By Lisa Seachrist
GAITHERSBURG, Md. - An FDA advisory panel recommended the agency expand the label for Immunex Corp.'s Enbrel to include patients suffering early, active rheumatoid arthritis (RA).
The FDA's Arthritis Advisory Committee voted 7 to 2 in endorsing Immunex's supplemental biologics license application (BLA) requesting the agency remove the requirement that RA patients fail other disease-modifying antirheumatic drugs (DMARDs) before initiating treatment with Enbrel (etanercept) to treat the signs and symptoms of RA. The panel also endorsed Enbrel as a way to delay the progression of structural damage to the joints in early RA by a vote of 9 to 0, but voted unanimously not to extend that label to later-stage disease.
"We are very pleased with the recommendations of the panel," said Peggy Phillips, executive chief operating officer for Seattle-based Immunex. "We are going to have discussions with FDA to determine the exact wording on the label. But we will have the limitation of failing a DMARD removed, and we will have some wording on the label about preventing structural damage."
While endorsing the product, the panel expressed concerns about the long-term safety of Enbrel. Specifically, the panel expressed concerns about whether Enbrel increases the risk of serious infections in patients prone to infections in the first place and whether five or 10 years down the road, patients receiving Enbrel are more likely to develop cancer.
Enbrel, a self-injectable, genetically engineered protein fusing two human tumor necrosis factor (TNF) receptors, works by binding TNF and blocking its ability to trigger the immune system to damage tissues. TNF is found at elevated levels in fluid around the joints of RA patients.
In November 1998, the FDA approved Enbrel for use in patients with moderate to severe RA who have not responded well to other DMARDs. The agency also granted a label indicating Enbrel may be used in combination with the most widely used DMARD, methotrexate.
In May 1999, the agency granted Immunex's request to expand Enbrel's label to include an indication for reducing the signs and symptoms of moderately to severely active polyarticular course juvenile rheumatoid arthritis in patients who had failed at least one DMARD.
Immunex presented the results of a pivotal study of 632 patients supporting the expansion of the label into the earliest stages of the disease. In order to be eligible for the study, patients had suffered from active RA, never been on methotrexate therapy, and had been diagnosed within three years.
The company tested methotrexate, 10 milligrams of Enbrel and 25 milligrams of Enbrel for one year. The trial was originally designed to show Enbrel was superior to methotrexate, but early in the study methotrexate was shown to slow the damage to joints in early arthritis. Anticipating high activity among patients on methotrexate, FDA suggested the company change the endpoint before any data had come in to demonstrate Enbrel isn't inferior to methotrexate. In addition, the data the company presented to the panel dealt only with the 25 milligram dose of Enbrel because it proved the best dosage.
The company examined how much the joint in the hands and feet eroded by using X-rays and a scoring system known as a modified Sharp method. The company also is using a scoring system based on the American College of Rheumatology criteria for assessing response to therapies. The ACR-N AUC score employed by the company evaluated Enbrel and methotrexate response over time.
Enbrel not only satisfied the requirement that it treat the signs and symptoms as well as methotrexate, but it also was shown to be statistically significantly better than methotrexate and was effective sooner than methotrexate.
When the company examined Enbrel's ability to delay progression of joint erosions, Enbrel proved better than methotrexate again when looking at the total Sharp score. That measure wasn't statistically significant. However, Enbrel prevented joint erosion in 75 percent of patients for one year while methotrexate prevented joint erosion over a year for only 57 percent of patients.
Early in its development, Enbrel was tested as a treatment for sepsis, but more patients receiving the drug died than those receiving the control therapy. In addition, once Enbrel was approved for RA, infections and deaths in the postmarketing period resulted in additional warning language in the product label. The panel was concerned there was a much increased risk of infections for patients treated with Enbrel. In the study the company found six infections that resulted in hospitalization or treatment with intravenous antibiotics for the 415 patients receiving any dose of Enbrel. The methotrexate group had five such infections.
Immunex has started clinical trials to assess the true risk of infectious complications in a variety of patients, especially those such as diabetics who are at higher risk for infection.
The panel had issues with the potential for Enbrel to cause malignancies, especially if it were to become an initial DMARD therapy. While noting there weren't any excess cancers identified to date, the company readily admitted the best data won't be available for at least five years, but told the panel it had already committed to following patients for five years and noted Wyeth-Ayerst had established Enbrel registries in Europe.
Panel consultant Lee Simon, a rheumatologist and associate professor of medicine at Deaconness Hospital and Harvard Medical School, pointed out to the panel that methotrexate itself had significant side effects including nausea, rash, and mouth ulcers. In addition, methotrexate has never been labeled as a DMARD.
"Enbrel's probably more tolerable than methotrexate," Simon said. "We don't know the long-term risks with Enbrel, but we don't known the long-term risks with methotrexate, which we consider the gold standard. I think it should fall from the gold standard."
The company also is developing Enbrel as a treatment for chronic heart failure, psoriatic arthritis, psoriasis and some cancers.
Immunex's stock (NASDAQ:IMNX) closed Tuesday at $61.187, up $6.125, or 11 percent.