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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 itís 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 weíll see when we look at the radiographic data of TNF inhibitors now that they are out and we have data that you will hear today and tomorrow.

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 youíve 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 Ö 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 wonít 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 youíve heard, itís already approved since last year for the treatment of advanced or refractory rheumatoid arthritis; patients who failed at least one disease-modifying antirheumatic drug. Itís is also approved for juvenile rheumatoid arthritis. Itís been shown - and Iíll 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 hereís etanercept and hereís TNF and hereís 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, letís 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 - weíve 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 1997 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 itís methotrexate. The important point that can be illustrated by each of these studies - but Iím 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 thatís 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 youíll see in a couple of minutes - out to 3 Ĺ 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.

Again, to point out some of the major clinical clues here is looking at the joint counts when the patients came into the studies and now out. This lists 24 months - data that I will present on Wednesday will go out to 36 months - illustrating that these 80% of patients who remain in this study do so and have very good clinical effect. I think this is illustrated in a different way looking at the ACR 20% response. The different colors here reflect six months, 12 months, 18 months, and 24 months follow-up. Looking at an ACR-20 versus an ACR-50 and ACR-70. What you can clearly see is that the patients continue to have a significant clinical benefit or they wouldnít have stayed in, or because of the criteria Iíve just alluded to. And in fact, out at 24 months almost 30% of the patients have a 70% improvement in their disease activity. We are trying to get a handle on how many patients really go into remission or have a dramatic response, and weíve set fairly strict criteria as to how we would define that. And itís defined as basically the following: having zero tender joint counts, zero swollen or the combination of no active joints. Not one or two but zero and also having a zero on a health assessment questionnaire, the disability index. Again, from left to right you can see that the follow-up is at 6 months, 12 months, etc. out to 30 months. And a large percentage of patients with refractory disease who continue on etanercept long term have what I would consider to be fairly significant clinical responses, as measured by these criteria.

With that in mind, let me shift and talk about the safety aspects of etanercept in the clinical trials reported to date. Again, to give you a background on the database and the number of patients, let me briefly review that. Here are the placebo-control trials in North America - Iím not talking about the European studies - 349 patients or 117 patient years, plus the open label trial experience to date, and thatís 364 patients which makes up a total of 1,713 patients that Iím going to talk about with regards to the safety database. The amount of time that the patients have been in this study obviously varies from those patients who entered early to those who are now moving along in the study. The take-home point is that we now have data out to 24 months in over 200 patients. More importantly, we have data out to 12 and 18 months in even larger numbers of patients. This is an open label database that will continue for the next several years and we hope would be able to update you on the long-term safety and efficacy of etanercept for several years, for obvious reasons.

With that in mind, let me briefly summarize the adverse events that have been reported in the literature regarding the controlled trials so that I can give you a comparison to what is now in the database with these open long term extension studies. This summarizes - and I wonít go through the details - the adverse events that were greater than 10% in frequency. All adverse events in the control trials that Iíve just alluded to. The only one that was more common statistically than any others, compared to etanercept with placebo, were injection site reactions. Thirty-seven percent versus 10%, 7.73 versus 0.62 when you look at events per patient years. Other events such as infections etc. were not as Ö were not more common in patients who received placebo versus etanercept. Now looking at the next slide, let me briefly walk you through a lot of this to illustrate the concept and not the details. These are the same side effects; headache, rash, rhinitis, nausea, diarrhea. The yellow is placebo. Those patients in the placebo-controlled trials who received placebo. The blue is etanercept in the controlled trials who received etanercept, and now in the open label continuation safety studies, the white. The take-home message is that in the long-term safety analysis of these studies is there was not an increased incidence of cumulative side effects. In other words, there was not an increased in some of these side effects reported in the clinical trials. Thatís with all side effects. Perhaps most importantly, and what we are interested in clinically and for our patients in their day to day activities, are the infectious related side effects. This illustrates again controlled trials, reported at least 3% or greater in frequency, from URIís to sinusitis, to flu, etc. etc. Again, pointing out in the placebo-controlled trials, the three that Iíve alluded to - not including the European study that youíll hear this week - there was not an increased incidence of adverse events from an infectious standpoint in those clinical trials. When we add the long-term safety of these 713 patients into that - this is the white bar now - you can see that with all infections versus URIís, sinusitis, skin infections and most seriously, infections associated with hospitalization and/or IV antibiotics, that the white bar is again not any higher than the blue or yellow bars. Indicating that in this 713 patient database there isnít a difference with the long-term safety.

Iíd just like to take a minute to review the post-marketing experience because Iím sure youíre all aware that in May there was an FDA change in the label. This was based on the fact that at that time 25,000 patients had received etanercept and there were reports of some serious infections and in fact six deaths. Let me review with you those six patients and explain to you the change in the label. These six deaths - again, we are in a database of 25,000 self-reporting by physicians - four women, two men. The time on etanercept ranged anywhere from as little as one week to six weeks. All had severe long-standing rheumatoid arthritis and all had significant risk factors for what we would consider high risk for infectious complications associated with rheumatoid arthritis. In fact, one was in renal failure, three had congestive heart failure, two had diabetes, two had extraarticular manifestations, and perhaps more importantly and perhaps disturbing, four had active infections of leg wounds and despite that still received etanercept as a therapy. The FDA label change basically said "be careful and donít use etanercept in patients with active, serious infections such as leg wounds and patients with pneumonia and bronchitis." Which is something I think we already knew but I think required a little reminder from the FDA.

With that in mind, let me give you a little bit of historical background then with some published data and with the placebo-controlled trials and now with etanercept in the post-marketing experience. These are four trials published in the last few years from a variety of different investigators which look at the infection-associated mortality in very large databases from different countries and different parts of the U.S. plus some from the U.S. that arenít on here, illustrating that our patients with rheumatoid arthritis do have an increased risk of infection. The mortality associated with etanercept in the clinical trials, the placebo-controlled trials, was lower than that that was perceived in the open market. As one would expect, placebo-controlled trials weed out those patients who have serious problems where they wonít be allowed to come in. This illustrates the post-marketing data to date. There is not an increased risk, at least in the post-marketing data as we know it today, with etanercept with serious infections that are associated with mortality. I think that is an important piece as we put all this together.

Finally, with adverse events and long-term treatment, let me spend a couple of minutes talking about malignancies. One of the roles that TNF has in our immune system normally is part of the surveillance not only for infections but potentially for malignancies. A concern that has been raised by many of us as we move down this era of targeted therapy is whether these drugs will have undue long-term side effects in particular malignancies. To date that is not the case, and let me illustrate the data. Again, in this 713 patient database, including those patients who were in the placebo-controlled trial, if you look at the NIH CR database as the control group, which is that patient age matched, sex matched, one would have expected 10.7 malignancies during this 1,152 patient years. We noted 9 malignancies, which ranged from lung, ovarian, bowel, breast, Hodgkin's, one localized parotid non-Hodgkinís and one prostate cancer. The conclusions to date are that there is no increased risk of malignancy with TNF inhibitors with the data now out to three years with our surveillance.

So in summary, what I would like to do with the long-term results and the placebo-controlled trials is to state what we already know. That etanercept is well tolerated, it is very effective in controlled trials and now in open label trials. The injection site reactions are the only events that are clearly attributable to etanercept. There is no cumulative long term toxicity. There has been no incidence of lupus or lupus-like syndromes or antibody syndromes associated with etanercept with the long term therapies.

With that as a summary with long-term refractory disease, let me now shift gears for the next five or ten minutes and talk about etanercept in early rheumatoid arthritis. The importance of intervening early in rheumatoid arthritis is now the standard. Thatís based on several pieces of data, and that is the functional status declines early with rheumatoid arthritis. Patients have disability within just two to three to five years at rates that are unacceptable. With the increased morbidity and increased mortality we shouldnít be waiting too long before we get into treating these patients. As all of us know, radiographic changes can occur early and in fact can occur within the first 12 months and by most of our patients, have occurred by two or three years. So not only from a humanistic and ethical standpoint, the data that I am going to show in a couple of minutes relates to the economic impact of this. As we are all aware, all of our current therapies as of a year before now really are associated with poor long-term sustained use, either because of lack of efficacy or because of significant toxicity.

The objectives of this trial were to determine if etanercept in patients with early rheumatoid arthritis - they had to have a rheumatoid factor positivity or have erosions. So these were people who were felt to have severe disease, have to never seen methotrexate, to be methotrexate naïve, and had to have disease duration less than three years. The questions were, does it influence the rate of joint damage? Secondly, is it clinically safe and effective in patients with early disease? And not assuming that one would expect anything different than the chronic patients. The primary end points were prospectively as one would do with a phase III study planned. The primary end points were change and Sharp score over 12 months, as well as clinical improvement measured by area under the curve of a new term called ACRN at six months as well as secondary outcomes looking at the ACR-20, ACR-50 and ACR-70 at six months of disease duration. This was a huge multi-center trial, 70-some sites or more, placebo-controlled, 632 patients randomized to receive etanercept 25 mg twice a week, etanercept 10 mg twice a week or methotrexate starting at a dose of 7.5 mg per week, rapidly escalating to 20 mg per week at eight weeks. If they had any disease activity between baseline at eight weeks they were put up to 20 because we wanted to make sure that methotrexate was given at the best doses, the highest doses that we thought were clinically effective, to compare with a drug with a biologic agent head-on in early disease. The analysis was by intent to treat, so patients were followed and analyzed if the study was discontinued.

I wonít go through the demographics of this, but to illustrate some of the major points: these people had active disease. It wasnít mild RA. As illustrated, 30 tender joint counts, 24 swollen joint counts and a C-Reactive protein in the range of 3.3 - 4.7. So these were early aggressive patients who had never seen methotrexate who were put onto this trial. The safety is very simple. There werenít any unusual side effects seen in this trial that we havenít seen already in the placebo-control trials or in the long term safety issues. More importantly, there were significantly fewer adverse events in the etanercept group versus methotrexate. There were fewer withdrawals in the etanercept group due to adverse events than compared to methotrexate, and there were significantly fewer infections in the etanercept compared to methotrexate. Again, for more details, stay tuned. The major outcome of this was radiographic changes, and again Iím not going to give all the details, but to summarize I think one of the major important clinical points of this study; many of the patients -in fact, 42 - could not tolerate 20 mg per week of methotrexate for a year. Twenty of those 42, or 48%, had no new erosions from baseline to the end of one year. If you were able to tolerate methotrexate - which 175 were - 59% of those patients had no new erosions, using doses that we all think are probably the maximum doses that we should use. These numbers are not statistically significant, however those patients receiving 25 mg of etanercept twice a week, 75% or 155 out of 206, had no new erosions from baseline to the end. What this study shows us is that both methotrexate and etanercept - like weíve seen in other studies with methotrexate - will slow the radiographic progression. There wasnít a third arm here comparing the combination of methotrexate and etanercept. One could hypothesize that the use of the combination would have added diverse synergistic benefits and we need to await the results of such studies before we can make those conclusions.

So in summary, the conclusions regarding efficacy with radiographic progression is that over 90% reduction in the predicted erosion of rheumatoid arthritis patients in this early RA trial and it prevents the development of new erosions in over 75% of patients who receive etanercept. So the conclusions of the etanercept and the ERA trial, or Early Rheumatoid Arthritis trial is that it reduces joint damage. Itís clinically effective in patients who have never seen methotrexate and as predicted and seen with the studies Iíve gone over in great detail, there are no new adverse events. It was safe and well-tolerated.

With that in mind, let me shift gears and spend the next few minutes talking about some other rheumatic diseases for which etanercept has been studied and for which we will see some results this meeting. First to point out that Iíve already summarized the adult, late and early disease, you will hear more about Stillís disease, ankylosis spondylitis, uveitis and Wagnerís disease as time evolves. There are clinical trials now underway looking at etanercept in these diseases. What Iíd like to spend some time talking about now is talking about JRA and psoriatic arthritis. Again, the challenge today was to give an overview of whatís going on but not to steal any thunder from anyone else, so Iím trying to go on that thin line here. Patients with JRA were all given etanercept at a dose of 0.4 mg per kg, not to exceed 25 mg twice a week. If they responded to that then they were randomized to give placebo for a few weeks or a few months or etanercept. It was felt, and the FDA had a pivotal role in designing this study along with the folks at Cincinnati and the pediatric rheumatologists, that it would be unethical to randomize children with refractory rheumatoid arthritis to a placebo arm to find out first whether they responded and then once they withdrew from this they were allowed to continue on this in an open label phase. So it would be just a four month period. This slide is a little cumbersome but it points out a couple of points that I want you to take home. First of all, it illustrates the number of patients who responded here. Both of these are looking at when all patients received etanercept. Looking at a 30%, 50% or 70% improvement. The pediatric criteria for measurements is a little different than for adults. They have a 30% criteria as opposed to our 20%, but I think you can see the same basic concept is that almost 90% of the children who had refractory polyarticular JRA responded to etanercept. After three months they were withdrawn to either receive placebo or to receive etanercept. As you can see, if you went back to placebo your disease activity did not do well as opposed to if you received etanercept long term the disease activity was continued to be minimized and efficacy was demonstrated in this clinical trial. 

Finally, in the last few minutes, let me briefly give you a summary of psoriasis and a capsule summary of the clinical data that you will see. But first, TNF - if you look in the plaques of patients with psoriatic arthritis - you will see TNF levels there. When you measure TNF level in involved versus uninvolved skin there is increased levels in the involved skin versus the uninvolved. Moreover, like with rheumatoid arthritis, if you were to measure TNF levels in the circulation or in the synovial fluid or synovial tissue you will see there are increased levels compared to controls. Levels that are in the range that someone would see with rheumatoid arthritis. So this clinical trial was to demonstrate whether etanercept improved the signs and symptoms of psoriatic arthritis, whether it improves psoriasis also, and whether it was safe. Whether there were undue effects seen in the psoriatic arthritis patient population that may not be seen in patients with rheumatoid arthritis or other diseases. This was a three month, randomized, placebo-controlled trial, 30 patients per arm; 30 etanercept, 30 placebo. The entry criteria were that you had to have at least three swollen joints or three painful joints and to have an inadequate response to a previous therapy. If you were taking other disease-modifying drugs, such as methotrexate or sulfasalazine, etc. you were allowed to stay on those drugs. However, any local treatment, topical treatments - particularly UV therapy - were discontinued for the study. I think the point that I want to make with this is that these were not patients with two or three joints, as illustrated here these had 25 tender joints, 18 swollen joints. These were patients with long-standing psoriatic arthritis who had significant disease. I wonít give you numbers, again not to steal the thunder from later this week, but to point out that if you could mirror the clinical results that weíve seen with rheumatoid arthritis you can imagine thatís what you will see with the psoriatic arthritis trial. Not only did it improve psoriatic arthritis, there was evidence that it improved the skin lesions as well.

I think the conclusions are fairly uniform and standard that we know etanercept is now approved in the United States and now in other countries for adult rheumatoid arthritis. In the United States itís approved for juvenile rheumatoid arthritis also. Itís safe and well tolerated. Over 1,700 patients have been treated in clinical trials. To date in the post marketing in the U.S. over 50,000 patients have received etanercept. It can be used alone or in combination with methotrexate. Trials are ongoing to look at the safety of the use of etanercept with other drugs that we use today, be it Plaquenil, sulfasalazine, Arava, etc. I think we can fairly safely conclude that itís effective in early rheumatoid arthritis, and more importantly, dramatically slow the radiographic changes. In fact, 75% of the patients have no new lesions over a one year period with receiving just monotherapy with etanercept. The preliminary data with Wagnerís and psoriatic arthritis is very encouraging and I think we will wait for further studies to look at this in a more rigorous fashion. I think also, clearly, etanercept and other TNF inhibitors have raised the bar for which new therapies, be they combinations of currently used drugs or new biological therapies, the numerous pathways, the bar has been raised to compete with this so that we can either beat them or equal them or some combination.