West Coast Editor

A week after disclosing positive Phase II data at ASCO with its topoisomerase II inhibitor Xanafide for secondary acute myeloid leukemia, Xanthus Pharmaceuticals Inc. has reached an agreement with the FDA for a Phase III registration trial that could provide the firm with a handle on a $300 million-plus market.

Although the space that includes AML and myelodysplastic syndrome (MDS) is complex, with many players, "there's nobody addressing [secondary AML]," noted Richard Dean, CEO of Cambridge, Mass.-based Xanthus. "Everybody's staying away, which is why our trials were so easy to accrue."

Secondary AML - that is, AML on top of MDS, or after exposure to chemotherapy or radiation - carries the worst prognosis of all forms.

"Sadly, there is no good therapeutic option for these patients," Dean said. "Sometimes, they're sent to best supportive care, or they'll take a flier with daunorubicin and ara-C. It's dealer's choice for the physician. If you get an aggressive [one], he's going to treat anyway, on hope."

But even with an approach such as daunorubicin plus ara-C (cytarabine), patients only get a remission rate of 12 percent to 25 percent "and then fall out of remission quickly, in four to five months," Dean said.

Enter Xanafide, which at the American Society of Clinical Oncology meeting yielded first results from a Phase II study in 88 patients with secondary AML. Forty-four percent achieved complete remission with or without hematopoietic recovery, the trial's primary endpoint. Subjects got a daily dose of Xanafide for five days in combination with a standard dose of ara-C as a continuous infusion for seven days.

Now, Xanthus has a special protocol assessment pact with the FDA for a Phase III study in combination with ara-C as initial remission induction therapy, and the company plans to enroll 350 patients, aiming to confirm Phase II remission data and prove superiority of Xanafide combined with ara-C vs. daunorubicin when paired with the same drug. The secondary endpoint will be duration of remission.

A preliminary survey of physicians by Xanthus found that about 33 percent of AML patients fall into the secondary class. Nine of the 10 doctors polled said no good treatment exists, and two-thirds said they would use a drug with Xanafide's profile.

"Right off the top, we could get about a $150 million market with this type of performance," Dean told BioWorld Today. "We then asked, 'What if our drug could be shown effective in the de novo [new] as well as secondary AML?' They said that if you had any clinical data, it would jump the market to about $250 million right away." If Xanthus could show the multidrug resistance that foils other approaches does not affect Xanafide, the market would grow to more than $300 million, Dean said.

The company is conducting more market research. Meanwhile, the plan is to start Phase II studies in de novo AML patients while the Phase III trial in secondary disease is well under way. It will decide later whether to seek a label or publish the de novo data and let physicians do as they see fit.

In late 1997, FDA clearance of Rituxan (rituximab, Genentech Inc. and Biogen Idec Inc.) for the treatment of low-grade non-Hodgkin's lymphoma recurrences was followed by ASCO data in various settings that led to significant off-label use, Dean noted, adding that if Xanafide is approved, it would be the first new first-line induction therapy for AML in 20 years.

Others making news lately in the AML space include Vion Pharmaceuticals Inc., of New Haven, Conn., which offered data this month from a Phase II trial testing Cloretazine (VNP40101M) as a single agent in a subset of 59 elderly patients with AML or high-risk MDS and unfavorable cytogenetics. The compound showed an overall response rate of 25 percent in results offered at the European Hematology Association meeting in Vienna, Austria.

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