Washington Editor

Novacea Inc. is shaking up its pipeline by abandoning oral vinorelbine (OV) in the face of higher-than-expected development costs, and it will instead focus on Asentar (DN-101) and AQ4N (banoxantrone).

"This is an example of making the tough but important portfolio decisions for a young biotechnology company," CEO Brad Goodwin told BioWorld Today. "We're focusing our resources on the most promising products in our portfolio."

Asentar already is in a confirmatory Phase III study for prostate cancer, and AQ4N is entering a Phase Ib/IIa trial for glioblastoma multiforme.

As part of the shift, Novacea has returned OV's U.S. and Canadian rights to Pierre Fabre Medicament SA, the company from which it licensed the product last summer. At the time, Novacea had envisioned it for metastatic breast cancer and possibly other cancers, and initial registration talks with the FDA indicated that a fairly simple study could support accelerated approval.

More recently, though, the FDA raised the bar in terms of study size, duration and difficulty, recommending a randomized, controlled trial for registration. That updated guidance markedly changed the equation from original plans for a single-arm, open-label monotherapy trial in about 100 patients with fourth-line metastatic breast cancer, representing "an increase in cost, time and complexity," Goodwin said.

Going forward, South San Francisco-based Novacea's near-term financing needs will be less pressing as it further advances and broadens clinical indications for Asentar and AQ4N. Chief Financial Officer Ed Albini said the company's fiscal reserves would sustain operations through the first quarter of 2008 in the absence of OV-related costs, three months longer than previously projected. Novacea had $39.5 million in cash, cash equivalents and marketable securities through June 30, but has yet to report its third-quarter figures.

"By making the decision that we've announced today," Goodwin added, "we're able to expand the development for both of those products in promising areas."

Asentar's Phase III trial is enrolling 900 men with androgen-independent prostate cancer in the U.S., Canada and Germany. Recruitment is expected to last until the second half of next year, and data could be available about a year later.

That trial follows a Phase II/III study in 250 patients, in which a combination of Asentar and docetaxel (Taxotere, from Sanofi-Aventis Group) demonstrated a 49 percent improvement in overall survival compared to docetaxel alone, as well as a 34 percent reduction in serious adverse events. However, the trial failed to achieve statistical significance on its primary endpoint, prostate-specific antigen response.

Asentar is a high-dose oral formulation of calcitriol, a potent, biologically active form of vitamin D that's long been used for cancer but is limited by hypercalcemia side effects. It binds to the nuclear vitamin D receptor, and Asentar's efficacy benefits come from cell-cycle arrest, apoptosis and inhibiting metastasis. Its safety benefits include an antithrombotic effect and a reduction in gastrointestinal toxicity.

In addition to prostate cancer, the company plans to begin studying the drug in a new but undisclosed indication early next year. Novacea might look at Asentar and docetaxel in non-small-cell lung cancer, or Asentar and gemcitabine (Gemzar, from Eli Lilly and Co.) in pancreatic cancer, but Goodwin stressed that such plans are not yet written in stone. "We'll make the final decision next year," he said, "and it may be one of those or it may be something else."

It's also being studied in a number of investigator-sponsored trials in undisclosed indications. Novacea, which plans to take an active role in its products' North American commercialization and seek partners abroad, has all worldwide rights to Asentar after developing the formulation through a license to underlying technology from Oregon Health & Sciences University in Portland.

AQ4N, a product with potential as monotherapy and in combination with other agents in multiple cancers, initially is in the dose-testing part of its Phase Ib/IIa trial to evaluate the safety and tolerability of 200-mg/m2, 450-mg/m2 and 750-mg/m2 administrations. The second part will further assess safety and tolerability, as well as efficacy, of the highest dose determined in part one.

The product is a prodrug designed to be activated in regions of tumor hypoxia, at which point it binds to DNA and blocks cancer cells from replicating. Early studies of human brain tumor biopsies have demonstrated that AQ4N is converted into its toxic form selectively in the hypoxic region of the tumors, and not in the adjacent normal tissues. "It spares, we believe, systemic toxicity," Goodwin said, adding that AQ4N addresses "one of the fundamental unmet medical needs in solid tumor biology," supplementing the shortcomings of radiation and chemotherapy in tumors' hypoxic areas.

Novacea, which expects to enroll about 60 patients in the Phase Ib/IIa study, also plans to expand the product's development into an additional indication next year. The company has North American rights to the drug from KuDOS Pharmaceuticals Ltd. in Cambridge, UK.

Dissolving the OV arrangement with Pierre Fabre, a division of Paris-based bioMerieux Pierre Fabre, does not penalize Novacea fiscally. But since its license, Novacea has spent about $7 million on the product, Albini told BioWorld Today, including $4 million in up-front and milestone payments and another $3 million for internal costs.

On Tuesday, its stock (NASDAQ:NOVC) lost 9 cents to close at $6.73.