Delving into the Latest Updates on Molidustat Sodium with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

BAY1053048（ナトリウム塩）, BAY85-3934（遊離塩基）, Molidustat

+ [8]

Target

HIF-PHs

Mechanism

HIF-PHs inhibitors(Hypoxia-inducible factor prolyl hydroxylase inhibitors)

Therapeutic Areas

Hemic and Lymphatic DiseasesUrogenital Diseases

Active Indication

Anemia in chronic kidney disease

Inactive Indication

Anemia of renal disease

Originator Organization

Bayer AG

Active Organization

Bayer AG

Inactive Organization

Bayer HealthCare AGBayer Schering Pharma AG

Drug Highest PhaseApproved

First Approval Date

JP (22 Jan 2021),

Anemia in chronic kidney disease

RegulationSpecial Review Project (CN)

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Structure/Sequence

Molecular FormulaC13H14N8NaO2

InChIKeyHCTDSMITRFYAKD-UHFFFAOYSA-N

CAS Registry1375799-59-9

Abstract:The development of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIFPHIs), such as Roxadustat (ROX), Enarodustat (ENA), Desidustat (DES), Vadadustat (VAD), Molidustat (MOL), and Daprodustat (DAP), has significant effects on anemia in chronic kidney disease. This review presents comprehensive information about the synthesis, pharmacology, and analysis of HIF-PHIs across several matrices. The literature has presented several approaches for quantifying HIF-PHIs in diverse sample matrices. Furthermore, HIF-PHIs exhibit similar modes of action, demonstrating distinct pharmacokinetic parameters. The pharmacological insights encompass their half-life, mechanism of action, absorption, distribution, metabolism, excretion, and therapeutic uses. Research indicates that most studies concentrate on hyphenated methodologies for drug estimation in various biological fluids. Consequently, this study assesses the biological efficacy of HIF-PHIs and elucidates the analytical methodologies currently employed for measurement across various matrices.

01 Dec 2024·Cellular and Molecular Life Sciences

Pharmacological induction of the hypoxia response pathway in Huh7 hepatoma cells limits proliferation but increases resilience under metabolic stress

Article

Author: Diaz, Olivier ; Perrin-Cocon, Laure ; Lalande, Alexandre ; Jacquemin, Clémence ; Mathieu, Cyrille ; Aublin-Gex, Anne ; Toesca, Johan ; El Orch, Walid ; Jacolin, Florentine ; Si-Tahar, Mustapha ; Vidalain, Pierre-Olivier ; Lotteau, Vincent

AbstractThe hypoxia response pathway enables adaptation to oxygen deprivation. It is mediated by hypoxia-inducible factors (HIF), which promote metabolic reprogramming, erythropoiesis, angiogenesis and tissue remodeling. This led to the successful development of HIF-inducing drugs for treating anemia and some of these molecules are now in clinic. However, elevated levels of HIFs are frequently associated with tumor growth, poor prognosis, and drug resistance in various cancers, including hepatocellular carcinoma (HCC). Consequently, there are concerns regarding the recommendation of HIF-inducing drugs in certain clinical situations. Here, we analyzed the effects of two HIF-inducing drugs, Molidustat and Roxadustat, in the well-characterized HCC cell line Huh7. These drugs increased HIF-1α and HIF-2α protein levels which both participate in inducing hypoxia response genes such as BNIP3, SERPINE1, LDHA or EPO. Combined transcriptomics, proteomics and metabolomics showed that Molidustat increased the expression of glycolytic enzymes, while the mitochondrial network was fragmented and cellular respiration decreased. This metabolic remodeling was associated with a reduced proliferation and a lower demand for pyrimidine supply, but an increased ability of cells to convert pyruvate to lactate. This was accompanied by a higher resistance to the inhibition of mitochondrial respiration by antimycin A, a phenotype confirmed in Roxadustat-treated Huh7 cells and Molidustat-treated hepatoblastoma cells (Huh6 and HepG2). Overall, this study shows that HIF-inducing drugs increase the metabolic resilience of liver cancer cells to metabolic stressors, arguing for careful monitoring of patients treated with HIF-inducing drugs, especially when they are at risk of liver cancer.

01 Nov 2024·Clinical and Experimental Nephrology

The comparison of four hypoxia-inducible factor prolyl hydroxylase inhibitors on drug potency and cost for treatment in patients with renal anemia

Article

Author: Imai, Atsuhiro ; Imai, Enyu

BACKGROUNDFive hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been approved for marketing in Japan. However, marked differences exist in terms of drug potency, dose requirement, and pharmacokinetics.METHODSThe primary evaluation in this study was the changes in hemoglobin levels, dose escalation, drug potency, and cost among HIF-PHIs, 3 months after the initiation of treatment.RESULTSAll patients treated with HIF-PHI between August 2020 and December 2023 were enrolled in this study. In total, 124 patients were administered daprodustat (N = 37), enarodustat (N = 44), molidustat (N = 13), or vadadustat (N = 30). The mean hemoglobin levels of daprodustat, enarodustat, molidustat, and vadadustat at 3 months were 11.7 g/dL, 11.8 g/dL, 12.2 g/dL, and 11.3 g/dL, respectively. At 3 months, the mean doses of daprodustat, enarodustat, molidustat, and vadadustat increased by 110%, 177%, 125%, and 152%, respectively, from the initial dose. The HIF-PHI potency indices (HPI) of daprodustat, enarodustat, molidustat, and vadadustat at 3 months were 0.168, 0.307, 0.184, and 0.254, respectively. At 3 months, the mean daily costs of daprodustat, enarodustat, molidustat, and vadadustat were JPY 345, JPY 434, JPY 206, and JPY 565, respectively.CONCLUSIONThe difference in dose escalation for anemia treatment among HIF-PHIs is due to differences in drug potency, where the HPI significantly differs among HIF-PHIs. The disparity between the HPI and the cost of the initial dose accounts for the variance in the daily costs of renal anemia treatment among HIF-PHIs.

100 Deals associated with Molidustat Sodium

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External Link

KEGG	Wiki	ATC	Drug Bank
D11273	-	B03XA	DB15642

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Anemia in chronic kidney disease	JP	Bayer AG	22 Jan 2021

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Anemia of renal disease	Discovery	JP	Bayer AG	12 Dec 2017
Anemia	Discovery	US	Bayer AG	28 Oct 2013
Chronic Kidney Diseases	Discovery	US	Bayer AG	28 Oct 2013

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03350347 (MIYABI ND-M, Pubmed \| Am J Nephrol) Manual	Phase 3	Anemia	164	molidustat	(bpuyoabbfd) = yqqkryrurt oujcoyrkee (mawpcgbdzd, 11.48 - 11.85) View more	Non-inferior	16 Sep 2021
				darbepoetin alfa	(bpuyoabbfd) = avzaqxzwzb oujcoyrkee (mawpcgbdzd, 11.31 - 11.74) View more
NCT03350321 (MIYABI ND-C, Pubmed \| Am J Nephrol) Manual	Phase 3	Anemia	162	Molidustat	(kygajdueda) = vkcpahqhbu oqucgrbgww (ajzpfgmrbg, 11.07 - 11.50) View more	Positive	16 Sep 2021
				ESA darbepoetin alfa	(kygajdueda) = qkvrafukyt oqucgrbgww (ajzpfgmrbg, 11.50 - 11.90) View more
NCT03418168 (Pubmed \| Ther Apher Dial) Manual	Phase 3	Anemia	51	Molidustat	(dzazyvwsvc) = ulxwhzzlpg xxllckssrn (amvjlixpjh, 40.3 - 68.9)	Positive	26 Jul 2021
MIYABI program (ERA2021)	Phase 3	Anemia	51	Molidustat 75 mg	usxsditofh(tjxyccjxml) = wgtpdbbmaj zbubqjmrfg (nndenhvnlb, 40.3 - 68.9)	Positive	29 May 2021
NCT03351166 (Pubmed \| Ther Apher Dial)	Phase 3	Anemia in chronic kidney disease	25	Molidustat	(yaxwnahirt) = azjztdtwbc baiywfgmhr (nwylxyvepp )	Positive	27 Jan 2021
NCT03350347 (MIYABI ND-M, ERA2020)	Phase 3	Anemia of renal disease	-	Molidustat	avwzsbmuwo(fhqivbnwzf) = zbtthufdcb znugwwzaak (hgaefvjsdf, 11.48 - 11.85) View more	Positive	07 Jun 2020
				Darbepoetin alfa	xdkacdfzze(oyxddejdal) = gnztbfvifi qkctganvnw (agukzkdbbe, 12.33)
NCT03350321 (MIYABI ND-C, ERA2020)	Phase 3	Anemia of renal disease erythropoietin	-	Molidustat	bxtrodlxby(mwbewsnoea) = xgzceseukp uhmoyeaylc (jwfcczbmdv, 11.07 - 11.50)	Positive	07 Jun 2020
				Darbepoetin alfa	bxtrodlxby(mwbewsnoea) = lkkglquqbm uhmoyeaylc (jwfcczbmdv )
ERA2018	Phase 2	Chronic Kidney Diseases	101	Molidustat	qcbdzdjnpc(rahcrnejnw) = an increase in TIBC values were observed in the molidustat group djovvhwdou (ucttumecdd ) View more	Positive	18 May 2018
				Placebo
ERA2016	Not Applicable	Anemia in chronic kidney disease	-	Molidustat 25 mg	(uwiihtaofh) = Treatment emergent adverse events (TEAE) were reported in 69.6% of molidustat treated subjects and in 53.1% of subjects on darbepoetin bckpibkwiz (abzqkwkvdr ) View more	-	14 May 2016
				Molidustat 50 mg
SO036 (ERA2016)	Phase 2	Chronic Kidney Diseases	121	Molidustat 25mg once daily	(jsarxlaavs) = Treatment emergent adverse events (TEAE) were reported in 66.3% of all molidustat treated subjects and in 80% of subjects on placebo goldvvyowx (fggifjmycs ) View more	Positive	14 May 2016
				Molidustat 50mg once daily