Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFN beta)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFN beta-1a subcutaneous and IFN beta-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFN beta-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFN beta therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFN beta in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFN beta. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers

Low Percentage of Signal Regulatory Protein α/β+ Memory B Cells in Blood Predicts Development of Anti-drug Antibodies (ADA) in Adalimumab-Treated Rheumatoid Arthritis Patients

An important goal for personalized treatment is predicting response to a particular therapeutic. A drawback of biological treatment is immunogenicity and the development of antibodies directed against the drug [anti-drug antibodies (ADA)], which are associated with a poorer clinical outcome. Here we set out to identify a predictive biomarker that discriminates rheumatoid arthritis (RA) patients who are more likely to develop ADA in response to adalimumab, a human monoclonal antibody against tumor necrosis factor (TNF)α. By taking advantage of an immune-phenotyping platform, LEGENDScreen™, we measured the expression of 332 cell surface markers on B and T cells in a cross-sectional adalimumab-treated RA patient cohort with a defined ADA response. The analysis revealed seven differentially expressed markers (DEMs) between the ADA+ and ADA− patients. Validation of the DEMs in an independent prospective European cohort of adalimumab treated RA patients, revealed a significant and consistent reduced frequency of signal regulatory protein (SIRP)α/β-expressing memory B cells in ADA+ vs. ADA− RA patients. We also assessed the predictive value of SIRPα/β expression in a longitudinal RA cohort prior to the initiation of adalimumab treatment. We show that a frequency of < 9.4% of SIRPα/β-expressing memory B cells predicts patients that will develop ADA, and consequentially fail to respond to treatment, with a receiver operating characteristic (ROC) area under the curve (AUC) score of 0.92. Thus, measuring the frequency of SIRPα/β-expressing memory B cells in patients prior to adalimumab treatment may be clinically useful to identify a subgroup of active RA subjects who are going to develop an ADA response and not gain substantial clinical benefit from this treatment

Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants

Abstract SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor‐interacting serine/threonine protein kinase 1 (RIPK1). This phase I first‐in‐human healthy participant study (NCT05795907) was comprised of three parts: randomized, double‐blind, placebo‐controlled single ascending dose (SAD; part 1a); 14‐day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open‐label, single‐dose part 1b (PK‐cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well‐tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half‐lives (geometric mean) ranged between 5.7–8.0 h and 7.2–8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF‐to‐unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166‐RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547)

Low Percentage of Signal Regulatory Protein α/β+ Memory B Cells in Blood Predicts Development of Anti-drug Antibodies (ADA) in Adalimumab-Treated Rheumatoid Arthritis Patients

An important goal for personalized treatment is predicting response to a particular therapeutic. A drawback of biological treatment is immunogenicity and the development of antibodies directed against the drug [anti-drug antibodies (ADA)], which are associated with a poorer clinical outcome. Here we set out to identify a predictive biomarker that discriminates rheumatoid arthritis (RA) patients who are more likely to develop ADA in response to adalimumab, a human monoclonal antibody against tumor necrosis factor (TNF)α. By taking advantage of an immune-phenotyping platform, LEGENDScreen™, we measured the expression of 332 cell surface markers on B and T cells in a cross-sectional adalimumab-treated RA patient cohort with a defined ADA response. The analysis revealed seven differentially expressed markers (DEMs) between the ADA+ and ADA- patients. Validation of the DEMs in an independent prospective European cohort of adalimumab treated RA patients, revealed a significant and consistent reduced frequency of signal regulatory protein (SIRP)α/β-expressing memory B cells in ADA+ vs. ADA- RA patients. We also assessed the predictive value of SIRPα/β expression in a longitudinal RA cohort prior to the initiation of adalimumab treatment. We show that a frequency of < 9.4% of SIRPα/β-expressing memory B cells predicts patients that will develop ADA, and consequentially fail to respond to treatment, with a receiver operating characteristic (ROC) area under the curve (AUC) score of 0.92. Thus, measuring the frequency of SIRPα/β-expressing memory B cells in patients prior to adalimumab treatment may be clinically useful to identify a subgroup of active RA subjects who are going to develop an ADA response and not gain substantial clinical benefit from this treatment

ABIRISK Consortium Recommendations for Terms and Definitions for Describing and Interpreting Unwanted Immunogenicity of Biopharmaceuticals

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies, and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those responses that affect clinical safety or efficacy, remain among the most common negative effects associated with this important class of drug therapies. Therefore, there is a growing need to elucidate the underlying causes and to evaluate methods for predicting and mitigating immunogenicity. Supported by the Innovative Medicines Initiative (IMI; www.imi-europe.org), the ABIRISK consortium (Anti-Biopharmaceutical [BP] Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu), was formed in 2012 with participants representing a network of leaders from various communities who have an interest in furthering the understanding and reducing the risk of BP immunogenicity: clinicians involved in the care of patients treated with various type of BPs, academic scientists researching mechanisms of immunogenicity, and EFPIA (European Federation of Pharmaceutical Industries and Associations) scientists involved in development of BPs. ABIRISK’s goal of improving the understanding of BP immunization should also lead to the generation of guidelines for drug development and the clinical care of patients. A prerequisite to understanding the impact of immunogenicity is to provide clear definitions around terms and concepts related to immunogenicity, its prediction, and associated clinical events. An overview of the concepts behind key terms and definitions adopted to date by ABIRISK is provided in this document along with a link to the documented ABIRISK terms and definitions that will be maintained on the ABIRISK website throughout the duration of the consortium. It is anticipated that refinement of definitions as well as introduction of new terms will be needed over the 5 year duration of the consortium’s work. In addition, ABIRISK will invite comment on these terms, definitions and concepts from other immunogenicity experts within the broader community of medical, academic, and pharmaceutical scientists outside of the ABIRISK consortium. Therefore, it is the consortium’s intention to maintain the most current version on the ABIRISK site for public use, review and comment

ABIRISK Consortium Recommendations for Terms and Definitions for Describing and Interpreting Unwanted Immunogenicity of Biopharmaceuticals

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies, and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those responses that affect clinical safety or efficacy, remain among the most common negative effects associated with this important class of drug therapies. Therefore, there is a growing need to elucidate the underlying causes and to evaluate methods for predicting and mitigating immunogenicity. Supported by the Innovative Medicines Initiative (IMI; www.imi-europe.org), the ABIRISK consortium (Anti-Biopharmaceutical [BP] Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu), was formed in 2012 with participants representing a network of leaders from various communities who have an interest in furthering the understanding and reducing the risk of BP immunogenicity: clinicians involved in the care of patients treated with various type of BPs, academic scientists researching mechanisms of immunogenicity, and EFPIA (European Federation of Pharmaceutical Industries and Associations) scientists involved in development of BPs. ABIRISK’s goal of improving the understanding of BP immunization should also lead to the generation of guidelines for drug development and the clinical care of patients. A prerequisite to understanding the impact of immunogenicity is to provide clear definitions around terms and concepts related to immunogenicity, its prediction, and associated clinical events. An overview of the concepts behind key terms and definitions adopted to date by ABIRISK is provided in this document along with a link to the documented ABIRISK terms and definitions that will be maintained on the ABIRISK website throughout the duration of the consortium. It is anticipated that refinement of definitions as well as introduction of new terms will be needed over the 5 year duration of the consortium’s work. In addition, ABIRISK will invite comment on these terms, definitions and concepts from other immunogenicity experts within the broader community of medical, academic, and pharmaceutical scientists outside of the ABIRISK consortium. Therefore, it is the consortium’s intention to maintain the most current version on the ABIRISK site for public use, review and comment