Jackie Syrop

A phase 1 equivalence study of ABP-215 (Mvasi, the first FDA-approved biosimilar bevacizumab) concludes that ABP-215 demonstrated pharmacokinetic (PK) similarity to the reference drug in healthy Japanese men.

 is an inhibitor of blood vessel growth and is 

 in the United States for chemotherapy and targeted therapy for colorectal, lung, glioblastoma, kidney, and cervical cancer. 

Safety profiles were comparable between subjects dosed with the reference and the biosimilar, and PK data in Japanese subjects were consistent with those previously shown in global studies. 

 by Vladimir Hanes, MD, and colleagues in 

The randomized, single-blind, single-dose, parallel-group study had as its primary endpoints maximum observed serum concentration (C

) and area under the serum concentration—time curve from time 0 to infinity (AUC

). Secondary endpoints included AUC from time 0 to time of last quantifiable concentration (AUC

), safety, tolerability, and immunogenicity. The study lasted 57 days. 

Each of the 2 study groups had 24 subjects; all had similar baseline characteristics and were between 18 and 45 years of age. All 48 study subjects completed the infusion; 46 completed the study because 2 were lost to follow-up. 

After a 3-mg/kg IV infusion, the geometric means (GM) of C

were71.2 μg/mL, 25,259 μg h/mL, and 22,499.3 μg h/mL, respectively, for ABP-215 and 70.16 μg/mL, 25,801 μg h/mL, and 22,604.6 μg h/mL, respectively, for bevacizumab. The GM ratios (90% CI) for C

were 1.015 (0.946-1.088), 0.979 (0.914-1.049), and 0.995 (0.941-1.053) for ABP-215 versus bevacizumab. All confidence intervals were within the prespecified bioequivalence margin of 0.80-1.25. 

Adverse events (AEs) occurred in 2 of 24 subjects receiving ABP-215 and 1 of 24 receiving reference drug. No subject experienced an infusion reaction or hypersensitivity AE in the first 2 days after study drug administration. There were no deaths or AEs leading to discontinuation, and no patient was positive for binding anti-drug antibodies. 

The researchers concluded that their data were consistent with the PK equivalence previously demonstrated in a single-dose PK study that included 202 healthy adult men in the United States and European Union, and thus add to the evidence of ABP-215 as a high-quality biosimilar to bevacizumab for use in Japan. 

Hanes V, Chow V, Pan Z, Markus R. A randomized, single-blind, single-dose study to assess the pharmacokinetic equivalence of the biosimilar ABP 215 and bevacizumab in healthy Japanese male subjects. 

2018;82:899-905. doi: 10.1007/s00280-018-3695-4.

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The researchers say that their data were consistent with the pharmacokinetic equivalence previously demonstrated in a single-dose PK study that included 202 healthy adult men in the United States and European Union, and thus add to the evidence of ABP-215 as a high-quality biosimilar to bevacizumab for use in Japan. 

Study Finds ABP 215 and Bevacizumab Demonstrate PK Similarity in Japanese Men

 considered a key step to optimizing anti—tumor necrosis factor (anti-TNF) treatment in patients with inflammatory bowel disease (IBD). The advent of biosimilars to Remicade (reference infliximab) creates the necessity of validating the utilization of Remicade-quantifying assays, which are optimized for Remicade, with biosimilar compounds. 

Therapeutic Advances in Gastroenterology 

found that 3 quantification assays optimized for TDM of Remicade can be used to monitor levels of the infliximab biosimilar Flixabi (sold in the United States as Renflexis). 

Portuguese researchers, led by Fernando Magro, MD, PhD, and colleagues, previously demonstrated that a number of Remicade quantification methods can be safely applied to quantify Remsima. This study extends those analyses to include Flixabi.

In addition, the researchers assessed the reactivity of anti-Remicade and anti-Remsima sera to Remicade and to its biosimilars, and showed that the anti-Remicade and anti-Remsima sera reacted to the different drugs in a similar fashion. Thus, the researchers determined the existence of Remicade, Flixabi, and Remsima cross-immunogenicity, which supports their high similarity and prevents their switching in nonresponders with antidrug antibodies. 

The researchers generated sera of known concentrations of Remicade, Remsima, and Flixabi by diluting the appropriate amount of each drug into a pool of sera extracted from donor controls. Each spiked concentration was repeated between 6 and 9 times and analyzed in duplicate. 

Samples were then quantified using 3 different Remicade-quantification assays: an in-house ELISA assay and 2 commercially available kits—the Quantum Blue infliximab quantitative lateral flow assay (Buhlmann; Schonenbuch, Switzerland) and the RIDASCREEN IFX monitoring (R-Biopharm, AG; Darmstadt, Germany). 

All tested Remicade-infliximab-optimized assays measured Flixabi as accurately as they measured Remicade and Remsima, with intra-class correlation coefficients between theoretical and measured concentrations varying from 0.920 to 0.990. Inter-assay agreement values for the same compounds were high (intra-class correlation coefficients varied from 0.936 to 0.995). 

“This study is, to our knowledge, the first to demonstrate that Remicade-optimized quantification methods can be used to measure Flixabi levels, while consolidating the previously published results concerning Remsima in this context,” the researchers conclude. “In fact, our results suggest that either R-Biopharm, Buhlmann, and the described in-house method can be used to measure Remicade biosimilars Remsima and Flixabi in an accurate fashion.” They said their findings demonstrating the existence of cross-immunogenicity between Remicade, Remsima and Flixabi is a finding that not only reinforces the similarity among these drugs, but also has some clinical implications: “Apatient medicated with Remicade or Remsima whose therapy fails due to the presence of anti-drug antibodies would not benefit from switching to Remicade, Remsima, or Flixabi.” 

Magro F, Rocha C, Viera AI, et al., on behalf of the Portuguese IBD Study Group (GEDII). The performance of Remicade-optimized quantification assays in the assessment of Flixabi levels. 

2018;11:1-9. doi: 10.1177/ 1756284818796956. 

Three quantification assays optimized for therapeutic drug monitoring of Remicade can be used to monitor levels of the infliximab biosimilar Flixabi (sold in the United States as Renflexis). 

Quantification Assays Optimized for Remicade Can Be Used to Monitor Biosimilar Flixabi

Rituximab is frequently used off-label as a treatment for relapsing-remitting multiple sclerosis (MS) because it induces the depletion of circulating B-cell and T-cell lymphocytes and targets CD20 protein in B cells that are responsible for the production of antibodies. 

recently presented at the European Committee for Treatment and Research in Multiple Sclerosis investigated the impact of rituximab on regulatory T-cells (Treg), which play a role in immune modulation and have been identified as promoting oligodendrocyte differentiation and remyelination. 

A total of 43 patients with MS, 19 with relapsing-remitting and 24 with progressive disease, received 1000 mg rituximab intravenously, followed by a maintenance dose of 1000 mg in 6 months. 

Researchers recorded circulating lymphocyte kinetics (B CD19/B CD20/B CD27/T CD4/T CD8/Treg/NK cells) before the first infusion (M0) and 6 months later (M6). Secondary outcomes were the annualized relapse rate (ARR), expanded disability status scale (EDSS), and MRI activity. 

Mean (SD) EDSS at baseline was 5.2 (1.4) and 5.3 (1.5) at 6 months, respectively. ARR significantly decreased at M6 from a mean 1.18 (1.2) to 0.18 (0.6) (

=.00094). MRI activity was reported in 11% of patients, compared with 56% at baseline. Levels of CD19+ and CD27+ memory B-cell lymphocytes were significantly depleted at M6 (both 

<.0001). Although percentages of CD8+ lymphocytes remained unchanged, a significant increase in CD4+ lymphocyte levels was found at M6 [M0: 44.7% (10.8) to M6: 52.6% (8.8); 

Among CD4+ T cells, activated Treg percentage remained unchanged. However, quiescent Treg significantly increased (M0: 1.56% [1.36] to M6: 2.3% [2.2]; 

=.036). There was no observed change in natural killer and natural killer T-cell populations. 

These results suggest that rituximab treatment is associated with an unexpected upregulation of circulating CD4+ lymphocytes and quiescent Treg levels, the latter of which the researchers hypothesize could reflect the reduced conversion of Treg into activated Treg in rituximab responders. However, future trials with a larger cohort and a longer follow-up are needed. 

presented at the same meeting compared rituximab with fingolimod, dimethyl fumarate, and natalizumab in patients with MS. Most had relapsing-remitting disease. Researchers found the odds of discontinuing treatment at 24 months or less was lower for patients taking rituximab versus fingolimod and dimethyl fumarate. The researchers said that rituximab demonstrated the lowest unadjusted disease activity outcomes of all the treatments, which are considered highly effective therapies. 

The study included 182, 271, 342, and 451 patients who initiated rituximab, fingolimod, dimethyl fumarate, and natalizumab, respectively, between January 2010 and October 2013. The primary outcome was the probability of drug discontinuation by the end of year 2. The researchers controlled for age, disease duration, type of MS, gender, and enhancing lesion at baseline. 

At 24 months, 46 (25.3%), 93 (34.3%), 161 (47.1%), and 147 (32.6%) patients discontinued rituximab, fingolimod, dimethyl fumarate, and natalizumab, respectively. Fingolimod versus rituximab had an adjusted odds ratio (aOR) of 1.96 (95% CI, 1.23-3.13; 

=.005) of discontinuation by 24 months. Dimethyl fumarate versus rituximab had an aOR of 3.32 (95% CI, 2.15-5.13; 

<.001). Natalizumab versus rituximab had an aOR of 1.50 (95% CI, 0.99-2.28; 

The leading cause of discontinuation of rituximab and natalizumab were issues involving insurance (9.9%), and being positive for John Cunningham Virus (12.6%), respectively. 

Adverse events were the leading cause for discontinuation of fingolimod (17%) and dimethyl fumarate (24.0%). Fewer rituximab-treated patients (14.8%) experienced disease activity during follow-up compared with fingolimod (34.7%, 

1. Maillart E, Ungureanu A, Derai D, et al. Impact of rituximab on Treg lymphocytes in MS patients. Presented at the European Committee for the Treatment and Research in Multiple Sclerosis annual meeting, October 10-12, 2018; Berlin, Germany. Abstract P554. https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/228398/elisabeth.maillart.impact.of.rituximab.on.treg.lymphocytes.in.ms.patients.html?f=media=3*search=rituximab*browseby=8.

2. Vollmer B, Nair K, Sillau S, Corboy J, Vollmer T, Alvarez E. Comparison of rituximab vs fingolimod, dimethyl fumarate and natalizumab in the treatment of multiple sclerosis: two year experience. Presented at the European Committee for the Treatment and Research in Multiple Sclerosis annual meeting, October 10-12, 2018; Berlin, Germany. Abstract P562. https://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/228406/brandi.vollmer.comparison.of.rituximab.vs.fingolimod.dimethyl.fumarate.and.html?f=menu=14*media=3*speaker=546718*browseby=8.

Research Underscores Rituximab's Utility in Treating MS

Results of a small Greek observational study suggest that biosimilar infliximab may be an effective alternative for the treatment of patients with inflammatory bowel disease (IBD) who have active disease and experienced a loss of response to innovator infliximab (Remicade). 

researchers led by Eleni Orfanoudaki, MD, department of gastroenterology, University Hospital of Heraklion, Heraklion, Greece, reported results of a switch to the biosimilar in 15 patients who failed to respond to other biologics, including the reference infliximab. The patients were switched to the biosimilar at 5 mg/kg on weeks 0, 2, 6, and every 8 weeks thereafter. 

The researchers noted that although there have been several studies on switching from the reference to the biosimilar in patients whose IBD is in remission, there have been no published results to date on the use of the biosimilar in patients with active disease and a history of loss of response to the reference.

Thus, they reported what they called “unexpected results” with the use of the biosimilar in patients with active IBD and secondary loss of response to innovator infliximab:

8 patients (57%) had a clinical response to the biosimilar by a Harvey Bradshaw Index (HBI) or a Simple Clinical Colitis Activity Index (SCAI) reduction of greater than 2 (

Mean (standard error) erythrocyte sedimentation rate decreased from 51 (6) to 31 (3) mm/h (

Mean C-reactive protein decreased from 10.3 (4.7) to 1.5 (0.4) mg/dL (

There were no available measurements of trough levels and anti-infliximab antibodies, however, and only limited endoscopic data for a few patients. Nonetheless, the results of the small observational study suggest that the biosimilar may be an effective alternative for IBD patients with active disease and loss of response to the reference, the researchers conclude. “The underlying mechanism of action of [the biosimilar] in these cases as well as a further validation of this finding could be assessed by future prospective controlled studies including drug pharmacokinetics," they wrote.

Orfanoudaki E, Drygiannakis I, Koutroubakis I. Letter: Is there a role for infliximab biosimilar in patients with inflammatory bowel disease with secondary loss of response to infliximab innovator? 

Jackie Syrop

Study Finds ABP 215 and Bevacizumab Demonstrate PK Similarity in Japanese Men

Quantification Assays Optimized for Remicade Can Be Used to Monitor Biosimilar Flixabi

Research Underscores Rituximab's Utility in Treating MS

Does Biosimilar Infliximab Have a Role After Secondary Loss of Response to Its Reference?