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MM-302 is a nanotherapeutic encapsulation of the anthracycline chemotherapy agent doxorubicin with anti-HER2 antibody fragments attached to its surface. Anthracyclines have known cardiotoxicities which historically have restricted their use in combination with HER2-targeted therapies.
"We are highly encouraged by these results. MM-302 was engineered to be a more effective treatment than free doxorubicin and to address the safety concerns associated with the traditional chemotherapy," said
Ulrik B. Nielsen, Co-Founder and Chief Scientific Officer, Merrimack Pharmaceuticals. "We've encapsulated doxorubicin in a liposomal membrane that is designed to travel through the blood to the tumor cell with limited uptake into normal tissue such as heart tissue. When it arrives at the tumor cell, the antibodies on the outside of the encapsulated medicine bind to the HER2 receptor and pull the medicine inside the cell, allowing the chemotherapy to be delivered locally within the tumor."
Merrimack is developing an image-based companion diagnostic, MM-DX-929, to predict response to liposomal chemotherapeutics, such as MM-302. A preclinical study presented at SABCS showed that tumor uptake of MM-DX-929 correlated well with treatment response to MM-302.
METHODOLOGY AND RESULTSA Phase I Study of MM-302, a HER2-targeted Liposomal Doxorubicin, in Patients with Advanced, HER2-positive (HER2+) Breast Cancer (Abstract #: P5-18-09)
To evaluate the safety and tolerability of MM-302, 34 patients with histologically confirmed HER2+ metastatic breast cancer were enrolled. Patients had received a median of seven prior therapies. The study used a standard 3 + 3 dose escalation design to determine the Phase II dose of MM-302. Patients were enrolled across five dose levels ranging from 8 mg/m 2 to 50mg/m 2 given every 4 weeks.
Overall MM-302 was well tolerated. The most frequent adverse events were fatigue (47%), nausea (41%) and decreased appetite (31%). Four patients had grade 3 or 4 toxicities. No dose limiting toxicities were observed and none of the patients treated thus far has had a decrease in cardiac ejection fraction.
Of the 22 evaluable patients in this heavily pretreated patient population, 12 patients achieved stable disease (SD) and two patients achieved a partial response (PR), resulting in a clinical benefit rate of 64%. One of the patients who achieved a PR had a 100% regression of their target lesion.
A Novel 64Cu-Liposomal PET Agent (MM-DX-929) Predicts Response to Liposomal Chemotherapeutics in Preclinical Breast Cancer Models (Abstract #: P4-02-05)
Preclinical models bearing BT474-M3 mammary and subcutaneous tumors were injected intravenously with MM-DX-929 prior to dosing with MM-302. PET/CT imaging was performed at 16 hours post MM-DX-929 injection, and tumor uptake was evaluated. Response to treatment was quantified as tumor volume changes measured over a 2-month period by MRI.
Tumor deposition of MM-DX-929 correlated well with treatment response to MM-302 (Spearman correlation coefficient of -0.891 and a p-value of 0.0004). MM-DX-929 accumulation in tumors prior to the start of the MM-302 treatment successfully predicted improved tumor growth inhibition following MM-302 treatment.
These findings support further development of MM-DX-929 as a potential diagnostic imaging agent to identify patients who are most likely to respond to liposomal therapies.
About Merrimack Pharmaceuticals, Inc.
Merrimack Pharmaceuticals is a biopharmaceutical company discovering, developing and preparing to commercialize innovative medicines paired with companion diagnostics for the treatment of serious diseases, with an initial focus on cancer. Merrimack applies Network Biology, its proprietary systems biology-based approach to biomedical research, throughout the research and development process. Merrimack currently has five therapeutic oncology candidates in clinical development.