Delving into the Latest Updates on Tovetumab with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

Anti-PDGFRa MAb, Tovetumab (USAN)

Target

PDGFRα

Mechanism

PDGFRα modulators(Platelet-derived growth factor receptor alpha modulators)

Therapeutic Areas

NeoplasmsNervous System DiseasesRespiratory Diseases+ [1]

Active Indication-

Inactive Indication

Advanced Lung Non-Small Cell CarcinomaAdvanced Malignant Solid NeoplasmGlioblastoma+ [3]

Originator Organization

Cambridge Antibody Technology

Active Organization-

Inactive Organization

MedImmune LLCCambridge Antibody Technology

AstraZeneca PLC

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Gene Sequence

Sequence Code 319372699L

Source: *****

Sequence Code 319372631H

Source: *****

BACKGROUNDWhile the anti-PDGFRA antibody olaratumab failed to confirm an impact on survival in unselected advanced soft tissue sarcoma (STS) patients, the level of expression and the prognosis of platelet-derived growth factor (PDGF) receptors and ligands in STS remain unclear.PATIENTS AND METHODSWe analyzed PDGF ligands and receptors' expression levels in a series of 255 patients with different histologies of STS [gastrointestinal stromal tumor (GIST), myxoid liposarcoma (MLPS), sarcoma with complex genomics, synovial sarcoma (SyS)] with Agilent single-color micro-arrays. We explored expression levels as prognostic values in univariate and multivariate analysis using R software (version 3.4.2).RESULTSComplex patterns of correlation of expression between ligands and receptors were observed for each histotype. PDGFA levels were highest in SyS and lowest in MLPS (P < 4 × 10^-9), PDGFB and C levels were lower in GIST (P < 2 × 10^-15 and P < 3 × 10^-9) while PDGFD expression was similar across histological subtypes. PDGF receptor (PDGFR) A expression was lowest in MLPS (P < 0.002), whereas PDGFRB and L expressions were lowest in GIST and SyS (P < 0.0004). Interestingly, high PDGFA expression levels were associated with higher risk of metastasis (P = 0.006), whereas PDGFD levels above average were associated with a reduced risk of metastasis (P = 0.01) in univariate and multivariate analysis.CONCLUSIONSThe expression of PDGF ligands and receptors varies across sarcoma histological subtypes. PDGFA and D expression levels independently and inversely correlate with the risk of metastatic relapse.

01 Jan 2021·The AAPS JournalQ3 · MEDICINE

A Novel Pharmacodynamic Biomarker and Mechanistic Modeling Facilitate the Development of Tovetumab, a Monoclonal Antibody Directed Against Platelet-Derived Growth Factor Receptor Alpha, for Cancer Therapy

Q3 · MEDICINE

Article

Author: Wang, Bing ; Vainshtein, Inna ; Schneider, Amy ; Liang, Meina ; Roskos, Lorin

Tovetumab (MEDI-575) is a fully human IgG2κ monoclonal antibody that specifically binds to human platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor signal transduction by PDGF ligands. The affinity of tovetumab determined using surface plasmon resonance technology and flow cytometry demonstrated comparable binding affinity for human and monkey PDGFRα. In single and repeat-dose monkey pharmacokinetic-pharmacodynamic (PK-PD) studies, tovetumab administration resulted in dose-dependent elevation of circulating levels of PDGF-AA, a member of the PDGF ligand family, due to displacement of PDGF-AA from PDGFRα by tovetumab and subsequent blockade of PDGFRα-mediated PDGF-AA degradation. As such, PDGF-AA accumulation is an indirect measurement of receptor occupancy and is a novel PD biomarker for tovetumab. The nonlinear PK of tovetumab and dose-dependent increase in circulating PDGF-AA profiles were well described by a novel mechanistic model, in which tovetumab and PDGF-AA compete for the binding to PDGFRα. To facilitate translational simulation, the internalization half-lives of PDGF-AA and tovetumab upon binding to PDGFRα were determined using confocal imaging to be 14 ± 4 min and 30 ± 8 min, respectively. By incorporating PDGFRα internalization kinetics, the model not only predicted the target receptor occupancy by tovetumab, but also the biologically active agonistic ligand-receptor complex. This work described a novel PD biomarker approach applicable for anti-receptor therapeutics and the first mechanistic model to delineate the in vivo tri-molecular system of a drug, its target receptor, and a competing endogenous ligand, which collectively have been used for optimal dose recommendation supporting clinical development of tovetumab.

01 May 2019·Clinical Lung CancerQ2 · MEDICINE

Phase 1b/2 Randomized Study of MEDI-575 in Combination With Carboplatin Plus Paclitaxel Versus Carboplatin Plus Paclitaxel Alone in Adult Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer

Q2 · MEDICINE

Article

Author: Blumenschein, George R ; Gadgeel, Shirish ; Takahashi, Toshiaki ; Dar, Mohammed ; Li, Xia ; Wheatley-Price, Paul

INTRODUCTIONPlatinum doublet chemotherapy has represented the standard of care in advanced non-small-cell lung cancer for decades. Targeting platelet-derived growth factor receptors (PDGFR) is a potential mechanism to improve the efficacy of first-line therapy. This randomized phase 1b/2 trial investigated the addition of the anti-PDGFRα monoclonal antibody MEDI-575 to first-line carboplatin/paclitaxel (CP) chemotherapy.PATIENTS AND METHODSThe phase 1b component was a dose-escalation study combining MEDI-575 with carboplatin area under the plasma concentration versus time curve 6 and paclitaxel 200 mg/m² (CPM), with the end point of identifying a recommended phase 2 dose. The phase 2 component randomized patients to CPM or CP, with primary end point of progression-free survival. Secondary end points included overall survival, overall response rate, and adverse event rates.RESULTSOverall, 99 patients were enrolled and received either CPM (n = 53; 4 phase 1b, 49 phase 2) or CP (n = 46). Demographics were as follows: 63/36 male/female, 78/21 aged ≤ 70/> 70 years; 37/62 squamous/nonsquamous, 42/53 Eastern Cooperative Oncology Group performance status 0/1. The phase 2 portion of the trial did not meet its primary end point: progression-free survival was shorter with CPM (4.6 vs. 5.5 months) than CP. No significant difference was seen in overall response rate (31.7% vs. 22.5%) or median overall survival (10.0 vs. 11.8 months). More serious adverse events were observed in patients receiving CPM (47% vs. 40%); in particular, 9 patients in the CPM group had significant gastrointestinal or respiratory adverse events (including abscess, perforation, and pneumothorax).CONCLUSIONThe addition of MEDI-575 to CP chemotherapy as first-line treatment of advanced non-small-cell lung cancer did not improve efficacy and resulted in increased toxicity.

100 Deals associated with Tovetumab

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External Link

KEGG	Wiki	ATC	Drug Bank
D10411	Tovetumab	-	DB12609

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Glioblastoma	Phase 2	US	MedImmune LLC	01 Jan 2011
Advanced Lung Non-Small Cell Carcinoma	Phase 2	HU	MedImmune LLC	16 Dec 2010
Advanced Lung Non-Small Cell Carcinoma	Phase 2	CA	MedImmune LLC	16 Dec 2010
Advanced Lung Non-Small Cell Carcinoma	Phase 2	PL	MedImmune LLC	16 Dec 2010
Advanced Lung Non-Small Cell Carcinoma	Phase 2	DE	MedImmune LLC	16 Dec 2010
Advanced Lung Non-Small Cell Carcinoma	Phase 2	US	MedImmune LLC	16 Dec 2010
Advanced Lung Non-Small Cell Carcinoma	Phase 2	FR	MedImmune LLC	16 Dec 2010
Advanced Lung Non-Small Cell Carcinoma	Phase 2	JP	MedImmune LLC	16 Dec 2010
Glioblastoma	Phase 2	-	Cambridge Antibody Technology	-
Non-Small Cell Lung Cancer	Phase 2	-	Cambridge Antibody Technology	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01268059 (CTgov)	Phase 1/2	Advanced Lung Non-Small Cell Carcinoma	99	Carboplatin+MEDI-575+Paclitaxel (Carboplatin/Paclitaxel + MEDI-575 - Phase 1b)	tfnzouivei(vrlpumrike) = eczzklgpgl xkcotyctng (pctooagdap, niobjusqka - kqmefzlmai) View more	-	23 Dec 2020
NCT01268059 (CTgov)	Phase 1/2	Advanced Lung Non-Small Cell Carcinoma	99	Carboplatin+Paclitaxel (Carboplatin/Paclitaxel - North America/European Union (EU))	ctkenmhmsa(fkhtrdmooe) = ttvmcmrfms rwyuwjhwnq (ukemmbxkhk, mvewzlzpki - zsllorlwgu) View more	-	23 Dec 2020
NCT01268059 (Pubmed) Manual	Phase 1/2	Non-Small Cell Lung Cancer First line	95	Carboplatin+Paclitaxel+MEDI-575	(aueueamril) = jlxqzwyfvm wpjqpvyfwo (dptexfdauc ) View more	Negative	01 May 2019
NCT01268059 (Pubmed) Manual	Phase 1/2	Non-Small Cell Lung Cancer First line	95	Carboplatin+Paclitaxel	(aueueamril) = oqjalecgkq wpjqpvyfwo (dptexfdauc ) View more	Negative	01 May 2019
NCT01268566 (CTgov)	Phase 2	Glioblastoma Multiforme \| Recurrent Glioblastoma	62	MEDI-575	tfsfwoacgr(binydgwjwt) = rrirzjizzb mxyxodyyxk (opgznyvsnq, mpzndupkyk - coobeluaht) View more	-	06 Apr 2017
NCT01268566 (Pubmed \| J Neurooncol) Manual	Phase 2	Recurrent Glioblastoma	56	MEDI-575	(jkqdxfvbvv) = tvxyolskwh hcojibshey (iwtxoowmhp, 8.1 - 24.9) View more	Negative	01 Jan 2017