Washington Editor

Shares in Corautus Genetics Inc. tumbled by nearly two-thirds Monday following the Atlanta company's announcement that it would stop a Phase IIb trial in angina patients who are not suitable for traditional revascularization procedures.

The stock (NASDAQ:VEGF) plummeted 68.5 percent, or $2.33, to close at $1.07 on heavy trading. Corautus decided to terminate patient enrollment in the GENASIS (Genetic Angiogenic Stimulation Investigational Study) trial of its VEGF-2 product based on the recommendation of an independent data monitoring committee, which saw very little chance for significant efficacy on the trial's primary endpoint relative to a safety risk signal. That endpoint measured the drug's ability to increase patients' exercise tolerance time, which is calculated by treadmill performance.

"This new information is inconsistent with our previous results," Corautus President and CEO Richard Otto said during a conference call, later adding that "we'll continue to study VEGF-2 in this patient population."

The company will continue to collect efficacy data until the last enrolled patient has been followed for six months. At that time, Corautus plans to lock the study database and perform unblinded endpoint analyses of efficacy. Safety data will be followed for 12 months from the date the last patient was enrolled.

"We're going to continue our internal study," Otto said, later noting that the company would not abandon the program unless its further analysis reveals that VEGF-2 is neither safe nor efficacious. The product is designed to produce a short-term expression of the VEGF-2 protein, stimulating new blood vessels to grow by promoting the migration and proliferation of endothelial cells in the heart.

Last month, the company voluntarily suspended the study's enrollment to fully investigate three serious adverse events of pericardial effusion that it believes were not drug related. Pericardial effusion is caused by excess fluid filling of the pericardial sac surrounding the heart. (See BioWorld Today, March 15, 2006.)

At that time, 295 patients had been enrolled in the trial, which originally was scheduled to enroll 404 patients. In response to the company's action, the FDA placed a clinical hold on the study.

The data monitoring committee received 90-day exercise tolerance time data on 220 patients, as well as findings on the same endpoint for 135 patients with six months of follow-up and 26 patients with a year's worth of follow-up.

Additional efficacy measurements that have yet to be analyzed include longer-term exercise tolerance time data, perfusion, time to 1 mm ST segment depression, angina class reduction, time to major adverse cardiac events, angina frequency reduction and the results of a quality-of-life assessment.

In the trial, defined doses of VEGF-2 in the form of naked plasmid DNA as a non-viral delivery vector were delivered to diseased heart muscle tissue by way of the Stiletto endocardial direct injection catheter system, a product from Boston Scientific Corp. in Natick, Mass.

Otto stressed that enrollment in clinical studies of VEGF-2 in diabetic neuropathy and peripheral artery disease would continue as planned.

Corautus, which put the brakes on financing plans last month, had about $31 million in cash reserves as of Dec. 31. Going forward, Chief Financial Officer Bob Atwood said that money could sustain operations through the end of next year's third quarter in the absence of costs associated with the GENASIS study.

CombinatoRx Drug Misses Endpoint

CombinatoRx Inc. said CRx-119 failed to hit its primary endpoint in reducing C-reactive protein (CRP) levels in a Phase II study of patients with chronic adult periodontitis, an immuno-inflammatory disease.

The combination drug candidate also missed a secondary endpoint, a reduction of periodontal pocket depth, in the randomized, blinded, placebo-controlled trial. Other secondary endpoints include a panel of immuno-modulatory cytokines, for which an analysis remains ongoing.

The exploratory study was designed for the Cambridge, Mass.-based company to compare and contrast the immuno-inflammatory properties of its portfolio of immuno-modulating product candidates. CombinatoRx's management cautioned that it would be premature to make conclusions based on the preliminary results prior to analyzing the cytokine data from the study and results from other studies, namely another Phase II trial of CRx-119 in rheumatoid arthritis. Those findings are due early next year.

That caution was echoed by analyst Eric Schmidt of New York-based SG Cowen LLC. "While it is possible CRx-119 is not an active combination," he wrote in a research note, "it is also possible the model is not sensitive to CRx-119's effects." He added that an ongoing periodontitis trial of CRx-102 will likely determine whether periodontitis is a good model; data are expected this quarter. Schmidt explained that periodontitis trials with multiple anti-inflammatory combinations would give the company information "on how each candidate modulates various cytokines," so based upon each candidate's cytokine profile, CombinatoRx "believes that it can better direct future studies toward clinical indications that match a drug's profile."

Cytokine data from CRx-119's biomarker study will be available later this quarter. The drug, which combines a low dose of the steroid prednisolone with amoxapine, was generally well tolerated, and there were no drug-related serious adverse events reported in the 62-patient periodontitis study. The most common adverse event observed with CRx-119 was drowsiness, a known side effect of amoxapine.

On Monday, shares in CombinatoRx (NASDAQ:CRXX) dropped 9 cents to $11.

Somaxon Gains On Sleep Drug Data

Somaxon Pharmaceuticals Inc. released positive Phase III results showing that 3-mg and 6-mg doses of Silenor (doxepin HCl) produced statistically significant results in adults with chronic insomnia.

In the study's primary endpoint, eight-hour wake after sleep onset, the drug produced a mean improvement of 26 minutes for the 3-mg dose compared to placebo (p<0.0001), and 31 minutes for the 6-mg dose (p<0.0001). Among other endpoints, both Silenor doses improved total sleep time: 415 minutes for 3 mg and 421 minutes for 6 mg, compared to 374 minutes for placebo (p<0.0001). After four weeks of nightly administration, total sleep time improvements remained statistically significant for both doses relative to placebo. Another measure, sleep efficiency, demonstrated results that were significant and consistent with those observed for total sleep time. On latency to persistent sleep, both 3 mg and 6 mg reduced the time to 27 minutes (p=0.011 and p=0.0018, respectively) compared to 45 minutes for placebo.

The San Diego company expects to report results from additional Phase III trials later this year, and plans to file a new drug application in the first quarter of next year.

On Monday, its stock (NASDAQ:SOMX) gained $1.26, or 8.2 percent, to close at $16.56.

In other clinical trial news:

• Myogen Inc., of Denver, said top-line results from the ARIES-1 trial showed that ambrisentan met its primary efficacy endpoint, a measure of the placebo-corrected mean change in six-minute walk distance at 12 weeks compared to baseline, in pulmonary arterial hypertension patients. Specifically, 10 mg of the oral endothelin receptor antagonist improved that measure by 51.4 meters (p=0.0001) and a 5 mg dose improved it by 30.6 meters (p=0.0084), compared to a decrease from baseline of 7.8 meters in the placebo group. The study missed a secondary endpoint, though. Time to clinical worsening did not reach statistical significance, which the company blamed on a relatively low incidence of clinical worsening events in the trial. Other secondary endpoints had clinically relevant improvements (p<0.05), but were not considered statistically significant due to the pre-specified approach for multiple comparisons. Nevertheless, the data triggered a $5.25 million milestone payment from GlaxoSmithKline plc, of London, per terms of the companies' sublicense agreement. The study is the second of two in a pivotal program evaluating ambrisentan, both of which began two years ago, and on the basis of their results, Myogen expects to submit a new drug application to the FDA in the fourth quarter. On Monday, its stock (NASDAQ:MYOG) lost $2.67 to close at $33.15. (See BioWorld Today, March 28, 2006.)

• Nuvelo Inc., of San Carlos, Calif., and Bayer HealthCare AG, of Leverkusen, Germany, began patient enrollment in a second Phase III trial of alfimeprase for acute peripheral arterial occlusion. The second of two overlapping multinational trials in the cardiovascular drug's pivotal program, it also is a randomized, double-blinded study comparing 0.3 mg/kg of alfimeprase to placebo. In total, both trials will enroll 600 patients and evaluate the avoidance of open vascular surgery within 30 days of treatment as their primary endpoint. The latest Phase III trial, known as NAPA-3 (Novel Arterial Perfusion with Alfimeprase-3), is the subject of a special protocol assessment agreement from the FDA. The first Phase III study, NAPA-2, got under way a year ago, and its enrollment is expected to close in the second half of this year. More recently, Nuvelo struck a potential $385 million deal on the drug with Bayer. On Monday, Nuvelo's shares (NASDAQ:NUVO) gained 31 cents, to close at $17.24. (See BioWorld Today, April 19, 2005, and Jan. 6, 2006.)