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Rheumatoid Arthritis Treatments

First, in a minute or two tell you a little bit about TNF. Secondly, then tell you a little bit about what etanercept is, how it’s put together and the role that it has in inhibiting TNF. Then for the meat of the talk, talk about the safety of etanercept, the clinical effect of etanercept in refractory rheumatoid arthritis, much of which is published. But more importantly, talk about the open-label continuation studies that are being done now. Then finally give you a capsule summary of some data that you are going to hear today and the rest of this week, with early rheumatoid arthritis with etanercept versus methotrexate plus psoriatic arthritis, and in addition, an update on patients who have received this who have juvenile rheumatoid arthritis.

Well, in summary, TNF has been shown to play a pivotal role in the events of rheumatoid arthritis. It is just one of those many cytokines, but it has an effect on a variety of other important events in the disease. Such as increasing inflammation by producing other cytokines, by interfering with the trapping of those cells with endothelium, and also with the destruction of tissue by inducing matrix palopergonases. I think that is going to be an important area that we’ll see when we look at the radiographic data of TNF inhibitors.

Briefly, to summarize, TNF is an important mediator in this disease process. It is produced primarily by activated macrophages, less commonly by synovial sites and T-cells. It is increased in the synovium and the synovial tissue and serum of patients with rheumatoid arthritis. It activates endothelium cells, it stimulates fibroblasts, it induces matrix palopergonases and it also can stimulate the production of other cytokines, such as IL-1, IL-6 and actually its own production. In addition, as you’ve heard, it also activates osteoclasts primarily via activation through interleukin 1 receptor antagonists.

With that as a background, let me just spend a couple of minutes explaining what soluble receptors are and the makeup of etanercept so we can understand what this product is. This is an activated macrophage from the synovium and it produces TNF here. TNF is cleaved from the cell surface by an enzyme called TACE, or TNF-alpha converting enzyme. Once TNF is produced it can go to other cells in the synovial fluid, synovial tissue or it can go systemically. It has its biologic or pathologic or normal effect by binding to cell bound receptors on a variety of cells. And it has to bind to two of these to co-link them for these cells to be activated. At the same time TNF is being produced by certain cells, it also … soluble receptors are being produced by these cells. Once these cells have been activated that same TACE enzyme cleaves these cell-bound receptors and they become circulating, or free, and we call them soluble TNF receptors.

Etanercept or Enbrel is basically a fusion protein of human soluble TNF, recombinant soluble TNF fusion proteins with a humanized IGF region of an IgG molecule. As illustrated in many studies - and I won’t go over in great detail here - it binds to both soluble and cell-bound TNF and lymphotoxin alpha. However it does not fix complement and does not kill cells in patients who are receiving this drug. In the studies that I am going to go over, the median half-life - although it varies from patient to patient based on size - is about 4.8 days. It is administered subcutaneously twice a week. The doses we use are 25 mg subcutaneously twice a week. As you’ve heard, it’s already approved since last year for the treatment of advanced or refractory rheumatoid arthritis; patients who failed at least one disease-modifying antirheumatic drug. It’s is also approved for juvenile rheumatoid arthritis. It’s been shown - and I’ll illustrate this data again - to be safe as a monotherapy or in combination with methotrexate.

So the molecule looks like this. These are these soluble receptors, humanized, that with recombinant techniques are bound to the FC region of an IgG-1 molecule. Normally those soluble receptors that you and I have circulating freely in us that are monomers have a half-life of a few seconds. This genetic construct of binding to the FC region gives it the increased half-life and the increased ability to bind to TNF and make TNF biologically inactive. This is illustrated on this slide, where here’s etanercept and here’s TNF and here’s the binding of etanercept to TNF so there is no TNF available that can go to these cells and bind to the cell-bound receptors and activate these cells to produce IL-1, IL-6, matrix petalopergonases, etc. TNF is still present in the patients but it is biologically inactive.

With that in mind, let’s now move on to the clinical data. First I want to review the results with patients, adults, who have received this who have long-standing disease, and also talk about those with early rheumatoid arthritis, which you will hear more about later today and the rest of this week. But first, let me give you a background on the amount of data that is available today so that you understand the spectrum from which these conclusions can be made. Clinical trials to date, in long-standing rheumatoid arthritis patients - we’ve studies 1,325. 

Let me briefly review those studies so that you will have that as the background from which the next few comments will come from. The etanercept versus placebo studies were published in the New England Journal of Medicine in 2006 and recently this spring in Annals of Internal Medicine, the phase II and phase III studies. You will see the European multi-center placebo-controlled trial later this meeting at the poster session on Monday. Earlier this year the combination of etanercept plus methotrexate was published by the New England Journal of Medicine. You heard last year, and you will hear an update this year from Dan Lovell regarding the experience of etanercept and juvenile rheumatoid arthritis. And finally you are going to hear about the important study of using etanercept in early rheumatoid arthritis and comparing it to methotrexate in patients who were methotrexate naïve.

So lets review in the next five minutes or so the efficacy of etanercept in the clinical trials to date. The things that I want to point out in these four studies - the four studies again are the phase II, phase III, the European study and the combination - is that these patients had long-standing disease, 10-15 years or longer. In addition they had active disease. They had 30-some odd tender joint counts and look at the uniformity from all of the studies listed here, and the number of swollen joints. So these patients by and large had failed two to three to four disease modifying antirheumatic drugs before coming into these clinical trials. These three are all placebo and this it the only trial combining etanercept with a common disease modifying drug. In that case it’s methotrexate. The important point that can be illustrated by each of these studies - but I’m using a slide from the Annals article earlier this year - is the quickness in which patients respond. As you can see here, within just two or three weeks, the number of tender and swollen joint counts has decreased on average of 35 or 25 down to numbers that are clearly clinically meaningful and patients start feeling better within three to four weeks. Looking at the more standard American College of Rheumatology clinical response criteria, the points that I want to illustrate on this slide are as follows: and that’s the consistency in these four studies. Again, the New England Journal article, the Annals, the European study - that you will hear about at this meeting - and the New England Journal combination, the ACR-20 response is in the ballpark of 70 except for the 59 here. In addition, the ACR-50 is fairly consistent and more importantly, perhaps, is those patients who have the most clear responses, again refractory patients, anywhere in the range of 15-20% receiving 25 twice a week. So the consistency of the clinical responses is what I want to illustrate.

With that in mind, let me spend the next few minutes talking about some data that I will present in more detail Wednesday and a concurrent session, that is the long-term safety and efficacy of etanercept. In these three clinical trials - not including the European - the numbers of patients to date comprise the largest clinical database we have with any biological agent followed this length. To date there are 713 patients which make up the studies I just mentioned, except the European study, who have been followed now - as you’ll see in a couple of minutes - out to 3 ½ years in some cases. Again, this illustrates the refractory nature, 3.2 disease-modifying antirheumatic drugs on average. Most were rheumatoid factor positive, and the mean disease duration of these patients was 12 years. Perhaps one of the most important aspects is to determine how many of these patients were to remain on this drug for the length of the follow-up period. These patients, with the exception of the few who are receiving the combination of methotrexate and etanercept, are only receiving etanercept. They are allowed to received concomitant corticosteroids and/or nonsteroidals but no other disease modifying drugs are allowed. If the disease is active enough that requires additional therapy then the patients are withdrawn from this long-term study. What this illustrates is - using a Kaplan-Marr estimation curve - is that 80% of the patients out to now, three years, continue to receive etanercept in this open label study to look at the long-term safety and efficacy of etanercept.