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Positive Results Reported From Phase II Trial of Isis 104838 in Rheumatoid Arthritis

CARLSBAD, Calif., Jan. 5 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc. (NASDAQ:ISIS) today reported data from a Phase 2 clinical trial which demonstrate that ISIS 104838, an antisense TNF-alpha inhibitor, produced a statistically significant disease response in patients with rheumatoid arthritis (RA). In the randomized, placebo-controlled trial, 157 evaluable RA patients received subcutaneous injections of either placebo or one of three dose regimens of 200 mg of ISIS 104838: every other week, once weekly or twice weekly. Patients receiving the once- and twice- weekly doses experienced similar responses to treatment, with 41% of evaluable patients achieving a 20% decrease in disease activity. In comparison, 23% of placebo-treated patients achieved a 20% decrease (p=0.04). Response to ISIS 104838 treatment was measured by the American College of Rheumatology (ACR 20) response criteria, a widely used index of RA severity.

"We are pleased with the activity ISIS 104838 demonstrated in this trial," said Jon T. Holmlund, M.D., Vice President, Development. "The responses in the trial were continuing to increase at the conclusion of 3 months of treatment. Therefore, we believe longer dosing or higher doses of ISIS 104838 may significantly enhance activity."

"Our Phase 2 data suggest that ISIS 104838 has the potential to offer several important competitive advantages over protein-based drugs, particularly with regard to side effect profile and cost. Moreover, as we develop our oral form of ISIS 104838, we look forward to the opportunity to dramatically increase patient convenience and the market potential," said Dr. Holmlund. "We are aggressively advancing the development of ISIS 104838 for the treatment of rheumatoid arthritis as an alternative to currently available drugs."

Isis plans to initiate additional Phase 2 trials to further explore dose, schedule and treatment duration of ISIS 104838 in patients with RA. The company is engaged in ongoing trials to optimize oral formulations for ISIS 104838 and other second-generation antisense drugs.

In total, 176 patients with RA enrolled in the study. The primary endpoint in the study was improvement in ACR 20 at day 85. Results from the total patient group and evaluable patients were comparable. The nineteen patients excluded from evaluation were evenly distributed across the study's four dose groups.

Additional highlights from the trial are as follows:
* Significantly more patients dropped out of the placebo group due to progression of their RA than the two highest ISIS 104838 dose groups (p=0.05)
* Each of the two highest ISIS 104838 dose groups independently showed improvement in ACR 20 scores at day 85
* 40% of evaluable patients who received ISIS 104838 once a week (p=0.09) and 41% who received the drug twice a week (p=0.08) experienced improved ACR 20 scores, compared to 23% of placebo patients
* Patients receiving the two highest doses of ISIS 104838 experienced a greater improvement over baseline in the number of swollen and tender joints than patients in the placebo group
* ISIS 104838 produced an acceptable safety profile in the Phase 2 trial
* No drug-related serious adverse events were reported
* The most frequent adverse event was injection site reaction.

The reactions were generally considered mild in nature and occurred principally in the first month of treatment and with similar frequency as reported for protein therapeutics.

These Phase 2 results add to Isis' strong portfolio of data demonstrating activity of ISIS 104838. Another component of this data package is the Phase 2 biomarker study which evaluated the biological effect of TNF-alpha inhibition by ISIS 104838 in 20 RA patients over a four-week treatment period. As reported earlier this year, ISIS 104838 accumulated in synovial tissue in a dose-dependent manner, reducing TNF-alpha mRNA levels in patients with RA who received 300 mg of the second-generation antisense drug (see company press release from September 18, 2003). The synovium, the lining surrounding joints, is inflamed in patients with RA.

ISIS 104838 is an antisense inhibitor of TNF-alpha, and a product of Isis' proprietary second-generation chemistry, called 2'-O-methoxyethyl. Based on clinical and preclinical data, second-generation drugs offer: increased potency over first-generation antisense drugs; a decreased side effect profile; enhanced subcutaneous administration; enhanced patient convenience and the potential for oral delivery.

According to the Arthritis Foundation, RA affects 2.1 million Americans, predominately women. RA is a systemic disease that affects the entire body and is one of the most common forms of arthritis. RA is characterized by the inflammation of the membrane lining the joint, or synovium, which causes pain, stiffness, warmth, redness and swelling. The synovium can invade locally and cause damage to bone and cartilage. Inflammatory cells release enzymes that may digest bone and cartilage. The involved joint can lose its shape and alignment, resulting in pain and loss of movement.

Source: Isis Pharmaceuticals, Inc.

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