istiratumab (MM-141) / Ipsen - LARVOL DELTA

Stability of grain and fodder yields in extra-early cowpea genotypes in Southeastern Niger. (PubMed, PLoS One) - "Notably, ten extra-early lines-BM22, BP02, BP15, MM142, 65B5080, BP18, BM21, BM13, MM141, and BM12-were identified as combining early maturity with high and stable grain and fodder yields. These lines should be further evaluated across diverse agroecological zones to confirm their adaptability and alignment with farmer preferences, prior to deployment as released varieties or as parents in cowpea improvement programs targeting climate-resilient, dual-purpose productivity in the Sahel."

Journal

Istiratumab exhibits antiproliferative activity in Ewing sarcoma and rhabdomyosarcoma (AACR 2025) - "Istiratumab inhibits ligand binding to abrogate PI3K/AKT signaling resulting in antiproliferative activity in various cancers alone and in combination with mTOR inhibitor everolimus or chemotherapy, including in a human Ewing sarcoma model...Antiproliferative effects of istiratumab were enhanced by addition of NT219 at 0.1 μM or panobinostat in the 3 Ewing sarcoma cell lines tested... Istiratumab has antiproliferative activity in sarcomas and will be evaluated in molecularly selected pediatric malignancies and Ewing sarcoma within the AcSé-ESMART trial."

Brain Cancer • CNS Tumor • Ependymoma • Ewing Sarcoma • Glioma • Hepatoblastoma • High Grade Glioma • Nasopharyngeal Carcinoma • Neuroblastoma • Oncology • Osteosarcoma • Pancreatic Cancer • Rhabdomyosarcoma • Sarcoma • Solid Tumor • ERBB3 • IGF1 • IGF2 • IRS1 • IRS2 • NRG1

Effect of MM-141 on gemcitabine and nab-paclitaxel potentiation in preclinical models of pancreatic cancer through induction of IGF-1R and ErbB3 degradation (ASCO-GI 2015) - Abstract #289; “ErbB3 and IGF-1R co-inhibition is required to inhibit AKT signaling in pancreatic adenocarcinoma cell lines. These receptors are associated with chemoresistance to gemcitabine and nab-paclitaxel, which is abrogated by co-administration with MM-141.”

Preclinical • Oncology • Pancreatic Cancer

"Other name MM141" (,@jpaArmand)

CARRIE: A Randomized, Double-blind, Placebo-controlled Phase 2 Study of Istiratumab (MM-141) plus Nab-Paclitaxel and Gemcitabine versus Nab-Paclitaxel and Gemcitabine in Front-line Metastatic Pancreatic Cancer (ESMO 2018) - P2; "Istiratumab failed to improve the efficacy of SOC chemotherapy in the front-line treatment of patients with metastatic PDAC and high IGF-1. High serum IGF-1 levels did not appear to be an adverse prognostic factor in this setting."

Clinical • Late-breaking abstract • P2 data • Pancreatic Cancer

Dual targeting of IGF-1R and ErbB3 as a potential therapeutic regimen for ovarian cancer. (PubMed, Sci Rep) - "Furthermore, in vivo efficacy of standard of care chemotherapies using a xenograft model of ovarian cancer was potentiated with istiratumab. Our results suggest a role for IGF-1R and ErbB3 in driving chemotherapy resistance of ovarian cancer."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

A Pore-Localizing CACNA1C-E1115K Missense Mutation, Identified in a Patient with Idiopathic QT Prolongation, Bradycardia, and Autism Spectrum Disorder, Converts the L-type Calcium Channel into a Hybrid Non-Selective Monovalent Cation Channel. (PubMed, Heart Rhythm) - "This CACNA1C-E1115K variant destroyed the LTCC's calcium selectivity and instead converted the mutant channel into a channel with a marked increase in sodium-mediated inward current and potassium -mediated outward currents. Despite the anticipated 50% reduction in LTCC, the creation of a new population of channels with accentuated inward and outward currents represents the likely pathogenic substrates for the patient's LQTS and arrhythmia phenotype."

Clinical • Journal • Atrial Fibrillation • Autism Spectrum Disorder • Cardiovascular • Genetic Disorders

CARRIE: A Phase 2 Study of MM-141 Plus Nab-paclitaxel and Gemcitabine in Front-line Metastatic Pancreatic Cancer (clinicaltrials.gov) - P2; N=88; Active, not recruiting; Sponsor: Merrimack Pharmaceuticals; Trial primary completion date: Aug 2017 ➔ Aug 2018

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

Merrimack: Clinical Trial Update (Merrimack) - “Observed safety profile of the MM-141 as a monotherapy appears comparable to expected toxicities with other IGF- 1 R and ErbB3 inhibitors”; “Recommended Phase 2 Dose of MM-141 was established for weekly dosing schedules at 20 mg/kg and for bi-weekly dosing schedules at 40 mg/kg”

P1 data • Oncology

Phase 1 Combination Study of MM-151 With MM-121, MM-141, or Trametinib (clinicaltrials.gov) - P1; N=5; Terminated; Sponsor: Merrimack Pharmaceuticals; N=32 ➔ 5; Recruiting ➔ Terminated; Sponsor decision

Enrollment change • Trial termination • Biosimilar • Colorectal Cancer • Head and Neck Cancer • Non Small Cell Lung Cancer

FDA grants Orphan Drug Designation to Merrimack Pharmaceuticals' MM-141 for the treatment of pancreatic cancer (Merrimack Press Release) - "Merrimack Pharmaceuticals...announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to their investigational drug candidate MM-141 for the treatment of pancreatic cancer....A Phase 2 study testing MM-141 in combination with nab-paclitaxel and gemcitabine in front line pancreatic cancer is expected to start in 2015."

Anticipated new P2 trial • Orphan drug • Oncology

First-in-human study of MM-141: A novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3 (ASCO-GI 2015) - Abstract #384; P1, N=15; NCT01733004; Merrimack Pharmaceuticals; “The analysis of pre- and post-treatment biopsies confirmed that IGF-1R and ErbB3 are expressed in patients previously exposed to sorafenib, and their levels are decreased after MM-141 exposure”

P1 data • Oncology

Merrimack Pharmaceuticals reports second quarter 2015 financial results (PRNewswire) - "Merrimack anticipates the following milestones in 2015: [1] Initiation of a clinical trial of MM-151 in EGFR-positive colorectal cancer; [2] Continued enrollment in HERMIONE, a Phase 2 clinical trial...[of] MM-302 in patients with HER2-positive metastatic breast cancer; [3] Continued enrollment in a Phase 2 clinical trial of MM-121 in patients with [mNSCLC]; and
[4] Continued enrollment in a Phase 2 clinical trial of MM-141 in patients with front-line metastatic pancreatic cancer...."

Anticipated enrollment status • Anticipated new trial • Breast Cancer • Colorectal Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer

Merrimack Pharma: Bank of America Merrill Lynch Health Care Conference (Merrimack) - Anticipated presentation of P1 data for advanced solid tumors at ASCO (May 30-Jun 03, 2014)

Anticipated P1 data • Oncology

A phase 1 atudy of MM-141 in patients with advanced solid tumors (clinicaltrials.gov) - P1, N=45; Sponsor: Merrimack; Recruiting; Primary completion date: Apr 2014 -> Aug 2014.

Trial primary completion date • Oncology

Merrimack Pharma: J. P. Morgan Healthcare Conference (35th Annual J.P. Morgan Healthcare Conference, Merrimack) - Anticipated data from P2 CARRIE trial (NCT02399137) for IGF-1+ metastatic front-line pancreatic cancer in 2018

Anticipated P2 data • Oncology • Pancreatic Cancer

Merrimack Pharma: J. P. Morgan Healthcare Conference (35th Annual J.P. Morgan Healthcare Conference, Merrimack) - Anticipated data from P2 CARRIE trial (NCT02399137) for IGF-1+ metastatic front-line pancreatic cancer in 2018

Anticipated P2 data • Oncology • Pancreatic Cancer

Merrimack Pharma: Cantor Fitzgerald Healthcare Conference (Merrimack) - "MM-141 IGF-1+ Patients Stayed on Therapy 80% Longer than IGF-1-Patients (n=27)"; "Phase 1 Data Presented at AACR 2015"

P1 data • Oncology

Merrimack Pharma: Annual Report 2013 (Merrimack) - Anticipated patent expiry of principle and methods of co-targeting IGF-1R and ErbB3 in human disease in US, EU, Canada, Australia and Japan in 2030; Anticipated expiry of patent family covering compositions, methods of use, and disease indications in EU and 7 other jurisdictions in 2032; Anticipated expiry of patents covering compositions, methods of use, disease indications and drug combination regimens related to MM-141 in 2033 

Anticipated patent expiry • Oncology

Merrimack Pharma: Annual Report 2014 (Merrimack) - Anticipated patent expiry of principle and methods of co-targeting IGF-1R and ErbB3 in human disease in US, EU, Canada, Australia and Japan in 2030; Anticipated expiry of patent family covering compositions, methods of use, and disease indications in US, EU, Japan and ROW in 2032; Anticipated expiry of patents in US, EU and 9 other jurisdictions covering compositions, methods of use, disease indications and drug combination regimens related to MM-141 in 2033; Anticipated expiry of patent in 2035

Anticipated patent expiry • Oncology

Merrimack Pharmaceuticals announces initiation of a phase 2 front-line clinical trial of MM-141 in biomarker-selected patients with metastatic pancreatic cancer (Merrimack Press Release) - "Merrimack Pharmaceuticals...today announced the initiation of a randomized, double-blinded, placebo-controlled Phase 2 clinical trial [NCT02399137] of MM-141...in combination with nab-paclitaxel and gemcitabine, versus nab-paclitaxel and gemcitabine alone in patients with newly-diagnosed metastatic pancreatic cancer who have high serum levels of free IGF-1...The primary endpoint of the trial is progression free survival (PFS)."

Enrollment open • Oncology • Pancreatic Cancer

Merrimack to present at the 2017 American Association for Cancer Research Annual Meeting (Merrimack Press Release) - "Presentations to include data on MM-310, a novel antibody-directed nanotherapeutic targeting EphA2, and istiratumab (MM-141)...Also highlighted at the conference will be preclinical data for MM-141 (istiratumab), a monoclonal bispecific antibody that acts as a tetravalent inhibitor of IGF1-R and HER3, and MM-161, a novel first-in-class pan-FGFR antibody."

Clinical data • Conference • Preclinical • Oncology

MM 141: Anticipated expiry of patents in US, Japan, Europe and ROW related to composition in 2032 (Merrimack) - Annual Report 2016: Anticipated expiry of patents in US and Europe covering methods of treating pancreatic cancer in 2035

Anticipated patent expiry • Oncology

Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE). (PubMed, Ann Oncol) - P2; "Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls."

Clinical • Journal • P2 data • ERBB3 • IGF1 • IGF1R • NRG1

Dual inhibition of IGF-1R and ErbB3 enhances the activity of gemcitabine and nab-paclitaxel in preclinical models of pancreatic cancer. (PubMed, Clin Cancer Res) - "Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRGDual IGF-1R/ErbB3 blocking enhanced chemo-sensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer."

Journal • Preclinical