Publications by authors named "Wendy J Komocsar"

Mirikizumab is a p19-directed anti-interleukin-23 antibody approved for the treatment of adults with moderate-to-severe ulcerative colitis (UC). Here, we report the first data of mirikizumab pharmacokinetics (PK) and exposure-response (E/R) relationships in pediatric participants (aged 2 to <18 years weighing >10 kg) with moderate-to-severe UC from the phase II, open-label study SHINE-1 (NCT04004611). PK parameters were analyzed using a model developed previously in adults with fixed-exponent allometry for body weight.

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Drug hypersensitivity reactions (DHRs) are a type of adverse drug reaction that can occur with different classes of drugs and affect multiple organ systems and patient populations. DHRs can be classified as allergic or non-allergic based on the cellular mechanisms involved. Whereas nonallergic reactions rely mainly on the innate immune system, allergic reactions involve the generation of an adaptive immune response.

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Background: To assess disease activity, steroid-free remission, and other clinical outcome assessments among pediatric patients with ulcerative colitis (UC) and Crohn's disease (CD) in the ImproveCareNow (ICN) registry.

Methods: Patients aged 2-17 years diagnosed with UC or CD between June 1, 2013 and December 31, 2019 were enrolled if they initiated a biologic after enrollment in the ICN registry and completed at least 12 months follow-up after first maintenance dose. Baseline (at biologic initiation) demographics were summarized using descriptive statistics.

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Article Synopsis
  • The study aimed to analyze treatment patterns and dosing of biologics in pediatric patients (ages 2-17) with ulcerative colitis (UC) or Crohn's disease (CD) over a period of 3 years using the ImproveCareNow registry data.* -
  • In patients with UC, corticosteroid and 5-ASA use decreased over time, while 6-MP/AZA and anti-TNFs increased; for CD, corticosteroid use also decreased, with an increase in methotrexate and anti-TNFs.* -
  • The study found that while corticosteroids were commonly used at the start, anti-TNFs were the most prevalent biologics, but the doses reported were significantly higher
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  • Master protocols are advanced clinical trial designs that enhance analytics and operations, aimed at benefiting both patients and drug developers, but their use in pediatric drug development has primarily been limited to oncology.* -
  • The article discusses how master protocols can facilitate pediatric drug programs mandated by the FDA and EMA, allowing for the use of adult trial data to inform pediatric efficacy and safety in small populations.* -
  • Janssen and Lilly are collaborating on a pediatric platform trial for Crohn's disease using Bayesian analysis, emphasizing the advantages of a unified study framework to expedite drug approvals and increase access to effective treatments for children.*
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Background: Ulcerative colitis (UC) often first presents during adolescence and early adulthood. Primary symptoms of UC are well known, yet similarities and differences of disease experience in adults and adolescents are not well characterized.

Methods: To understand the health-related quality of life (HRQoL) and symptomatic experience of UC, in-depth interviews were conducted in the US with 21 adults (20-70 years) and 14 adolescents (12-17 years).

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Background: Clinical guidelines recommend pneumococcal and tetanus vaccinations in patients with rheumatoid arthritis (RA). Baricitinib is an oral, selective Janus kinase (JAK) 1/JAK 2 inhibitor and is approved for the treatment of moderately to severely active RA in adults in over 50 countries including European countries, the USA, and Japan. This substudy evaluated pneumococcal conjugate and tetanus toxoid vaccine (TTV) responses in patients with RA receiving baricitinib.

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Objective: To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52-week, randomized, placebo-controlled, double-blind studies in which patients were treated with the BAFF-blocking IgG4 monoclonal antibody tabalumab.

Methods: Patient samples were obtained from SLE patients from the ILLUMINATE-1 and ILLUMINATE-2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52.

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Objectives: The efficacy and safety of 2 different dosing regimens of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor (BAFF), were evaluated in patients with rheumatoid arthritis.

Methods: In this phase 3, multicenter, randomized study, 1004 patients (intention-to-treat population) received subcutaneous 120 mg tabalumab every 4 weeks (120/Q4W), 90 mg tabalumab every 2 weeks (90/Q2W), or placebo over 24 weeks. At baseline, a loading dose double the planned dose (ie, 240 mg, 180 mg, or placebo) was administered.

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Objectives: Randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX-IR).

Methods: 1041 patients with moderate-severe RA despite ongoing MTX enrolled in a 52-week study evaluating subcutaneous tabalumab 120 mg every four weeks (120/Q4W) or 90 mg every two weeks (90/Q2W) versus placebo. Primary endpoints were American College of Rheumatology 20% (ACR20) response rate and Health Assessment Questionnaire-Disability Index change from baseline at 24 weeks and modified Total Sharp Score (mTSS) change at 52 weeks.

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The potential immunotoxicity of tabalumab was assessed as a component of standard pre-clinical toxicology studies in cynomolgus monkeys. To evaluate potential tabalumab-associated immunosuppression after antigen challenge, cynomolgus monkeys were administered placebo control or tabalumab in three immunotoxicological safety studies. Study 1, a 4-week pilot study, evaluated biweekly intravenous (IV) control, and 0.

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Introduction: The objective of this study was to evaluate the long-term safety and efficacy of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor, in rheumatoid arthritis (RA) patients.

Methods: Patients with RA who completed one of two 24-week randomized controlled trials (RCTs) participated in this 52-week, flexible-dose, open-label extension study. Patients in RCT1 received intravenous placebo, 30-mg tabalumab or 80-mg tabalumab every 3 weeks, and patients in RCT2 received subcutaneous placebo or 1-, 3-, 10-, 30-, 60- or 120-mg tabalumab every 4 weeks (Q4W).

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The development and regulatory approval of immunomodulatory pharmaceuticals to treat many human diseases has increased significantly over the last two decades. As discussed by FDA and ICH guidelines, all human pharmaceuticals in development should be evaluated for potential adverse effects on the immune system. Developmental immunotoxicology (DIT) focuses on the concern that early-life (during pre-/post-natal development) exposure to agents which target the immune system may result in enhanced susceptibility to immune-related disease (e.

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Article Synopsis
  • Exposure to p38alpha MAPK inhibitors in Beagle dogs leads to acute toxicity characterized by symptoms like decreased activity, diarrhea, and fever, alongside severe lymphoid tissue damage and hemorrhages.
  • The earliest noticeable changes include lymphocyte death in gut-associated lymphoid tissue, progressing to inflammation and additional tissue damage in lymph nodes and spleen.
  • These toxic effects were specific to dogs, as similar observations were not found in other tested species like mice, rats, or monkeys, highlighting the unique response to p38alpha MAPK inhibition in dogs.
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Results from earlier experiments in our laboratories revealed that both selective and non-selective inhibitors of cyclooxygenase-2 possess little potential for decreasing in vitro phagocytosis by rat macrophages or canine neutrophils, and no potential for decreasing in vivo phagocytosis by the intact murine immune system. We have also demonstrated that pharmacologically relevant doses and concentrations of these drugs do not reduce canine complement activation, superoxide anion generation, leukocytic chemotaxis or transmigration of leukocytes through endothelial monolayers. We now report the results of immunotoxicology studies to assess the effects of the drugs on cell-mediated immunity.

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Results from earlier experiments in our laboratories revealed that both selective and nonselective inhibitors of cyclooxygenase-2 possess little potential for decreasing in vitro phagocytosis by rat macrophages or canine neutrophils and no potential for decreasing in vivo phagocytosis by the intact murine immune system. We now report the results of studies to assess in vitro and ex vivo effects of the drugs on 1) canine complement activation, 2) generation of superoxide anion and hydrogen peroxide (oxidative burst) by canine neutrophils, and 3) leukocytic chemotaxis and transmigration through endothelial cell monolayers. In vitro concentrations of naproxen sodium, SC-236, SC-245, and SC-791 ranging from 0.

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Although both experimental and clinical literature contain reports suggestive of associations between enhanced susceptibility to soft tissue infections and nonsteroidal anti-inflammatory drug (NSAID) use, the immunotoxicological potential of this class of therapeutic agents has not been thoroughly investigated. In consideration of the widespread clinical use of these agents, we have initiated studies of the interaction between NSAIDs (both nonselective and selective COX-2 inhibitors) and the immune system. This communication describes the conduct and results of assessments of the effects of NSAIDs on the in vitro phagocytic activity of rat macrophages and canine neutrophils and on the functional activity of the intact murine mononuclear phagocytic system.

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