Tolerability and Safety of Switching from Rituximab to Ocrelizumab: Evaluating Factors Associated with Infusion Related Reactions

Background Ocrelizumab and rituximab are frequently used treatments for multiple sclerosis (MS). Data on switching from rituximab to ocrelizumab is limited. Objectives To assess the frequency, severity, and factors of infusion related reactions (IRRs) in patients with MS who switch from rituximab to ocrelizumab, compared to those who stay on rituximab. Methods Prospective study on MS patients aged 18–65, on rituximab for at least 2 cycles, who either switched to ocrelizumab (switch group) or stayed on rituximab (comparator group) (n = 100 each). Participants were followed for IRRs, safety, and tolerability over 12 months. Results The proportion of IRRs in patients who continue on rituximab (14%) were similar to those who switched to ocrelizumab on Day 1 (14%; p = 1.000) and Week 24 (12%; p = 0.647) but higher than at Day 15 (4%; 0.005). The risk of IRRs for the switch group was associated with the presence of B cells (CD19 and/or CD20 counts ≥1%) increasing by 5.01 (1.49, 16.82) times on Day 1 (p = 0.007). Antidrug antibodies to ocrelizumab were not associated with IRRs. No other safety concerns were identified in switching to ocrelizumab. Conclusion IRRs are similar between both groups, which suggests that it is safe to switch from rituximab to ocrelizumab.

A survey of pharmacokinetic bioanalytical methods in biosimilar biological license applications (BLAs) for the assessment of target and antidrug antibodies effects

The presence of circulating targets and antidrug antibodies can influence the ability of a bioanalytical method to measure therapeutic protein (TP) concentration relevant to exposure-response evaluations. This project surveyed biosimilar submissions for their bioanalytical methods. Survey results revealed that 97% of pharmacokinetic methods designed to measure theoretically free or partial-free TPs with respect to target indeed measured free or partial-free TPs when considering experimental testing results for target effects. Antidrug antibody effect is less often evaluated. The observed trend of measuring biologically active forms of TP is consistent with the scientific understanding that pharmacokinetics of biologically active forms is more likely to be relevant to the clinical responses and evaluation of clinically meaningful differences to contribute to biosimilarity assessments.

An Integrated Analysis of Dostarlimab Immunogenicity

Monoclonal antibodies that block the interaction between programmed cell death 1 (PD-1) and its ligand (PD-L1) have revolutionized cancer immunotherapy. However, immunogenic responses to these new therapies—such as the development of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)—may represent a significant challenge to both efficacy and safety in some patients. Dostarlimab (TSR-042) is an approved, humanized, anti-PD-1 monoclonal antibody that has shown efficacy in multiple solid tumor types. Here, we report the results of an immunogenicity analysis of dostarlimab monotherapy in patients enrolled in the GARNET trial, a multicenter, open-label, single-arm phase 1 study. Overall, 477 of 478 patients (99.8%) were included in the analysis of dostarlimab antibody prevalence, and 349 out of 478 enrolled patients (73.0%) were evaluable for treatment-emergent antibodies to dostarlimab. The incidence of treatment-emergent ADAs was 2.5% at the recommended therapeutic dose (500 mg Q3W for the first 4 doses, 1000 mg Q6W until discontinuation), which is comparable to other anti-PD-(L)1 drugs. NAbs were detected in only 1.3% of patients. In the small percentage of patients who developed ADAs, there was no evidence of altered efficacy or safety of dostarlimab at the recommended dosing regimen. These findings demonstrated that treatment with dostarlimab was associated with a low risk of eliciting clinically meaningful ADAs over the course of this study, and dostarlimab is already approved by health authorities.

Novel methodology comparing two assay formats for the assessment of immunogenicity from clinical trial samples

Aim: We present a novel methodology to compare results between distinct immunogenicity assays, performed by two laboratories, for the same biotherapeutic. Materials & methods: Human serum pools from clinical trials were generated to provide representative immunogenicity titers. Pools were evaluated at two laboratories in a blinded fashion to assess the effect of assay format and laboratory change on clinical interpretation of immunogenicity results. Results: The laboratories validated two different assay formats and demonstrated comparable sensitivity and drug tolerance. Overall, the comparisons in assay format and laboratory ensured a comparable ability to detect treatment-emergent antidrug antibodies for a biotherapeutic. Conclusion: We have established an approach, using pooling of patient samples, that allows for the interlaboratory comparisons without creating duplicative results.

Efficacy and safety of levilimab in combination with methotrexate in subjects with rheumatoid arthritis: Results of phase II AURORA study

Levilimab (LVL) is a monoclonal antibody against the interleukin-6 receptor (IL6R). The article presents data obtained during 56 weeks of the AURORA phase II study.Objective: to evaluate the efficacy safety and immunogenicity of LVL in methotrexate (MTX) resistant patients with active rheumatoid arthritis (RA).Materials and methods. 105 patients with active RA were randomized in a 1:1:1 ratio into two LVL or placebo groups. LVL was administered subcutaneously at a dose of 162 mg every week (QW) or every other week (Q2W). All patients received MTX. After evaluating the primary endpoint of 20% improvement in ACR criteria (ACR20) at week 12, patients in the placebo group were switched to LVL Q2W. The study duration was 56 weeks. The frequency, profile, degree and severity of adverse events were determined in each group for safety assessment. The immunogenicity of LVL was determined by the proportion of patients with identified binding and neutralizing antidrug antibodies. Results. LVL in both regimens was superior to placebo. At week 12, the incidence of ACR20 achievement was 77.1% (LVL QW), 57.1% (LVL Q2W), and 17.1% (placebo) with 95% confidence intervals [37.53; 82.54] (p<0.0001) and [19.08; 68.42] (p=0.003) for the effect difference between LVL and placebo groups. The clinical response, more pronounced in the LVL QW group, persisted until week 52 with an increase in the proportion of patients with ACR50/70, low activity and RA remission. The most common treatment-related adverse events were laboratory abnormalities (predominantly grade 1–2) such as neutropenia, elevated alanine aminotransferase, aspartate aminotransferase levels, hypercholesterolemia, and elevated triglyceride levels. Antidrug antibodies were not identified.Conclusion. In MTX-resistant patients with active RA, the efficacy of both LVL regimens at a dose of 162 mg in combination with MTX was significantly superior to MT monotherapy. LVL QW lead to highest treatment response. LVL has been shown to be well tolerated and low immunogenicity. LVL safety profile is similar to IL6R inhibitors.

Critical reagent generation, characterization, handling and storage workflows: impact on ligand binding assays

The foundation of pharmacokinetics and antidrug antibodies assay robustness relies on the use of high-quality reagents. Over the past decade, there has been increasing interest within the pharmaceutical industry, as well as regulators, on defining best practices and scientific approaches for generation, characterization and handling of critical reagents. In this review, we will discuss current knowledge and practices on critical reagent workflows and state-of-the-art approaches for characterization, generation, stability and storage and how each of these steps can impact ligand-binding assay robustness.

Statistical methods of screening cut point determination in immunogenicity studies

Background: Currently, screening cut point (CP) calculated from an assay validation with replicates are applied to an immunogenicity study with nonreplicates, for which the antidrug antibodies rate is determined. IID treats the replicate of a sample as coming from another independent sample. AVE uses average results from each sample across runs but inter-assay variability is reduced. Therefore, we propose a random effect model (REM) for calculating CP. Materials & method: We investigate impact of noncompatibility design between validation and immunogenicity studies on CP and compare these methods. Conclusion: IID may not fit for use when replicates’ variability dominates all sources of uncertainty. REM considers covariance structure of repeated measurements. CP by REM is smaller than that by IID but larger than that by AVE.

Effectiveness and Safety of Nonmedical Switch From Adalimumab Originator to SB5 Biosimilar in Patients With Inflammatory Bowel Diseases: Twelve-Month Follow-Up From the TABLET Registry

BackgroundFew data are currently available about SB5 in inflammatory bowel diseases (IBD). The aim of this study was to assess the effectiveness and safety of SB5 in a cohort of patients with IBD in stable remission switched from the adalimumab (ADA) originator and in a cohort of patients with IBD naïve to ADA.MethodsWe prospectively enrolled patients with IBD who started ADA treatment with SB5 (naïve cohort) and those who underwent a nonmedical switch from the ADA originator to SB5 (switching cohort). Clinical remission and safety were assessed at baseline and at 3, 6, and 12 months. In addition, in a small cohort of patients who were switched, we assessed the ADA serum trough levels and antidrug antibodies at baseline, 3, and 6 months.ResultsIn the naïve cohort, the overall remission rate at 12 months was 60.42%, whereas in the switching cohort it was 89.02%. Fifty-three (36.3%) patients experienced an adverse event, and injection site pain was the most common; it was significantly more frequent in the switching cohort (P = 0.001). No differences were found in terms of ADA serum trough levels at baseline, 3, and 6 months after switching. No patient developed antidrug antibodies after the switch.ConclusionsWe found that SB5 seemed effective and safe in IBD, both in the naïve cohort and in the switching cohort. Further studies are needed to confirm these data in terms of mucosal healing.