10-31-2013, 10:41 AM
Merrimack Pharmaceuticals, a Cambridge Massachusetts biomedical company has announced that its drug MM-121, an ErbB3 antibody, did not meet the meet the primary endpoint in a recent Phase II trial. This has had a negative effect on Merrimack share prices. The open-label, randomised trial was carried out to test the effectiveness of MM-121 (SAR256212) in combination with paclitaxel in patients with platinum-resistant or refractory advanced ovarian cancers. The primary end-point was progression free survival (PFS) in the overall population. However, the company announced that in a sub-population of patients who were positive for a combination of two biomarkers, the use of MM-121 may be of benefit. These biomarkers are linked to ErbB3 signalling. Merrimack entered into an exclusive global license and collaboration agreement for MM-121 with Sanofi in 2009.
ErbB3 (HER3) is a member of the epidermal growth factor receptor (ErbB; EGFR) family. Its expression has been linked to decreased survival in ovarian cancer. It is an activator of phosphoinositide 3-kinase (PI3K) signalling in ErbB1 (EGFR), ErbB2 (HER2) and [hepatocyte growth factor receptor (MET)] addicted cancers. ErbB3 reactivation has been identified as a mechanism by which cancers become resistant to ErbB inhibitors. While targeting of the EGFR family generally had shown limited clinical efficacy in ovarian cancer, studies supported the hypothesis that ErbB3 supports ovarian cancer cell growth and proliferation. RNA interference studies on primary ovarian cancers and ovarian cancer cell line suggested that in a subset of cells, ErbB3 participates in an autocrine signal-transducing loop involving neuregulin 1 (NRG1). Interference with this loop results in decreased cell growth in a three-dimensional cell culture model in vitro and a decrease in disease progression and increased survival in vivo in a xenograft mouse model of ovarian cancer. Use of MM-121 in this in vivo model resulted in a significant inhibition of tumour growth. MM-121 in cancer cell lines blocked ErbB3 ligand-dependent activation induced by ERbB1, ErbB2 or MET. It was most effective both in vitro in the cell lines characterised by ligand-dependent activation of ErbB3 and also in vivo against xenografts in which there was evidence of ligand-dependent ErbB3. A lung cancer mouse model which had become resistant to cetuximab, along with increased heregulin expression and ErbB3 activation, remained sensitive if cetuximab treatment was accompanied by MM-121 treatment. In this case, ErbB3 reactivation was blocked. Therefore, the finding in the Phase II trial of MM-121 with paclitaxel that a sub-population of ovarian cancer patients with biomarkers mechanistically linked to ErbB3 signalling may benefit from the drug despite the failure to hit the primary end-point target for the whole cohort was somewhat consistent with pre-clinical studies. The goal of using MM-121 is to inhibit ErbB3 signalling, thereby restoring sensitivity, delaying resistance and enhancing the anti-tumour effect of a therapeutic partner such as paclitaxel.
The failure on the primary end-point in the ovarian cancer Phase II trial followed a previous failure in another Phase II trial to hit a primary end-point of 40% progression-free survival rate at four months in 50 patients with non-small cell lung cancer patients whose disease had "progressed on an anti-EGFR tyrosine kinase inhibitor." However, Gavin MacBeath, the co-founder and Vice-President of translational research at Merrimack is “encouraged by the biomarker findings in this trial, which are consistent with our preclinical hypotheses.” Evaluation of the drug, in partnership with Sanofi, continues on second line ER/PR+ metastatic breast cancer, ER/PR+ neoadjuvant breast cancer, triple-negative neoadjuvant breast cancer and on other non-small cell lung cancer cohorts.
Sources
SCHOEBERL, B. et al., 2010. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer research, 70(6), pp. 2485-2494
SHENG, Q. and LIU, J., 2011. The therapeutic potential of targeting the EGFR family in epithelial ovarian cancer. British journal of cancer, 104(8), pp. 1241-1245
SHENG, Q. et al., 2010. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell, 17(3), pp. 298-310
TANNER, B. et al., 2006. ErbB-3 predicts survival in ovarian cancer. Journal Of Clinical Oncology: Official Journal Of The American Society Of Clinical Oncology, 24(26), pp. 4317-4323
http://www.fiercebiotech.com/story/sanof...2013-10-30 [Accessed 30 October 2013].
http://www.fiercebiotech.com/press-relea...-sar256212 [Accessed 30 October 2013].
ErbB3 (HER3) is a member of the epidermal growth factor receptor (ErbB; EGFR) family. Its expression has been linked to decreased survival in ovarian cancer. It is an activator of phosphoinositide 3-kinase (PI3K) signalling in ErbB1 (EGFR), ErbB2 (HER2) and [hepatocyte growth factor receptor (MET)] addicted cancers. ErbB3 reactivation has been identified as a mechanism by which cancers become resistant to ErbB inhibitors. While targeting of the EGFR family generally had shown limited clinical efficacy in ovarian cancer, studies supported the hypothesis that ErbB3 supports ovarian cancer cell growth and proliferation. RNA interference studies on primary ovarian cancers and ovarian cancer cell line suggested that in a subset of cells, ErbB3 participates in an autocrine signal-transducing loop involving neuregulin 1 (NRG1). Interference with this loop results in decreased cell growth in a three-dimensional cell culture model in vitro and a decrease in disease progression and increased survival in vivo in a xenograft mouse model of ovarian cancer. Use of MM-121 in this in vivo model resulted in a significant inhibition of tumour growth. MM-121 in cancer cell lines blocked ErbB3 ligand-dependent activation induced by ERbB1, ErbB2 or MET. It was most effective both in vitro in the cell lines characterised by ligand-dependent activation of ErbB3 and also in vivo against xenografts in which there was evidence of ligand-dependent ErbB3. A lung cancer mouse model which had become resistant to cetuximab, along with increased heregulin expression and ErbB3 activation, remained sensitive if cetuximab treatment was accompanied by MM-121 treatment. In this case, ErbB3 reactivation was blocked. Therefore, the finding in the Phase II trial of MM-121 with paclitaxel that a sub-population of ovarian cancer patients with biomarkers mechanistically linked to ErbB3 signalling may benefit from the drug despite the failure to hit the primary end-point target for the whole cohort was somewhat consistent with pre-clinical studies. The goal of using MM-121 is to inhibit ErbB3 signalling, thereby restoring sensitivity, delaying resistance and enhancing the anti-tumour effect of a therapeutic partner such as paclitaxel.
The failure on the primary end-point in the ovarian cancer Phase II trial followed a previous failure in another Phase II trial to hit a primary end-point of 40% progression-free survival rate at four months in 50 patients with non-small cell lung cancer patients whose disease had "progressed on an anti-EGFR tyrosine kinase inhibitor." However, Gavin MacBeath, the co-founder and Vice-President of translational research at Merrimack is “encouraged by the biomarker findings in this trial, which are consistent with our preclinical hypotheses.” Evaluation of the drug, in partnership with Sanofi, continues on second line ER/PR+ metastatic breast cancer, ER/PR+ neoadjuvant breast cancer, triple-negative neoadjuvant breast cancer and on other non-small cell lung cancer cohorts.
Sources
SCHOEBERL, B. et al., 2010. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer research, 70(6), pp. 2485-2494
SHENG, Q. and LIU, J., 2011. The therapeutic potential of targeting the EGFR family in epithelial ovarian cancer. British journal of cancer, 104(8), pp. 1241-1245
SHENG, Q. et al., 2010. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell, 17(3), pp. 298-310
TANNER, B. et al., 2006. ErbB-3 predicts survival in ovarian cancer. Journal Of Clinical Oncology: Official Journal Of The American Society Of Clinical Oncology, 24(26), pp. 4317-4323
http://www.fiercebiotech.com/story/sanof...2013-10-30 [Accessed 30 October 2013].
http://www.fiercebiotech.com/press-relea...-sar256212 [Accessed 30 October 2013].
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