Delving into the Latest Updates on Nerigliatin with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [2]

Target

glucokinase

Action

activators

Mechanism

glucokinase activators(Glucokinase activators)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus, Type 2

Inactive Indication

Diabetes Mellitus, Type 1Obesity

Originator Organization

Pfizer Inc.

Active Organization

PegBio Co., Ltd.

Inactive Organization

Pfizer Inc.

License Organization-

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC22H20N6O4

InChIKeyMASKQITXHVYVFL-UHFFFAOYSA-N

CAS Registry1245603-92-2

主要目的:通过糖化血红蛋白（ HbA1c）自基线到治疗24周后变化，评价在联合盐酸二甲双胍的条件下， PB-201与安慰剂相比对二甲双胍单药治疗血糖控制不佳的2型糖尿病患者的有效性。次要目的:在联合盐酸二甲双胍条件下，评价PB-201的安全性和治疗52周后的有效性。完善PB-201及其代谢产物的群体药代动力学模型，系统性定量研究人口学特征、糖尿病病程、合并用药等指标对药代动力学（ PK）特征的影响。

[Translation]

Primary objective: To evaluate the efficacy of PB-201 compared with placebo in patients with type 2 diabetes who have poor glycemic control on metformin monotherapy, in combination with metformin hydrochloride, by measuring the change in glycated hemoglobin (HbA1c) from baseline to 24 weeks of treatment. Secondary objective: To evaluate the safety of PB-201 in combination with metformin hydrochloride and its efficacy after 52 weeks of treatment. To improve the population pharmacokinetic model of PB-201 and its metabolites, and to systematically and quantitatively study the effects of demographic characteristics, diabetes duration, and concomitant medication on pharmacokinetic (PK) characteristics.

Start Date10 Jun 2022

Sponsor / Collaborator

PegBio Co., Ltd.

NCT05326490

/ Unknown statusPhase 3

A Multi-center, Randomized, Double-Blinded, Parallel and Placebo-Controlled Phase III Clinical Study to Evaluate the Efficacy and Safety of PB-201 in Type 2 Diabetic Mellitus Patients With Poor Glycemic Control Via Metformin Hydrochloride Monotherapy

This is a Multi-center, Randomized, Double-Blinded, Parallel and Placebo-Controlled Phase III Clinical Study to Evaluate the Efficacy and Safety of PB-201 in Type 2 Diabetic Mellitus Patients with Poor Glycemic Control via Metformin Hydrochloride Monotherapy

Start Date30 May 2022

Sponsor / Collaborator

PegBio Co., Ltd.

CTR20212666

/ RecruitingPhase 3

一项评价PB-201对未经治疗的2型糖尿病患者的有效性和安全性的多中心、随机、双盲、平行、维格列汀和安慰剂对照的III期临床研究

[Translation] A multicenter, randomized, double-blind, parallel, vildagliptin- and placebo-controlled Phase III clinical study to evaluate the efficacy and safety of PB-201 in patients with untreated type 2 diabetes

主要目的:通过糖化血红蛋白（HbA1c）自基线到治疗24周后的变化，评价PB-201与维格列汀和安慰剂相比对未经治疗的2型糖尿病患者的有效性。次要目的:评价PB-201的安全性和治疗52周后的有效性。完善PB-201及其代谢产物的群体药代动力学模型，系统性定量研究人口学特征、糖尿病病程、合并用药等指标对PK特征的影响。

[Translation]

Primary objective: To evaluate the efficacy of PB-201 compared with vildagliptin and placebo in untreated patients with type 2 diabetes by the change in glycated hemoglobin (HbA1c) from baseline to 24 weeks of treatment. Secondary objective: To evaluate the safety of PB-201 and the efficacy after 52 weeks of treatment. To improve the population pharmacokinetic model of PB-201 and its metabolites, and to systematically and quantitatively study the effects of demographic characteristics, diabetes duration, and concomitant medication on PK characteristics.

Start Date29 Dec 2021

Sponsor / Collaborator

PegBio Co., Ltd.

100 Clinical Results associated with Nerigliatin

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100 Translational Medicine associated with Nerigliatin

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100 Patents (Medical) associated with Nerigliatin

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25

Literatures (Medical) associated with Nerigliatin

01 Jan 2024·Clinical Pharmacokinetics

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

Article

Author: Lin, Zhigang ; Liang, Ruifang ; Cao, Fangrui ; Ding, Ke ; Niu, Shu ; Song, Ling ; Xu, Michael ; Liu, Dongyang ; Yao, Xueting

PB201 is an orally active, partial glucokinase activator targeting both pancreatic and hepatic glucokinase. As the second glucokinase activator studied beyond phase I, PB201 has demonstrated promising glycemic effects as well as favorable pharmacokinetic (PK) and safety profiles in patients with type 2 diabetes mellitus (T2DM). This study aims to develop a population PK/pharmacodynamic (PD) model for PB201 using the pooled data from nine phase I/II clinical trials conducted in non-Chinese healthy volunteers and a T2DM population and to predict the PK/PD profile of PB201 in a Chinese T2DM population. We developed the PK/PD model using the non-linear mixed-effects modeling approach. All runs were performed using the first-order conditional estimation method with interaction. The pharmacokinetics of PB201 were well fitted by a one-compartment model with saturable absorption and linear elimination. The PD effects of PB201 on reducing the fasting plasma glucose and glycosylated hemoglobin levels in the T2DM population were described by indirect response models as stimulating the elimination of fasting plasma glucose, where the production of glycosylated hemoglobin was assumed to be stimulated by fasting plasma glucose. 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 population PK model established for non-Chinese populations was shown to be applicable to the Chinese T2DM population as verified by the PK data from the Chinese phase I study. 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.

02 Sep 2023·Xenobiotica

Empirical scaling factor for predicting human pharmacokinetic profiles of disproportionate metabolites using the Css–MRTpo method and chimeric mice with humanised livers

Article

Author: Suemizu, Hiroshi ; Kamimura, Hidetaka ; Uehara, Shotaro ; Yoneda, Nao

Predicting plasma concentration-time profiles of disproportionate metabolites in humans is crucial for evaluating metabolites according to the Safety Testing guidelines. We evaluated Css-MRTpo, an empirical method, using chimeric mice with humanised livers capable of generating human-disproportionate metabolites. Azilsartan and AZ-M2 were administered to humanised chimeric mice, and pharmacokinetic parameters were obtained. Pharmacokinetic data for DS-1971a and DS-M1 in humanised chimeric mice were obtained from the literature. The human plasma concentration-time profiles of these compounds were simulated using the Css-MRTpo method. 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.

01 Jul 2023·CPT: Pharmacometrics & Systems Pharmacology

Development of a PBPK model to quantitatively understand absorption and disposition mechanism and support future clinical trials for PB‐201

Article

Author: Li, Haiyan ; Yao, Xueting ; Liu, Dongyang ; Xu, Min ; Zhang, Miao ; Lei, Zihan ; Yu, Ziheng

AbstractPB‐201 is the second glucokinase activator in the world to enter the phase III clinical trials for the treatment of type 2 diabetes mellitus (T2DM). Combined with the efficacy advantages and the friendly absorption, distribution, metabolism, and excretion characteristics, the indication population of PB‐201 will be broad. Because the liver is the primary organ for PB‐201 elimination, and the elderly account for 20% of patients with T2DM, it is essential to estimate PB‐201 exposure in specific populations to understand the pharmacokinetic characteristics and avoid hypoglycemia. Despite the limited contribution of CYP3A4 to PB‐201 metabolism in vivo, the dual effects of nonspecific inhibitors/inducers on PB‐201 (substrate for CYP3A4 and CYP2C9 isoenzymes) exposure under fasted and fed states also need to be evaluated to understand potential risks of combination therapy. To grasp the unknown information, the physiologically‐based pharmacokinetic (PBPK) model was first developed and the influence of internal and external factors on PB‐201 exposure was evaluated. Results are shown that the predictive performance of the mechanistic PBPK model meets the predefined criteria, and can accurately capture the absorption and disposition characteristics. Impaired liver function and age‐induced changes in physiological factors may significantly increase the exposure under fasted state by 36%–158% and 48%–82%, respectively. 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.

100 Deals associated with Nerigliatin

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15009

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 3	Hong Kong	PegBio Co., Ltd.	30 Sep 2021
Diabetes Mellitus, Type 2	Phase 3	Taiwan Province	PegBio Co., Ltd.	30 Sep 2021
Diabetes Mellitus, Type 2	Phase 3	China	PegBio Co., Ltd.	30 Sep 2021
Diabetes Mellitus, Type 1	Preclinical	China	PegBio Co., Ltd.	13 Nov 2021
Obesity	Preclinical	Singapore	Pfizer Inc.	01 Jan 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01044537 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	50	Placebo	(cujojympmh) = jcumdopssq pqnhcsvdcl (sqvyytcqnp, xdnbyqeacg - kjprugjlun) View more	-	10 Mar 2017
NCT01272804 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	61	Placebo	(grdlcfuewz) = qducycehxd sbsvhxjkmj (acldpyklce, qsjhmpoouy - qsgmgihlxz) View more	-	01 Feb 2017
NCT01517373 (CTgov)	Phase 2	Diabetes Mellitus, Type 2	304	Placebo (Placebo)	qkkterbvun(zxkjcqjhru) = rtzwlfeslc iickjzlqne (uvlpfkgkxo, iivbcaqakt - eftovndzlz) View more	-	31 Jan 2017
				PF-04937319 10 mg (PF-04937319 10 mg)	qkkterbvun(zxkjcqjhru) = nkccflqoot iickjzlqne (uvlpfkgkxo, enpgaerpdl - lwtzvulevd) View more
NCT01933672 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	33	PF-04937319 (PF-04937319 Split-Dose (150+100 mg))	weijpkmcfw(mhvdpmqiat) = pfnhasuqyi trsfttxhzv (tiyrlmwvku, nnqmodynsg - jiczdbpjvd) View more	-	27 Sep 2016
				PF-04937319 (PF-04937319 Once-Daily (300 mg))	weijpkmcfw(mhvdpmqiat) = kylsppitsi trsfttxhzv (tiyrlmwvku, pxuvppjzcl - qeiernlvha) View more
NCT02292433 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	12	Placebo	(jhhwcypwxg) = gvxzrjrpie rdtzxkilde (welewhuzvn, yoguaseplg - wbmnaqjlaz) View more	-	15 Mar 2016
NCT02206607 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	39	PF-04937319 (PF-04937319 150+100 mg IR)	mdjsxxghlo(mryempdhmo) = xubdztztad tjnknnlpsl (mdtbhvadaz, cjthfmlids - issztslyka) View more	-	04 Mar 2016
				PF-04937319 (PF-04937319 250 mg MR1)	mdjsxxghlo(mryempdhmo) = tjiqprzhbo tjnknnlpsl (mdtbhvadaz, hmmplbqhnd - rwnwsmowrc) View more
NCT01517373 \| NCT01475461 (Pubmed \| Diabetes Obes Metab)	Phase 2	Diabetes Mellitus, Type 2 Add-on	639	PF-04937319 50mg	yuavsnhzfz(kjtxfidpob) = Hypoglycaemia was reported in 2.5% of patients (on placebo), 5.1% of patients (on PF-04937319 100mg), 1.8% of patients (on sitagliptin) and 34.4% of patients (on titrated glimepiride) iovivkfrpm (bbuccnzvjp )	-	01 Aug 2015
				PF-04937319 100mg