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Sanofi gives back rights to Merrimack cancer drug

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Sanofi gives back rights to Merrimack cancer drug

After a series of late-stage failures, Sanofi has returned the rights to the cancer compound MM-121 to Merrimack Pharmaceuticals.

MM-121, a monoclonal antibody designed to block ErbB3 activation in patients with heregulin-positive tumours, has been tested in Phase II trials in partnership with the French giant in ovarian, breast and lung cancer. However, none of them have met their primary endpoints and Sanofi has decided  to pull the plug, although it will continue to fund the existing MM-121 Phase II programme for the next six months.

SAR256212 (MM-121)

SAR256212 (MM-121) HER3 ErbB3 antibody

SAR256212 (MM-121) HER3 ErbB3 antibody

Targeting ErbB3

ErbB3 is a kinase-dead critical mediator of pro-survival signaling through PI3K/AKT activation and potentially through activation of other pathways involved in proliferation, differentiation, and survival of cancer cells.20 Signaling is mediated by ErbB3 ligands such as heregulin (HRG) and epidermal growth factor receptor (EGFR) ligands like betacellulin (BTC).21 Signaling through ErbB3 is a major mechanism by which cancer cells acquire resistance to targeted therapies (including EGFR and HER2 inhibitors); chemotherapies; and, potentially, radiotherapy.20,21References:
20. Schoeberl et al. Cancer Res. 2010;70:2485-2494; 21. Schoeberlet al. Sci Signal. 2009;2:ra31;  

Investigational anti-ErbB3 mAB

SAR256212 is an investigational fully human monoclonal antibody that targets the HER3 (ErbB3) receptor.21 SAR256212 potently inhibits ligand-induced signaling through HER3.21 By targeting ErbB3, SAR256212 blocks heregulin (HRG1-β1) binding to HER3, induces HER3 internaliztion and degradation, and blocks BTC-induced phosphorylation of HER3, leading to inhibition of HRG1-β1- and BTC-induced survival signaling.20 SAR256212 activity has been evaluated in a broad range of preclinical tumor xenograft models.21

The clinical significance of these findings is currently under investigation.

SAR256212 | Sanofi Oncology Pipeline

http://www.sanofioncology.com › Our Pipeline

SAR256212 (MM-121). SAR256212 (MM-121) HER3 ErbB3 antibody. Targeting ErbB3. ErbB3 is a kinase-dead critical mediator of pro-survival signaling …

VIDEO...http://www.sanofioncology.com/pipeline/SAR256212.aspx

 

Clinical development

SAR256212 is being codeveloped with Merrimack Pharmaceuticals Inc. SAR256212 is currently being investigated in a phase I trial in patients with refractory advanced solid tumors; in a phase I/II trial, in combination with erlotinib, in patients with NSCLC; in a phase I trial in combination with the investigational agent SAR245408 in solid tumors; in a phase I trial in combination with cetuximab and irinotecan in solid tumors; and in a phase I trial in combination with multiple chemotherapeutic agents in solid tumors. SAR256212 is also being investigated in a phase II trial in ER/PR+ HER2- breast cancer patients in combination with exemestane. In combination with paclitaxel, SAR256212 is being studied in a phase II trial in ER/PR+ HER2- breast cancer and TNBC, and a phase II trial in platinum-resistant/refractory ovarian cancer.

ER=estrogen receptor; HER2=human epidermal growth factor receptor 2; PR=progesterone receptor; TNBC=triple negative breast cancer.

SAR256212 is an investigational agent and has not been approved by the FDA or any other regulatory agency worldwide for the uses under investigation

ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.
Cancer Res. 2010 Mar 15;70(6):2485-94. doi: 10.1158/0008-5472.CAN-09-3145. Epub 2010 Mar 9.

An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation.

Schoeberl B1, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, Fulgham A, Song Y, Nielsen UB, Engelman JA, Wong KK.

Author information

  • 1Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts, USA.

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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