When they took the gene combination that they had fastened together and put it into a batch of living,dividing animal cells,the genes enteredd the cells and began to do what genes are supposed to do-make proteins. Those proteins are separated out from the animal cell culture and purified. The proteins that genes make is Etanercept-a novel hybrid of human antibody-human TNF-alpha receptor. When Enbrel,carried by the blood,arrives at the joints where TNF-alpha is acting up,it grabs tightly onto the TNF-alpha.  This prevents the TNF-alpha from attaching to receptors on cells in the joint and starting a cascade of inflammatory reactions. This kind of molecular manipulation of genes and cells is called genetic engineering.

 

Etanercept is a soluble receptor formed from the fusion of two p75 TNF receptors to human immunoglobulin (IgG). Etanercept binds primarily to TNF-alpha. Because it has a half-life of 4.3 days, it is administered subcutaneously twice weekly (at a dose of 25 mg). There are substantial differences in pharmacokinetic properties among the biologic DMARDs being developed for the treatment of patients with RA.  Etanercept, infliximab, and adalimumab are produced in Chinese hamster ovary cells; anakinra is produced in an Escherichia coli expression system. The resultant fusion protein is a soluble molecule that binds TNF-a at high affinity. A number of placebo controlled clinical trials have shown the efficacy of etanercept in patients with active rheumatoid arthritis who have failed prior DMARD therapy. Using the 25mg dose SC twice weekly, 59-75% of patients were found to improve by ACR 20 criteria (20% improvement), and 40-57% improved by ACR 50 criteria (50% improvement).

 

Long term-sustained efficacy has also been shown in an ongoing open label trial. At 18 months, patients have maintained their clinical improvement. Entanercept is also approved by the FDA for use in patients with polyarticular juvenile rheumatoid arthritis. Radiographic studies in rheumatoid arthritis have tested the ability of etanercept to prevent or slow radiographic erosions. 832 patients were an average disease duration of one year were randomized to receive etanercept 25 mg, etanercept 10 mg, or methotrexate (mean dose, 18.3 mg/week).  After one year of treatment, Sharp scores had only increased by 0.8, 1.4 and 1.3 units, respectively. All three treatment groups dramatically reduced the rate of radiographic progression, confirming the ability of etanercept alone to slow the progression of rheumatoid arthritis. Similar to a monoclonal antibody, etanercept when given as a therapeutic agent, binds TNF-a in the circulation, preventing interaction with the cell surface TNF-a receptors and clears TNF-a from the circulation. Etanercept inhibits TNF activity.

 

Etanercept has a long half-life of 70 hours after a standard 25mg dose. It is currently available only in a 25mg dose and is given by self-administered subcutaneous (SC) injection twice weekly. Intermittent or occasional dosing has not been studied.  Etanercept has a rapid onset of action within the first 1-2 weeks of therapy with some continued improvement over the next 4 weeks.

 

Adverse events were mild throughout the clinical trials. There was an increase frequency of injection site reactions in the etanercept groups, 37% Vs 10% in the placebo group. The injection site reactions were mild. There was not an overall difference between the etanercept group and the placebo groups in the rates of infection, cancer, or death from any cause.  There was an increase in mild upper respiratory infection symptoms in the etanercept group. No increase was seen in the frequency of anti-ds-DNA antibodies and no patients developed clinical SLE as has been seen with studies with monoclonal antibodies against TNF. Approximately 1% of patients developed anti-etanercept antibodies but these antibodies were non-neutralizing. A study adding etanercept to methotrexate showed no additional toxicitys.

 

In vitro studies suggested that TNF is a critical and proximal mediator of the inflammatory pathway in the rheumatoid joint. Proof-of-concept for this hypothesis has now been provided by animal studies and clinical trials. Not only does TNF inhibition dramatically reduce markers of inflammation but it also slows or halts structural damage, and these effects appear to be as potent in early disease as they are in late disease. In human terms, these efficacies should translate to less functional disability and higher quality of life.

 

The robust responses to treatment with TNF inhibitors in rheumatoid arthritis and inflammatory bowel disease are likely to be the tip of the iceberg. Any chronic (noninfectious) inflammatory disease that is primarily macrophage-driven could be a potential target for anti-TNF therapy. For example, pilot trials are now underway to evaluate the efficacy of TNF inhibitors in Wegeners granulomatosis, psoriatic arthritis, congestive heart failure and others illnesses.

 

The potential contribution of interleukin-1, independent of TNF-a, in chronic inflammatory states remains to be clarified but it is likely that a combined approach to inhibit both monokines will be even more potent than either solitary approach. Finally, the rebound in disease activity that occurs after cessation of anti-TNF therapy is a sobering reminder that the inflammatory cascade has been interrupted by neutralizing TNF, but that the underlying cause(s) of the disease itself, has not been addressed.

 

Tumor necrosis factor alpha (TNF-a) is a pro-inflammatory cytokine produced by macrophages and lymphocytes. It is found in large quantities in the rheumatoid joint and is produced locally in the joint by synovial macrophages and lymphocytes infiltrating the joint synovium. The pro-inflammatory effects of TNF-a suggests that inhibition of TNF-a would be clinically useful in rheumatoid arthritis.  The effect of these agents on rates of infection, cancer or the clinical recognition of these problems has yet to be answered in the general rheumatoid arthritis population. Cost and insurance reimbursement may limit availability. Whether these agents should or will replace methotrexate as the DMARD of first choice is to be answered only as the use of these agents increases.

 

In the second approach to TNF inhibition, soluble TNF-R have been engineered as fusion proteins in which the extracellular ligand-binding portion of the huTNF-RI or huTNF-RII is coupled to a human immunoglobulin-like molecule. Although TNF-RI is thought to mediate most of the biological effects of TNF in vivo, engineered sTNF-RI and sTNF-RII constructs both appear to be effective in vivo inhibitors of TNF. Etanercept (sTNF-RII:Fc; Enbrel®) is the best studied of the sTNF-R and is approved for the treatment of rheumatoid arthritis in adults and in children.  It is a dimeric construct in which two sTNF-RII (p75) are linked to the Fc portion of human IgG1. The dimeric receptor has a significantly higher affinity for TNF-a than the monomeric receptor (50-1000-fold higher), and the linkage to the Fc structure significantly prolongs the half-life of the construct in vivo. Although it also has an unnatural linkage site, anti-etanercept antibodies have been infrequent.

 

Etanercept (Enbrel) This fusion protein combines two p75 TNF receptors with an Fc receptor to form an immunoglobulin-looking molecule that decoys the pro-inflammatory cytokine TNF. By doing so, it decreases the binding of TNF to its cellular receptors and thus avoids the downstream development of tissue inflammation and damage. It is both highly effective and, to date, safe.  It not only leads to a clinical improvement over that obtained with MTX alone, but it has been shown to be disease-modifying. Infection risk is increased in those patients who have actively infected skin ulcers or diabetes. No increased risk of tumors or autoimmune disorders has been found. At this time, it is most commonly employed when patients have not had an excellent response to full-dose MTX.

 

Etanercept was approved by the FDA in 1998  for use with methotrexate, or may be used alone in the treatment of rheumatoid arthritis . Dose: 25 mg subcutaneously twice weekly.  The combination of etanercept and MTX has been demonstrated to be effective in RA patients who are MTX partial responders.Clinical trials showed that the addition of etanercept (25 mg twice weekly) to ongoing MTX therapy (10 to 25 mg weekly) resulted in a significant improvement in the signs and symptoms of RA at 24 weeks. At 24 weeks, 71% of the patients receiving etanercept plus MTX and 27% of those receiving placebo plus MTX met the ACR20 criteria (p < 0.001). In addition, 39% of the patients receiving etanercept plus MTX and 3% of those receiving placebo plus MTX met the ACR50 criteria (p < 0.001). Finally, 15% of the patients receiving etanercept plus MTX and 0% of those receiving placebo plus MTX met the ACR70 criteria (p < 0.05).
 
The international, double-blind, placebo-controlled clinical trial of infliximab in 428 patients with RA who had received continuous MTX for at least 3 months and then had infliximab (3 or 10 mg/kg) injected every 4 or 8 weeks (q4w, q8w) demonstrated significant efficacy for this anti-TNF-alpha mAb.  At 30 weeks, ACR20 was achieved in 50%, 53%, 52%, and 58% of patients receiving 3 mg/kg every 8 or 4 weeks or 10 mg/kg every 8 or 4 weeks, respectively, plus MTX compared with 20% of patients receiving placebo plus MTX (p < 0.001 for each of the four infliximab regimens versus placebo). The corresponding ACR20 response rates at 54 weeks were 42%, 48%, 59%, and 59%, respectively, of patients on infliximab plus MTX versus 17% of patients on placebo plus MTX (p < 0.001 for each regimen versus placebo).
 
An ACR50 improvement was achieved at week 30 in 27%, 29%, 31%, and 26% of those in the same infliximab plus MTX treatment groups, compared with 5% of patients on placebo plus MTX (p < 0.001). The corresponding ACR50 response rates for the infliximab treatment regimens at 54 weeks were 21%, 34%, 39%, and 38%, respectively, versus 8% for placebo plus MTX (p < 0.001). At 30 weeks, an ACR70 improvement was achieved in 8%, 11%, 18%, and 11% of patients in the same infliximab plus MTX treatment groups, compared with 0% of patients on placebo plus MTX (p < 0.001). The corresponding ACR70 response rates at 54 weeks were 10%, 17%, 25%, and 19% for infliximab plus MTX versus 2% for placebo plus MTX (p < 0.001).

 

ENBREL is a TNF inhibitor that can be used alone. When TNF molecules attach to immune cells in the joints, they help trigger the inflammation process. Soluble TNF receptors, produced naturally in the body, capture and inactivate TNF before it can attach to immune cells.  ENBREL supplements the bodys own soluble TNF receptors, capturing TNF molecules before they have a chance to attach to the immune cells and trigger inflammation. By interrupting the inflammation process,  ENBREL has been shown to both reduce short-term RA symptoms and inhibit the progressive long-term damage to the joints. ENBREL is indicated for reducing signs and symptoms and inhibiting the progression of structural damage in patients with moderately to severely active rheumatoid arthritis.

 

In addition to RA, ENBREL is also approved for reduction in signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis (JRA) in patients 4 years of age and older who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).  ENBREL is also indicated for reducing signs and symptoms of active arthritis in patients with psoriatic arthritis and ankylosing spondylis.

 

In medical studies, people with RA using ENBREL reported significant reductions in pain, fatigue, and the amount of time feeling stiff in the morning. In one study of 234 people with RA, those who took ENBREL experienced significantly  a) Less pain (56% for ENBREL vs. 4% for placebo) b) Less fatigue (26% for ENBREL vs. 5% for placebo)  c) Less time feeling stiff in the morning (83% for ENBREL vs. 18% for placebo)  In medical studies of ENBREL users with RA, most people reported rapid improvement in symptoms and experienced relief that continued for an extended period of time.  In a 2-year study of 207 ENBREL users with RA, over 60% began to see results within the first few months of treatment, achieved their maximum response within 4 to 5 months of treatment, and maintained that response level for the duration of the study.

 

In a 42-month study of 628 ENBREL users with RA, the majority began to see results within the first few months of treatment and achieved their maximum response within 4 to 5 months.  Individual results may vary. In medical studies, ENBREL worked for about two out of three adults with RA who used it. In medical studies, ENBREL worked for about three out of four children with JRA who used it. In medical studies, ENBREL worked for about 50% of psoriatic arthritis patients who used it.

 

ENBREL is a protein. If ENBREL were taken by mouth, stomach acids would break it down just as they do with the proteins in food and prevent the ENBREL from working. But by injecting ENBREL, you allow it to enter the bloodstream intact and go directly to work. ENBREL is a self-injected drug administered under the skin, twice a week, at doses 72 to 96 hours apart. Many ENBREL users have discovered that self-injection offers many benefits: a) Theres no need to go to a doctors office for treatment. b) You give yourself the injections in your own home. c) You determine the twice-weekly schedule thats best for you. Doses should be taken 72 to 96 hours apart; most ENBREL users choose either a Monday/Thursday or a Tuesday/Friday schedule. d)  Theres no need for routine laboratory monitoring specifically for ENBREL. Careful medical management by your health care professional is recommended. Furthermore, ENBREL is the first and only TNF inhibitor for RA that can be used alone

 

SINCE THE PRODUCT WAS FIRST INTRODUCED, SERIOUS INFECTIONS, SOME INVOLVING DEATH, HAVE BEEN REPORTED IN PATIENTS USING ENBREL. MANY OF THESE INFECTIONS OCCURRED IN PATIENTS WHO WERE PRONE TO INFECTIONS, SUCH AS THOSE WITH ADVANCED OR POORLY CONTROLLED DIABETES. RARE CASES OF TUBERCULOSIS HAVE ALSO BEEN REPORTED. ENBREL SHOULD BE DISCONTINUED IN PATIENTS WITH SERIOUS INFECTIONS. DO NOT START ENBREL IF YOU HAVE AN INFECTION OF ANY TYPE OR IF YOU HAVE AN ALLERGY TO ENBREL OR ITS COMPONENTS. ENBREL SHOULD BE USED WITH CAUTION IN PATIENTS PRONE TO INFECTION. CONTACT YOUR PHYSICIAN IF YOU HAVE ANY QUESTIONS ABOUT ENBREL OR INFECTIONS.

 

There have been reports of serious nervous system disorders such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes. Tell your doctor if you have ever had any of these disorders or if you develop them after starting ENBREL. There have also been rare reports of serious blood disorders, some involving death. Contact your doctor immediately if you develop symptoms such as persistent fever, bruising, bleeding, or paleness. It is unclear if ENBREL has caused these nervous system or blood disorders. If your doctor confirms serious blood problems, you may need to stop using ENBREL.

 

The most frequent adverse events in placebo-controlled RA clinical trials involving 349 adults were injection site reactions (ISR) (37%), infections (35%), and headache (17%). Only the rate of ISR was higher than that of placebo. The most frequent adverse events in a methotrexate-controlled clinical trial of 415 adults with early-stage RA were infections (64%), ISR (34%), and headache (24%). Of these, only the rate of ISR was higher than that of methotrexate. Patients have been observed in clinical trials for over 3 years. The incidence of malignancies has not increased with extended exposure to ENBREL and is similar to the projected background rate.

 

Adverse events in the psoriatic arthritis trial were similar to those reported in RA clinical trials.

 

In a study of 69 patients with JRA, infections (62%), headache (19%), abdominal pain (19%), vomiting (13%), and nausea (9%) occurred more frequently than in adults. The types of infections reported in JRA patients were generally mild and consistent with those commonly seen in children. Serious adverse reactions reported rarely were chicken pox (3%), gastroenteritis (3%), serious infections (2%), depression/personality disorder (1%), skin ulcer (1%), inflammation in parts of the upper digestive tract (1%), and diabetes (1%).