exposure-response relationships will be observed for biosimilars and efficacy thresholds for therapeutic drug monitoring can be used interchangeably., Conclusions: It is likely that biosimilars will be widely used for the treatment of IBD due to their cost savings and comparable efficacy. Nevertheless, robust post-marketing studies and pharmacovigilance are warranted in the coming years., (© 2015 John Wiley & Sons Ltd.)