Search

Background: Several studies reported lower drug concentrations with subcutaneous natalizumab compared to intravenous natalizumab. With the emergence of extended interval dosing, gaining more insight into lower concentrations after subcutaneous administration is essential., Methods: We compared serum trough concentrations between subcutaneous and intravenous administration within a matched cohort (n = 50)., Results: Subcutaneous administration (n = 25) was associated with lower concentrations compared to intravenous administration (n = 25) (log-B=-0.28, p = 0.01). In an exploratory group of 11 patients receiving extended interval dosing of subcutaneous natalizumab, the median trough concentration was even lower., Conclusion: Subcutaneous natalizumab can lead to lower drug concentrations, potentially limiting extended interval dosing., Competing Interests: Declaration of competing interest L.M.Y.G. had nothing to disclose. S.L. has nothing to disclose. A.A.T. has nothing to disclose. J.H. has nothing to disclose. F.C.L. has nothing to disclose. T.R. has received funding for research from Genmab; received consulting fees from Novartis. J.K. has received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche Ltd, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trials of Immunic (payments to institution only). E.C.T. has received honorarium for consulting work from Biogen, Janssen, Merck, Novartis, and Roche. She has received travel grants to attend or speak at educational meetings from Biogen, Merck, Roche and Novartis. Z.L.E.v.K. has nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure., Methods: Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model., Results: The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength., Interpretation: These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent form and a less potent, functionally monovalent form. Total NAT and endogenous IgG4 concentrations vary considerably across patients. This study assessed the concentration of intact NAT, and how it relates to total NAT and endogenous IgG4 levels in blood and saliva., Methods: Paired serum and saliva samples from a small cohort of relapsing-remitting multiple sclerosis patients were measured for levels of intact NAT, total NAT, IgG and IgG4., Results: Intact NAT concentration was dependent on both total NAT and endogenous IgG4 levels. Low endogenous IgG4 led to a higher ratio of intact NAT to total NAT, while the opposite was observed in subjects with high endogenous IgG4. Serum and saliva measurements show good concordance., Conclusions: Intact NAT concentration is influenced by both NAT pharmacokinetics and endogenous IgG4 levels. Patients with low IgG4 levels can have high concentrations of intact NAT even with lower levels of total NAT, which may explain cases of NAT-associated progressive multifocal leukoencephalopathy (PML) in such patients. Monitoring both forms of NAT could better guide dosing, maximizing drug efficacy and safety., Competing Interests: Declaration of competing interest At the time of writing, Dr. Bradley Messmer was CSO of Aegirbio AB and received stock compensation from Aegirbio AB. J. Foley has received research support from Biogen, Octave, and Genentech. He received speakers' honoraria from Biogen. He has participated in advisory boards for Biogen, Horizon, Sandoz, and TG Therapeutics. He is the founder of InterPro Biosciences. L.J.P, I.F.P, R.H, T.H and E.T.C report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Site-specific immunomodulators (SSIs) are a novel class of therapeutics made from inactivated bacterial species designed to regulate the innate immune system in targeted organs. QBECO is a gut-targeted SSI that is being advanced clinically to treat and/or prevent inflammatory bowel disease, cancer, and serious infections of the gastrointestinal (GI) tract and proximal organs, and QBKPN is a lung-targeted SSI that is in clinical development for the treatment and/or prevention of chronic inflammatory lung disease, lung cancers and respiratory tract infections. While these SSIs have demonstrated both safety and proof-of-concept in preclinical and clinical studies, detailed understanding of their trafficking and biodistribution is yet to be fully characterized., Methods: QBECO and QBKPN were radiolabeled with [ 89 Zr] and injected subcutaneously into healthy mice. The mice underwent Positron Emission Tomography (PET) imaging every day for eight days to track biodistribution of the SSIs. Tissue from the site of injection was collected and immunohistologically probed for immune cell infiltration., Results: Differential biodistribution of the two SSIs was seen, adhering to their site-specific targeting. QBKPN appeared to migrate from the site of injection (abdomen) to the cervical lymph nodes which are nearer to the respiratory tract and lungs. QBECO remained in the abdominal region, with lymphatic trafficking to the inguinal lymph nodes, which are nearer to GI-proximal tissues/organs. Immune infiltration at the site of injection comprised of neutrophils for both SSIs, and macrophages for only QBKPN., Conclusion: Radiolabeling of SSIs allows for longitudinal in vivo imaging of biodistribution and trafficking. PET imaging revealed differential biodistribution of the SSIs based on the organotropism of the bacteria from which the SSI is derived. Trafficking from the site of injection to the targeted site is in part mediated via the lymphatics and involves macrophages and neutrophils., Competing Interests: Declaration of competing interest SK is an employee of Qu Biologics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)