Alteon Inc. voluntarily suspended enrollment in its ongoing Phase II trials of alagebrium after preclinical data indicated high doses of the therapy could be associated with liver cell alterations and tumors.
The company's stock (AMEX:ALT) fell 25.9 percent Friday, or 28 cents, to close at 80 cents.
The suspension comes after the company's researchers found data in December from a two-year toxicity study indicating that male Sprague Dawley rats exposed to high doses of alagebrium over their natural lifetime developed dose-related increases in liver cell alterations and tumors. The liver tumor rate was slightly above the expected background rate in that rat gender and species.
"Part of the reason we are acting in a cautious manner is we think it is prudent to do so, being that this is the first evidence contrary to anything other than alagebrium being a very safe drug," said Kenneth Moch, Alteon's CEO and president.
The plan now is to further analyze preclinical data and to conduct preclinical experiments before resuming enrollment. Alteon also intends to discuss the issue with the FDA.
The preclinical experiments planned for the coming months will explore the mechanism by which the liver tumors developed and the relevance of such tumors to human exposure. Results should be available by the middle of this year.
"We're trying to hopefully prove that the findings are relevant to rats, but not to humans," Moch told BioWorld Today, adding that the preclinical work now under way is "explicitly designed to explore the mechanism and to show the relevance or lack of relevance to human exposure."
Alagebrium is Alteon's only product in clinical development and the subject of several trials: a Phase IIb systolic hypertension trial called Spectra (Systolic Pressure Efficacy and Safety Trial of Alagebrium), which began in March 2004; a Phase IIa heart failure trial called Pedestal (Patients With Impaired Ejection Fraction and Diastolic Dysfunction: Efficacy and Safety Trial of Alagebrium), which began in April 2004; and a Phase II study recently begun in erectile dysfunction.
Parsippany, N.J.-based Alteon also is studying the product in a Phase II trial for endothelial dysfunction at Johns Hopkins University School of Medicine under grants from the National Heart, Lung and Blood Institute and the Society of Geriatric Cardiology.
The suspension does not affect patients already enrolled in the clinical trials and they will continue treatment. However, it might affect the time frame for the trials. Alteon had expected to complete enrollment in the Spectra trial during the first half of this year and was looking to have systolic hypertension data in the second half.
"We expect that this will delay enrollment for the Spectra trial by a quarter or so," Moch said.
The Spectra trial is in the middle of enrolling 400 patients, while enrollment for the Pedestal trial was almost complete with 20 patients. The double-blind, placebo-controlled trial for erectile dysfunction is enrolling 40 patients.
It is the first indication that alagebrium might have safety issues. Earlier preclinical toxicity studies found no mutagenic or carcinogenic activity in either rats or mice. Alteon also completed four key genotoxicity studies, none of which indicated any potential carcinogenic risk in man. Cumulative human safety data also has not shown issues of carcinogenicity. More than 1,200 patients have been involved in the product's clinical trials to date.
"We do not think there's an increase in patient risk," Moch said.
Alagebrium chloride is an A.G.E. (advanced glycation end-product) crosslink breaker, which works by directly reversing the stiffening of the vasculature that leads to systolic hypertension and heart failure. A.G.E.s, when formed and cross-linked, can cause a loss of flexibility and function in body tissues, organs and vessels. Alagebrium also has shown promise in preclinical studies in kidney disease, atherosclerosis and other disorders.
The product is not partnered, although Alteon expects to enter discussions following the release of Phase IIb data. Alteon might retain marketing rights for certain indications in North America.
It isn't the first bump in the road for alagebrium. The product, once called ALT-711, failed to show statistical significance in reducing systolic blood pressure by office-cuff measurement in Phase IIb trials in July 2003. But researchers did see signs of efficacy and activity, prompting Alteon to move forward with additional Phase II studies. (See BioWorld Today, July 18, 2003.)
Alteon, which has other A.G.E. crosslink breakers in preclinical development, raised $10 million last month in a private placement meant to fund the Phase II alagebrium trials. That money, added to the company's existing funds, gave Alteon about a year's worth of cash. (See BioWorld Today, Jan. 10, 2005.)