Fei Hua

Anti-IL21 receptor monoclonal antibody (ATR-107): Safety, pharmacokinetics, and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study.

Safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ATR‐107, a fully human monoclonal anti‐IL‐21 receptor (IL‐21R) antibody, administered as ascending single doses, subcutaneously or intravenously, was evaluated in a placebo‐controlled, double‐blind trial in healthy subjects. The dose levels were 3–300 mg by SC and 30–120 mg by IV. The most important adverse events were hypersensitivity reactions occurring in three out of six subjects in 300 mg SC cohort and considered as dose limiting toxicity. More than 75% of the subjects who received ATR‐107 developed anti‐drug antibodies (ADAs), which had no discernible impact on PK or safety. The PK of ATR‐107 appeared to be dose ‐proportional. T1/2 was shorter than typical therapeutic antibodies. Bioavailability of ATR‐107 was about 30%. IL‐21R occupancy was measured in circulating B cells in the 60 and 120 mg IV cohort. The data indicated that single dose of ATR‐107 was able to maximally occupy IL‐21Rs through at least Day 42. Further escalation in the FIH study was halted partially due to the high rates of ADA formation. In conclusion, ATR‐107 had a prolonged PD effect measured by IL‐21R occupancy; was highly immunogenic after single dose administration and had PK properties with rapid clearance and low bioavailability.

A pharmacokinetic comparison of anrukinzumab, an anti- IL-13 monoclonal antibody, among healthy volunteers, asthma and ulcerative colitis patients.

AIMS Anrukinzumab is an anti-IL13 monoclonal antibody. The goals of this study are to characterize the pharmacokinetics of anrukinzumab in healthy volunteers and different disease states and to identify covariates. METHODS A population pharmacokinetic (PK) model was developed in NONMEM, using data from five clinical studies including healthy volunteers, asthma and ulcerative colitis (UC) patients. Different dosing regimens including different routes of administration were also included in the data. RESULTS The PK of anrukinzumab were described by a two compartment model with first order absorption and elimination. The population estimates (relative standard error) of the volumes of distribution in the central (Vc ) and peripheral (Vp ) compartments were 3.8 (4.6%) and 2.2 l (8.7%), respectively. In non-UC patients, the population estimate of the systemic clearance (CL) and inter-compartmental CL was 0.00732 l h(-1) (4.9%) and 0.0224 l h(-1) (15.4%). For subcutaneous administration, the absorption rate constant was 0.012 h(-1) (6.6%) and bioavailability was nearly 100% in healthy and mild to moderate asthma patients. Both V and CL increased with body weight. CL (but not V) decreased with increasing baseline albumin concentrations. UC patients had an increased CL of 72.3% (10.5%), after correction for differences in body weight and albumin. Moderate to severe asthma patients had decreased bioavailability compared with other populations. CONCLUSIONS Anrukinzumabs PK behave like a typical antibody. UC patients were identified to have a faster CL of anrukinzumab than healthy volunteers and asthma patients. This finding suggests a higher dose level may be required for this population.

Using a Systems Pharmacology Model of the Blood Coagulation Network to Predict the Effects of Various Therapies on Biomarkers

A number of therapeutics have been developed or are under development aiming to modulate the coagulation network to treat various diseases. We used a systems model to better understand the effect of modulating various components on blood coagulation. A computational model of the coagulation network was built to match in‐house in vitro thrombin generation and activated Partial Thromboplastin Time (aPTT) data with various concentrations of recombinant factor VIIa (FVIIa) or factor Xa added to normal human plasma or factor VIII‐deficient plasma. Sensitivity analysis applied to the model revealed that lag time, peak thrombin concentration, area under the curve (AUC) of the thrombin generation profile, and aPTT show different sensitivity to changes in coagulation factors’ concentrations and type of plasma used (normal or factor VIII‐deficient). We also used the model to explore how variability in concentrations of the proteins in coagulation network can impact the response to FVIIa treatment.

Phase 1 dose-escalating study to evaluate the safety, pharmacokinetics, and pharmacodynamics of a recombinant factor Xa variant (FXaI16L )

Essentials FXaI16L is a recombinant zymogen‐like variant of activated coagulation factor X (FXa). A phase 1 dose escalation clinical trial of FXaI16L was conducted in healthy adults. FXaI16L was safe and tolerated at doses up to 5 μg/kg; no dose‐limiting toxicity was observed. Data support further development of FXaI16L for patients with acute hemorrhagic conditions.

A mechanistic PK/PD model for two anti-IL13 antibodies explains the difference in total IL-13 accumulation observed in clinical studies

ABSTRACT IMA-638 and IMA-026 are humanized IgG1 monoclonal antibodies (mAbs) that target non-overlapping epitopes of IL-13. Separate first-in-human single ascending dose studies were conducted for each mAb. These studies had similar study designs, but mild to moderate asthmatics were recruited for the IMA-638 study and healthy subjects were recruited for the IMA-026 study. IMA-638 and IMA-026 showed similar pharmacokinetic (PK) profiles, but very different total IL-13 (free and drug bound IL-13) profiles; free IL13 was not measured. IMA-026 treatment induced a dose-dependent accumulation of total IL-13, while IMA-638 treatment led to a much smaller accumulation without any clear dose-response. To understand the differences between the two total IL-13 profiles and to predict the free IL-13 profiles for each mAb treatment, a mechanistic PK/pharmacodynamic model was developed. PK-related parameters were first fit to the mean PK profiles of each mAb separately; thereafter, the target-related parameters were fit to both total IL-13 profiles simultaneously. The IL-13 degradation rate was assumed to be the same for asthma patients and healthy subjects. The model suggests that an approximately 100× faster elimination of IL-13-IMA-638 complex than IL-13-IMA-026 complex could be responsible for the differences observed in total IL-13 profiles for the two mAbs. Furthermore, the model predicts that IMA-638 administration results in greater and more prolonged free IL-13 inhibition than equivalent dosing of IMA-026 despite similar binding KD and PK profile. In conclusion, joint modeling of two similar molecules provided mechanistic insight that the elimination rate of mAb-target complex can regulate the degree of free target inhibition.

P516 Discrepancy between fecal biomarkers and their intestinal gene expression in ulcerative colitis: Results from an anti-IL-13 antibody study

Methods: A questionnaire about disease (type, localization, diagnosis, treatment and surveillance) was distributed to IBD patients who attended outpatient gastroenterology clinic at our Hospital. The answers were categorized as appropriate or inappropriate. Demographic data, education level and features of the disease were recorded. Results: 73 patients were included (41 females) with a mean age of 44 years-old and a mean duration of IBD of 9.4 years. There were 42 patients with Ulcerative Colitis, 29 with Crohn’s disease and 2 with unclassified IBD. The mean of appropriate answers was 53.6%. The type of IBD was correctly marked in 86% of patients whereas the specific localization of the disease was recognized in only 27%. 95% of the responders considered colonoscopy important in diagnosis. Only 55% of the patients were aware of the increased risk of bowel cancer. A better performance in the questionnaire was associated with: younger patients at diagnosis (r = 0.593; p = 0.000) and at the time of the questionnaire (r = 0.451; p = 0.000), a higher education level (F = 5.976; p = 0.001), presence of Crohn’s Disease (65% versus 46%, F = 6.990; p = 0.000), previous hospitalization (60% versus 42%, t = 4.197; p = 0.000) or surgery related to the disease (66% vs 51%, t = 2.401; p = 0.019) and multiple past medications (including 2 anti-tumor necrosis factor therapy) (F = 4.194; p = 0.000). Conclusions: The age, the educational level of the patient and the severity of the disease requiring hospitalization, surgery or aggressive therapy, were associated with a better knowledge of the disease. The low percentage (marginally positive) of appropriate responses highlights the need for better educational strategies.

A Quantitative Systems Pharmacology Model of Blood Coagulation Network Describes In Vivo Biomarker Changes in Non-Bleeding Subjects.

Essentials Baseline coagulation activity can be detected in non‐bleeding state by in vivo biomarker levels. A detailed mathematical model of coagulation was developed to describe the non‐bleeding state. Optimized model described in vivo biomarkers with recombinant activated factor VII treatment. Sensitivity analysis predicted prothrombin fragment 1 + 2 and D‐dimer are regulated differently.

Mo1207 Discrepancy Between Fecal Biomarkers and Their Intestinal Gene Expression in Ulcerative Colitis: Results From an Anti-IL-13 Antibody Study

Methods: A questionnaire about disease (type, localization, diagnosis, treatment and surveillance) was distributed to IBD patients who attended outpatient gastroenterology clinic at our Hospital. The answers were categorized as appropriate or inappropriate. Demographic data, education level and features of the disease were recorded. Results: 73 patients were included (41 females) with a mean age of 44 years-old and a mean duration of IBD of 9.4 years. There were 42 patients with Ulcerative Colitis, 29 with Crohn’s disease and 2 with unclassified IBD. The mean of appropriate answers was 53.6%. The type of IBD was correctly marked in 86% of patients whereas the specific localization of the disease was recognized in only 27%. 95% of the responders considered colonoscopy important in diagnosis. Only 55% of the patients were aware of the increased risk of bowel cancer. A better performance in the questionnaire was associated with: younger patients at diagnosis (r = 0.593; p = 0.000) and at the time of the questionnaire (r = 0.451; p = 0.000), a higher education level (F = 5.976; p = 0.001), presence of Crohn’s Disease (65% versus 46%, F = 6.990; p = 0.000), previous hospitalization (60% versus 42%, t = 4.197; p = 0.000) or surgery related to the disease (66% vs 51%, t = 2.401; p = 0.019) and multiple past medications (including 2 anti-tumor necrosis factor therapy) (F = 4.194; p = 0.000). Conclusions: The age, the educational level of the patient and the severity of the disease requiring hospitalization, surgery or aggressive therapy, were associated with a better knowledge of the disease. The low percentage (marginally positive) of appropriate responses highlights the need for better educational strategies.