The U.S. Food and Drug Administration (FDA) cleared Mersana Therapeutics’ Investigational New Drug (IND) application to begin Phase I clinical trials for its lead investigational antibody-drug conjugate drug candidate XMT-1522. The investigational compound is Mersana’s first pipeline product, and defines a new class of HER2-targeted therapies. The investigational drug is based on Mersana’s Fleximer® technology.
The drug is being co-developed with Takeda Pharmaceutical. Under the terms of the agreement Mersana will, based on the FDA clearance of this IND, receive a $20 million milestone payment.
Earlier this year, in February, Takeda, through its wholly owned subsidiary Millennium Pharmaceuticals,, entered into a strategic partnership with Mersana to co-develop XMT-1522. The execution of the Phase I trial will be managed by Mersana. The company will also retain full commercial rights in the United States and Canada while Takeda will have rights in rest of world.
Current ADC Development
Industry-wide there are 60 antibody-drug conjugates in clinical development. Today 40 of these investigational compounds are in phase I trials, 16 in phase II and 4 phase III. Currently, there are two licensed ADCs on the market. In 2015 17 novel ADCs entered the clinic while an additional 7 have entered clinical trials in 2016. Many of the ADCs in phase I trials are not identifying a target disease, but are broadly recruiting for solid tumors. With more than 10 ADCs, breast and lung cancer are common diseases for ADCs. Of the 30 different targets for solid tumors 11 target breast cancer and 9 lung cancer.
A promising approach
“XMT-1522 represents a promising therapeutic approach for cancer patients with significant unmet medical needs and we are pleased to be in a position to move this therapy into clinical development.” said Donald A. Bergstrom, M.D. Ph.D., Chief Medical Officer, Mersana Therapeutics.
“We have designed a robust phase I program that will allow us to better understand the potential of XMT-1522 to address the needs of several patient groups who currently have limited options,” Bergstrom added.
Breast and Gastric cancers
XMT-1522 is an anti-HER2 antibody-drug conjugate. The investigational drug incorporates HT-19, a novel, proprietary anti-HER2 antibody optimized for cytotoxic payload delivery. The antibody is conjugated with Mersana’s Dolaflexin platform which includes its Fleximer biodegradable hydrophilic polymer technology and proprietary auristatin payload.
XMT-1522 provides a drug load or drug-to antibody ratio (DAR) of approximately 12 molecules per antibody, specifically designed to improve potency while simultaneously increasing tolerability. XMT-1522 has the potential to extend HER2-targeted therapy beyond the current HER2-positive populations into patients with lower levels of HER2 expression.
Early and pre-clinical results
Early and pre-clinical data presented during the 2015 annual meeting of the American Society for Cancer Research (AACR) and the 2015 San Antonio Breast Cancer Symposium (SABCS) has shown nanomolar potency in cultured tumor cells with HER2 receptor densities as low as 10,000 per cell. This data also shows that XMT-1522 is typically 1-3 logs more potent than ado-trastuzumab emtansine, also known as T-DM1 (Kadcyla®; Genentech/Roche), an antibody-drug conjugate consisting of the antibody trastuzumab linked to the cytotoxic agent emtansine, also called DM1, a thiol-containing maytansinoid.
Researchers at Mersana have further shown that XMT-1522 is active across a panel of 25 tumor cell lines  and in a range of models representing HER2+ disease where current HER2-targeted therapies, including ado-trastuzumab emtansine, are not active. XMT-1522 is also active in models representing HR+ and HR- HER2 IHC 1+ and 2+ disease. [Note]
In mouse xenograft studies XMT-1522 has excellent pharmacokinetic properties and achieves complete tumor regressions at well- tolerated doses. In one high HER2-expressing model of gastric cancer (800,000 HER2 receptors/cell), complete regressions was achieved with a single 1 mg/kg dose of XMT-1522. To achieve comparable activity with ado-trastuzumab emtansine, a dose of 10 mg/kg is required. 
One of the unique features of XMT-1522 is that it is non-competitive with existing therapies – trastuzumab or pertuzumab (Perjeta®; Genentech/Roche) – for HER2 binding. A triple combination of XMT-1522 + trastuzumab + pertuzumab in the same mouse xenograft model mentioned above, resulted in tumor regressions where the same doses of XMT-1522 alone or the trastuzumab/pertuzumab doublet result in tumor stasis.
In a low HER2-expressing breast cancer model (79,000 HER2/cell) and gastric cancer model (22,000 HER2/cell) models, complete regressions was achieved with single 1 mg/kg or 0.67 mg/kg doses of XMT-1522, respectively while ado-trastuzumab emtansine is inactive at doses ≥10 mg/kg.
In non-human primates XMT-1522 demonstrated good stability of the drug-conjugate in plasma with t1/2 ~5 days (comparable to antibody t1/2) and minimal exposure to free payload.
One of the interesting findings in early and pre-clinical studies is that despite the high potency of XMT-1522 in low HER2 tumor models, researchers did not observe XMT-1522-related toxicity in critical HER2-expressing tissues including heart and lung. The preclinical data further support testing XMT-1522 as a single agent in tumors with low HER2 expression where current HER2- directed therapies are not indicated. Finally, the combination of XMT-1522 with trastuzumab and/or pertuzumab achieves efficient cytotoxic payload delivery while retaining the potential for full inhibition of HER2 signaling, which may be necessary to improve on current regimens in HER2-driven tumors.
Phase I protocol
The Phase I protocol will evaluate XMT-1522 in patients with advanced HER2-positive breast and gastric cancer, as well as advanced breast cancer with low HER2 expression and HER2-expressing non-small cell lung cancer.
“Our partnership with Mersana exemplifies our approach of uniting Takeda’s experience in bringing novel oncology therapies to market with promising drug discovery technology like Mersana’s Fleximer to help drive science forward for patients with unmet medical needs,” noted Phil Rowlands, Interim Head, Oncology Therapeutic Area Unit, Takeda.
In addition to developing novel antibody-drug conjugates with select pharmaceutical partners, including Takeda, Mersana is also developing its own portfolio of next-generation Fleximer-ADCs with superior properties not found with current ADC technologies to address unmet needs and improve patient outcomes in multiple oncology indications.
[Note]: IHC or or Immunohistochemistry is a staining process performed on fresh or frozen breast cancer tissue removed during biopsy. It is used to show whether or not the cancer cells have HER2 receptors and/or hormone receptors on their surface. This information plays a critical role in treatment planning.