Delving into the Latest Updates on Venadaparib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

NOV-1401 (National OncoVenture)

+ [4]

Target

PARP1 x PARP2

Mechanism

PARP1 inhibitors(Poly (ADP-Ribose) polymerase 1 inhibitors), PARP2 inhibitors(Poly (ADP-Ribose) Polymerase 2 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System Disorders

Active Indication

Advanced gastric carcinomaHRD positive cancer

Inactive Indication

Advanced Malignant Solid NeoplasmBreast CancerEsophageal Carcinoma

Originator Organization

Ildong Pharmaceutical Co., Ltd.

Active Organization

Idience Co., Ltd.Startup

EirGen Pharma Ltd.

Inactive Organization

Syneos Health (Beijing) Inc.Ltd.

National OncoVenture

Drug Highest PhasePhase 1/2

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC23H23FN4O2

InChIKeyYNBQAYKYNYRCCA-UHFFFAOYSA-N

CAS Registry1681017-83-3

AbstractAimVenadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects.MethodsIn this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing.ResultsTwelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457–0.9094) and 1.02 (0.9088–1.1339) in Koreans, and 0.77 (0.6871–0.8609) and 0.96 (0.9017–1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated.ConclusionThe overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.

02 Mar 2023·Molecular Cancer Therapeutics

Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety

Article

Author: Hong, Chang-Hee ; Yoo, Yeongran ; Lim, Jong-Ha ; Yang, Ji-Hoon ; Lee, Myongjae ; Park, Young-Whan ; Kim, Jeong-Ah ; Baek, Nam Seok ; Jeong, Jinah ; Park, Sun-Young ; Je, In-Gyu ; Lee, Won Sik ; Song, Dong Keun ; Moon, An-Na ; Jang, Eunhye ; Ha, Kyoung Soo ; Park, Joon-Tae ; Lee, Yoonsuk ; Lee, Sungsook ; Choi, SungKu ; Kim, Jeong Eun ; Lee, Jung Woo

AbstractPARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

Frontiers in Cellular and Infection Microbiology

Novel anti-Acanthamoeba effects elicited by a repurposed poly (ADP-ribose) polymerase inhibitor AZ9482

Article

Author: Feng, Meng ; Zhou, Qingtong ; Han, Wei ; Chen, Lijun ; Jing, Wenwen ; Cheng, Xunjia

IntroductionAcanthamoeba infection is a serious public health concern, necessitating the development of effective and safe anti-Acanthamoeba chemotherapies. Poly (ADP-ribose) polymerases (PARPs) govern a colossal amount of biological processes, such as DNA damage repair, protein degradation and apoptosis. Multiple PARP-targeted compounds have been approved for cancer treatment. However, repurposing of PARP inhibitors to treat Acanthamoeba is poorly understood.MethodsIn the present study, we attempted to fill these knowledge gaps by performing anti-Acanthamoeba efficacy assays, cell biology experiments, bioinformatics, and transcriptomic analyses.ResultsUsing a homology model of Acanthamoeba poly (ADP-ribose) polymerases (PARPs), molecular docking of approved drugs revealed three potential inhibitory compounds: olaparib, venadaparib and AZ9482. In particular, venadaparib exhibited superior docking scores (−13.71) and favorable predicted binding free energy (−89.28 kcal/mol), followed by AZ9482, which showed a docking score of −13.20 and a binding free energy of −92.13 kcal/mol. Notably, the positively charged cyclopropylamine in venadaparib established a salt bridge (through E535) and a hydrogen bond (via N531) within the binding pocket. For comparison, AZ9482 was well stacked by the surrounding aromatic residues including H625, Y652, Y659 and Y670. In an assessment of trophozoites viability, AZ9482 exhibited a dose-and time-dependent anti-trophozoite effect by suppressing Acanthamoeba PARP activity, unlike olaparib and venadaparib. An Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis assay revealed AZ9482 induced trophozoite necrotic cell death rather than apoptosis. Transcriptomics analyses conducted on Acanthamoeba trophozoites treated with AZ9482 demonstrated an atlas of differentially regulated proteins and genes, and found that AZ9482 rapidly upregulates a multitude of DNA damage repair pathways in trophozoites, and intriguingly downregulates several virulent genes. Analyzing gene expression related to DNA damage repair pathway and the rate of apurinic/apyrimidinic (AP) sites indicated DNA damage efficacy and repair modulation in Acanthamoeba trophozoites following AZ9482 treatment.DiscussionCollectively, these findings highlight AZ9482, as a structurally unique PARP inhibitor, provides a promising prototype for advancing anti-Acanthamoeba drug research.

100 Deals associated with Venadaparib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 2	KR	Idience Co., Ltd.Startup	16 Sep 2021
Advanced gastric carcinoma	Phase 2	CN	Idience Co., Ltd.Startup	28 Jun 2021
Advanced gastric carcinoma	Phase 2	US	Idience Co., Ltd.Startup	28 Jun 2021
Advanced gastric carcinoma	Phase 2	KR	Idience Co., Ltd.Startup	28 Jun 2021
Esophageal Carcinoma	Phase 2	KR	Idience Co., Ltd.Startup	01 Jan 2021
Esophageal Carcinoma	Phase 2	US	Idience Co., Ltd.Startup	01 Jan 2021
Esophageal Carcinoma	Phase 2	CN	Idience Co., Ltd.Startup	01 Jan 2021
HRD positive cancer	Phase 2	KR	Idience Co., Ltd.Startup	06 Nov 2019
Advanced Malignant Solid Neoplasm	Phase 2	KR	Idience Co., Ltd.Startup	29 Aug 2017
Solid tumor	Phase 2	KR	National OncoVenture	29 Aug 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04725994 (ASCO2024)	Phase 1	Metastatic Gastric Carcinoma HRD gene mutations	26	Venadaparib plus irinotecan	(bgxhslleqw) = wavbipixws xajsugadgq (lchpqiasdu ) View more	Positive	24 May 2024
				Placebo plus irinotecan	(riszjmkfvy) = yhpjmviqos lecgfeovcd (jbuvwyktpx, 2.9 - 5.5)
NCT04174716 (ASCO2023) Manual	Phase 1	Pancreatic Cancer \|	8	Venadaparib (ATMmASXL1m)	(rsalpjiggj) = oquyzatgru njdxmghqik (cgjhzwqrhf ) View more	Positive	31 May 2023
				Venadaparib (ATMmASXL1wt)	(rsalpjiggj) = kyfcshnyww njdxmghqik (cgjhzwqrhf ) View more
NCT04174716 (VASTUS, ESMO2021)	Phase 1/2	Breast Cancer	14	Venadaparib	(yitxqbfjju) = 8/14 (57%) ifroijozwx (waaocsomfi ) View more	-	16 Sep 2021
NCT03317743 (ASCO2021) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	32	Venadaparib	(zdlolfixqm) = Frequently observed adverse drug reactions were as follows – Anemia (56%), nausea (38%) and neutropenia (25%). kphbfvaesj (xdbrythvtf )	Positive	20 May 2021
				Venadaparib (BRCAm(+))