SAN DIEGO, Calif. – Three promising new rheumatoid arthritis (RA) drugs— including an oral small-molecule inhibitor that targets a novel adenosine receptor (AR) and a new anti-tumor necrosis factor-alpha (TNF-α) agent—may soon augment the rheumatologist's ever-expanding armamentarium, according to new research presented here at the 69th Annual Meeting of the American College of Rheumatology.

Early findings from a phase II trial on CF101, an orally administered A₃AR agonist, suggest that 1.0 mg twice a day reduces disease activity in RA.

At 12 weeks, 66 of 84 evaluable patients receiving 1.0 mg twice daily of CF101 achieved response rates of ACR 20, 50, and 70 at percentages of 58%, 30%, and 8%, respectively, the study found.

In addition, all patients taking the novel drug showed an 80% reduction in tender and swollen joints at 12 weeks. The agent was "safe and well-tolerated," the study found.

Moreover, an analysis of A₃AR expression at baseline in 17 patients showed that it may be a surrogate marker for response to the new agent. In this double-blind randomized trial, study participants had failed one to four conventional disease-modifying antirheumatic drugs (DMARDS) and were in an active disease state. The trial comprised a 4-week washout period, and patients were randomly assigned to receive 0.1 mg, 1.0 mg, or 4.0 mg twice daily for 12 weeks of treatment.

The A₃AR is a relatively new target in inflammation. Researchers originally identified this compound in cancer studies. "Once we realized what the mechanism is, we thought it would make sense to target autoimmunity and inflammation," Pnina Fishman, PhD, of Can-Fite BioPharma, Ltd, in Petach-Tikva, Israel, tells CIAOMed. Studies have shown that adenosine receptors play an important role in curbing inflammation, according to Dr. Fishman. She and colleagues explain that CF101 downregulates NF-κB, which results in increased TNF-α levels.

"We are pinpointing both cytokines, proteins that induce apoptosis, and autoreactive T-cells, and, last but not least, we are also targeting TNF-α," Dr. Fishman adds, noting that the new drug aims higher up in the inflammation cascade than TNF inhibitors and other biologic therapies.

"Patients who fail methotrexate (MTX) may benefit from this new agent," she says. "It's a small molecule, low-cost drug that is easier for patients to tolerate."

Can-Fite BioPharma plans to submit an investigational new drug application to the US Food and Drug Administration (FDA) at the end of November, and the company plans to initiate Phase IIb trials in the US in March or April 2006.

Small molecule drugs will be key

"It is certainly going to be very beneficial if we have new small-molecule drugs available for RA," David Karp, MD, PhD, chief of rheumatic disease at the University of Texas-Southwestern in Dallas, tells CIAOMed. "Although rheumatologists are much more accepting of biologic therapy, these drugs do have to be given parenterally by injection or infusion," he continues, adding that there are impediments in terms of cost and difficulty with administration.

With CF101, the mechanism of action makes sense, as MTX also acts on adenosine, according to Dr. Karp. While this is not a placebo-controlled trial, it did show that patients taking the medication responded with a decrease in tender and swollen joints, he points out. "It's an interesting concept that needs the rigor of a double-blind randomized controlled trial."

"If you were to ask patients and physicians for the perfect combination of therapies, it would be a specific therapy directed toward the biological causes of RA that was easy to take," Dr. Karp says. "An oral agent that specifically targeted TNF would be the ‘holy grail,' and I am not certain that we will see this any time soon, although people are working on it."

Dr. Karp adds that biologics are more specific then oral agents at targeting pathways in inflammatory disease.

New TNF-blocker may offer nonresponders another choice

CNTO 148 (golimumab), an experimental fully human anti-TNF-α monoclonal antibody, may hold some advantages over existing biologics,² a new study suggests.

In the trial, adults with RA of >3 months' duration, despite MTX therapy, were randomly assigned to CNTO 148 50 mg or 100 mg every 2 or 4 weeks, or to placebo. Clinical effect was seen in all four dose groups, and there was no clear dose-response relationship.

A significantly higher proportion of patients in the combined CNTO 148 groups achieved the ACR 30 response compared with the placebo group: 63% versus 37%, respectively. Additionally, more patients in all of the four active treatment groups achieved ACR 50 and ACR 70 responses, compared with patients taking placebo, the study showed.

"One advantage is the monthly subcutaneous dosing," lead researcher Jonathan Kay, MD, associate clinical professor at Harvard Medical School and director of clinical trials in the rheumatology unit at Massachusetts General Hospital in Boston, tells CIAOMed. "It is also a fully human monoclonal antibody."

Preclinical studies suggest that CNTO 148 is two to four times more potent in in vitro and in vivo models than infliximab.

The new agent will also give patients who don't respond to available TNF-inhibitors another choice. "Given that each of these monoclonal antibodies may bind to a different epitope on TNF-α, they may be slightly different, and therefore, if a patient is unresponsive to one anti-TNF therapy, then there is a chance they may be responsive to another," Dr. Kay says. "The availability of golimumab would allow for another potential beneficial treatment for patients with RA."

Dr. Karp agrees. "There are some theoretical reasons why certain monoclonal antibodies that target the same molecule, like TNF, may have fewer side effects, and that is perhaps one reason to develop more of these agents," he says. In addition, Dr. Karp tells CIAOMed that "there is pretty good data [showing] that patients who fail one agent have a good chance of success with another, so having [golimumab] available may provide another choice."

Novel antifolate drug looks promising

An open-label, nonrandomized pilot study of a novel antifolate agent, CH-1504, shows that the agent is both safe and extremely effective.³

In the study, patients with advanced RA received either 6.67 mg daily oral dosing of CH-1504 or 10 mg once weekly oral dosing or MTX for 24 weeks.

Findings showed that 90% of patients taking CH-1504 met ACR 20 criteria compared with 40% of those taking MTX. Moreover, patients taking the study drug reached ACR 20 rapidly—with 60% meeting these criteria at 1 month of treatment. No serious adverse events were reported, the study showed.

Research has shown that much of the toxicity of MTX can be attributed to its polyglutamylated and or hydroxylated metabolites, and the new drug possesses neither quality, the study authors point out.

"They show rather remarkable efficacy for this compound, with 90% of patients achieving ACR 20 and 40% of patients achieving ACR 50," Dr. Karp says. "This is as good or better than what we see with biologics, but this was not a randomized controlled trial; it was open-label and lacks methodological rigor."

However, based on these results, he says, "we can be optimistic that this would be a new therapy that ought to be pursued."

References

1. Nahir MA, Reitblat T, Molad Y, et al. Early phase II clinical trial in RA patients treated with CF101, an A₃ adenosine receptor agonist. Presented at: 69^th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract L7.

2. Kay J, Matteson EL, Dasgupta B, et al. Subcutaneous injection of CNTO 148 compared with placebo in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, dose-ranging trial. Presented at: 69^th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 1921.

3. Castaneda O, Nair G. An open-label, nonrandomized pilot clinical trial of a novel metabolically stable antifolate, CH-1504, in the treatment of advanced rheumatoid arthritis. Presented at: 69^th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 1502.