Interview with Dr. Isakson, Director of COX-2 Technology for Searle, from MedicineNet:-
MedicineNet is delighted to provide our viewers
with the following exclusive interview with the Director of
COX-2 Technology for the Searle Pharmaceutical Company,
which was responsible for developing and testing CELEBREX.
Peter Isakson, Ph.D., Director of COX-2 Technology
Searle Pharmaceuticals Interviewed By William C. Shiel M.D.
Chief Editor, MedicineNet
January 29, 1999
MedicineNet (by Dr. Shiel): As a practicing rheumatologist
(arthritis specialist), I am well acquainted with celecoxib
(Celebrex) and the COX-2 story. Applications of the drug
and its advantages were major topics at a recent national
meeting (of rheumatologists) in San Diego.
MedicineNet: Dr. Isakson, why should patients be excited
about Celebrex?
Dr. Isakson: I think Celebrex provides a form of
arthritis therapy that is different from what's available
now. Current arthritis anti-inflammatory therapy with the
aspirin-like drugs (NSAIDs) has a high degree of
effectiveness. That is, each of the NSAIDs can treat
arthritis, including the pain, but they also carry along
potential side effects in the gastrointestinal (GI) tract
that can be serious. Approximately 100,000
hospitalizations and 16,000 deaths occur annually in the United
States simply due to the ingestion of the aspirin-like
drugs, and that's a serious problem. Celebrex is targeted
to the COX-2 in a way that leaves alone the other enzyme,
COX-1, and has been shown not to cause the GI ulcers to
anywhere near the extent that the nonsteroidals such as
naproxen (ALEVE and others) or ibuprofen do. So, for the
patient, we think Celebrex will provide the effectiveness
of the currently available therapy without some of the
serious side effects that can occur with the
nonsteroidals.
MedicineNet: More specifically, in regard to the
labeling of Celebrex in the Physicians' Desk Reference, the
risks of gastrointestinal bleeding have been reported in
the lay press as an issue. Can you address that concern?
Dr. Isakson: The part of the label you're
referring to, which is the standard gastrointestinal
warning carried by all NSAIDs, refers to a rate of 2-4%
serious gastrointestinal events per year for people taking
NSAIDs. In fact, the data we collected during a very
careful analysis during a large clinical trial experience,
suggested that the rate of occurrence of these events was
very low in patients taking Celebrex, on the order of 2 in
5000 patients, for a rate of 0.04%. The strength of our
data allowed us to get the F.D.A. to agree to put this
information in as a qualifier to the standard
gastrointestinal warning. We think this qualifier is an
important distinction from all of the other NSAIDs that are
currently available. So I wouldn't look at it as a
concern. In fact, it is quite a distinction to have any
change in the label, especially with regard to that
warning.
MedicineNet: A common question asked by patients
is "how long will it be before I can expect my
inflammation to decrease?" Realizing that various
conditions respond differently, can you comment in a
general sense?
Dr. Isakson: Sure. I think we should talk about
rheumatoid arthritis and osteoarthritis separately. In the
clinical trials with rheumatoid arthritis, a classic
inflammatory disease, the earliest time point for
evaluation, which is typical in a clinical trial setting,
is at 2 weeks. And at 2 weeks, the level of improvement
with Celebrex is essentially achieved and sustained with
further treatment over the 3 month to 6 month periods that
we've reviewed.
Osteoarthritis is not a classic inflammatory disease,
but pain is a characteristic feature of the disease.
Therefore, we initiated, as part of some of our clinical
trials, a program where we evaluated patients using the
American Pain Society questionnaire. This questionnaire is
a new way to monitor pain in a more chronic setting. In
those trials, we observed a significant improvement of the
pain in 1 to 2 days, which continued to improve over the
first week of therapy. From week 1 on, the treatment effect
was sustained at about the same level. I should qualify
that by saying that we were looking at a whole population
of people being treated. It is important to note that the
effects of treatment may vary from patient to patient.
MedicineNet: If a patient needs to discontinue
the medication for a complication, a common question might
be "how long is it still in my system"? Dr.
Isakson, what is the half-life of Celebrex? (The half-life
is the time that it takes the body to naturally eliminate a
drug so that the blood level is reduced by one half.)
Dr. Isakson: The half-life of Celebrex is about
11 to 12 hours which means that it is expelled from the
body within about 2 1/2 to 3 days after discontinuing the
medicine.
MedicineNet: My understanding is that Celebrex is an
indicated drug for osteoarthritis and adult rheumatoid
arthritis. Is it true that the drug has not yet been
studied in children (juveniles)?
Dr. Isakson: That's correct. Our clinical
program was designed for adults, meaning 18 years and
older, so no one under the age of 18 has been in our
trials. We currently have a program ongoing, though, to
assess Celebrex in younger patients, with the idea that it
could potentially be beneficial in juvenile rheumatoid
arthritis. That's where we would like to go next with
Celebrex in terms of arthritis therapy.
MedicineNet: Nonsteroidal anti-inflammatory
drugs are oftentimes used in clinical practice for a
variety of purposes beyond the stated indications as listed
in the Physicians' Desk Reference recommendations and by
the F.D.A. A classic example involves inflammatory
conditions which may be temporary, such as sprains and
strains. At this time can you speak to other uses of
Celebrex?
Dr. Isakson: Celebrex is specifically indicated
for the treatment of osteoarthritis and rheumatoid
arthritis. There currently is no data to support the use
of Celebrex for other conditions. Nevertheless, we do have
trials, either ongoing or soon to begin, in other potential
uses, for example in back pain and sprains and strains.
MedicineNet: Because of the pharmacology of
Celebrex, there might theoretically be a potential for use
of Celebrex in Alzheimer's disease and colon cancer
prevention. Any comments?
Dr. Isakson: Sure. One of the most exciting
aspects of working on this whole COX-2 inhibitor program
has been seeing it evolve from treating the signs and
symptoms of arthritis and then seeing it broaden out into
other areas as we have gained a better understanding of
actually what the nonsteroidals do. There is a very
compelling case for COX-2 being involved in treating colon
polyps and eventually colon cancer, and this, of course, is
a very serious disease and a major medical issue. There is
very good epidemiological evidence that the nonsteroidals
can reduce the occurrence of colon cancer by 40 or 50%. We
have had a very active program in the research area, the
preclinical animal model area, the results of which
supported the notion that a drug such as Celebrex, a
selective COX-2 inhibitor, might have some utility there.
And we're just in the process of completing our first
clinical trial in a patient population that is highly
susceptible to developing colon polyps. We will know the
results of that study fairly soon. Assuming the outcome
will be positive, we'll be potentially moving into other
areas of colon polyp prevention.
We also have a program for Alzheimer's where there is
somewhat less compelling but nevertheless extremely
interesting epidemiological data that suggests that
nonsteroidals, the aspirin-like drugs, might have a role in
retarding the progression of Alzheimer's. The animal model
data is harder to get, there are no good animal models, so
we went directly into a clinical trial, which is moving
along very well. We should know, probably by the end of the
year, whether or not the concept of using Celebrex in the
treatment of Alzheimer's has some merit. And if it does,
that would clearly be another important advance and
potential use of this class of drugs.
MedicineNet: In terms of effectiveness rate
(efficacy), does Celebrex have advantages over other
nonsteroidal anti-inflammatory drugs currently on the
market?
Dr. Isakson: The data that we have obtained in
our extensive arthritis trials, both for rheumatoid
arthritis and osteoarthritis, suggests that the basic
efficacy of a selective compound like Celebrex is roughly
the same as the best NSAIDs, for example, naproxen. Our
original hypothesis was that NSAIDs, in fact, are COX-2
inhibitors, and a specific COX-2 inhibitor, then, should
have the same spectrum of antiarthritic activity as the
NSAIDs, just without the side effects. In terms of the
overall effectiveness for a patient, that may turn out to
be different, because the side effect profile clearly
affects the overall use of the drug and its effectiveness.
Therefore, if you look more at how the patient overall is
able to tolerate the drug and function in their daily life,
there is certainly the potential for Celebrex to have an
advantage over other NSAIDs.
MedicineNet: What are the most common side
effects reported with Celebrex? Among the most commonly
reported side effects according to the current F.D.A.
information were gastrointestinal symptoms. Given that
Celebrex is a COX-2 inhibitor drug, what do you propose is
the mechanism for the development of these side effects?
Dr. Isakson: The top three gastrointestinal side
effects noted in the studies of Celebrex were dyspepsia
(upset stomach), diarrhea, and abdominal pain. Other
reported significant side effects were headache, upper
respiratory tract (breathing passages) infection, and
sinusitis. To help explain these findings, I think that it
is important to understand how trial study information is
collected. A clinical trial setting is not equivalent to
what happens out in the community with a physician and a
patient. In a trial setting, patients are asked to take a
new drug. However, the patients are unaware if they are
receiving the study drug, a placebo, or a standard NSAID.
They are then asked to register any complaints they might
have. And they do. Even in the group given a sugar pill or
placebo, the top three complaints are typically headache,
dyspepsia, and abdominal pain, depending on the exact
wording. And those complaints are identical to what we saw
in the clinical trial with Celebrex--headache, dyspepsia,
and abdominal pain. The only distinction was that we saw
somewhat of a lower incidence of headache with Celebrex. In
terms of these complaints, there was not much of a
difference between the placebo and Celebrex.
Additionally, the study results don't indicate how
serious the complaints are. Another way to evaluate the
severity of complaints is to gauge the number of people who
withdraw from the study because they are having more
troublesome side effects. The rate of patient withdrawal
due to these adverse effects was very low in the trial and
difficult to distinguish from the withdrawal rate seen with
placebo, and was, in fact, lower than what was seen with
the other nonsteroidals. In summary, it appears that any
time you add something to the digestive tract of that
patient population you will get some complaints, and it is
not clear to us yet whether the complaints really reflect
the drug or simply the clinical trial setting.
MedicineNet: The data published by the F.D.A.
strongly supports what you've just said about the placebo
having the potential for side effects. I noticed that 1 out of 5, or
20% of patients on the placebo, developed a
headache! That was very impressive but is probably
consistent with your experience in conducting placebo
studies.
Dr. Isakson: Yes, it is. The other very common
side effect reported was upper respiratory tract
infections, which can develop whether or not the patient is
taking one of these drugs.
MedicineNet: (Aside information for the next
question: Platelets are irregular disc-shaped elements of
the blood which assist in natural blood clotting. During
normal blood clotting, the platelets group together or
aggregate. This aggregation is blocked by traditional
NSAIDs.)
Dr. Isakson, in the published reports, I noticed that
there were five "platelet studies." As a
clinical rheumatologist (arthritis specialist), I can see a
potential for an extremely powerful advantage that a drug
that was strictly a COX-2 inhibitor would have because of
its lack of an effect on blood clotting elements, the
platelets. Can you address that point?
Dr. Isakson: The whole platelet part of the
Celebrex story was very important to us for two reasons.
First, as you allude, there is a potential medical benefit
if a drug doesn't have an effect on the blood platelets.
Second, in terms of establishing a true distinction for
Celebrex, the platelet provided us with the one tissue
source that was easily accessible, easily monitored, and
that we knew was only driven by COX-1. So we had a double
reason for wanting to evaluate the platelet effects very
carefully, which we did in five studies.
We found that even with increasing the dose of Celebrex
to 600 mg twice a day, or 1200 mg per day, we saw
absolutely no effect on platelet aggregation. This dose is
three to six times higher than the full therapeutic dose in
osteoarthritis and rheumatoid arthritis, at what we call a
supertherapeutic, or above therapeutic dose range. By
contrast, the NSAIDs caused a very dramatic effect on
platelet aggregation in those same studies. These findings
were confirmed by bleeding time studies, which are much
more difficult to conduct and have a much higher degree of
variability, but nevertheless were consistent in
demonstrating that Celebrex had no effect on bleeding
time. The results of these studies were very important
for us, again from the medical standpoint, but also in
distinguishing Celebrex as a separate and distinct type of
therapy.
MedicineNet: In a clinical context, patients are
often treated with anticoagulants (blood thinning
medications) either chronically or acutely, for example,
after an operation. What about the use of Celebrex in a
patient who is being treated with the blood thinners,
heparin, Coumadin, or warfarin?
Dr. Isakson: One of the advantages of Celebrex
is its lack of the platelet effect. There wouldn't
necessarily be a concern with taking Celebrex and any of
those agents. With Coumadin, there are additional
potential reactions, both by displacement of protein
binding as well as interference with metabolism.
Therefore, we conducted a drug interaction study between
Celebrex and Coumadin, or warfarin, and found no adverse
effects whatsoever. We have not conducted any studies
directly related to heparin.
MedicineNet: Does Celebrex adversely affect the
liver and/or the kidney?
Dr. Isakson: We've examined possible negative
effects of Celebrex on both the liver and kidney through
our clinical data base and to some extent done some studies
to specifically address the kidney. In terms of the liver,
neither in preclinical or in clinical settings have we seen
anything that would suggest that Celebrex has a deleterious
effect on the liver. In the patient populations we
reviewed, we looked very carefully at liver function tests,
the classical sort of serum evaluations, and didn't find
anything that was distinct from what was observed with a
placebo.
The potential effect of Celebrex on the kidney was of
particular interest, because the NSAIDs are thought to have
negative effects on the kidney, at least in certain
individuals, and in rare instances can precipitate kidney
failure. In examining the overall clinical data base
specifically for effects on the kidney, we found an
incidence of effects that is slightly higher than the
placebo and the same as other NSAIDs. Although this is
nothing to be alarmed about, the effects on the kidney do
not clearly distinguish Celebrex from the NSAIDs, as is the
case with its effects on the liver and blood platelets.
MedicineNet: NSAIDs can have negative inotropic
effects on the heart; that is, they can affect the power of
cardiac muscle and pose some risk in a patient with
congestive heart failure. Have you noticed any effects
with Celebrex related to the heart?
Dr. Isakson: No specific studies have been done
in that particular patient population. We have scoured the
extensive data base for cardiovascular events, and again we
were unable to find anything which differentiated Celebrex
from the placebo. Patients with congestive heart failure
were excluded from these trials, although a few
participated who have the condition, but in general that
was an exclusion. We haven't directly looked at patients
with congestive heart failure, but we are considering at
least conducting a safety study for this group.
MedicineNet: Dr. Isakson, aside from the obvious
advantage that Celebrex has in terms of its decreased side
effect profile generally, are there other specific
advantages for elderly patients?
Dr. Isakson: What we have found in looking at
our data base (we do have a fairly large number of elderly
within that data base), that the number and severity of
complaints, particularly in the gastrointestinal area with
the NSAIDs, increases in the elderly population. I think
that is probably consistent with your clinical practice and
the general thinking. The data for gastrointestinal side
effects with Celebrex in the elderly population do not
appear to be distinctly different from those in younger
patients. So we think that Celebrex will offer an
advantage for the elderly. I also believe that the markedly
reduced rate of ulcer formation noted with Celebrex could
well translate into a sense of less fear in the elderly
taking this drug. The elderly is a group that is already
taking a lot of drugs and they can be uncertain about
medications. So, the peace of mind factor, I think, could
be a major benefit for them.
MedicineNet: In patients taking Celebrex,
whether they are young or old, are there recommended lab
tests that should be monitored clinically?
Dr. Isakson: Nothing that pertains specifically
to Celebrex. Certainly, if the patient has rheumatoid
arthritis and is taking other medications, such as
methotrexate, periodic lab tests would be done anyway, but
nothing beyond what you would use in your ordinary practice
with those patients.
There are some NSAIDs for which
periodic lab testing is recommended, and the fact that lab
testing is unnecessary for Celebrex may indeed be an
additional advantage for Celebrex in clinical practice.
MedicineNet: Are there problems with taking antacids with
Celebrex?
Dr. Isakson: No.
MedicineNet: So if a patient is taking an
antacid, are there difficulties with the absorption of
Celebrex or its beneficial effects?
Dr. Isakson: We saw a slight decrease in the
absorption of Celebrex with antacids, but not enough to be
clinically meaningful. It would not be sufficient to cause
any change in the dose regimen.
MedicineNet: How frequently is Celebrex taken
and is it necessary to either eat or abstain from eating
prior to taking Celebrex?
Dr. Isakson: We think one of the advantages of
Celebrex is the flexibility it offers the patient in terms
of when to take the drug and in what context. For
osteoarthritis, the recommended dose is 200 mg per day,
which can be taken either singly or in divided doses. And,
although we found that the absorption is slightly increased
when Celebrex is taken with a meal (and that's a good
thing), the difference is not enough to alter the dosing
regimen. Therefore, Celebrex can be taken either with or
without meals, whichever the patient would prefer.
Additionally, the 200 mg can be taken either in the morning
or at night. So there's a great deal of versatility in the
dosing.
For rheumatoid arthritis, the recommended dose is 100 mg
twice daily or 200 mg twice daily, with flexibility for the
physician to increase the amount, if necessary for a
particular patient.
MedicineNet: Will Celebrex be more costly than a
current nonsteroidal anti-inflammatory drug (NSAID)?
Dr. Isakson: Although this is not my area, I am
familiar with the pricing of Celebrex. Celebrex will not be
more expensive than current prescription drugs. One of our
guiding principles has been that we think Celebrex is a
valuable medication that should be available to a wide
patient population. Taking this into consideration, our
commercial department priced Celebrex at the lowest end of
the prescription NSAID market and considerably lower,
actually, than some of the newer drugs. So, the pricing is
at a level where if a physician is going to write a
prescription for an anti-inflammatory drug, cost is not an
issue.
MedicineNet: Dr. Isakson, thank you for such a
fine review of the COX-2 story and issues related to
CELEBREX.
medicinenet.com
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