On April 12,2000--The FDA Arthritis Advisory unanimously recommended approval of Enbrel (TM) -(etanercept) for use to delay radiographic progression of joint damage in patients with early RA,and voted in favor of approval of Enbrel for use to improve signs and symptoms of patients with early stage disease.

 

Enbrel is a synthetic (man-made) protein that binds to TNF. Enbrel thereby acts like a sponge to remove most of the TNF molecules from the joints and blood. This prevents TNF from promoting inflammation and the fever, pain, tenderness, and swelling of joints in patients with RA.

 

The panel's recommendations were based on data presented by officials of Immunex Corporation,the bulk of which were the radiologic and clinical results of a phase III randomized,double-blind,muti-centre trial that included 632 adults who had RA for less than 3 years and had never been treated previously with methotrexate.

 

The 632 participants in the Enbrel "ERA" study were randomized to receive either 25mg or 10mg of Enbrel,or up to 20mg of methotrexate (MTX) per week for 12 months. To ensure blinding of study treatments,patients received both injection and pills. Enbrel by injection twice weekly plus placebo pills weekly or MTX pills weekly plus placebo injections twice weekly. Patients enrolled in this study had  RA for a relatively short time (mean of 1 year),and had very active disease (mean tender and swollen joint counts of 30 and 24, respectively,and reported a mean diration of 4 hours of morning stiffness). All patients had risk factors for rapidly progressive,erosive RA including the presence of rheumatoid factor and or erosions on baseline x-rays of the hands, wrists and feet.

 

The ability of Enbrel and MTX to delay joint damage characteristic of RA was assessed using x-ray criteria,measured by the modified total Sharp scoring method,a validated method used in clinical trials to quantify progression or lack of thereof,of joint destruction. X-rays of the hands/wrists and feet of each patient were obtained at baseline and at six and 12 months. Digitized images of each x-ray were scored for 2 of 6 physicians (5 radiologists and 1 rheumatologist)  who were trained in the total Sharp scoring method. The assessors were blinded to study treatment and the chronlogical order of the images.

 

The modified total Sharp scoring method required 17 joints of each hand/wrist and 6 joints of each forefoot were also scored for joint space narrowing on a scale of 0 (no damage) to 5. Sixteen joints of each hands/wrist and 5 joints of each forefoot were also scored for joint space narrowing on a scale of 0 (no damage)  to 4. The erosion score and the narrowing score wer added to determine the total Sharp Score (TSS).

 

The co-primary endpoint of the study was the effect on markers of activity of RA as measured by the ACR-N AUC,which uses the ACR standard composite scoring method including assessment of  71  joints for tenderness and 68 joints for swelling,a physician's and patient's global assessment of disease,a patient's assessment of pain,using a visual analog scale,a patient's assessment of disability (Health Assessment Questionnaire), and blood serum levels of ESR and CRP. Each patient is assigned an actual percentage improvement from baseline on these criteria on each visit (the ACR-N). The ACR-N AUC represents the average amount of improvement over all of the visits for each patient. The mean ACR-N AUC for the patients in each group is used to compare the groups.

 

The FDA approved Enbrel on November 2,1998 to treat moderately to severely active RA in patients who have an inadequate response to one or more DMARDs. The FDA included children and teen-agers (age 4 to 17 years) in the Enbrel label when it granted the drug a new indication on May 28,1999 for the treatment of moderately to severely polyarticular-course juvenile RA patients who have had an inadequate response to one or more DMARDs.

 

In postmarketing use serious infections and sepsis,including fatalities,have been reported. Many of these events occurred in patients predisposed to infections, such as those with advanced or poorly controlled diabetes. Discontinue Enbrel in patients with serious infections or sepsis. Do not start Enbrel in the presence of sepsis infection (including chronic or localized).or allergy to Enbrel or its components. Use caution in patients predisposed to infection. The most adverse events in adult clinical trials in RA (n=349) were injection site reactions  (ISR) 37%,infections (35%),and headache (17%). Malignancies were rare (+> 1 %). Only the rate of ISR were higher than placebo.

 

In a JRA study (n=69),infections (62%),headache (19%), abdominal pain (19%),abdominal pain (19%),vomiting (13%) and nausea (9%) ocurred more frequently then adults. The types of infections reported in JRA patients were generally mild and consistent with those seen in outpatient pediatric populations.  Serious adverse reactions rarely were varicella (3%), gastroenteritis  (3%),depression/personality disorder (1%),cutaneous ulcer (1%),and esophagitis/gastritis (1%).

 

The current label for Enbrel states that the drug should not be used with patients who develop a serious infection or who have sepsis. Immunex and Wyeth Ayerst are updating this label,advising doctors not to start the drug in patients who have an active infection. Additionally,physicians should exercise caution when considering the use of Enbrel in patients with a history of recurring infections or with underlying conditions that may predispose patients to infections, such as poorly controlled diabetes. Patients who develop a new infection should be monitored closely

 

Since Enbrel was approved,the drug has been prescribed to more than 25,000 patients and more than 1,500 clinical trials participants are being monitored for long-term efficacy and safety. Adverse events reported to the companies are similar to those addressed in the FDA approval package insert for Enbrel. At this point,there has been no apparent of reported events with increased and longer-term usage of Enbrel In post-marketing surveillence of more than 25,000 patients on Enbrel over the first five months since launch,30 patients treated with Enbrel are reported to have developed serious infections including several cases of sepsis. Six of the patients with infections died,a number of whom had a history of chronic or recurrent infections,pre-existing infections, diabetes mellitus or other conditions that predisposed to infections,in addition to their severe RA.

 

The mortality rate due to infection reported during the first 5 months of post-marketing experience is consistent with the rate observed in the clinicl trials and also in a RA population not taking Enbrel. There has been no evidence of increased risk for opprtunistic infection associated with Enbrel.

 

The most frequently reported adverse events in studies with Enbrel were mild to moderate injection reactions. The long-term effects of Enbrel treatment,on the development or course of activity and/or chronic infection,malignancy and autoimmune disease is unknown.Patients with a serious infection,including sepsis or who are allergic to Enbrel or any of its components should not take the drug. If patients develop an infection while on Enbrel they should talk with their doctor and be monitored very closely.