Gloucester Pharmaceuticals and its lead agent romidepsin continue to lead a charmed life, as the histone deacetylase inhibitor was approved for second-line therapy of cutaneous T-cell lymphoma on Nov. 5. Not only did FDA's approval come a week ahead of the PDUFA date, but the drug was okayed on the basis of two single-arm trials despite an advisory committee determination in September that future drugs would need randomized, controlled trials for approval in that setting.

Gloucester plans to bring romidepsin, under the brand name Istodax , to market by January 2010; whether the privately held biotech will do so on its own remains to be seen. However, the company is pursuing an ambitious development program for the molecule, with pivotal data in peripheral T-cell lymphoma expected next year and other studies ongoing in multiple myeloma and solid tumors.

Based in Cambridge, Mass., Gloucester has raised roughly $100 million since its founding in 2003, including a $29 million Series D that closed in August (Also see "Gloucester Pharma Snags $29 Million Series D" - Pink Sheet, 25 August, 2009.). In an interview, Gloucester CEO Alan Colowick said his firm's financial health gives it a variety of options in moving forward with romidepsin.

"The Series D gave us the optionality and the flexibility to be able to consider all options and we're really finalizing those plans right now," he said. "We feel very good about the drug and what it's going to mean for patients, we're committed to getting this to patients as soon as possible and really expect to be able to achieve that in the January timeframe."

Gloucester plans to finalize its launch and ongoing development plans within the next few weeks, Colowick added, and is open to going it alone or with a partner. The company previously had said that CTCL, a form of non-Hodgkin's lymphoma that afflicts about 1,500 new U.S. patients annually, is a narrow-enough indication that a firm of its size could conduct a very focused marketing effort.

Gloucester is talking to and receiving "significant interest" from a number of suitors, big and small, Colowick said, including those that have sales and marketing operations up and running already. But such capacity might not be the deciding factor in picking a potential partner, he added.

"There are other companies out there that view the asset as we do, that this is an ideal asset to start a commercial effort around as well in the hematology space because it's really a much more focused marketplace than the general oncology marketplace is," Colowick said. "So there are a number of companies I think that would view this as a very interesting first and flagship product to enter into this space."

Duration of response seen as differentiating factor

Istodax will compete in the CTCL arena with Merck's Zolinza (vorinostat), also an HDAC inhibitor, along with Eisai's Ontak (denileukin) and Targretin (bexarotene), both of which have different mechanisms of action.

Colowick said his company would differentiate Istodax in the market through its demonstrated median 15-month duration of response, which outstrips its competitors, even though the compound was not studied head-to-head against any of those other drugs.

The two registrational trials, one sponsored by Gloucester and the other by the National Cancer Institute, studied romidepsin in 167 patients, with a primary efficacy endpoint of objective response rate, defined as the proportion of patients with investigator-confirmed complete response (no evidence of disease) or partial response (?50 percent improvement in disease).

The ORR rates in the two trials were similar (34 percent in Gloucester's trial, 35 percent in NCI's), with each posting a complete response rate of 6 percent. Median duration of response was 15 months in Gloucester's study and 11 months in the other, with a median time to first response of two months in each study.

At a late summer meeting of FDA's Oncology Drugs Advisory Committee, romidepsin was voted to have a favorable risk/benefit ratio by a tally of 10-1. However, during the same meeting, ODAC also voted 6-3 (with one abstention) that FDA should require randomized, controlled trials for future drugs aimed at CTCL (Also see "Allos' Folotyn and Gloucster's Istodax: Exceptions That Prove The Rule?" - Pink Sheet, 2 September, 2009.).

HDAC inhibitors work by altering a second layer of cellular regulation. Despite their potential in cancer, the class has a mixed development history, with many projects having been discontinued due to toxicity findings (Also see "Day Two At ODAC: Reviewing Drugs To Treat T-Cell Lymphoma In A Difficult Class" - Pink Sheet, 31 August, 2009.). Due to their non-specificity, HDAC inhibitors block a variety of enzymes critical for normal cell function, which can result in serious side effects. The increased tolerance for adverse events in the oncology setting also makes cancer the most promising area for HDAC inhibitors.

Romidepsin is no different than its classmates - its label carries a warning that due to risk of QT prolongation, patients should be tested for normal ranges of potassium and magnesium before receiving the drug. Labeling further warns of the possibility of thrombocytopenia, leukopenia and anemia; patients' hematological parameters should be monitored and dosing adjusted accordingly.

-Joseph Haas (j.haas@elsevier.com)

Gloucester's Istodax Gains FDA Approval Ahead Of New Regulatory Requirements

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