demcizumab (OMP-21M18) / Mereo Biopharma, BMS - LARVOL DELTA

Delta-like Ligand 4 Inhibitors Induce Pulmonary Arterial Hypertension in Clinical Trials (AHA 2024) - "The most common antibody used was Demcizumab(6), followed by Navicixizumab(2), Dilpacimab(2), ABL001(2), and Enoticumab(1). DLL-4 inhibition treatment for malignancies has demonstrated PAH as a side effect. These results are in accordance with our previous observation that unopposed JAG-1-NOTCH3 signaling, induces pulmonary vascular SMC proliferation and PAH. Discontinuation of DLL-4 inhibitors leads to resolution of disease."

Clinical • Cardiovascular • Oncology • Pulmonary Arterial Hypertension • Respiratory Diseases • NOTCH3

DRUG-INDUCED PULMONARY HYPERTENSION IN CANCER PATIENTS (CHEST 2023) - "Drugs identified included tyrosine kinase inhibitors (TKI) in 70% of cases, including dasatinib, bosutinib and ponatinib. Other drugs included proteasome inhibitor (carfilzomib) and monoclonal antibody (demcizumab)... In our cohort, drug-induced PAH was mostly related to TKIs. Drug cessation and treatment with pulmonary vasodilator therapy resulted in improved pulmonary pressures and clinical status. Pulmonary hypertension was often reversible and more than half the patients were weaned off vasodilator therapy."

Clinical • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Cardiovascular • Chronic Lymphocytic Leukemia • Chronic Myeloid Leukemia • Hematological Disorders • Hematological Malignancies • Hypertension • Leukemia • Melanoma • Multiple Myeloma • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Transplantation

YOSEMITE: A 3 arm double-blind randomized phase 2 study of gemcitabine, paclitaxel protein-bound particles for injectable suspension, and placebo (GAP) versus gemcitabine, paclitaxel protein-bound particles for injectable suspension and either 1 or 2 truncated courses of demcizumab (GAD) (ESMO 2017) - P2; "The addition of either 1 or 2 truncated courses of demcizumab to 1st-line gemcitabine and Abraxane did not improve the efficacy compared to GAP in patients with 1st line metastatic pancreatic cancer. GAD therapy was generally well tolerated."

P2 data • Hepatocellular Cancer • Pancreatic Cancer

Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer (EOC): The SIERRA multi-institutional open-label phase Ib trial (SGO 2020) - "Two of five patients with prior bevacizumab treatment had an objective response, and two others had confirmed stable disease (≥12 weeks). Demcizumab in combination with paclitaxel has a manageable toxicity profile and showed activity in patients with heavily pretreated platinum-resistant ovarian cancer. Ongoing investigation is evaluating the next-generation bispecific VEGF/DLL4 antibody, navicixizumab, in combination with paclitaxel."

Clinical • P1 data • Fallopian Tube Cancer • Fatigue • Gynecologic Cancers • Hematological Disorders • Hypertension • Neutropenia • Oncology • Ovarian Cancer • Pain • Pulmonary Arterial Hypertension

NOTCH signalling in ovarian cancer angiogenesis. (PubMed, Ann Transl Med) - "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."

Journal • Review • Oncology • Ovarian Cancer • Solid Tumor

Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia. (PubMed, Theranostics) - "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...This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. 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."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • T Acute Lymphoblastic Leukemia

Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: The SIERRA open-label phase Ib trial. (PubMed, Gynecol Oncol) - "Demcizumab in combination with paclitaxel has a manageable toxicity profile and showed activity in patients with heavily pretreated platinum-resistant ovarian cancer."

Clinical • Journal • P1 data • Fallopian Tube Cancer • Fatigue • Gynecologic Cancers • Hypertension • Oncology • Ovarian Cancer • Pulmonary Arterial Hypertension • Solid Tumor

OncoMed: Jefferies Global Healthcare Conference 2016 (OncoMed) - Anticipated data from P1 trial (NCT02722954) of demcizumab + pembrolizumab in solid tumors in H1 2017; Anticipated completion of enrollment in P2 YOSEMITE trial (NCT02289898) of demcizumab in combination with gemcitabine and Abraxane for pancreatic cancer in H2 2016

Anticipated enrollment status • Anticipated P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

OncoMed: 2017 Outlook (OncoMed) - Anticipated analysis of event-driven OS data of P2 YOSEMITE trial (NCT02289898) of demcizumab in combination with gemcitabine and Abraxane for pancreatic cancer in mid-2017 and year-end 2017; Anticipated presentation of interim data from P2 YOSEMITE trial in pancreatic cancer at a medical meeting in H2 2017; Anticipated interim safety and efficacy data from P1b trial (NCT02722954) of demcizumab + Keytruda in solid tumors in H1 2017; Anticipated presentation of interim data from P1b trial in solid tumors at medical meeting in H2 2017; Anticipated completion of enrollment of P1b trial in solid tumors in 2017; Anticipated response, PFS and safety data from P2 DENALI trial (NCT02259582) in NSCLC in H1 2017; Anticipated final analysis of OS from P2 DENALI trial in NSCLC at year-end 2017

Anticipated enrollment status • Anticipated P1 data • Anticipated P2 data • Gastrointestinal Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer

OncoMed achieves $72.5 million in milestone payments from Celgene; Announces year-end cash balance (GlobeNewswire) - "OncoMed achieved the $70 million safety milestone from Celgene based on an analysis of available Phase 1b and blinded interim Phase 2 clinical trial safety data associated with the demcizumab..."; Anticipated survival data of P1b pancreatic cancer study of demcizumab and Abraxane combination in ASCO GI 2016; Anticipated intiation of P1b of demcizumab in combination with pembrolizumab in Q1 2016; Anticpated enrollment Completion of P2 YOSEMITE trial; Anticipated results from P1b ovarian cancer trial of demcizumab plus paclitaxel; Anticipated P1b data of tarextumab plus chemotherapy in SCLC at 16th IASLC conference; Anticipated top-line results from the Phase 2 'ALPINE' trial; Anticipated initiation of P1b trial of Brontictuzumab in colorectal cancer; Anticipated initiation of P1a data of OMP-305B83."

Anticipated conference • Anticipated enrollment status • Anticipated new P1 trial • Anticipated P1 data • Anticipated P2 data • Commercial • Gastrointestinal Cancer • Hematological Malignancies • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Small Cell Lung Cancer

A Study of Demcizumab Plus Pembrolizumab +/- Chemotherapy (clinicaltrials.gov) - P1; N=64; Recruiting; Sponsor: OncoMed Pharmaceuticals, Inc.

New P1 trial • Biosimilar • Oncology

A phase 1b study of the anti-cancer stem cell agent demcizumab (DEM), pemetrexed (PEM) & carboplatin (CARBO) in pts with 1st line non-squamous NSCLC (ASCO 2015) - Presentation time: Monday, Jun 1, 8:00 AM - 11:30 AM; Abstract #8045; P1, N=39; NCT01189968; "One of 33 (3%) evaluable pts had a RECIST CR, 15 (45%) had a PR & 13 had SD. The Kaplan Meier estimated median progression free survivals for the 2.5, 5, truncated 5 & truncated 7.5 mg/kg pts were 4.3, 5.3, not yet reached & 4.4 months, respectively. Eight pts who discontinued the study for a reason other than progression (6 continued to receive CARBO &/or PEM off-study) were progression-free through Days 314+, 408+, 448+, 456+, 546+, 677+ 680+ & Day 850."

P1 data • Non Small Cell Lung Cancer • Oncology

A phase 1B study of anti-DLL4 (Delta-Like Ligand 4) antibody demcizumab (DEM) with pemetrexed (PEM) and carboplatin (CARBO) in patients with 1st-line non-squamous NSCLC (ELCC 2015) - Abstract #114P; P1b, N=39; NCT01189968; Sponsor: OncoMed Pharmaceuticals; "One of 33 (3%) evaluable patients had a RECIST complete response, 15 (45%) a partial response and 13 (39%) stable disease for a clinical benefit rate of 88%. Eight patients at 5 and 7.5 mg/kg of DEM (6 off study for reasons other than progression) were progression free for >300 days; 6 ongoing on Days 408 + , 448 + , 456+ (no current therapy), 546 + , 677+ (no current therapy) & 680 + , and 2 with progression after 314 & 850 days."

P1 data • Non Small Cell Lung Cancer • Oncology

OncoMed announces first quarter 2017 financial results and demcizumab DENALI results (GlobeNewswire) - P2, N=82; NCT02259582; "The company is reporting top-line results from...'DENALI' clinical trial of demcizumab...in combination with carboplatin and pemetrexed in front-line non-squamous non-small cell lung cancer (NSCLC)...demcizumab treatment failed to meet its efficacy endpoints when compared to placebo, with better outcomes apparent in the placebo group. Specifically, the ORR was 28% versus 52% (p=0.04) and CBR was 79% versus 92% (p=0.17) in the pooled demcizumab arms and the placebo arm, respectively."

P2 data • Non Small Cell Lung Cancer • Oncology

A phase 1b study of the anti-cancer stem cell agent demcizumab (DEM), pemetrexed (PEM) & carboplatin (CARBO) in pts with 1st line non-squamous NSCLC (ESMO 2014) - Presentation time: 27.09.2014, 12:45 - 13:45; Abstract #1240P; P1, N=39; “As a result, DEM treatment was limited to 63 days in cohorts 5 & 6. One of 32 (3%) evaluable pts had a RECIST CR, 13 (41%) had a PR and 14 had SD. The Kaplan Meier estimated median progression free survivals for the 2.5, 5, truncated 5 & truncated 7.5 mg/kg pts were 4.3, 5.3, not yet reached & 4.4 months, respectively. Five pts who discontinued the study for a reason other than progression (3 continued to receive CARBO & PEM off-study) were progression-free through Days 223+, 243+, 457+, 497+, 680+ and a sixth pt (who continued to receive CARBO & PEM off-study) progressed at Day 850.” 

P1 data • Non Small Cell Lung Cancer • Oncology

A study of carboplatin and pemetrexed plus OMP-21M18 in subjects with non-squamous non-small cell lung cancer (clinicaltrials.gov) - P1, N=32; Recruiting; Completion date: May '12 -> Jun ' 14

Completion date • Trial delayed • Non Small Cell Lung Cancer • Oncology

A phase 1b study of the anti-cancer stem cell agent demcizumab (deM), pemetrexed (PeM) & carboplatin (Carbo) in patients (pts) with 1st line non-squamous nsClC. (ALCC 2016) - "Conclusions: the truncated dem regimen was generally well tolerated with encouraging activity observed. the optimal dem dose of truncated 5mg/kg q3wks is being evaluated in an ongoing randomized Phase 2 study (denAlI)."

Biomarker • Cancer stem cells • Clinical • Myeloid-derived suppressor cells • Biosimilar • Cardiovascular • Heart Failure • Non Small Cell Lung Cancer • Oncology

YOSEMITE: 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 (clinicaltrials.gov) - P2; N=207; Completed; Sponsor: OncoMed Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed

Trial completion • Biosimilar • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor

OncoMed Pharmaceuticals announces full year and fourth quarter 2015 financial results and 2016 guidance (OncoMed Press Release) - "Key 2016 milestones and anticipated events - Demcizumab: [1] Initiate a Phase 1b trial of demcizumab plus anti-PD-1 (pembrolizumab) in solid tumor patients in the first quarter; [2] Present updated survival data from the demcizumab P1b NSCLC trial mid-year; [3] Complete enrollment in the Phase 2 YOSEMITE clinical trial in patients with first-line pancreatic cancer by year end.  Data from this study are expected to be available in the first half of 2017; [4] Continue enrollment in the Phase 2 DENALI clinical trial in patients with first-line non-squamous NSCLC.  Data from [this] trial are anticipated in late 2017-2018."

Anticipated enrollment status • Anticipated new P1 trial • Anticipated P1 data • Anticipated P2 data • Gastrointestinal Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer

A phase 1b, open-label, dose escalation and expansion study of demcizumab plus pembrolizumab in patients with locally advanced or metastatic solid tumors (EORTC-NCI-AACR 2017) - "Demcizumab plus pembrolizumab therapy was well tolerated, but there was no evidence of enhanced antitumor activity."

Non Small Cell Lung Cancer • Prostate Cancer

Preclinical and clinical activity of anti-DLL4 (demcizumab) in combination with gemcitabine plus nab-paclitaxel in pancreatic cancer (AACR 2014) - Presentation time: Not available; Abstract #CT417; Abstract not available.

Anticipated clinical data • Oncology • Pancreatic Cancer

OncoMed: ASCO GI 2016 (OncoMed) - Anticipated completion of enrollment in P2 YOSEMITE trial (NCT02289898) in combination with gemcitabine and Abraxane for pancreatic cancer in 2016; Anticipated data from P2 YOSEMITE trial (NCT02289898) in combination with gemcitabine and Abraxane for pancreatic cancer in early 2017

Anticipated enrollment status • Anticipated P2 data • Gastric Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer

OncoMed announces abstracts accepted for presentation at the 2015 ASCO Annual Meeting (OncoMed Press Release) - "OncoMed will present new clinical data from clinical trials of its lead anti-cancer stem cell therapeutics, demcizumab and tarextumab. Final data from OncoMed's Phase 1b clinical trial of tarextumab (anti-Notch2/3, OMP-59R5) in small cell lung cancer...[and] New data from the company's Phase 1b clinical trials of demcizumab (OMP-21M18, anti-DLL4) in pancreatic cancer and non-small cell lung cancer (NSCLC) will be presented in posters during the meeting."

Anticipated conference • Anticipated P1 data • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer

A phase 1b study of demcizumab plus pemetrexed and carboplatin in patients with 1st line non-small cell lung cancer (NSCLC) (EORTC-NCI-AACR 2012) - Presentation time: Friday, Nov 09, 2012; P1, N=12; "Demcizumab when combined with pemetrexed & carboplatin was generally well tolerated with fatigue & asymptomatic hypertension being the most common drug related toxicities; Encouraging early clinical activity has been observed”

P1 data • Non Small Cell Lung Cancer • Oncology

A study of gemcitabine and demcizumab (OMP-21M18) with or without Abraxane as 1st-line treatment in subjects with locally advanced or metastatic pancreatic cancer (clinicaltrials.gov) - P1, N=50; Sponsor: OncoMed; Recruiting; Completion date: Jan 2014 -> Dec 2014.

Trial completion date • Oncology • Pancreatic Cancer