brontictuzumab (OMP-52M51) / Mereo Biopharma - LARVOL DELTA

Clinical Outcomes With Notch Inhibitors in Notch-Activated Recurrent/Metastatic Adenoid Cystic Carcinoma. (PubMed, Cancer Med) - "NOTCH inhibitors demonstrate activity in NOTCH-activated ACC, surpassing the efficacy of observation or prior systemic therapies. However, limited PFS and progression of nontarget lesions suggest the potential need for combination therapy to address ACC heterogeneity."

Clinical data • Journal • Retrospective data • Adenoid Cystic Carcinoma • Oncology • NICD • NOTCH1

Characterization of Epstein-Barr Virus-associated smooth muscle tumor in an immunocompromised patient (ACMG 2024) - P=N/A, P2 | "Down regulated pathways were early estrogen response, late estrogen response, inflammatory response, complement, coagulation, IL-2/STAT5 signalling, KRAS signalling up, androgen response, TNF-alpha signalling via NF-kB and apical junction.In EBV-SMT, up regulation of cancer genes involved in cell proliferation (RIT1, NPM1), epigenetic chromatin reprogramming (TET3, NSD1) and anti-tumor immune response (BTK, BCL3, ICOSLG), and down regulation of cancer genes involved in signalling events in both innate and adaptive immunity (JAK2, GATA3), maintenance of genomic stability (CDK12, MSH6) and inhibition of smooth muscle cell migration (EGFL7) could have driven tumorigenesis.Potential therapeutic targets among up regulated cancer genes include BTK, NOTCH1 and NSD1 which could be targeted with bruton tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, or zanubrutinib, NOTCH1 inhibitor such as brontictuzumab (NCT02662608) and DNA methytransferase inhibitors..."

Clinical • IO biomarker • Epstein-Barr Virus Infections • Human Immunodeficiency Virus • Infectious Disease • Oncology • Transplantation • ACKR3 • BCL3 • CALD • CASP8 • CDH11 • CDK12 • CDKN1A • CEBPA • COL1A1 • DAXX • FAT1 • GATA3 • ICOSLG • IFNG • IL2 • JAK2 • KLF3 • KLF4 • KRAS • MEF2C • MSH6 • NOTCH1 • NPM1 • NSD1 • RIT1 • STAT5 • TNFA

Anti-NOTCH1 therapy with OMP-52 M51 inhibits salivary adenoid cystic carcinoma by depressing epithelial-mesenchymal transition (EMT) process and inducing ferroptosis. (PubMed, Toxicol Appl Pharmacol) - "Intriguingly, low-dose OMP-52 M51 strongly facilitated the capacity of ferroptosis inducer erastin to trigger ferroptotic cell death, revealing that OMP-52 M51 could improve the sensitivity of ACC cells to ferroptosis. In vivo, OMP-52 M51 administration suppressed tumor growth and induced ferroptosis in the constructed ACC xenograft mouse model. Collectively, our findings demonstrated that NOTCH1 inhibition by OMP-52 M51 represses the proliferation and epithelial-mesenchymal transition (EMT) in ACCs, and promotes ferroptosis, revealing the potential therapeutical application of OMP-52 M51 in ACC."

Journal • Adenoid Cystic Carcinoma • Oncology • Salivary Gland Cancer • GPX4 • NICD • NOTCH1

Efficacy of NOTCH inhibitors (Ni) relative to prior systemic therapy or observation in patients (pts) with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) (ESMO 2023) - "Ni included AL101, a gamma-secretase inhibitor, or OMP-52M51, an antibody targeting N1...The efficacy of Ni compares favorably with efficacy of systemic therapies administered prior to Ni. The limited PFS and high rate of tumor progression on non-target lesions suggests Ni combination therapy may be necessary to address ACC heterogeneity."

Clinical • Metastases • Adenoid Cystic Carcinoma • Oncology • NOTCH1

Targeting NOTCH1 in combination with antimetabolite drugs prolongs life span in relapsed pediatric and adult T-acute lymphoblastic leukemia xenografts. (PubMed, Exp Hematol Oncol) - "Hence, targeting the NOTCH1 signaling pathway may be an effective option to overcome relapsed and refractory T-ALL.Here, we focused on the therapeutic activity of the NOTCH1-specific monoclonal antibody OMP-52M51 in combination either with drugs used during the induction, consolidation, or maintenance phase in mice xenografts established from pediatric and adult relapsed NOTCH1 mutated T-ALL samples...In agreement, both in vitro and in vivo, the greatest effect on leukemia growth reduction was achieved by anti-NOTCH1 therapy in combination with antimetabolite drugs. This result was further corroborated by the longer life span of mice treated with the anti-NOTCH1 in combination with antimetabolites, indicating a novel Notch-targeted therapeutic approach that could ameliorate pediatric and adult T-ALL patients outcome with relapse disease for whom so far, no other therapeutic options are available."

Combination therapy • Journal • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • FBXW7 • NOTCH1

A computational guided, functional validation of a novel therapeutic antibody proposes Notch signaling as a clinical relevant and druggable target in glioma. (PubMed, Sci Rep) - "We functionally assessed the biological effects of the first-in-human tested blocking antibody against Notch1 receptor (brontictuzumab, BRON) in a collection of glioma stem-like cell (GSC) models and compared its effects to genetic Notch1 inhibition as well as classical pharmacological Notch inhibitor treatment using gamma-secretase inhibitor MRK003. We note that the observed phenotype seems only in part due to Notch1 blockage and the drug candidate leads to activation of off target signals. Further studies addressing a possible emergence of therapy resistance due to WNT activation need to be conducted. We further validated our 3D disease modeling technology to be of benefit for drug development projects."

Clinical • Journal • Glioblastoma • Glioma • Oncology • Solid Tumor • HES1 • IDH1 • NOTCH1

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

Oncomed announces multiple abstracts accepted for presentation at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire) - "Among the abstracts accepted for presentation are Phase 1a data for single-agent brontictuzumab (anti-Notch1, OMP-52M51) in advanced solid tumors, including initial results from an expansion cohort of patients whose tumors demonstrate an overexpression of the activated form of Notch1 as measured by a companion biomarker.  In addition, biomarker data for vantictumab (anti-Fzd7, OMP-18R5) in non-small cell lung cancer, as well as results of preclinical studies for OncoMed’s anti-DLL4/VEGF bispecific (OMP-305B83), will also be presented."

Anticipated conference • Anticipated P1 data • Anticipated preclinical • Biomarker • Non Small Cell Lung Cancer • Oncology

OncoMed: J.P.Morgan Healthcare Conference (OncoMed) - Anticipated data from P1 trial (NCT01703572) in hematological malignancies in H2 2016

Anticipated P1 data • Hematological Malignancies • Oncology

OncoMed: 2017 Outlook (OncoMed) - Anticipated initiation of enrollment in P1b trial of brontictuzumab in combination with Lonsurf for 3L colorectal cancer in H1 2017

Anticipated enrollment status • Colorectal Cancer • Oncology

OncoMed: Cantor Fitzgerald Healthcare Conference (OncoMed) - Anticipated data from biomarker-selected expansion cohorts from P1a trials in advanced solid tumors (NCT01778439) and hematological malignancies (NCT01703572) in H2 2015

Anticipated P1 data • Oncology

OncoMed: Clinical Trial Update (OncoMed) - “Manageable safety profile, Diarrhea is most common on-target toxicity”; “Single-agent Ph 2 dose of 1.5 mg/kg Q3W”; “Plasma half-life of 1.5 days”; “Encouraging early signs of anti-tumor activity in Notch1 ICD-high patients”

P1 data • Oncology

OncoMed: Clinical Trial Update (OncoMed) - “The primary on target toxicity of OMP-52M51 is diarrhea”; “The MTD of single agent OMP-52M51 has not been reached and dose escalation continues”; “Thus far the half life of OMP-52M51 is approximately 4 days (at 2.5mg/kg Q4W), PK data supports change from a q 28 to q 21 day dosing”; “There is potential evidence of CTC reduction in two patients with baseline > 20 CTCs/mL (mCRC and cholangiocarcinoma) with OMP-52M51 treatment”; “Some suggestion of single agent activity has been noted in a patient with mCRC and a patient with HER2-mBC with stable disease > 120 days”

P1 data • Breast Cancer • Colorectal Cancer • Oncology

OncoMed's phase 2 trial of tarextumab in small cell lung cancer does not meet endpoints (OncoMed Press Release) - P2, N=145; NCT01859741; "OncoMed Pharmaceuticals...today reported top-line results from...PINNACLE clinical trial of tarextumab...in previously untreated patients with extensive-stage small cell lung cancer...the trial did not meet its primary endpoint of progression-free survival or secondary endpoints of overall survival and biomarkers reflective of Notch pathway gene activation...it will discontinue enrollment in the Phase 1b clinical trial of brontictuzumab...in combination with trifluridine/tipiracil (Lonsurf®) in third-line colorectal cancer patients."

Enrollment closed • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Small Cell Lung Cancer

OncoMed: AACR-NCI-EORTC 2015 (OncoMed) - “BRON was generally well tolerated”; “The recommended single-agent phase 2 dose is 1.5 mg/kg Q3W”; “The main toxicity of BRON is on-target diarrhea. Other less common events included fatigue, nausea, and vomiting: Diarrhea is a known on-target effect of Notch inhibition and was controlled in most cases”; “BRON has shown single-agent efficacy, where several pts had stable disease and two patients had a partial response, particularly in the biomarker-defined population (NICD high): Activity observed in ACC, CRC, and breast cancer”; “The dose cohorts at or above 1.5 mg/kg Q3W showed clear target engagement in blood and the tumor”

P1 data • Oncology

OncoMed: Annual Report 2015 (OncoMed) - Anticipated expiry of patents in US and ex-US related to composition of matter and method of use in 2029; Anticipated expiry of patents in US and ex-US related to certain uses of brontictuzumab in 2025 or 2031; Anticipated expiry of patents relating to brontictuzumab, certain of its uses and/or related biomarkers between 2025 to 2035

Anticipated patent expiry • Oncology

OncoMed: Cantor Fitzgerald Healthcare Conference 2016 (OncoMed) - Anticipated data from P1b trial of brontictuzumab in combination with FOLFIRI in colorectal cancer in 2017

Anticipated P1 data • Colorectal Cancer • Oncology

Brontictuzumab: Anticipated expiry of patents in US and ex-US related to composition-of-matter and method-of-use in 2029 (OncoMed) - Annual Report 2016: Anticipated expiry of patents in US and ex-US related to certain uses of brontictuzumab in 2025, 2029 or 2031; Anticipated expiry of patents related to brontictuzumab, certain of its uses and/or related biomarkers between 2032 to 2037

Anticipated patent expiry • Oncology

A Dose Escalation Study of OMP-52M51 in Subjects With Lymphoid Malignancies (clinicaltrials.gov) - P1; N=53; Recruiting; Sponsor: OncoMed Pharmaceuticals, Inc.; Trial primary completion date: Dec 2014 ->Dec 2015

Trial primary completion date • Biosimilar • Oncology

Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy. (PubMed, J Exp Clin Cancer Res) - "DLL4 effectively stimulates Notch1 signaling in NOTCH1-mutated MCL and is expressed by the microenvironment in MCL lymph nodes. Our results indicate that specific inhibition of the Notch1-ligand-receptor interaction might provide a therapeutic alternative for a subset of MCL patients."

Journal

A Phase 1 dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors. (PubMed, Ann Oncol) - P1; "An efficacy signal was noted in subjects with ACC and Notch1 pathway activation. NCT01778439."

Clinical • Journal • P1 data

Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells. (PubMed, Oncogene) - "All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients."

Journal

Dissecting molecular mechanisms of resistance to Notch1-targeted therapy in T-cell acute lymphoblastic leukemia xenografts. (PubMed, Haematologica) - "...We previously demonstrated that the Notch1-specific neutralizing antibody OMP52M51 prolongs survival in T-cell acute lymphoblastic leukemia patient-derived xenografts bearing NOTCH1/FBW7 mutations...Conversely, in another model resistance developed after only 43 days of treatment despite persistent down-regulation of Notch signaling and it was accompanied by modulation of lipid metabolism and reduced surface expression of Notch1. Our findings shed light on heterogeneous mechanisms adopted by the tumor to evade Notch1 blockade and support clinical implementation of antibody-based target therapy for Notch-addicted tumors."

Journal • Tumor Mutational Burden

Alterations of Notch pathway in patients with adenoid cystic carcinoma of the trachea and its impact on survival. (PubMed, Lung Cancer) - "NOTCH1 mutation is associated with activation of Notch pathway in ACC of the trachea. NOTCH1 is a potential target for therapeutic intervention in patients with ACC of the trachea."

Clinical • Journal