After failing - at least for now - to reach an agreement with the FDA, Thallion Pharmaceuticals Inc. decided to advance an ex-U.S. pivotal program for Shigamabs in the treatment of Shigatoxin-producing E. coli (STEC) bacterial infections.

Geoffery Houlton, an analyst with Loewen, Ondaatje, McCutcheon Ltd., said the FDA's usual focus on safety is "less of an issue" for Shigamabs. The drug is a dual monoclonal antibody specifically targeted to the Stx1 and Stx2 toxins secreted by STEC and has been well tolerated in four Phase I trials with no serious adverse events reported.

Instead, Houlton suggested that the disagreement is likely tied to efficacy endpoints. The standard endpoint for STEC infection is Hemolytic Uremic Syndrome (HUS), a life-threatening condition that involves red blood cell destruction, acute renal failure and low platelet count. Yet only 10 percent to 15 percent of STEC patients progress to that point, making it a difficult endpoint for a trial.

In April, Thallion participated in a joint advisory panel convened by the FDA's Center for Drug Evaluation and Research to discuss composite endpoints Thallion had proposed as alternatives to HUS. Houlton said Thallion wanted to evaluate progression of the disease earlier in the process, when symptoms include bloody diarrhea, fever, dehydration and renal disease.

Lloyd Segal, CEO of Montreal-based Thallion, declined to elaborate specifically on the discussions with the FDA, which he said are ongoing. "We think there are some very good people at the FDA thinking as hard and deep about this drug as we are," he said. But while he's "hopeful" that an agreement will be reached, he added that he's "not banking on it."

Segal also noted that STEC is a problem that needs to be addressed quickly. The food-borne bacterial infection affects about 314,000 people annually in the industrialized world and was responsible for high-profile spinach outbreaks and beef recalls. Children and the elderly are most susceptible to STEC, and although a diagnostic can pinpoint the Stx1 and Stx2 toxins, there is no treatment available other than to "hydrate and wait," he said.

So Thallion is moving forward with plans to submit regulatory documents in Europe, Canada and South America and expects to begin a pivotal Phase II/III trial in these countries in the first half of 2008. The first part of the trial, which Segal said always was intended to be conducted outside the U.S., will randomize 45 patients to receive control, 1 mg/kg of Shigamabs, or 3 mg/kg of Shigamabs. After an independent monitoring board reviews the data, the initial participants will move into a larger trial involving 300 to 350 patients.

Segal said Thallion already has had encouraging discussions with the European, Canadian and South American regulatory authorities about the trial, although endpoints have not been finalized. He added that the company has "taken great pains" to arrange the trial so that U.S. trial sites can be added once an agreement is reached with the FDA.

Shigamabs was developed by Montreal-based Caprion Pharmaceuticals Inc., which changed its name to Thallion after acquiring Montreal-based Ecopia Biosciences Inc. earlier this year. (See BioWorld Today, Jan. 5, 2007, and Feb. 21, 2007.)

Caprion also developed CAP-232, a synthetic cyclic peptide that acts on the glycolytic pathway regulating energy production in tumor cells. The drug previously completed an exploratory Phase IIa trial in melanoma, and Thallion currently is enrolling a Phase II renal cell carcinoma study in Europe.

Meanwhile, Ecopia contributed ECO-4601, a small-molecule Ras-MAPK inhibitor that was well-tolerated in the initial portion of a Phase I/II cancer trial. The second portion of the trial completed enrollment in August, and data are expected by the end of the year.

Segal said Thallion is "actively in discussions" with potential partners for Shigamabs and ECO-4601.

As part of the Caprion/Ecopia merger, Thallion raised $45 million in a private placement.

The company reported C$29.2 million (US$30.3 million) in cash, equivalents, short-term investments and tax credits receivable as of Aug. 31, the end of its fiscal third quarter. Net loss for the quarter was C$5.3 million, or C17 cents per share.

Shares of Thallion (TSE:TLN) lost C9 cents to close at C63 cents on Monday.