Washington Editor

Sonus Pharmaceuticals Inc. is moving forward with pivotal development plans for its lead product, Tocosol Paclitaxel, after completing a special protocol assessment for a single Phase III trial.

"It really is a very important milestone for us," Sonus President and CEO Michael Martino said, "and for what our team has been working very hard to achieve."

He added that the FDA-approved plan also validates the company's regulatory strategy, which should appeal to investors and potential partners. Sonus, which has long planned to seek a partner for the product's late-stage development and commercialization, had $15.1 million in cash and marketable securities through March 31. In the previous three months, it posted a $4.8 million net loss.

"We really think that we are moving into a sweet spot here," Martino told BioWorld Today, "where a deal is doable on good terms."

The Bothell, Wash.-based company said it already began start-up activities for the study, with enrollment expected to begin within three to six months in a staged process as some sites come on line before others. About 150 centers are expected to participate, including about two-thirds overseas.

The protocol calls for a comparison of Tocosol Paclitaxel to Taxol in breast cancer patients. About 800 subjects will be equally randomized to treatment with one of the drugs to test their effects on antitumor efficacy, tolerability and safety.

The pre-study agreement with the FDA indicated that the trial's design and analysis methods would adequately form the basis for a new drug application, laying out a statistical plan to submit for approval based on objective response rate as its primary endpoint, and also subsequent supplements based on progression-free survival and overall survival as secondary endpoints. The trial is set up to demonstrate non-inferiority on the primary endpoint.

"It's a very versatile design," Martino said, "that we think mitigates the remaining risk with the product."

The study's progress and interim data evaluations will be overseen by an independent data monitoring committee comprising oncologists and biostatisticians. Should it meet the primary endpoint, Sonus will be able to analyze for superiority on all endpoints that could lead to an expanded label claim.

The company said its formulation of paclitaxel, delivered by way of a vitamin E-based oil-in-water emulsion technology, is designed to overcome limitations associated with Taxol and generic paclitaxel-based chemotherapy. For example, it has been developed to avoid undesirable or treatment-limiting side effects, with Phase II data from more than 200 patients suggesting the drug is well tolerated, and it does not require lengthy preparation processes prior to administration.

"We know from our Phase II studies that we can administer Tocosol Paclitaxel at 100 mg/m2 reliably, repeatedly and predictably, week in and week out, with a very favorable side effect profile," Martino said. "But 175 mg/m2 of Taxol could never be administered on a weekly basis. The potential implication of that is a much greater dose intensity, which could translate to better efficacy."

Sonus also noted that as a result of Tocosol Paclitaxel's biocompatible solvent system, it can be delivered more conveniently. Martino said clinical pharmacology data reported at this year's American Society of Clinical Oncology meeting showed that "we have significantly impacted and improved the pharmacokinetics of the product." Those findings demonstrated that among equal 175 mg/m2 doses of Tocosol Paclitaxel and Taxol, in which the former is delivered in a 15-minute administration while the latter takes three hours, there is nearly 70 percent more exposure to free paclitaxel in those receiving Tocosol Paclitaxel compared to those on Taxol.

The company did not disclose its Phase III dosing plans, though Martino said enrollment would take between six months and nine months from the first to last patient. Collecting the objective response data could take an additional eight months, with three more months of data packaging prior to a regulatory submission. So conservatively projecting the future, he added that an application should be filed by the middle of 2007.

In the long term, Sonus intends to continue to study the product in other types of tumors and patients. But Martino acknowledged that the company would expect heavy off-label use for Tocosol Paclitaxel should it receive an initial approval down the road.

Earlier this year, citing cost issues, Sonus said it would focus its efforts going forward on that product in backing out of a previously proposed $30 million merger with Synt:em, a company based in Nimes, France. (See BioWorld Today, March 18, 2005.)

Elsewhere in Sonus' portfolio is a program applying its delivery technology to a family of camptothecin analogues, which has advanced far enough to get into clinical studies early next year, though funding obstacles remain an issue.

On Friday, the company's shares (NASDAQ:SNUS) fell 15 cents to close at $3.39, after trading as high as $3.80.