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Merck, Endocyte to Study Vintafolide, Companion Imaging Agent in Multiple Folate-expressing Cancers

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By Turna Ray

A new collaboration between Merck and Endocyte to advance the latter's investigational cancer drug vintafolide with a companion diagnostic agent for identifying folate-expressing tumors will initially focus on ovarian and non-small cell lung cancer indications.

The deal, which gives Merck worldwide commercialization rights to vintafolide, could extend the drug's indications to as many as six other cancers, potentially netting Endocyte nearly $900 million in milestone payments.

"The collaboration will include development [of vintafolide] in ovarian cancer, NSCLC, and multiple other cancer indications," Mike Sherman, Endocyte's CFO, told PGx Reporter. "There is no limitation to the indications which may be pursued." Endocyte estimated that there are more than a million new cancer patients each year whose tumors overexpress folate receptors.

Endocyte is currently studying vintafolide – which combines the vitamin B9 folate and the chemotherapy agent desacetylvinblastine monohydrazide – in a Phase III study involving ovarian cancer patients who are resistant to platinum-based therapy and in a Phase II study involving NSCLC patients. In both trials, researchers are injecting patients with etarfolatide, a folate-targeting imaging agent, to gauge which have tumors overexpressing folate receptors and therefore will respond best to the folate conjugate.

As a member of the vitamin B family, folates play a role in cell survival, but they can also be combined with anti-cancer drugs to target folate receptor proteins on the surface of cancer cells. Drug developers exploring folate conjugates believe these agents might be able to specifically hone in on tumors and decrease adverse events, since folate receptors usually occur in low levels in normal tissues.

Previously published studies suggest that between 80 percent and 90 percent of epithelial ovarian cancers and around 70 percent of NSCLC tumors overexpress folate receptors.

Under the terms of the deal with Merck, Endocyte will receive an initial payment of $120 million, but could receive approximately $880 million in milestone payments if it successfully develops and commercializes the drug in six indications. Since both the folate conjugate and the imaging agent are proprietary to Endocyte, if vintafolide receives regulatory approval, the company will garner an equal share of the drug profits in the US and an undisclosed "double digit percentage royalty" in non-US markets.

Sherman did not reveal which indications beyond ovarian cancer and NSCLC Endocyte will target.

Additionally, the deal gives Endocyte the right to co-promote vintafolide with Merck in the US and gives Merck the exclusive right to sell the drug in the rest of the world.

On the companion diagnostic side, Endocyte will develop, manufacture and globally commercialize the imaging agent etarfolatide.

Sherman highlighted a number of reasons for Endocyte's decision to pair an imaging diagnostic with vintafolide. For example, etarfolatide injections will be less invasive than other diagnostic technologies that require tumor biopsies. Furthermore, the imaging-based approach "lends itself to real-time assessments of receptor status rather than relying on prior biopsies, which may not reflect the current disease state," Sherman said.

With the help of a molecular imaging agent, healthcare providers will be able "to assess receptor presence throughout disease" rather than just one biopsy site, he explained. Furthermore, since the chemical design of the therapeutic and the diagnostic imaging agent is similar, both products are likely to target the same tumor cells, which "provides some confirmation of functional binding site in advance of therapy," Sherman added.

Since the Phase III ovarian cancer trial, called PROCEED, and the Phase II NSCLC study have already begun, Endocyte will be responsible for executing these investigations under its collaboration with Merck.

The randomized, double-blind PROCEED trial will enroll more than 400 folate-receptor-positive ovarian cancer patients who are resistant to platinum therapy. They will be randomized to receive vintafolide plus pegylated liposomal doxorubicin or PLD plus placebo. In the trial, researchers will compare progression-free survival and overall survival for the different treatments.

At last year's American Society of Clinical Oncology's annual meeting, researchers from Endocyte and elsewhere reported data from a Phase II study that compared platinum-resistant ovarian cancer patients' outcomes when they were given a vintafolide/PLD combination regimen or PLD alone. Progression-free survival more than doubled in patients treated with vintafolide plus PLD compared to just PLD.

In this earlier study, the "largest improvement [was] observed in patients with all tumors imaged as positive for folate receptor expression." Women who overexpressed folate receptors experienced a 62 percent decrease in their risk of progression when treated with the vintafolide-containing regimen compared to women receiving chemotherapy alone.

In this patient subset, median progression-free survival for those treated with vintafolide/PLD was 5.5 months versus to 1.5 months for those receiving PLD. Additionally, 17 percent of patients with folate receptor-overexpressing tumors also experienced tumor shrinkage while receiving the EC145-based therapy compared to just over 6 percent of patients whose tumor shrank when treated with chemotherapy alone.

In the Phase II NSCLC study, researchers will evaluate vintafolide as a second-line treatment in 180 folate receptor overexpressing patients. This trial will compare patients' progression-free survival in three treatment arms. In the first arm, NSCLC patients will be treated with vintafolide alone; patients in the second arm will receive taxotere alone, and in the third arm patients will receive vintafolide plus taxotere.

Endocyte expects the final progression-free survival data from both the PROCEED and NSCLC trials by 2014.

"We will wait to file in the US with Phase III PROCEED data," Sherman said. He added that the company plans to submit in the second half of 2014 a new drug application with the US Food and Drug Administration for vintafolide. At that time, Endocyte will also seek orphan drug designation for vintafolide as a treatment for folate receptor-overexpressing platinum-resistant ovarian cancer.

According to the National Cancer Institute, an estimated 22,280 women will be diagnosed with ovarian cancer this year and 15,500 women will die of the disease. As of Jan. 1, 2009, the NCI reported there were approximately 182,758 women alive with a history of ovarian cancer, which would classify folate-receptor expressing ovarian cancer as a rare disease.

Endocyte announced in March that it intends to file in the third quarter of this year for conditional marketing authorization with European regulators for the folate conjugate and the companion diagnostic agent. "The Phase III PROCEED trial would serve as the confirmatory trial should conditional authorization be granted," Sherman said.


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