VIENNA, Austria- Apratastat, a novel, oral, small-molecule dual inhibitor of tumor necrosis factor-alpha (TNF-α)-converting enzyme (TACE) and matrix metalloproteinases (MMPs), has been shown in early trials to target two of the factors known to cause inflammation in rheumatoid arthritis (RA), according to new safety data presented Thursday at the Annual European Congress of Rheumatology of the European League Against Rheumatism (EULAR).
Apratastat (TMI-005, APS) blocks secretion of soluble TNF-α and down regulates multiple MMPs, which have been implicated in cartilage destruction and bone erosions of RA. In the new study, RA patients aged 18 years or older on a stable dose of methotrexate (MTX) ranging from 7.5 to 20 mg/week were randomly assigned to receive 50 mg or 150 mg of apratastat or placebo twice daily for 4 weeks.
Apratastat was well tolerated at both dose levels, the study showed. Moreover, there were no serious adverse events (AEs) or deaths. Overall, 81.3% of the 16 study subjects reported one or more adverse events that were either mild or moderate in severity including arthralgia, peripheral edema, headache, and nausea. One subject in the 150-mg group discontinued treatment on day 15 because of worsening of RA symptoms.
In the study, there were no clinically significant elevations of laboratory parameters including hepatic aminotransferases.
Potential benefits forecasted
"It is oral and this should be of benefit to patients," says lead researcher Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas. "It has a dual action, but primarily on TACE-and it could be doubly effective."
In terms of safety, the trials to date do show evidence of infusion reactions, he says. "Other than that, its safety profile will have to be explored in larger patient populations and its effectiveness will also have to be explored," Dr. Fleishmann tells CIAOMed.
"If it is effective clinically, then I think it is the next generation [of biologic RA therapies]," he says. While still too early to draw any major conclusion, it may be of benefit in diseases other than RA as well, he says.
New compound may have advantages over other small molecule inhibitors in development
"The big deal here is that the two small molecule oral agents that are first out of the barn, so to speak, are this one and the Scios' orally available p38 MAP kinase inhibitor," says Phillip Mease, MD, of the department of internal medicine at the Swedish Medical Center and Seattle Rheumatology Associates in Seattle, Washington. "The one issue that has arisen [with the latter] has been some degree of liver enzyme elevations, which has been plaguing MAP kinase all along with neurologic side effects," Dr. Mease tells CIAOMed. "This one looks much cleaner based on [this] safety data."
The potential for greater ease of administration and the possibility that it may be less expensive are also benefits, he says.
Going forward: controlling signs and symptoms of RA and decreasing joint destruction
"The issue that will begin to be focused on as these drugs come along is how efficacious they are in controlling signs and symptoms of RA and how similar or not they are to parenteral TNF at decreasing joint destruction," Dr. Mease says. Because this agent down regulates MMP, " it's got that additional chance of positively affecting disease progression as evident by x-ray progression," he says.
Another issue is safety. "What is the safety profile going to be for oral agents?' he asks, noting that the fact that apratastat had no hepatic aminotransferase elevations in this trial is "a plus."
Reference:
Fleischmann R, Kivitz,AJ, Franklin C, et al. A randomized, double-blind, placebo-controlled, sequential-dose study of the safety of apratastat (TMI-005), a novel oral dual inhibitor of TNF-alpha-converting enzyme/metalloproteinase, in patients with rheumatoid arthritis on a background of methotrexate. Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract THU0071.