Delving into the Latest Updates on AGS-16C3F with Synapse

Overview

Basic Info

Drug Type

Antibody drug conjugate (ADC)

Synonyms

Anti-ENPP3-MMAF

+ [1]

Target

ENPP3 x Tubulin

Action

inhibitors

Mechanism

ENPP3 inhibitors(Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 inhibitors), Tubulin inhibitors

Therapeutic Areas

NeoplasmsUrogenital DiseasesOther Diseases

Active Indication-

Inactive Indication

Advanced Renal Cell CarcinomaMetastatic Renal Cell CarcinomaPapillary Renal Cell Carcinoma

Originator Organization

Agensys, Inc.

Active Organization-

Inactive Organization

Astellas Pharma Global Development, Inc.

Astellas Pharma, Inc.

Agensys, Inc.

License Organization-

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC39H65N5O8

InChIKeyMFRNYXJJRJQHNW-DEMKXPNLSA-N

CAS Registry745017-94-1

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Sequence Code 186372L

Sequence Code 186366H

AbstractTrial InformationClinicalTrials.gov Identifier: NCT02639182 Sponsor: Astellas Pharma, Inc. Principal Investigator: Christian Kollmannsberger IRB Approved: YesLessons LearnedThe primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS-16C3F, versus axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC) was not met. Median progression-free survival, the primary endpoint, was 2.9 months with AGS-16C3F and 5.7 months with axitinib (HR, 1.676; 95% CI, 1.107–2.537; p = .015), per investigator assessment The safety profile for each study drug was as expected, with the most commonly reported adverse events being fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. These results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.BackgroundAGS-16C3F is a novel antibody-drug conjugate that targets cell-surface ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) and is conjugated to a microtubule disruptive agent. Here we present findings from a phase II study of AGS-16C3F versus axitinib in metastatic renal cell carcinoma (mRCC).MethodsPatients with mRCC of any histology and disease progression during or after their last treatment regimen were randomized 1:1 to intravenous AGS-16C3F 1.8 mg/kg every 3 weeks or oral axitinib 5 mg twice daily (starting dose). The primary objective was investigator-assessed progression-free survival (PFS) of AGS-16C3F versus axitinib (RECIST version 1.1).ResultsIn the total population (N = 133), 63% (n = 84) of patients had completed the study at data cutoff (August 21, 2019). Median PFS was 2.9 months with AGS-16C3F and 5.7 months with axitinib (hazard ratio [HR], 1.676; 95% confidence interval [CI], 1.107–2.537; p = .015). There were no significant differences between arms in secondary efficacy endpoints, including overall survival (13.1 months, AGS-16C3F and 15.4 months, axitinib; HR, 1.079; 95% CI, 0.681–1.707; p = .747). In the safety population (n = 131), the most commonly reported adverse events were fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. The incidence of diarrhea was lower in the AGS-16C3F arm than in the axitinib arm (17% vs. 48%), and ocular toxicities were more frequent in the AGS-16C3F arm than in the axitinib arm (44% vs. 26%).ConclusionThe investigational compound, AGS-16C3F, did not meet the primary endpoint of this trial. These study results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.

26 Feb 2019·Blood Advances

In vitro and in vivo efficacy of an anti-CD203c conjugated antibody (AGS-16C3F) in mouse models of advanced systemic mastocytosis

Article

Author: Arock, Michel ; Baral, Viviane ; Zhang, Yanyan ; Louache, Fawzia ; Doñate, Fernando ; Launay, Jean-Marie ; He, Liang ; Wedeh, Ghaith ; Kouros-Mehr, Hosein ; Beghi, Florian ; Bibi, Siham ; Wittner, Monika

AbstractAntibody-drug conjugates (ADCs) are a new class of therapeutics that use antibodies to deliver potent cytotoxic drugs selectively to cancer cells. CD203c, an ecto-nucleotide pyrophosphatase-phosphodiesterase 3, is overexpressed on neoplastic mast cells (MCs) in systemic mastocytosis (SM), thus representing a promising target for antibody-mediated therapy. In this study, we have found that human neoplastic MC lines (ROSAKIT D816V and ROSAKIT D816V-Gluc), which express high levels of CD203c, are highly and specifically sensitive to the antiproliferative effects of an ADC against CD203c (AGS-16C3F). In these cell lines, AGS-16C3F induced cell apoptosis at very low concentrations. To characterize the effects of AGS-16C3F on leukemia progression in vivo, ROSAKIT D816V-Gluc NOD-SCID γ mouse models of advanced SM (AdvSM) were treated with AGS-16C3F or an ADC control for 2 weeks. Whereas AGS-16C3F had no apparent toxicity in xenotransplanted mice, in vivo neoplastic MC burden significantly decreased in both hematopoietic and nonhematopoietic organs. Furthermore, animals treated with AGS-16C3F had prolonged survival compared with the animals treated with control ADC, and AGS-16C3F efficiently prevented disease relapse. In conclusion, these preclinical studies identified CD203c as a novel therapeutic target on neoplastic MCs, and AGS-16C3F as a promising ADC for the treatment of patients with AdvSM.

15 Sep 2018·Clinical Cancer ResearchQ1 · MEDICINE

Phase I Trials of Anti-ENPP3 Antibody–Drug Conjugates in Advanced Refractory Renal Cell Carcinomas

Q1 · MEDICINE

Article

Author: Morrison, Karen ; Redman, Bruce G. ; Sangha, Randeep S. ; Motzer, Robert J. ; Doñate, Fernando ; Thompson, John A. ; Molina, Ana M. ; Ernst, D. Scott ; Heath, Elisabeth I. ; Choueiri, Toni K. ; Pili, Roberto ; Anand, Banmeet ; Trave, Fabio ; Kim, Stella K. ; Kollmannsberger, Christian K. ; Reyno, Leonard ; Wiseman, Aya

AbstractPurpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody–drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC).Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary–derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks.Results: The AGS-16M8F study (n = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7–83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100–143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5–141 weeks).Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. Clin Cancer Res; 24(18); 4399–406. ©2018 AACR.

100 Deals associated with AGS-16C3F

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Renal Cell Carcinoma	Phase 2	Canada	Astellas Pharma Global Development, Inc.	03 May 2016
Metastatic Renal Cell Carcinoma	Phase 2	United States	Astellas Pharma Global Development, Inc.	03 May 2016
Papillary Renal Cell Carcinoma	Phase 2	United States	Agensys, Inc.	18 Jul 2012
Papillary Renal Cell Carcinoma	Phase 2	Canada	Agensys, Inc.	18 Jul 2012
Advanced Renal Cell Carcinoma	Phase 2	United States	Astellas Pharma, Inc.	01 Aug 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02639182 (CTgov)	Phase 2	Metastatic Renal Cell Carcinoma	133	AGS-16C3F (AGS-16C3F)	cyvrpusrec(ieyfqydmgm) = ojtvdpdhjz shnkkpdkaj (idboceopeu, jvfatfgapz - blzkdxfjuu) View more	-	23 Sep 2020
				Axitinib (Axitinib)	cyvrpusrec(ieyfqydmgm) = iivirvxxfn shnkkpdkaj (idboceopeu, jxjtmhkkkw - ctfzbpzjvd) View more
NCT01114230 \| NCT01672775 (Pubmed \| Clin Cancer Res) Manual	Phase 1	Renal Cell Carcinoma	60	AGS-16M8F	(tvxmionzcq) = kuytnhfzvc liwanhhtho (pnievnaiyd ) View more	Positive	15 Sep 2018
				AGS-16C3F	(hlgfmeixuq) = flktyuptol piokfuebbp (lnmkmmzitt ) View more

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Translational Medicine

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Deal

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Core Patent

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Clinical Trial

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Approval

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Biosimilar

Competitive landscape of biosimilars in different countries/locations. Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3.

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