Healthcare resource utilization of patients with warm autoimmune hemolytic anemia initiating first line therapy of oral corticosteroids with or without rituximab.

This retrospective cohort study described real-world treatment patterns and healthcare resource utilization (HCRU) of patients with warm autoimmune hemolytic anemia (wAIHA) initiating treatment with first-line (1L) oral corticosteroids (OCS) + rituximab (R) compared to 1L OCS. Patients with a wAIHA diagnosis code (D59.11) between 8/2020-3/2022 were identified using US pharmacy and medical claims databases. Patients initiating 1L OCS ± R were identified (date of initiation = 'index date') with a 1-year pre-index period and a variable (minimum 1-year) follow-up period. The final sample comprised 77 1L OCS + R patients and 400 1L OCS patients (~ 60% female, mean age > 64 years). Over the 1-year follow-up, HCRU was higher in the OCS + R cohort with higher mean number of physician office visits (22.9 and 14.4; p < 0.01), including hematology/oncology office visits, and higher utilization of rescue therapy (59.7% and 33.3%; p < 0.01), driven by higher use of injectable corticosteroids. Patients in OCS + R and OCS groups completed 1L therapy after a similar mean duration of 103.5 and 134.6 days, respectively (p = 0.24). In the majority of patients, second-line (2L) therapy was initiated at a similar timepoint: 66.2% OCS + R and 72.0% OCS cohorts (p = 0.31) initiated 2L in a mean of 218.3 and 203.2 days (p = 0.76) after the end of 1L treatment, respectively. The addition of rituximab in 1L did not extend the remission period, with most patients in both cohorts initiating 2L therapy within less than 1 year of completing 1L treatment. 1L OCS + R patients also had substantial HCRU burden. More effective novel therapies are needed to address the high unmet need in wAIHA.

Phase 3, multicentre, randomised, placebo-controlled study evaluating the efficacy and safety of ustekinumab in patients with systemic lupus erythematosus.

OBJECTIVE: Evaluate the efficacy and safety of ustekinumab, an anti-interleukin-12/23 p40 antibody, in a phase 3, randomised, placebo-controlled study of patients with active systemic lupus erythematosus (SLE) despite receiving standard-of-care. METHODS: Active SLE patients (SLE Disease Activity Index 2000 (SLEDAI-2K) ≥6 during screening and SLEDAI-2K ≥4 for clinical features at week 0) despite receiving oral glucocorticoids, antimalarials, or immunomodulatory drugs were randomised (3:2) to receive ustekinumab (intravenous infusion ~6 mg/kg at week 0, followed by subcutaneous injections of ustekinumab 90 mg at week 8 and every 8 weeks) or placebo through week 48. The primary endpoint was SLE Responder Index (SRI)-4 at week 52, and major secondary endpoints included time to flare through week 52 and SRI-4 at week 24. RESULTS: At baseline, 516 patients were randomised to placebo (n=208) or ustekinumab (n=308). Following the planned interim analysis, the sponsor discontinued the study due to lack of efficacy but no safety concerns. Efficacy analyses included 289 patients (placebo, n=116; ustekinumab, n=173) who completed or would have had a week 52 visit at study discontinuation. At week 52, 44% of ustekinumab patients and 56% of placebo patients had an SRI-4 response; there were no appreciable differences between the treatment groups in the major secondary endpoints. Through week 52, 28% of ustekinumab patients and 32% of placebo patients had a British Isles Lupus Assessment Group flare, with a mean time to first flare of 204.7 and 200.4 days, respectively. Through week 52, 70% of ustekinumab patients and 74% of placebo patients had ≥1 adverse event. CONCLUSIONS: Ustekinumab did not demonstrate superiority over placebo in this population of adults with active SLE; adverse events were consistent with the known safety profile of ustekinumab. TRIAL REGISTRATION NUMBER: NCT03517722.

Evaluating Potential Disease-Mediated Protein-Drug Interactions in Patients With Moderate-to-Severe Plaque Psoriasis Receiving Subcutaneous Guselkumab.

This open-label, multicenter, phase I therapeutic protein-drug interaction study was designed to evaluate the potential effect of guselkumab, a fully human anti-interleukin-23 immunoglobulin G1 lambda monoclonal antibody, on the pharmacokinetics of a cocktail of representative cytochrome P450 (CYP) probe substrates (midazolam (CYP3A4), S-warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and caffeine (CYP1A2)). Fourteen participants with psoriasis received a single subcutaneous dose of guselkumab 200 mg on day 8 and an oral probe cocktail on days 1, 15, and 36. Blood samples were collected for measuring plasma concentrations of these probe substrates on days 1, 15, and 36. No consistent trends in observed maximum plasma concentration and area under the curve from time 0 to infinity values of each probe CYP-substrate before (day 1) and after guselkumab treatment (days 15 and 36) could be identified in each individual patient, suggesting that the use of guselkumab in patients with psoriasis is unlikely to influence the systemic exposure of drugs metabolized by CYP isozymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2). The probe cocktail was generally well-tolerated when administered in combination with guselkumab in patients with psoriasis. Clinicaltrials.gov Identifiers: NCT02397382.

The first-in-human study of CNTO 7160, an anti-interleukin-33 receptor monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis.

AIMS: To assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 7160, an anti-interleukin-33 receptor (IL-33R) monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis (AD). METHODS: In Part 1 of this Phase I, randomized, double-blind, placebo-controlled study, healthy subjects (n = 68) received single ascending intravenous (IV) CNTO 7160 dose (0.001 to 10 mg/kg) or placebo. In Part 2, patients with mild asthma (n = 24) or mild AD (n = 15) received 3 biweekly IV CNTO 7160 doses (3 or 10 mg/kg) or placebo. RESULTS: CNTO 7160 was generally well tolerated, with 1 serious adverse event of severe cellulitis reported (AD, CNTO 7160, 3 mg/kg). CNTO 7160 exhibited nonlinear PK (0.01-10 mg/kg). Mean clearance decreased with increasing dose (2.43 to 18.03 mL/d/kg). CNTO 7160 PK was similar between healthy subjects and patients with asthma or AD (3 or 10 mg/kg). Free sIL-33R suppression was rapid and dose dependent. Ex vivo inhibition of p38 phosphorylation of basophils was dose-dependent (1-10 mg/kg) and sustained inhibition (≥75%) was observed at higher doses (3 or 10 mg/kg). PK/PD modelling and simulation suggests that 1 mg/kg IV every 2 weeks provides adequate systemic drug exposure for sustained inhibition of p38 phosphorylation of basophils. Despite confirmation of target engagement, no apparent CNTO 7160 clinical activity was observed in patients (asthma or AD). CONCLUSION: This first-in-human study provides PK, PD and safety data, supporting further clinical investigation of CNTO 7160 in patients with asthma and AD.

Pharmacokinetic-pharmacodynamic modeling of apratastat: a population-based approach.

Apratastat is an orally active, potent, and reversible dual inhibitor of tumor necrosis factor-α converting enzyme (TACE) and matrix metalloproteinases (MMPs). This study characterizes the pharmacodynamic (PD) effect of apratastat following oral administration on tumor necrosis factor-alpha (TNF-α) release. Data were obtained from 3 clinical studies carried out in healthy subjects. Apratastat was administered orally in these studies as single doses or multiple doses (twice daily). The inhibition of TNF-α release by apratastat was investigated in studies of in vitro, ex vivo, and in vivo. Inhibitory E(max) models were used to characterize the inhibition of TNF-α release in both in vitro and ex vivo studies. Apratastat inhibited TNF-α release with a population mean IC(50) of 144 ng/mL in vitro and of 81.7 ng/mL ex vivo, respectively. The relationship between TNF-α and apratastat plasma concentration in the endotoxin-challenged study in healthy subjects was well characterized by a mechanism-based PD population model with IC(50) of 126 ng/mL. Apratastat can potently inhibit the release of TNF-α in vitro, ex vivo, and in vivo. Even though the dosage provided adequate exposure to inhibit TNF-α release, apratastat was not efficacious in rheumatoid arthritis (RA). This inconsistency between TNF-α inhibition and the clinical response requires further investigation.

Integrated population pharmacokinetics of etanercept in healthy subjects and in patients with rheumatoid arthritis and ankylosing spondylitis.

Etanercept pharmacokinetics in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis were assessed separately with distinct models using population pharmacokinetics methods of limited precision. The different model structures and associated significant covariates identified by these earlier methods made it difficult to compare etanercept pharmacokinetics among disease groups. This integrated analysis aimed to establish a framework to evaluate previously established population pharmacokinetic models of etanercept, and to identify consistent and important demographic and disease factors that affected etanercept pharmacokinetics in a diverse population of healthy subjects and patients with RA and AS. In this integrated analysis, cumulative rich and sparse etanercept concentration data from 53 healthy volunteers, 212 patients with RA, and 346 patients with AS were examined and compared using nonlinear mixed effect methodology implemented the in NONMEM VI software package. A more precise estimation method (FOCEi) was employed and compared with the first-order method in population pharmacokinetics model building and evaluation. The integrated analysis found that an optimal population pharmacokinetics model with a 2-compartment structure adequately characterized etanercept pharmacokinetics in all subject groups. Health status or disease type did not significantly affect etanercept pharmacokinetics. In adult patients with RA and AS, age and body weight do not significantly affect etanercept pharmacokinetics.

Pharmacokinetic and pharmacodynamic properties of TRU-015, a CD20-directed small modular immunopharmaceutical protein therapeutic, in patients with rheumatoid arthritis: a Phase I, open-label, dose-escalation clinical study.

BACKGROUND: TRU-015 is a small modular immunopharmaceutical protein drug that binds to CD20 and effectively depleted B cells in nonhuman primates. OBJECTIVE: The aim of this clinical study was to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties, immunogenicity, and tolerability of TRU-015 in patients with rheumatoid arthritis (RA). METHODS: This Phase I, open-label, dose-escalation clinical study was conducted at 4 medical centers in the United States. Patients with RA who were receiving stable-dose methotrexate were enrolled in 1 of 8 dose groups and received TRU-015 as a single IV dose of 0.015, 0.05, 0.15, 0.5, 1.5, 5, or 15, or 2 IV doses of 15 mg/kg, administered 7 days apart (30 mg/kg). Patients were enrolled in the next higher dose cohort based on the tolerability observed in the prior cohort. Prior to TRU-015 infusion, patients were premedicated with an antihistamine and acetaminophen and may have received a corticosteroid at the investigator's discretion. Serum samples were collected for analysis of PK properties (serum t((1/2))) and neutralizing antibodies to TRU-015; enzyme-linked immunosorbent assays and a cell-based neutralizing assay were used to evaluate samples from patients. PD response was measured using B-cell (CD19(+)-cell) count using flow cytometry at prespecified time points. Tolerability was assessed during drug infusion and at prespecified time points after infusion using physical examination and laboratory analysis. Patients were followed for >or=4 weeks and until B-cell recovery. RESULTS: Thirty-seven patients were enrolled. Most were female (81%) and white (95%); the mean age was 53 years. Serum t((1/2)) ranged from 12 to 19 days. B-cell depletion generally increased in degree and duration with increasing doses. No neutralizing antibodies to TRU-015 were detected. Mild adverse events (AEs) included back pain, headache, peripheral edema, and upper respiratory infection (5 patients each). Mild urticaria occurred in 1 patient. Grade 3 AEs included hypertension, arthralgia, and urticaria and bronchospasm (1 patient each). No dose-limiting toxicity was found. CONCLUSIONS: In this small population of patients with RA, the C(max) and the AUC appeared to increase in a dose-proportional manner. The mean t((1/2)) ranged from 12 to 19 days. TRU-015 was associated with dose-dependent B-cell depletion and an acceptable tolerability profile.