Mersana is advancing a robust pipeline of ADC therapies across multiple tumor types that have the potential to radically improve patients’ lives by increasing survival and quality of life.
XMT-1522: A potent HER2-targeted ADC targeting patients not addressed by currently approved HER2 therapies
XMT-1522, is a Dolaflexin ADC targeting HER2-expressing tumors. HER2 belongs to a family of signaling molecules that are highly and preferentially expressed on the surface of various cancer cells, and are known to play a role in promoting tumor cell growth. Currently approved HER2-targeted therapies are indicated only for patients with high expression of HER2 due to amplification of the HER2 gene, and who are referred to as HER2-positive. There is a significantly larger population of patients with low-to-moderate HER2 expression for whom treatment options are more limited. We are focused on leveraging the properties of XMT-1522 for HER2-expressing patient populations where existing approved HER2 therapies are either not indicated or have failed. XMT-1522 is currently in Phase 1 development in patients with HER2-expressing breast cancer, non-small cell lung cancer (NSCLC), and gastric cancer.
Our development plan for XMT-1522 is supported by extensive preclinical data in animal models that represent diverse levels of HER2 expression across multiple tumor types. Our data demonstrate that XMT-1522 achieved durable complete regressions across many of the tested tumor models representing the indications of interest. Furthermore, XMT-1522 also demonstrated improved efficacy relative to traditional ADCs, even in tumor models where the target antigen is expressed at moderate to low levels, and showed the potential to be used in combination with other HER2-targeted agents as well as checkpoint inhibitors. We have established in animal models that XMT-1522 is stable in circulation, has predictable pharmacokinetics, and an acceptable safety profile.
XMT-1536: A first-in-class ADC targeting NaPi2b, a clinically validated ADC target
XMT-1536 is a Dolaflexin ADC targeting NaPi2b-expressing tumors. NaPi2b is an antigen highly expressed in 75 to 90% of both non-squamous NSCLC and epithelial ovarian cancer. NaPi2b was evaluated as an ADC (lifastuzumab vedotin) by Genentech, Inc., in studies that indicated that NaPi2b could be safely targeted by an ADC, with evidence of clinical activity in ovarian cancer. XMT-1536 is currently in Investigational New Drug Application, or IND, enabling studies, and we expect it to enter clinical development in early 2018.
In our preclinical studies, XMT-1536 induced complete tumor regressions in an ovarian cancer model and an NSCLC adenocarcinoma model after three weekly doses of 3 mg/kg. In comparison, lifastuzumab vedotin failed to induce tumor regressions when similarly administered in three weekly doses of 3 mg/kg. XMT-1536 was also tested in eight patient-derived tumor models of NSCLC adenocarcinoma, where it led to complete or near-complete tumor regressions in five of eight models, and significant tumor growth delay in two of the remaining three models. These tumor regressions were durable at least 45 days post-dosing. Similarly, XMT-1536 was tested in fifteen ovarian patient-derived xenograft models where it led to complete or near complete tumor regressions in nine models and partial regressions in three models. Retrospective evaluation of NaPi2b expression appears to correlate with responses to XMT-1536. In an exploratory repeat dose non-human primate study of XMT-1536, no neutropenia was observed at payload doses that were at least four times the highest non-severely toxic dose of lifastuzumab vedotin and at least two times the dose that caused fatal neutropenia with lifastuzumab vedotin in non-human primates.1
 Lin et al, ClinCancer Res 2015, 21:5139-5150;
Our vision is to leverage the power of our technologies to develop a leading ADC pipeline. We have multiple active programs at the discovery stage with the objective of bringing a new drug candidate forward into clinical development every twelve to twenty-four months.