Covariate effects and population pharmacokinetic analysis of the anti-FGFR2b antibody bemarituzumab in patients from phase 1 to phase 2 trials.

PURPOSE: A population pharmacokinetic (PK) analysis of the anti-fibroblast growth factor receptor 2b antibody, bemarituzumab, was performed to evaluate the impact of covariates on the PK and assess whether dose adjustment is necessary for a future phase 3 trial. METHODS: Serum concentration data were obtained from three clinical trials, with 1552 bemarituzumab serum samples from 173 patients, and were analyzed using nonlinear mixed-effects modeling. RESULTS: A two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment best described the bemarituzumab serum concentration data. The final model estimated a typical linear clearance (CL) of 0.311 L/day, volume of distribution in the central compartment (Vc) of 3.58 L, distribution clearance (Q) of 0.952 L/day, volume of distribution in the peripheral compartment (Vp) of 2.71 L, maximum drug elimination by nonlinear clearance (Vmax) of 2.80 µg/day, and Michaelis-Menten constant (Km) of 4.45 µg/mL. Baseline body weight, baseline albumin, gender, and chemotherapy were identified as statistically significant covariates on the PK of bemarituzumab. Given the low interindividual variability of bemarituzumab key PK parameters (CL and Vc) and the small or modest effect of all statistically significant covariates on bemarituzumab exposure at steady-state, no covariate is expected to have clinically meaningful effects on bemarituzumab exposure. CONCLUSION: No covariate had a clinically meaningful impact on bemarituzumab exposure. These results indicate that dose adjustment of bemarituzumab is not necessary, based on the aforementioned covariates, for a future phase 3 trial in gastric and gastroesophageal junction adenocarcinoma population with FGFR2b overexpression in combination with mFOLFOX6.

Population pharmacokinetic analysis of phase 1 bemarituzumab data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial.

PURPOSE: To report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab. METHODS: Nonlinear mixed-effect modeling was used to analyse PK data. In vitro binding affinity and receptor occupancy of bemarituzumab were determined. Simulation was conducted to estimate dose and schedule to achieve an empirical target Ctrough in a phase 2 trial (FIGHT, NCT03694522) for patients receiving first-line treatment combined with modified 5-fluourouracil, oxaliplatin and leucovorin (mFOLFOX6) for gastric and gastroesophageal junction adenocarcinoma. RESULTS: Bemarituzumab PK is best described by a two-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination from the central compartment. Albumin, gender, and body weight were identified as the covariates on the linear clearance and/or volume of distribution in the central compartment, and no dose adjustment was warranted. An empirical target of bemarituzumab Ctrough of ≥ 60 µg/mL was projected to achieve > 95% receptor occupancy based on in vitro data. Fifteen mg/kg every 2 weeks, with a single dose of 7.5 mg/kg on Cycle 1 Day 8, was projected to achieve the target Ctrough on Day 15 in 98% of patients with 96% maintaining the target at steady state, which was confirmed in the FIGHT trial. CONCLUSION: A projected dose and schedule to achieve the target Ctrough was validated in phase 1 of the FIGHT trial which supported selection of the phase 2 dose and schedule for bemarituzumab.

The Role of Fibroblast Growth Factor 10 Signaling in Duodenal Atresia.

INTRODUCTION: Duodenal atresia (DA) is a congenital bowel obstruction requiring major surgery in the first week of life. Three morphological phenotypes are described, reflecting increasing degrees of obstruction and discontinuity of the duodenum. The cause of DA is not known. Tandler's original "solid cord" hypothesis conflicts with recent biological evidence, and is unable to account for differing DA types. In humans, a genetic etiology is supported by the association between Trisomy 21 and DA, and reports of familial inheritance patterns. Interruption of FGF10/FGFR2b signaling is the best demonstrated genetic link to DA in mice, with 35-75% of homozygous knockout embryos developing DA. PURPOSE: This review examines the current evidence surrounding the etiology of DA. We focus on research regarding FGF10/FGFR2b signaling and its role in duodenal and other intestinal atresia. Further, we outline planned future research in this area, that we consider necessary to validate and better understand this murine model in order to successfully translate this research into clinical practice. CONCLUSION: Determining the etiology of DA in humans is a clinical and scientific imperative. Fgf10/Fgfr2b murine models represent current science's best key to unlocking this mystery. However, further research is required to understand the complex role of FGF10/FGFR2b signaling in DA development. Such complexity is expected, given the lethality of their associated defects makes ubiquitous interruption of either Fgf10 or Fgfr2b genes an unlikely cause of DA in humans. Rather, local or tissue-specific mutation in Fgf10, Fgfr2b, or their downstream targets, is the hypothesized basis of DA etiology.

Effect of attenuation of fibroblast growth factor receptor 2b signaling on odontoblast differentiation and dentin formation.

Attenuation of fibroblast growth factor receptor (FGFR) 2b signaling suppresses the differentiation of oral epithelial stem cells to ameloblasts, their survival and viability remaining unaffected; however, its effect on dentin formation is unknown. This study aimed to clarify the effect of attenuation of FGFR2b signaling on odontoblast differentiation and dentin formation. Initially, we used a murine rtTA transactivator/tetracycline promoter system for inducible and reversible attenuation of FGFR2b signaling in adult mice. Experimental animals overexpressed soluble FGFR2b (sFGFR2b), and wild-type controls were selected from the same litter (WT group). Histological analysis of CMV mice confirmed the obliteration of the enamel and ameloblast layer, and micro CT analysis revealed a significant increase in dentin thickness in CMV mice rather than in WT mice (P < 0.05). On analyzing the expression of dentin-related differentiation factors, DSPP, nestin, and OCN were upregulated in CMV mice compared to WT mice after 2 weeks of attenuation of FGFR2b signaling. Thereafter, on overexpressing sFGFR2b in dental pulp stem cells, RUNX2 and ALP were upregulated; however, DSPP, nestin, and OCN were downregulated in CMV mice compared to WT mice. The present results show that attenuation of FGFR2b signaling in the oral epithelium specifically induced odontoblast differentiation and promotes early-stage dentin calcification in dental pulp tissue.

In vitro morphological bud formation in organ-like three-dimensional structure from mouse ES cells induced by FGF10 signaling.

Embryonic stem (ES) cells have a pluripotent ability to differentiate into a variety of cell lineages in vitro. Using an embryoid body (EB) culture system, we developed a gut-like three-dimensional structure from mouse ES cells (the ES 3-D structure). Genetic studies implicate fibroblast growth factor 10 (FGF10)-FGF receptor 2b (FGFR2b) signaling as a critical regulator of lung bud morphogenesis in the embryonic foregut. The aim of the present study was to form a putative respiratory tract in the ES 3-D structure. By local application of FGF10 protein, we successfully demonstrated in vitro morphological formation of putative primitive respiratory tract-like processes, or buds, in the ES 3-D structure. Such organs that are differentiated from ES cells may provide new insights into tissue engineering and regenerative medicine.