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Columns : Apr 1, 2013 ( )
Exploiting Folate Pathways to Treat Cancer
Endocyte Uses an Imaging Agent to Select Patients Likely to Respond to Its Therapies!--h2>
Endocyte designs targeted small molecule drug conjugates (SMDCs) for the treatment of cancer and other diseases. All of the company’s SMDCs also come with a companion diagnostic imaging agent that helps to predict which patients will benefit most from a therapeutic. This dual approach for personalized therapy is improving the treatment of platinum-resistant ovarian cancer, according to the firm, which says SMDCs for other diseases are in the pipeline.
Endocyte formed in 1996 to design a drug delivery system based on technology discovered by Philip Low, Ph.D., at nearby Purdue University. Dr. Low, CSO at Endocyte, found that folate can transport drugs into cells. Most cells have receptors for folate, a B vitamin needed to carry out cell division. Rapidly dividing cancer cells particularly overexpress the folate receptor and use a different pathway than healthy cells to obtain folate. Endocyte researchers exploit this alternate pathway by attaching drugs to folate to kill cancer cells.
“This means that we can target highly potent drugs directly into cancer cells without harm to healthy cells,” says Ron Ellis, president and CEO.
Many potent cancer drugs have been discovered and tested by drug companies over the years, but they’ve been abandoned due to their high toxicity when tested in patients. Endocyte took an older, off-patent cancer drug and attached it to folate to create vintafolide (MK-8109/EC145). This drug candidate is in a Phase III trial in patients with platinum-resistant ovarian cancer.
Vintafolide has a companion diagnostic, etarfolatide (EC20), to select patients most likely to respond. A marketing authorization application for conditional approval of vintafolide and etarfolatide for platinum-resistant ovarian cancer was accepted by the European Medicines Agency (EMA) in November 2012.
Merck teamed up with Endocyte in April 2012 to develop and commercialize vintafolide. The partnership is worth up to $1 billion if all milestones are met. In addition to continuing trials of platinum-resistant ovarian cancer, Merck will evaluate the potential of vintafolide for the treatment of other cancer types. The partnership underscores Merck’s goal of building a portfolio of oncology therapies that use a companion diagnostic to assess patients most likely to benefit from a treatment.
The chemotherapeutic component of vintafolide is a type of vinca alkaloid taken up only by cancer cells. For the treatment of patients with platinum-resistant ovarian cancer, vintafolide is combined with Doxil® (pegylated liposomal doxorubicin). The firm says the drug combination increases the likelihood of killing cancer cells, since treating tumors with more than one drug makes it harder for cancer cells to develop resistance.
“Vintafolide’s toxicity profile gives us great flexibility to combine it with other drugs,” says Ellis. Many other drugs cannot be combined because their additive toxicities are too dangerous for clinical use.
Vintafolide was tested in an international, multicenter Phase II trial of 149 women with platinum-resistant ovarian cancer. Patients received vintafolide plus Doxil or Doxil alone until either disease progression or death. The primary endpoint was progression-free survival. Patients taking vintafolide plus Doxil had a median progression free survival of 5 months, compared to 2.7 months for patients receiving Doxil alone.
However, in patients who tested the most positive for a specific folate receptor, the delayed progression-free survival increased from 1.5 months to 5.5, or 260%. “If you don’t have the receptor, the drug doesn’t work as well. That’s a remarkable result,” says Ellis. A Phase III trial of vintafolide in platinum-resistant ovarian cancer is under way, as well as a Phase II/III trial of vintafolide in non-small-cell lung cancer.
The folate receptor that predicted patient response to vintafolide was identified with etarfolatide, the companion molecular imaging agent designed to screen patients who are likely to respond. “Our development strategy is to start with a diagnostic to assess quickly and easily which tissues and organs a chemotherapy drug will target,” says Ellis.
More importantly, tumors in patients are assessed to see if they contain the folate receptor. Tumor cells that highly express the folate receptor are more likely to be killed by the targeted therapy.
The EMA granted vintafolide the equivalence of orphan drug status in March 2012, because the drug shows exciting early results in patient populations that do not have effective treatments. “There’s probably no other cancer more in need of an effective treatment than platinum-resistant ovarian cancer,” says Ellis.
SMDCs for other types of cancer are made by attaching different drugs, or warheads, to the folate ligand. All the warheads are drugs discovered elsewhere that proved too toxic alone in patients. The revived drugs fall into well-known classes of cancer therapies, such as platinums, microtubule destablizers, and vinca alkaloids, and are highly prescribed worldwide. By attaching them to folate, “we’re designing versions that are a thousand to a million times more potent, yet less toxic,” says Ellis.
Endocyte researchers also can replace folate with a different targeting ligand to attach to other receptors. One drug candidate targets a different receptor on prostate cancer cells, which generally do not express folate receptors. A companion diagnostic confirms that this drug targets prostate tumors. “We can make our therapies modular by changing the warhead or ligand to create a different drug,” says Ellis.
Another program targets activated macrophages, an important cell type in inflammatory diseases like rheumatoid arthritis, Crohn’s disease, and psoriasis. Endoctye has a drug that knocks out, or deactivates, these activated macrophages. Imaging data show that the drug targets human-activated macrophages, and results from animal studies are encouraging.
Endocyte intends to develop and market some of its products by itself. The firm is also open to collaborations with companies that have a proprietary drug that could be made more potent or less toxic by attaching it to folate or another appropriate ligand.
Location: 3000 Kent Avenue, Suite A1-100, West Lafayette, IN 47906
Phone: (765) 463-7175
Number of Employees: 75
Focus: Endocyte develops targeted small molecule drug conjugates and companion imaging diagnostics to treat cancer and other diseases.
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