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Investigational Therapy:
Genmab A/S recently announced that HuMax (TM)-IL 15,a human monoclonal antibody that targets a cytokine known as IL-15,demonstrated
potent activity in arresting inflammation in a preclinical trial study. HuMax IL 15 was shown effective in neutralizing IL
15 activity in various cellular models,as well as mice engrafted with inflammatory tissue from RA patients.
According to a press release from the company,IL 15 is an important disease target because it is an immune system signalling
molecule that appears early in the chain of events that ultimately leads to inflammatory disease. IL 15 induces both the production
of TNF alpha, another cytokine that has shown to play a pivotal role in inflammation,as well as the recruitment of inflammatory
T cells. These T cells in turn promote the production of more IL 15,and the cycle escalates.
"HuMax-IL 15 may be the first of a new generation of anti-inflammatory agents that work via a unique 3-prolonged approach,stopping
both mediators of inflammation and neovascularisation", said Professor Jan G.J.van de Winkel,Chief Scientific Officer
of Genmab.
The study's authors explain that inflammatory diseases where IL-15 plays a role include arthritis,inflammatory bowel
disease,celiac diseases and psoriasis. Il-15 is also involved in the development of new blood vessels, or neovascularisation,that
can support both inflammation and cancer. Genmab in collaboration with Immunex Corporation,is currently preparing HuMax IL-15
for human clinical trials,which are expected to start,later this year.
Enbrel "absorbs" excessive TNF. Remicade is called a monoclonal antibody,meaning it is a protein against TNF where
it sticks to TNF like a magnet would stick to a piece of iron. It's made,however,with a mouse part,and a human protein is
added to make it less allergic or immunogenic. So it works a bit differently,and it has the possibility that that one could
be allergic to the mouse part of Remicade. But,giving methotrexate,with it,decreases the reaction. Chimeric means it's
made of two animals,one is mouse and the other is human.
Standard therapy today is early intervention with either a biologic, arava, or methotrexate. Every drug has possible
side effects. One can't drink alcohol with mtx because of liver concerns,and other problems. It can affect the kidneys on
rare occassions,it can affect the bone marrow on rare occassions and some patients may encounter mouth sores or in the nose.
Biologics are quicker acting,and has less side effects. MTX requires more monitoring,then say,Enbrel.
Biologics agents seem to show less x-ray damage down more than MTX. In a Enbrel trial of early RA patients it showed
faster response and better response,but the response was better for Enbrel (-ACR response in patient with early RA) In the
longer term the ACR response was approximately + 10 % more efficacious in the longer term.
At the Albany Medical Centre it has been shown that Arava can be combined with the biollogics safely. Kineret will
probably be used in patients who are not quite doing as well on either one of the biologic agents such as Enbrel and Remicade
or methotrexate.
In placebo contolled trials,meaning the patients and the doctors don't know if the trial participants are getting
methotrexate or a placebo. (sugar composition). comparative studies such as comparing head to head,clinical trials with data
that have been published,show that 40 % of patients do not respond to methotrexate. Enbrel has a little better response and
more likely to work then MTX.
Reserchers combined anakinra or Kineret with Enbrel,and there was a increased risk of infection. They are studying
if that's dose related or how to adjust the dose so they can be used safely. The combination is not a standard recommendation,currently.
Mixing Kineret with MTX or with Leflunomide (Arava) has been show to be efficacious and safe in certain patients.
Minocycline is an anti-biotic that has shown to be effective in treating patients with early,very mild arthritis,but
most rheumatologist will skip minocycline,and go to MTX or a biologic for patients with long-standing or severe rheumatoid
arthritis. There have been 59 cases of lupus induced by the use of this medication in the U.S.
Methotrexate is the "gold standard" currently in North America. SSZ used previously more in Europe is being used
more often. Biologics is a wonderful drug for those not respondent to MTX. But cost,is the main current limitations. We do
not have a 10 year long term history regarding biologic therapy like we do on methotrexate.
It is only in the late 90's that full-dose-subcutaneous injection was commonly introduced as being more efficacious
and with lesser side effects then the pill form. The use of methotrexate is not "dead" in North America.
DE27 (Adamilumab),Humira has a feature of easier administeration. It has recently,recieved FDA approval. Scientists
are working on a biologic that can be administered in pill form. Many future studies are being conducted.
When rheumatologists in this country were surveyed in 1999, 47% of them viewed combination DMARDs as appropriate initial
therapy, and 46% of that group had used combination DMARDs for more than 30% of their patients. Aggressive therapy, usually
in combination, may be appropriate for some patients.
That is counterbalanced by a second survey of Canadian and US rheumatologists in 1996, where there was some preference
expressed for a single agent, if possible, in the treatment of rheumatoid arthritis.
With our new drugs, we have changed our vocabulary and our goals when we think of treatment for rheumatoid arthritis.
Our goals are: no constitutional symptoms, returning to work, minimizing the impact of this disease on daily living, and changing
the course of disease progression. We have made our biggest leap in the last several years with discussion about slowing,
stopping, and perhaps even reversing this previously relentless chronic disease.
Ideally, you would like a drug that is effective not just for symptoms, but one that inhibits disease progression, has
that efficacy sustained over long periods of time, and is safe and well tolerated with minimal monitoring required. We would
like that to be simple, perhaps monotherapy.
Rheumatologists are moving from that first treatment paradigm to this. Our current approach still may be initial treatment
with traditional DMARDs, but then quickly adding drugs, including a biologic agent. That evolution emphasizes early aggressive
treatment, biologics, monotherapy if possible, or combinations for non- or partial responders, and the potential to reduce
or discontinue our previous drug.
What is the paradigm change in terms of therapy for rheumatoid arthritis? In the last few years, we understand the severity
and the nature of rheumatoid arthritis more than we ever have. What are those paradigm shifts? (1) we're using disease modifying
antirheumatic drugs (DMARDs) earlier; (2) we're using aggressive methotrexate therapy; (3) we're using combination therapy;
and (4) we're using biologics.
In terms of early DMARD use, there are 2 issues that most physicians want to address. If I use a DMARD early, will it
make a long-term difference to my patients? And, if I use a DMARD early, will I have a better clinical response? The concept
that initiating a DMARD early may have a longer-term benefit on the patient. Are there any data to support that? There are
at least 2 studies to suggest it.
The first is a study by Lard. He took a group of patients who, within 2 weeks after presenting with their diagnosis,
were started on a DMARD. He took another group of patients and waited a mean of 4 months and then started a DMARD. The delay,
on average, is about 4 months. These populations weren't exactly matched, but they were pretty closely matched.
If you look at the radiological outcome, the Sharp score, those patients who were treated early had a reasonable reduction
in Sharp score, whereas those patients who were only 4 months delayed on average had quite a significant increase in Sharp
score over time. That suggests earlier treatment will have a long-term benefit.
The second study has to do with disability outcomes. This study by comes out of British Columbia. They did a hydroxychloroquine
(Plaquenil) trial. They did a 9-month, double-blind, placebo-controlled trial. At the end of 9 months, they put the placebo
patients on Plaquenil. They watched the patients who got Plaquenil at the beginning of the study, and watched those patients
receiving Plaquenil 9 months later, ie a delay, to see whether, long term, there would be a difference.
If you look at improvement in those patients who got Plaquenil at the beginning, in terms of disability, there is a 57,
58, and 60 in standard deviation units. The patient population that started 9 months later, out to 33 months later, didn't
match their counterparts. They still had more disability after 3 to 4 years and were not up to the base of those individuals
who started on Plaquenil initially. Aggressive, early therapy could make a long-term difference. We've seen it radiologically
and in terms of clinical outcomes.
What about methotrexate? What about better response to DMARDs in early versus late disease? If I use a DMARD early, will
I have a better response than late? There are not a lot of data to support that. I'm going to give you 2 pieces of data that
are certainly suggestive, but not definitive.
One of these pieces of data comes from the trials with etanercept. They looked at the Stanford Health Assessment Questionnaire
(HAQ) outcomes, the disability outcomes, in patients in the Moreland trial, which was monotherapy late disease, an average
of about 10 to 12 years of disease, versus the outcomes in the Early Rheumatoid Arthritis (ERA) trial in patients who were
treated with under 3 years of disease. Other than disease activity, for the baseline outcomes of tender joints, swollen joints,
etc, they were comparable.
Investigators had 2 comparable populations, 1 early, 1 late, and they asked the question: Using the same dose of etanercept,
do you have a better response? These data show, in the ERA trial, there was a difference between these 2 populations, a better
improvement in HAQ if you treated early.
The second study is a meta-analysis. This is a study by Anderson. It's probably the only study done in terms of asking
the question, "Earlier treatment, better response?" This is published in Arthritis and Rheumatism.
There were various DMARDs used. They looked at Plaquenil, azathioprine (Imuran), and methotrexate. They even looked at
Prosorba (protein A-based extracorporeal immunoadsorption, silica).
The concept is, if you treat people with a short disease duration, regardless of their treatments, in general,
your sedimentation rate is improved, your swollen joint count is improved, and your tender joint count is improved. This is
the proportion of those people who are improving by at least 20%.
If you treat them late, if they're treated at 5 to 10 years, there is a significant difference. Suggestive, but not definitive,
data indicate if you treat earlier, you're more likely to have a response.
What about aggressive methotrexate dosing? Are there any data to say that higher doses of methotrexate make a difference
versus lower doses? Dan Furst did a study. He asked the question whether 20 mg of methotrexate over 14 weeks is any better
than 10 mg over 14 weeks.
Here is the percentage of patients with American College of Rheumatology (ACR) 50 and with improvement of at least 50%.
The 20-mg dose improved more at tender joint count, swollen joint count, global joint count, and activities of daily living
(ADLs) relative to 10 mg.
These data say higher doses work better than lower doses, that 20 mg is better than 10 mg. The median dose of methotrexate
used about 3 years ago, when they did a pharmaceutical survey in the United States, was 11 mg. Another study that suggests
the possibility that methotrexate works well is the Early Rheumatoid Arthritis trial. We think about etanercept as one of
the gold standards.
Can we take methotrexate, which is our gold standard, raise the dose in 2 months to 20 mg, and compete with etanercept?
In the first 4 months, you don't compete. To an extent, etanercept worked quicker. By 12 months, the 2 look almost identical.
There is only a 5% difference between etanercept and methotrexate in terms of clinical outcomes at 1 year. These are very
good outcomes. Most of the other disease modifiers and biologics aren't going to beat methotrexate.
So why use it? Or, why not use it? Here is the concept. Radiologically, at 2 years, there was a minor difference between
etanercept and methotrexate. The Sharp score point differences were about 2.
However, it's clear that, over time, radiological outcomes are linear. It was thought to be only 6 years, but now we're
talking 15 to 20 years. The concept is, if these 2 curves continue to diverge, by 5 years, there is going to be a 5 Sharp
score point difference and at least that from then on.
How long does it take to notice a difference, radiologically, in terms of change in Sharp score? Nobody knows, but I'll
give you a number anyway. About a 50 Sharp score point difference and your grandmother can tell the difference between those
2 x-rays.
Therefore, if it's 5 years, it doesn't take very long for those 2 x-rays to be different. If you continue methotrexate,
you will have different x-rays than if you were on etanercept.
Over time, the tolerability isn't as good with methotrexate, so that 74% of the patients stay on etanercept for 24 months,
and 59% of the patients stay on methotrexate. There is a difference between the two. Methotrexate makes some people feel sick.
Etanercept makes them feel good. If the cost would come down, everybody would be switching to etanercept.
What about combination therapy? There are 3 ways to combine DMARDs. You can add a DMARD in those partially responsive.
That's called step up. We can use them in parallel from the beginning, or we can use step down. We can use multiple DMARDs
at the beginning and, as the patient responds, keep removing DMARDs until you're back down to baseline, maybe with monotherapy.
That's the induction and maintenance concept.
I'm showing you one piece of data. You've seen lots of add-on therapies, because that's the way the trials are being
designed. The step-up therapy here is leflunomide. In patients who are partially responsive to methotrexate, the combination
is a 51 ACR 20 compared with methotrexate alone, which means you continue on it. There is quite a difference. There appears
to be a clinical added benefit to adding leflunomide in patients who are partially responsive to methotrexate. These are some
data that suggest combination therapy is not bad.
What about parallel design? Two studies recently asked the following question: At the beginning, if I initiate methotrexate
and sulfasalazine, will it be better than either alone? Two studies say no. Initiating sulfasalazine and methotrexate at the
same time is not better than either methotrexate or sulfasalazine alone.
These are data using the Disease Activity Score (DAS) and the ACR 20 scores. What about triple therapy? Jim Ardell added
triple therapy at the beginning and asked whether it was better than Plaquenil, sulfasalazine, or methotrexate alone. He had
striking results. The triple therapy at the beginning was much better than the others.
There were a couple of problems with the study. It was pretty long. There were long-duration patients, about 10 years.
The number of patients who were methotrexate naïve was quite considerable, and most of the patients failed about .9 DMARDs.
It's an unusual population, but these studies were done a number of years ago when methotrexate wasn't on everybody's
"radar screen." It's still an unusual population. This study is critical to be reproduced in early rheumatoid arthritis because
it says that the toxicity wasn't any different whether you were on triple, double, or single therapy.
There are a couple of open-label trials. There is a triple therapy trial -- methotrexate, sulfasalazine, and Plaquenil
versus methotrexate and sulfasalazine, or methotrexate and Plaquenil. It was triple therapy versus double therapy versus single
therapy. The single therapy was methotrexate.
They showed triple therapy worked quite well. The problem in this study is they used methotrexate at low doses up to
15 mg. I don't know that triple therapy is better than high-dose methotrexate. I don't think we'll ever see the study.
This is another trial. In this trial they used combination therapy along with corticosteroids versus corticosteroids
and sulfasalazine. It was actually quadruple therapy versus sulfasalazine, plus or minus cortisone. You didn't have to add
cortisone. The results were very good.
The combination therapy was excellent. The problem is their comparator was sulfasalazine and I'm not sure this combination
is any better than high-dose methotrexate.
There is step-down. The key trial for step-down was the COBRA trial (comparison of combined step-down prednisolone, methotrexate
and sulfasalazine with sulfasalazine alone in early rheumatoid arthritis). It was high-dose steroids for a short period of
time and then eventually tapered off.
They used a methotrexate combination, and a sulfasalazine combination. All triple therapy was compared with sulfasalazine
alone. Notice the clinical results. Patients on triple therapy did extremely well until you stopped the prednisone. Then they
came back to the baseline. They came back to what sulfasalazine alone looked like. After you dropped the steroids, they looked
clinically alike.
The only difference was a significant difference in the radiologic outcomes when you added low-dose methotrexate
along with sulfasalazine, and the prednisone versus sulfasalazine alone. This is triple therapy slowing progression relative
to sulfasalazine. At 1 year, the patients on sulfasalazine were allowed to go onto any therapy they wanted.
Over the next 5 years, those patients on sulfasalazine never caught up. That may have to do with the DMARDs they went
on, but the sulfasalazine group never caught up to the triple-therapy group. At this point, remember, you're only on sulfasalazine.
You've already stopped the prednisone and the methotrexate. It's an interesting concept that with early aggressive therapy,
tapering off "the bad guys," and leaving a simple drug on, you may end up with a significant difference radiologically.
Biologic therapy says that if you fail methotrexate and you add a disease modifier, like a biologic, you have good data.
There are good ACR 20s and 50s in combination: etanercept versus methotrexate.
With infliximab you have to use methotrexate, good data. Anakinra (Kineret) just came on the market recently. What
you see, again, are reasonable data.
These time courses are a little different. You can't compare study with study but, in general, it says if doctors add
a biologic to those patients partially responsive to methotrexate, they have additional clinical benefit. This is not a positively
established fact.
In these trials, you never had the biologic arm alone. You had the methotrexate arm. You had the combination arm. But,
you never had the biologic arm. How do doctors know that you really need methotrexate?
There is an uncanny concept with the ACR 20 outcomes. If you used etanercept as monotherapy, the ACR 20 was 60. If you
used it and added methotrexate, the ACR 20 outcome was 71, not very different.
Leflunomide as monotherapy, the ACR 20 outcome was 46. In those patients who were partially responsive to methotrexate,
it was 46.
If you look at anakinra (Kineret), it was 38 by monotherapy, and adding methotrexate, it was 37. You've got to wonder
whether you really needed the methotrexate if those numbers look alike. Those are the data. It's food for thought.
What's new? Scientists have made great gains in terms of the clinical and radiological outcomes with tumor necrosis factor
(TNF) antagonists. The next new agent to come out in terms of TNF-Humira (Adalimumab). This is a fully human anti-TNF monoclonal
antibody with a half-life of about 2 weeks. It fixes complement.
It's able to lyse cells like infliximab. It kills those cells that actually make TNF. It was given subcutaneously once
a week as monotherapy. The results were quite good. The ACR 20s were comparable to anything else we've seen, around 55%. The
ACR 20s were about 25% or 30%. That is good. This is once-weekly subcutaneous administration in a severe population of patients.
What happens if I have a partial response patient population on methotrexate? Using an average dose of about 16.8 mg,
patient disease duration was 12.3 years.
What happens when you add subcutaneous Humira (DE 27-formerly )every second week in those patients who were partially
responsive? ACR 20 is about 65%. Reasonable. ACR 50 at the 40-mg dose was quite high at 53%, and ACR 20 was 26.9%. This value
was higher than we see in most studies, but notice the 80-mg dose was slightly less, in terms of efficacy, than the 40-mg
for reasons that are unclear.
This study was not powered to tell the difference between doses, so we still don't know what the minimally effective
dose is. At least we can say there is good benefit if you give subcutaneous D2E7 every second week.----Keystone.
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