Delving into the Latest Updates on Tesevatinib with Synapse

Overview

Basic Info

Drug Type

Autologous CAR-T

Synonyms

Tesevatinib (USAN/INN)

+ [2]

Target

EGFR x HER2 x HER3 x HER4 x SRC family x VEGFR

Mechanism

EGFR antagonists(Epidermal growth factor receptor erbB1 antagonists), HER2 antagonists(Receptor protein-tyrosine kinase erbB-2 antagonists), HER3 antagonists(Receptor tyrosine-protein kinase erbB-3 antagonists)

+ [3]

Therapeutic Areas

NeoplasmsRespiratory DiseasesNervous System Diseases+ [4]

Active Indication-

Inactive Indication

Brain metastasesBreast CancerMetastatic Malignant Neoplasm to the Leptomeninges+ [5]

Originator Organization

Exelixis, Inc.

Active Organization-

Inactive Organization

Exelixis, Inc.

Kadmon Corp. LLC

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC24H25Cl2FN4O2

InChIKeyHVXKQKFEHMGHSL-QKDCVEJESA-N

CAS Registry781613-23-8

AbstractTesevatinib is a potent oral brain penetrant EGFR inhibitor currently being evaluated for glioblastoma therapy. Tesevatinib distribution was assessed in wild-type (WT) and Mdr1a/b(-/-)Bcrp(-/-) triple knockout (TKO) FVB mice after dosing orally or via osmotic minipump; drug–tissue binding was assessed by rapid equilibrium dialysis. Two hours after tesevatinib dosing, brain concentrations in WT and TKO mice were 0.72 and 10.03 μg/g, respectively. Brain-to-plasma ratios (Kp) were 0.53 and 5.73, respectively. With intraperitoneal infusion, brain concentrations were 1.46 and 30.6 μg/g (Kp 1.16 and 25.10), respectively. The brain-to-plasma unbound drug concentration ratios were substantially lower (WT mice, 0.03–0.08; TKO mice, 0.40–1.75). Unbound drug concentrations in brains of WT mice were 0.78 to 1.59 ng/g. In vitro cytotoxicity and EGFR pathway signaling were evaluated using EGFR-amplified patient-derived glioblastoma xenograft models (GBM12, GBM6). In vivo pharmacodynamics and efficacy were assessed using athymic nude mice bearing either intracranial or flank tumors treated by oral gavage. Tesevatinib potently reduced cell viability [IC50 GBM12 = 11 nmol/L (5.5 ng/mL), GBM6 = 102 nmol/L] and suppressed EGFR signaling in vitro. However, tesevatinib efficacy compared with vehicle in intracranial (GBM12, median survival: 23 vs. 18 days, P = 0.003) and flank models (GBM12, median time to outcome: 41 vs. 33 days, P = 0.007; GBM6, 44 vs. 33 days, P = 0.007) was modest and associated with partial inhibition of EGFR signaling. Overall, tesevatinib efficacy in EGFR-amplified PDX GBM models is robust in vitro but relatively modest in vivo, despite a high brain-to-plasma ratio. This discrepancy may be explained by drug-tissue binding and compensatory signaling.

01 Sep 2018·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies

Q4 · MEDICINE

Article

Author: Wakelee, Heather A ; Miles, Dale ; Adjei, Alex ; Padda, Sukhmani K ; Lensing, Janet L ; Sikic, Branimir I ; Das, Millie ; Molina, Julian ; Frymoyer, Adam

PURPOSETo evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules.METHODSPatients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine C_max, and AUC. Patients remained on study until progressive disease or unacceptable AEs.RESULTSIn XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68 mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300 mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set.CONCLUSIONSFor oral XL647, the MTD was 4.68 mg/kg or 350 mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300 mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.

01 Jan 2017·World Journal of Nephrology

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

Article

Author: Sweeney, William E ; Frost, Philip ; Avner, Ellis D

AIMTo investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD).METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model (from PN30 to PN90) to assess efficacy and toxicity in animals where developmental processes are complete. The following parameters were assessed: Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by: Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis (active VEGFR2/KDR) was assessed by Western analysis.RESULTSThis study demonstrates that: (1) in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis: EGFR, ErbB2, c-Src and KDR; and (2) this reduction of kinase activity resulted in significant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.

100 Deals associated with Tesevatinib

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External Link

KEGG	Wiki	ATC	Drug Bank
D11772	Tesevatinib	-	DB11973

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Polycystic Kidney, Autosomal Recessive	Phase 3	US	Kadmon Corp. LLC	24 Aug 2017
Recurrent Glioblastoma	Phase 3	US	Kadmon Corp. LLC	01 Jun 2016
Polycystic Kidney, Autosomal Dominant	Phase 3	US	Kadmon Corp. LLC	25 Dec 2015
Brain metastases	Phase 3	US	Kadmon Corp. LLC	01 Nov 2015
Metastatic Malignant Neoplasm to the Leptomeninges	Phase 3	US	Kadmon Corp. LLC	01 Nov 2015
Non-small cell lung cancer stage IIIB	Phase 3	US	Kadmon Corp. LLC	14 Dec 2011
Breast Cancer	Phase 3	US	Exelixis, Inc.	01 Jun 2008
Non-Small Cell Lung Cancer	Phase 3	US	Exelixis, Inc.	01 Jun 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03203642 (CTgov)	Phase 2	Polycystic Kidney, Autosomal Dominant	80	Tesevatinib (Tesevatinib)	crqovnecro(jvcwpttoho) = apqslqbojh excbassqzb (hqyurtphdr, olxhnkzgvy - cpulwrzbub) View more	-	06 Feb 2023
NCT03203642 (CTgov)	Phase 2	Polycystic Kidney, Autosomal Dominant	80	Placebo (Placebo)	crqovnecro(jvcwpttoho) = xcsbkwippf excbassqzb (hqyurtphdr, dmhrwprhnm - tojpwwnovs) View more	-	06 Feb 2023
NCT01559363 (CTgov)	Phase 1/2	Polycystic Kidney, Autosomal Dominant	69	Tesevatinib (Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing)	(vcklslqdoj) = ovcdbergqm dlctfxxuqa (ukylwxyinf, qhqobylibu - lusoiphxgu) View more	-	08 Nov 2022
NCT01559363 (CTgov)	Phase 1/2	Polycystic Kidney, Autosomal Dominant	69	Tesevatinib (Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing)	(vcklslqdoj) = hcfmwjhvni dlctfxxuqa (ukylwxyinf, ycurtvnyjx - veurqcrhwu) View more	-	08 Nov 2022
KD019-101 \| SILK (ASN2019)	Phase 1/2	Polycystic Kidney, Autosomal Dominant	13	Tesevatinib 50 mg QD	tqqwgncwar(popktxlqst) = Grade 3 AEs were reported in 3 patients (CHF, HTN, and Herpes zoster) and were considered unlikely or unrelated to study drug xmpcddykst (gkrnsfndte ) View more	Positive	05 Nov 2019
ASN2016	Not Applicable	Polycystic Kidney Diseases	24	Tesevatinib 50 mg	splwfrbrqm(kofpaemzhm) = iwbrjsscmp puhghhlnyv (cxnjxnczrx ) View more	Positive	15 Nov 2016
NCT02154529 (ASCO2016)	Phase 1/2	Metastatic human epidermal growth factor 2 positive carcinoma of breast	8	Tesevatinib 300 mg QD	(iquubyjdev) = Grade 3 diarrhea and Grade 3 QTc prolongation ughahlqven (gjfhbwinnl )	-	20 May 2016
NCT02154529 (ASCO2016)	Phase 1/2		8	Tesevatinib 350 mg QD		-	20 May 2016
ASN2015	Not Applicable	Polycystic Kidney, Autosomal Dominant	46	Tesevatinib 150 mg/day	wmpgqqdtls(wntkhwxqeo) = In oncology trials the most common adverse events (AEs) were EGFR inhibitor AEs of acneiform rash and diarrhea. cqgcefulok (vrntdmaonv ) View more	Negative	03 Nov 2015
ASN2015	Not Applicable	Polycystic Kidney, Autosomal Dominant	46	Tesevatinib 100 mg/day		Negative	03 Nov 2015
ASCO2008	Phase 1	Advanced Malignant Solid Neoplasm	31	XL647	(bcgooxyait) = qnhuaoagrd nfbokudfpe (efibozqhdr )	-	20 May 2008
ASCO2008	Phase 2	Non-Small Cell Lung Cancer	41	XL647 350 mg (intermittent cohort)	aiwfdaptvo(ennfcajvgv) = kyibbdtsbh ypkszaukvn (nfqycbwthz ) View more	-	20 May 2008
ASCO2007	Phase 1	Advanced Malignant Solid Neoplasm	-	XL647	(acuruzkayr) = jnulnmengn ttubshlncn (rcpjwjwskb ) View more	-	20 Jun 2007
ASCO2005	Phase 1	Advanced Malignant Solid Neoplasm	12	XL647	(jbjvashqqs) = jrvrrxdsdl nrxkvbwjdv (caihthaoim ) View more	-	01 Jun 2005