Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of ...treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.
To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients.
The study combined ...retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme‐linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data.
ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2–20.2) and 0% (0–5.9) at 3 months, 17.6% (11.4–26.4) and 0% (0–25.9) at 6 months, 17.7% (12.6–37.5) and 34.1% (11.4–46.3) at 12 months, 50.0% (25.9–87.5) and 37.5% (25.9–77.4) at 15 months and 50.0% (25.9–87.5) and 66.7% (37.7–100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1–3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0–8.7; infliximab: HR 2.7, 95% CI 1.1–6.8), moderate disease activity (DAS28 3.2–5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3–33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2–6.3).
The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.
This mechanistic trial compared the pharmacodynamics and safety of lixisenatide and liraglutide in combination with optimized insulin glargine with/without metformin in type 2 diabetes (T2D).
This ...was a multicenter, randomized, open-label, three-arm trial comparing lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg once daily for 8 weeks in combination with insulin glargine after optimized titration. The primary end point was change from baseline to week 8 in incremental area under the postprandial plasma glucose curve for 4 h after a standardized solid breakfast (AUC PPG0030-0430 h). Changes from baseline in gastric emptying, 24-h plasma glucose profile, HbA1c, fasting plasma glucose (FPG), 24-h ambulatory heart rate and blood pressure, amylase and lipase levels, and adverse events (AEs) were also assessed.
In total, 142 patients were randomized and treated. Lixisenatide 20 µg achieved greater reductions of AUC PPG0030-0430 h compared with liraglutide (marginal mean 95% one-sided CI treatment difference, -6.0 -7.8 h ⋅ mmol/L -108.3 (-140.0) h ⋅ mg/dL vs. liraglutide 1.2 mg and -4.6 -6.3 h ⋅ mmol/L -83.0 (-114.2) h ⋅ mg/dL vs. liraglutide 1.8 mg; P < 0.001 for both), and gastric emptying was delayed to a greater extent than with liraglutide 1.2 and 1.8 mg (P < 0.001 for treatment comparisons). FPG was unchanged in all treatment arms. At week 8, mean ± SD HbA1c was 6.2 ± 0.4% (44 ± 5 mmol/mol), 6.1 ± 0.3% (44 ± 4 mmol/mol), and 6.1 ± 0.3% (44 ± 4 mmol/mol) for lixisenatide 20 µg and liraglutide 1.2 and 1.8 mg, respectively. At week 8, both liraglutide doses increased marginal mean ± SE 24-h heart rate from baseline by 9 ± 1 bpm vs. 3 ± 1 bpm with lixisenatide (P < 0.001). Occurrence of symptomatic hypoglycemia was higher with lixisenatide; gastrointestinal AEs were more common with liraglutide. Lipase levels were significantly increased from baseline with liraglutide 1.2 and 1.8 mg (marginal mean ± SE increase 21 ± 7 IU/L for both; P < 0.05).
Lixisenatide and liraglutide improved glycemic control in optimized insulin glargine-treated T2D albeit with contrasting mechanisms of action and differing safety profiles.
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 (IFNβ)-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, IFNβ-1a subcutaneous and IFNβ-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNβ-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 IFNβ 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 IFNβ 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 IFNβ. 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.
Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of ...treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.
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).
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.
Many biopharmaceuticals (BPs) are known to be immunogenic in the clinic, which can result in modified pharmacokinetics, reduced efficacy, allergic reactions and anaphylaxis. During recent years, ...several technologies to predict immunogenicity have been introduced, but the predictive value is still considered low. Thus, there is an unmet medical need for optimization of such technologies. The generation of T cell dependent high affinity anti-drug antibodies plays a key role in clinical immunogenicity. This study aimed at developing and evaluating a novel in vitro T cell:PBMC assay for prediction of the immunogenicity potential of BPs. To this end, we assessed the ability of infliximab (anti-TNF-α), rituximab (anti-CD20), adalimumab (anti-TNF-α) and natalizumab (anti-α4-integrin), all showing immunogenicity in the clinic, to induce a CD4+ T cells response. Keyhole limpet hemocyanin (KLH) and cytomegalovirus pp65 protein (CMV) were included as neo-antigen and recall antigen positive controls, respectively. By analyzing 26 healthy donors having HLA-DRB1 alleles matching the European population, we calculated the frequency of responding donors, the magnitude of the response, and the frequency of BP-specific T cells, as measured by 3H-thymidine incorporation and ELISpot IL-2 secretion. KLH and CMV demonstrated a strong T cell response in all the donors analyzed. The frequency of responding donors to the BPs was 4% for infliximab, 8% for adalimumab, 19% for rituximab and 27% for natalizumab, which is compared to and discussed with their respective observed clinical immunogenicity. This study further complements predictive immunogenicity testing by quantifying the in vitro CD4+ T cell responses to different BPs. Even though the data generated using this modified method does not directly translate to the clinical situation, a high sensitivity and immunogenic potential of most BPs is demonstrated.
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