Delving into the Latest Updates on Demcizumab with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

Anti-DLL4 monoclonal antibody(OncoMed Pharmaceuticals), Anti-delta-like ligand 4 monoclonal antibody(OncoMed Pharmaceuticals), Demcizumab (USAN/INN)

+ [2]

Target

DLL4

Mechanism

DLL4 inhibitors(Delta-like protein 4 inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [2]

Active Indication-

Inactive Indication

Metastatic Colorectal Carcinomametastatic non-small cell lung cancerMetastatic Pancreatic Ductal Adenocarcinoma+ [5]

Originator Organization

Mereo BioPharma 5, Inc.

Active Organization-

Inactive Organization

Mereo BioPharma 5, Inc.

Celgene Corp.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

RegulationOrphan Drug (US)

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Structure/Sequence

Sequence Code 319372683L

Source: *****

Sequence Code 9976311H

Source: *****

The purpose of this study is to test the efficacy and safety of an experimental drug, demcizumab, when given in combination with pembrolizumab. Demcizumab is a humanized monoclonal antibody and was developed to target cancer stem cells. Demcizumab may block the growth of cancer stem cells, the remaining cancer cells, and it may also impair the productive growth of new blood vessels, which tumors need to grow and spread.
This study is sponsored by OncoMed Pharmaceuticals, which is referred to as OncoMed or the Sponsor in this consent form.

Start Date01 Jan 2016

Sponsor / Collaborator

Celgene Corp.

NCT02289898

/ CompletedPhase 2

A 3-Arm Phase 2 Double-Blind Randomized Study of Gemcitabine, Abraxane® Plus Placebo Versus Gemcitabine, Abraxane® Plus 1 or 2 Truncated Courses of Demcizumab in Subjects With 1st-Line Metastatic Pancreatic Ductal Adenocarcinoma

This is a randomized, double blind, 3 arm (1:1:1) study in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
The purpose is to test the efficacy and safety of demcizumab, when given in combination with gemcitabine and Abraxane® compared to placebo. The administration of gemcitabine and Abraxane® is a standard treatment for patients with metastatic pancreatic ductal adenocarcinoma.

Start Date20 Apr 2015

Sponsor / Collaborator

Mereo BioPharma 5, Inc.

[+1]

EUCTR2014-003355-56-BE

/ Not yet recruitingPhase 2

A 3-Arm Phase 2 Double-Blind Randomized Study of Gemcitabine, Abraxane® plus Placebo versus Gemcitabine, Abraxane® plus 1 or 2 Truncated Courses of Demcizumab in Subjects with 1st-Line Metastatic Pancreatic Ductal Adenocarcinoma - Yosemite

Start Date17 Apr 2015

Sponsor / Collaborator

Mereo BioPharma 5, Inc.

100 Clinical Results associated with Demcizumab

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100 Translational Medicine associated with Demcizumab

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100 Patents (Medical) associated with Demcizumab

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8

Literatures (Medical) associated with Demcizumab

01 Jan 2021·TheranosticsQ1 · MEDICINE

Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia

Q1 · MEDICINE

ArticleOA

Author: Indraccolo, Stefano ; Tadokoro, Carlos E ; Xiong, Huizhong ; Maraver, Antonio ; Aifantis, Iannis ; Garambois, Veronique ; Trimarchi, Thomas ; Furtado, Glaucia C ; Parkhurst, Christopher N ; Singh, Amartya ; Gómez-López, Gonzalo ; Brengues, Muriel ; Herranz, Daniel ; Lobry, Camille ; Gobert, Michael ; Khiabanian, Hossein ; Minuzzo, Sonia ; Lira, Sergio A ; Mancini, Maicol ; Lafaille, Juan J ; Shen, Shiqian

The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer. Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4⁺CD8⁺ T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.

01 Dec 2020·Annals of Translational MedicineQ4 · MEDICINE

NOTCH signalling in ovarian cancer angiogenesis

Q4 · MEDICINE

Review

Author: Perez-Fidalgo, Jose Alejandro ; Simon, Soraya ; Ortega, Belen ; Samartzis, Eleftherios Pierre ; Boussios, Stergios

The Notch signalling pathway is involved in the new vessel formation process by regulating tip and stalk cells, which are key cells in the sprout formation. This process is essential in both normal ovary and cancer angiogenesis and is regulated by Notch-VEGF crosstalk. Furthermore, Notch has been linked in ovary with stem cell maintenance and epithelial mesenchymal transition processes. Dysregulation of the Notch pathway is frequent in ovarian cancer (OC) and it has been associated with impaired survival and advanced stages or lymph node involvement. Notch also plays a role in chemoresistance to platinum. In this context, this pathway has emerged as an attractive target for precision medicine in OC. Two main targets of this pathway concentrate the clinical development of compounds blocking Notch: gamma secretase and Delta-like ligand 4. Most of the clinical trials including OC patients have been developed in phase I or phase Ib. Despite being in an early phase, both of these compounds, navicixizumab or demcizumab, two monoclonal antibodies targeting Dll4, showed promising efficacy data in platinum-resistant OC patients in recent studies. This review will focus on the mechanisms of the Notch pathway with special interest in angiogenesis regulation and the implication of Notch as a potential therapeutic target in OC.

01 May 2020·Gynecologic OncologyQ2 · MEDICINE

Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: The SIERRA open-label phase Ib trial

Q2 · MEDICINE

Article

Author: Robert Stagg ; Katelyn F. Handley ; Kathleen N. Moore ; Robert L. Coleman ; Graziela Zibetti Dal Molin ; Robert Burger ; Anil K. Sood

OBJECTIVESTo evaluate the safety and preliminary efficacy of demcizumab (DLL4 targeted IgG2 humanized monoclonal antibody; potent inhibitor of the Notch pathway) in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer (EOC); and to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD).METHODSWe conducted a 3 + 3 dose-escalation trial in patients with recurrent, platinum-resistant EOC with RECIST v. 1.1 measurable disease and ≤4 prior chemotherapy regimens. Two dosing cohorts (2.5 mg/kg and 5 mg/kg) were targeted; however, an intermediate dose level (3.5 mg/kg) was to be evaluated if the 5 mg/kg dose was not tolerable. Demcizumab was administered on days 1 and 15 and paclitaxel, weekly on days 1, 8, and 15 for each of three 28-day cycles: the 3-cycle doublet could be repeated once if safe. Thereafter, paclitaxel was administered until unacceptable toxicity or disease progression.RESULTSNineteen patients were enrolled. No dose-limiting toxicities (DLT) were observed; however, the intermediate dose level (3.5 mg/kg) was enrolled and expanded based on emerging safety data from other trials in the demcizumab program. The MTD was not reached. The most common treatment emergent adverse events (TEAE) were diarrhea (68%), fatigue (58%), peripheral edema (53%), and nausea (53%). Pulmonary hypertension, grade 2 (n = 2) and grade 1 (n = 1), was observed. Overall response rate (ORR) was 21% (95% CI: 6-45%); clinical benefit rate (CBR) was 42% (95% CI: 20-66%).CONCLUSIONSDemcizumab in combination with paclitaxel has a manageable toxicity profile and showed activity in patients with heavily pretreated platinum-resistant ovarian cancer.

100 Deals associated with Demcizumab

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External Link

KEGG	Wiki	ATC	Drug Bank
D10353	Demcizumab	-	DB12734

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
metastatic non-small cell lung cancer	Phase 2	IT	Mereo BioPharma 5, Inc.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	US	Mereo BioPharma 5, Inc.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	BE	Mereo BioPharma 5, Inc.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	AU	Mereo BioPharma 5, Inc.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	BE	Celgene Corp.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	IT	Celgene Corp.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	ES	Mereo BioPharma 5, Inc.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	ES	Celgene Corp.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	US	Celgene Corp.	01 Feb 2015
metastatic non-small cell lung cancer	Phase 2	AU	Celgene Corp.	01 Feb 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02259582 (DENALI, CTgov)	Phase 2	metastatic non-small cell lung cancer \| Non-squamous non-small cell lung cancer	82	Placebo (Placebo/Placebo Arm (Arm 1))	alydizzxjt(wjemelsmay) = gczmorswpb rowedxisgg (wwtiawgcim, rwtrrsauqs - iwtfvbhbnj) View more	-	20 Aug 2018
				Demcizumab+Placebo (Demcizumab/Placebo Arm (Arm 2))	alydizzxjt(wjemelsmay) = udzzmlhezg rowedxisgg (wwtiawgcim, mgsxzqssas - cqjkvczhgh) View more
NCT02289898 (YOSEMITE, CTgov)	Phase 2	Metastatic Pancreatic Ductal Adenocarcinoma	207	Placebo (Placebo/Placebo Arm)	bhnricmtuw(rvicydfzvl): Hazard Ratio (HR) = .930 (95% CI, 0.630 - 1.375), P-Value = 0.7158	-	08 Aug 2018
				Demcizumab+Placebo (Demcizumab/Placebo and Demcizumab/Demcizumab)
NCT01189968 (Pubmed \| Target Oncol) Manual	Phase 1	Non-Small Cell Lung Cancer First line	46	pemetrexed+carboplatin+Demcizumab	(kswbpblcuk) = zwnvjttrdm zqgqgpirkg (jjajflaupx ) View more	Positive	01 Feb 2018
NCT02259582 (DENALI, GlobeNewswire) Manual	Phase 2	Non-squamous non-small cell lung cancer First line	82	Carboplatin+Pemetrexed Disodium Hydrate+demcizumab	(ntdbkecbnd) = eviarompfg mkepaqhlpd (wwkhdjqnqu ) View more	Negative	08 May 2017
				Carboplatin+Pemetrexed Disodium Hydrate+Placebo	(ntdbkecbnd) = qpocyuiulc mkepaqhlpd (wwkhdjqnqu ) View more
NCT01189968 (ASCO2016)	Phase 1	Non-squamous non-small cell lung cancer	46	Demcizumab (2.5 mg/kg)	ndfgvmawti(ruboqftnsx) = Increased BNP values are an early indicator of the cardiac effects of DEM & mildly elevated values were used to start treatment with a cardioprotective ACE inhibitor or carvedilol elwiaynecs (tvvzswlrcn ) View more	Positive	20 May 2016
				Demcizumab (5 mg/kg)
NCT01189929 (ASCO_GI2016) Manual	Phase 1	Pancreatic Cancer First line	56	gemcitabine+demcizumab	(romekvgpsu) = DEM was limited to 70 days in cohorts 4, 5, 6 & 7. apijpwxwnv (qwyrsugtrh ) View more	Positive	01 Feb 2016
				gemcitabine+nab-paclitaxel+demcizumab
NCT01189968 (ASCO2014)	Phase 1	Non-Small Cell Lung Cancer First line	-	Demcizumab	(gfcluspbmd) = vupsxigzzn ucekbtolzo (inowsukgui ) View more	-	20 May 2014
NCT01189929 (ASCO_GI2014)	Phase 1	Pancreatic Cancer	57	Demcizumab	(voqnkwyqow) = hdheayswys onsvujtwjb (mtrcznjnml )	-	20 Jan 2014