PF-04937319 / Pfizer, PegBio - LARVOL DELTA

Empirical scaling factor for predicting human pharmacokinetic profiles of disproportionate metabolites using the Css-MRTpo method and chimeric mice with humanised livers. (PubMed, Xenobiotica) - "Azilsartan, DS-1971a, and PF-04937319 produced human disproportionate metabolites, AZ-M2, DS-M1, and PF-M1, respectively. The predicted human pharmacokinetic profiles of PF-04937319 and PF-M1 were obtained from a previous study, and their outcomes were re-evaluated.Our findings revealed that the plasma concentrations of the three metabolites were unexpectedly underpredicted, whereas the three unchanged drugs were reasonably predicted. Further, the introduction of the empirical scaling factor of 3, obtained from six model compounds, improved the predictability of metabolites, suggesting the potential usefulness of the Css-MRTpo method in combination with humanised chimeric mice for predicting the pharmacokinetic profiles of disproportionate metabolites at the early stage of new drug development."

Journal • PK/PD data • Preclinical

Population Pharmacokinetic/Pharmacodynamic Analysis of the Glucokinase Activator PB201 in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus: Facilitating the Clinical Development of PB201 in China. (PubMed, Clin Pharmacokinet) - "Covariate analyses revealed enhanced absorption of PB201 by food and decreased systemic clearance with ketoconazole co-administration, while no significant covariate was identified for the pharmacodynamics...The final population PK/PD model predicted persistent and dose-dependent reductions in fasting plasma glucose and glycosylated hemoglobin levels in the Chinese T2DM population receiving 50/50 mg, 100/50 mg, and 100/100 mg PB201 twice daily for 24 weeks independent of co-administration of metformin. Overall, the proposed population PK/PD model quantitatively characterized the PK/PD properties of PB201 and the impact of covariates on its target populations, which allows the leveraging of extensive data in non-Chinese populations with the limited data in the Chinese T2DM population to successfully supported the waiver of the clinical phase II trial and facilitate the optimal dose regimen design of a pivotal phase III study of PB201 in China."

Journal • PK/PD data • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Development of a PBPK model to quantitatively understand absorption and disposition mechanism and support future clinical trials for PB-201. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The nonspecific inhibitor (fluconazole) and inducer (rifampicin) may separately increase/decrease PB-201 systemic exposure by 44% and 58% under fasted state, and by 78% and 47% under fed state. Therefore, the influence of internal and external factors on PB-201 exposure deserves attention, and the precision dose can be informed in future clinical studies based on the predicted results."

Journal • Diabetes • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus • CYP2C9 • CYP3A4

A Multi-center, Randomized, Double-Blinded, Parallel, Active and Placebo-Controlled Phase 3 Clinical Study of the glucokinase activator PB-201 in Treatment-naive Patients with Type 2 Diabetes Mellitus: A Study Protocol. (PubMed, Diabetes Obes Metab) - P3 | "This pivotal study will offer critical information regarding efficacy and safety of PB-201 in Chinese treatment naive T2DM participants which would help to establish robust evidence for the benefit-risk evaluation of this drug."

Clinical • Journal • P3 data • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Study to Evaluate the Efficacy and Safety of PB-201 in Type 2 Diabetic Mellitus Patients With Poor Glycemic Control Via Metformin Hydrochloride Monotherapy (clinicaltrials.gov) - P3 | N=546 | Not yet recruiting | Sponsor: PegBio Co., Ltd.

Monotherapy • New P3 trial • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Study to Evaluate the Safety and Efficacy of PB-201 in Treatment-naive Patients With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P3 | N=672 | Recruiting | Sponsor: PegBio Co., Ltd. | Initiation date: Jan 2022 ➔ Sep 2021

Trial initiation date • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Study to Evaluate the Safety and Efficacy of PB-201 in Treatment-naive Patients With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P3; N=672; Recruiting; Sponsor: PegBio Co., Ltd.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator PB-201 and its effects on the glucose excursion profile in drug-naïve Chinese patients with type 2 diabetes: a randomised controlled, crossover, single-centre phase 1 trial. (PubMed, EClinicalMedicine) - P1 | "Further investigation of PB-201 100 mg twice daily in confirmatory trials is warranted. PegBio."

Clinical • Journal • P1 data • PK/PD data • Diabetes • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

Study to Evaluate the Safety and Efficacy of PB-201 in Treatment-naive Patients With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P3; N=672; Not yet recruiting; Sponsor: PegBio Co., Ltd.

Clinical • New P3 trial • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A novel Css-MRTpo approach to simulate oral plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite in humans using chimeric mice with humanized livers. (PubMed, Xenobiotica) - "Transformed M1 gave an almost-flat concentration-time profile on Day 14, which was consistent with the curve observed in humans. Application of this novel method to other MIST-related compounds is discussed."

Journal • Preclinical

Study to understand efficacy and safety of investigational agent (PF-04937319) compared to approved agent (Glimepiride) in patients with diabetes on metformin (clinicaltrials.gov) - P2; N=300; Not yet open; Phase shift; P1 ->P2; New P2 trial

New trial • Phase shift • Diabetes

Study to understand efficacy and safety of investigational agent (PF-04937319) compared to approved agent (Glimepiride) in patients with diabetes on metformin (clinicaltrials.gov) - P2, N=300; Not yet recruiting -> Recruiting

Enrollment open • Diabetes

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus. (PubMed, Sci Rep) - "...The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%)...Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity."

Journal

Dorzagliatin Differentiates from Early Generation of Glucokinase Activators: An Enzyme Kinetics Study (ADA 2019) - "Partial GKAs such as AZD1656 and PF-04937319 showed β<1 and were less effective in blood glucose control. Lastly, α values for 5 GKAs all seem to fall in the range of 0.005 to 0.016, thus not appear to correlate with the behavior in clinical trials. The current study provides valuable insight to elucidate some key properties contributing to successful development of a GKA that repairs the glucose sensor function and remodels homeostasis."