Delving into the Latest Updates on Arhalofenate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Arhalofenate (USAN/INN), Arhalofenate acid, Metaglidasen

+ [4]

Target

PPARγ x URAT1

Mechanism

PPARγ antagonists(Peroxisome proliferator-activated receptor γ antagonists), URAT1 inhibitors(Uric acid transporter 1 inhibitors)

Therapeutic Areas

Immune System DiseasesCongenital DisordersEndocrinology and Metabolic Disease+ [2]

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2GoutHyperuricemia

Originator Organization

CymaBay Therapeutics, Inc.

Active Organization-

Inactive Organization

Xian Janssen Pharmaceutical Ltd.

CymaBay Therapeutics, Inc.

Kowa Co., Ltd.

+ [1]

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC19H17ClF3NO4

InChIKeyBJBCSGQLZQGGIQ-QGZVFWFLSA-N

CAS Registry24136-23-0

PURPOSE OF REVIEWDespite effective available treatments, gout management is often unsuccessful in getting patients to target serum urate goal and in managing flares in the setting of comorbidities. Studies addressing future treatment options for short- and long-term management are reviewed.RECENT FINDINGSURAT-1 blocking agents have been helpful but have had limitations related to effects on renal function, lack of efficacy with renal impairment, and potential to increase renal stones. Dotinurad may function in the setting of decreased renal function. Arhalofenate has anti-URAT-1 activity and may also blunt gout flares. A new xanthine oxidase inhibitor (XOI), tigulixostat, is under study. New uricase treatments manufactured in combination with agents that can reduce immunogenicity may make uricase treatment simpler. A unique strategy of inhibiting gut uricase may offer the benefits of avoiding systemic absorption. For gout flares, IL-1β inhibitor studies in progress include different dosing schedules. Dapansutrile, an oral agent under investigation, inhibits activation of the NLRP3 inflammasome and may be an effective anti-inflammatory. New treatments for gout that are under study may work in the setting of comorbidities, simplify management, utilize new mechanisms, or have reduced side effects.

02 Dec 2023·Expert Opinion on Drug Metabolism & Toxicology

Overview of the pharmacokinetics and pharmacodynamics of URAT1 inhibitors for the treatment of hyperuricemia and gout

Review

Author: Song, Danni ; Mao, Jiale ; Hou, Zihan ; Ma, Aijinxiu ; Zhao, Xu

INTRODUCTIONHyperuricemia is a common metabolic disease, which is a risk factor for gouty arthritis and ureteral stones and may also lead to cardiovascular and chronic kidney disease (CDK). Therefore, hyperuricemia should be treated early. Xanthine oxidase inhibitors (XOIs) and uricosuric agents (UAs), which target uric acid, are two types of medications that are used to treat gout and hyperuricemia. XOIs stop the body from producing excessive uric acid, while UAs eliminate it rapidly via the kidneys. Urate transporter 1 (URAT1) belongs to the organic anion transporter family (OAT) and is specifically localized to the apical membrane of the epithelial cells of proximal tubules. Unlike other organic anion transporter family members, URAT1 identifies and transports organic anions that are primarily responsible for urate transport.AREAS COVEREDThis article reviews the pharmacokinetics and pharmacodynamics of the existing URAT1 inhibitors to serve as a reference for subsequent drug studies.EXPERT OPINIONThe URAT1 inhibitors that are currently used as clinical drugs mainly include dotinurad, benzbromarone, and probenecid. Results indicate that RDEA3170 may be the most promising inhibitor, in addition to SHR4640, URC-102, and MBX-102, which are in the early stages of development.

24 Mar 2022·The Journal of Clinical Endocrinology & MetabolismQ2 · MEDICINE

CAR-T Cells Targeting TSHR Demonstrate Safety and Potent Preclinical Activity Against Differentiated Thyroid Cancer

Q2 · MEDICINE

Article

Author: Du, Yaying ; Cai, Miaomiao ; Yang, Zhifang ; Wang, Ge ; Li, Hanning ; Zhang, Tongcun ; Li, Xingrui ; Wu, Yonglin ; Zhou, Xiang ; Liao, Xinghua ; Xu, Tao ; Dong, Menglu ; Hua, Dongyu ; Li, Shuyu ; Yang, Xue ; Cui, Xiaoqing

AbstractBackgroundChimeric antigen receptor T cells (CAR-Ts) have demonstrated remarkable efficacy in hematological cancers but have not yet translated in treating solid tumors. The significant hurdles limiting CAR-T therapy were from a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present TSH receptor (TSHR) as a putative target for CAR-T therapy of differentiated thyroid cancer (DTC).MethodsWe undertook a large-scale screen on thyroid cancer tissues and multiple internal organs through bioinformatical analysis and immunohistochemistry to date TSHR expression. Using 3 previously described monoclonal antibodies, we generated 3 third-generation CAR-Ts. We tested anti-TSHR CAR-T in vitro activity by T-cell function and killing assay. Then we tested preclinical therapeutical efficacy in a xenograft mouse model of DTC and analyzed mice’s physical conditions and histological abnormalities to evaluate anti-TSHR CAR-T’s safety.ResultsTSHR is highly and homogeneously expressed on 90.8% (138/152) of papillary thyroid cancer, 89.2% (33/37) of follicular thyroid cancer, 78.2% (18/23) of cervical lymph node metastases, and 86.7% of radioactive iodine resistance diseases. We developed 3 novel anti-TSHR CAR-Ts from monoclonal antibodies M22, K1-18, and K1-70; all 3 CAR-Ts mediate significant antitumor activity in vitro. Among these, we demonstrate that K1-70 CAR-T can have therapeutical efficacy in vivo, and no apparent toxicity has been observed.ConclusionTSHR is a latent target antigen of CAR-T therapy for DTC. Anti-TSHR CAR-T could represent a therapeutic option for patients with locoregional relapsed or distant metastases of thyroid cancer and should be tested in carefully designed clinical trials.

100 Deals associated with Arhalofenate

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External Link

KEGG	Wiki	ATC	Drug Bank
D09579	-	-	DB11811

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperuricemia	Phase 3	US	CymaBay Therapeutics, Inc.	01 May 2011
Diabetes Mellitus, Type 2	Phase 3	IN	CymaBay Therapeutics, Inc.	01 May 2006
Diabetes Mellitus, Type 2	Phase 3	AR	CymaBay Therapeutics, Inc.	01 May 2006
Diabetes Mellitus, Type 2	Phase 3	US	CymaBay Therapeutics, Inc.	01 May 2006
Diabetes Mellitus, Type 2	Phase 3	IL	CymaBay Therapeutics, Inc.	01 May 2006
Gout	Phase 3	-	Kowa Co., Ltd.	-
Gout	Phase 3	-	Kowa Co., Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02252835 (Pubmed \| J Rheumatol)	Phase 2	Gout	32	Arhalofenate 600 mg + Febuxostat 80 mg	ynwspxtrpi(kdaxurmtog) = whuqrzyqtw rxnfjfnaeu (ukuofwulpk ) View more	-	01 Mar 2017
				Arhalofenate 800 mg + Febuxostat 40 mg	ynwspxtrpi(kdaxurmtog) = iymfjojmxs rxnfjfnaeu (ukuofwulpk ) View more
NCT02252835 (EULAR2015)	Phase 2	Gout	-	Arhalofenate 600 mg	wicxwigjuf(kvdfgknwhl) = one case of elevated transaminases that emerged after the initiation of febuxostat afeeonuvir (ipoczdaahw ) View more	-	10 Jun 2015
				Febuxostat 80 mg
NCT01399008 (CTgov)	Phase 2	Gout	100	Allopurinol+Colchicine+Arhalofenate (Arhalofenate 400 mg)	(sjmvrhojco) = tvlsmwemmd sofefwxiij (cxkvauzpqn, fokysmxiwf - gqfiqstqmv)	-	28 Jul 2014
				Allopurinol+Colchicine+Arhalofenate (Arhalofenate 600 mg)	(sjmvrhojco) = tnzyqmpdce sofefwxiij (cxkvauzpqn, ewucpbised - yohoqjhqkc)
EULAR2012	Not Applicable	-	-	Arhalofenate acid	dmkxiawmav(nnqinzgvby) = apzbyqkhmg egrozuhwsy (jujfkqaadx ) View more	-	06 Jun 2012
				Probenecid	suoirnaaec(sjjuyzclts) = lfrclyrohw tfjjlxpuuf (uycqfrrmrf ) View more