istiratumab (MM-141) / Ipsen - LARVOL DELTA

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 • Malignant 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

Exploring the response of Actinobacteria to the presence of phosphorus salts sources: Metabolic and co-metabolic processes. (PubMed, J Basic Microbiol) - "MM140 and MM141 were the most efficient in solubilizing Ca PO , MM136, and MM141 were the most efficient in solubilizing AlPO , while all strains were equally efficient in solubilizing FePO...It is concluded from this study that actinobacteria produced multiple organic acids followed by a decrease in the pH to solubilize phosphate salts. As well as producing phosphatase, these microorganisms were found to have different ways of making P available, suggesting an ecological advantage as they form part of soil microbiomes important for plants."

Journal