MolMed (short for Molecular Medicine) has two anticancer therapies in Phase III clinical trials. The candidates are based on distinctly different technology platforms.
MolMed, headquartered in Milan, Italy, at the San Raffaele Biomedical Science Park, is developing a first-in-class vascular targeting agent that selectively homes in on the tumor vasculature. The agent, called NGR-hTNF, uses a tumor-homing peptide (NGR) to deliver human cytokine tumor necrosis factor (hTNF) to slow or block tumor progression.
The technology originated through a collaboration with the Burnham Institute, where peptides that bind only to human vascular tissue were discovered in phage display libraries. The highly specific NGR was selected, and researchers at the San Raffaele Institute fused it to hTNF.
NGR-hTNF targets the blood vessels that nourish tumors through specific binding of both moieties of the molecule to the neovasculature endothelium. Animal models confirm that NGR-hTNF directly acts on the vasculature to suppress tumor growth. NGR-hTNF shows broad therapeutic potential for the treatment of very different types of solid tumors, both common and rare, according to the company.
Clinical trials started in 2003, and since then, clinical investigators have obtained evidence of antitumor activity in a series of tumors including colorectal cancer, liver cancer, ovarian cancer, small-cell lung cancer, soft tissue sarcomas, and mesothelioma.
NGR-hTNF is now being investigated in pivotal Phase III trials for malignant pleural mesothelioma. An IND was recently cleared by the FDA to include clinical centers in the U.S. NGR-hTNF also is in Phase II trials for six more solid tumor types.
It’s been known since the 1980s that TNF has potent antitumor activity. However, patients treated with TNF alone experience severe toxicity side effects. “We took a different approach by attaching TNF to a peptide that delivers it directly to tumors for maximal antitumor activity,” says Claudio Bordignon, M.D., a hematologist and the firm’s CEO.
This provides powerful antitumor activity at doses that are 100 times lower than the known toxic dose of TNF, Dr. Bordignon reports. Because of the tiny doses needed, TNF shows no significant toxicity issues in patients. In fact, no toxicity has been reported for patients with non-small-cell lung cancer treated for up to two years with NGR-hTNF, he notes.
NGR-hTNF also works well in combination with chemotherapy agents, such as cisplatin or doxorubicin. “There’s a specific rationale for giving NGR-TNF with chemotherapy,” explains Dr. Bordignon. In the first few hours after injection with TNF, capillary leakage increases, which, in turn, promotes penetration of chemotherapy drugs into the tumor.
The protocol for using NGR-hTNF in non-small-cell lung cancer is to treat patients with first-line chemotherapy in combination until the maximum tolerated dose of the chemotherapy agent is reached. Then NGR-hTNF is continued alone as a maintenance therapy. When all other treatments options are exhausted for a patient, NGR-hTNF can be added as a maintenance therapy.