PHILADELPHIA, Pa., October 29, 2000 - Amgen (NASDAQ: AMGN) today announced that anakinra or interleukin-1 receptor antagonist (IL-1ra), an investigational rheumatoid arthritis (RA) therapy not yet approved by the U.S. Food and Drug Administration, may accelerate reduction in joint damage progression and improvement in the health-related quality of life for RA patients, according to results of several studies presented this week at the American College of Rheumatology (ACR) annual meeting.
Bone and Joint Data
In a double-blind, multicenter study, 472 patients were randomized to receive 30 mg, 75 mg or 150 mg daily treatment or placebo. After 6 months, the placebo patients were re-randomized to treatment with one of the anakinra doses. The patients were evaluated by radiographs using a modified Sharp assessment tool, which measures joint destruction based on erosive damage and joint space narrowing of the hand and wrist. The sum of these two subscales provides the total Sharp score. Increases in scores signify progressive structural destruction.
In the first analysis, patients treated with anakinra for a full year experienced an accelerated slowing of joint destruction in the second 6-month period relative to the significant improvements in the first 6 months of treatment. After six months, anakinra-treated patients experienced nearly twice the rate of reduction in joint destruction as the placebo group (increase in Sharp score of 1.86 vs. 3.61, respectively, p=0.002). After an additional six months of therapy, patients on anakinra experienced an increase of 1.18 compared with 1.32 in the placebo group (p<0.001). This accelerated improvement in benefit was seen at both 75 and 150 mg doses.
"Not only did patients on anakinra see benefits as early as six months on treatment, but the longer they were on therapy, the more improvement they experienced," said co-author Dr. Barry Bresnihan, professor of rheumatology, University College Dublin. "This suggests that anakinra may have a cumulative effect on joint destruction."
The second analysis assessed the effect of anakinra on progressive joint damage in RA patients after 12 months of treatment. Patients treated with anakinra for a full year fared nearly twice as well as those who switched from placebo to anakinra therapy after six months. The increase in modified Sharp score after anakinra treatment for one year was 2.1, compared with 3.8 for the switch group (p=0.015). Significant improvement among the anakinra-treated was seen both in the individual dose groups and the erosive damage and joint space narrowing subscales.
In an effort to quantify the bone protective qualities of anakinra using an animal model, researchers administered IL-1ra to rats with inflammation (paw swelling plus massive infiltration of bone marrow and adjacent soft tissues by leukocytes) and skeletal damage (reduced bone mineral density and severe bone resorption). The highest doses of IL-1ra reduced bone erosion by 61 percent and osteoclasts (cells that resorb bone) by 74 percent, compared to no therapy.
Quality of Life Studies
In two study analyses, anakinra rapidly and significantly improved the health-related quality of life of RA patients as measured by the Health Assessment Questionnaire (HAQ), an eight-scale tool that assesses a patient's ability to perform standard activities of daily living. Each scale ranges from zero (able to function without any difficulty) to three (unable to function). A weighted sum of the scale scores is the HAQ disability index (HAQ-DI). A lower score indicates better health-related quality of life.
In the first analysis of a randomized, double-blind, placebo-controlled study (n=419), patients treated with anakinra plus methotrexate had significantly greater improvements in HAQ-DI scores from baseline after just 4 weeks of therapy and saw continued improvement through 24 weeks compared with methotrexate alone. Treated patients experienced nearly half of the eventual 24-week improvement by week four, and nearly two-thirds of the improvement by week 8. Patients receiving 1.0 mg/kg and 2.0 mg/kg doses of anakinra improved 35 percent to 45 percent from their baseline score.
At 4 weeks, improvement in HAQ-DI was 0.26 (p<0.05) among patients receiving the 1.0 mg/kg dose and 0.25 (p<0.05) for the 2.0 mg/kg dose versus only 0.10 for placebo. At 8 weeks, the improvement measured 0.32 (p<0.05) at the 1.0 mg/kg dose and 0.36 (p<0.01) at the 2.0 mg/kg dose versus only 0.15 for placebo. At 12 weeks, improvement was 0.35 (p<0.05) for 1.0 mg/kg and 0.39 (p<0.01) for 2.0 mg/kg, versus 0.16 for placebo. Finally, at 24 weeks, improvement was 0.37 (p<0.05) at 1.0 mg/kg and 0.51 (p<0.01) at 2.0 mg/kg, versus 0.15 for placebo. Decreases in the HAQ-DI of 0.19 to 0.22 are considered clinically important.
In a second analysis of the same patients, researchers characterized the effects of 6-month anakinra therapy on the eight distinct quality of life scales comprising the HAQ. They combined patients receiving either 1.0 mg/kg or 2.0 mg/kg of anakinra plus methotrexate in a comparison with patients on methotrexate alone.
The patients receiving anakinra experienced significant improvement compared with placebo in six measures: reaching (-0.29 vs. 0.07, p=0.005), hygiene (-0.23 vs. 0.14, p=.019), eating (-0.40 vs. -0.07, p=0.004), dressing and grooming (-0.38 vs. -0.09, p= 0.011), grip (-0.45 vs. -0.19, p=0.025), and arising (-0.37 vs. -0.16, p=0.043). Overall, patients taking anakinra experienced at least 20 percent improvement in five measures. A majority (55 percent) of the anakinra patients reported a capability to perform functions with some or no difficulty and, averaging across all of the HAQ scales, 19 percent achieved a state of no impairment in function compared with 7 percent of placebo patients.
Quality of life is an important factor for RA patients. A recent quality of life survey conducted by the Arthritis Foundation found that 70 percent of RA patients could not exercise or complete basic household chores, 66 percent reported greater difficulty getting out of bed, 63 percent of those who held a job when diagnosed have since stopped working, 50 percent have given up social activities with family and friends, and 32 percent say they cannot get dressed when the disease is at its worst. Further, 81 percent of patients feel frustration because RA takes away the feeling of being in control.
"Completing basic everyday tasks, such as eating and dressing, is extremely difficult for many rheumatoid arthritis patients," said Dr. Stanley Cohen, study author, clinical associate professor, department of internal medicine, Southwestern Medical School in Dallas. "There is a need for newer therapies that can make a significant difference in patients' quality of life."
About anakinra
As previously reported, the potential of anakinra or IL-1ra to reduce both inflammation and bone and cartilage destruction, thereby slowing disease progression, suggests that the molecule may provide a meaningful benefit to patients with RA.
Interleukin-1 (IL-1) is a mediator of joint inflammation and destruction. When IL-1 binds to its receptor, the immune system starts a chemical reaction to fight off infections and decrease tissue injury and cell death. Usually, naturally-occurring IL-1Ra balances this process by directly and selectively blocking the deleterious effects of IL-1, making sure the receptor is no longer free to bind IL-1. However, in RA patients, there is a persistent activation of the immune system, which leads to an overabundance of proteins like IL-1 that induce structural damage and inflammation.
Anakinra is a recombinant form of natural IL-1Ra and is designed to competitively bind to IL-1 receptors, interfering with the action of excess IL-1 that RA patients produce and thereby regulating the inflammatory imbalance between IL-1 and IL-1Ra.
Amgen has filed for regulatory approval of anakinra in the United States, Canada, Europe and Australia.
Amgen is a global biotechnology company that discovers, develops, manufactures and markets cost-effective human therapeutics based on advances in cellular and molecular biology.
EDITOR'S NOTE: An electronic version of this news release may be accessed via our Web site at www.Amgen.com. Visit the Corporate Center and click on Amgen News. Journalists and media representatives may sign up to receive all news releases electronically at time of announcement by filling out a short form in the Amgen News section of the Web site.
CONTACT:
Amgen, Thousand Oaks
Rebecca Hamm, 805/447-3872 (media)
Cary Rosansky, 805/447-4634 (investors)