Terry...fyi
Tysabri: The inside story
06 March 2005
On February 17, Elan and its partner, Biogen, announced promising
results from a two-year trial on their multiple sclerosis (MS) drug,
Tysabri.
Within days, they learned of a fatality and a second case of viral
symptoms from patients using a combination of Tysabri and Biogen's
Avonex drug.
Lars Ekman, head of research and development of Elan, talks about the
countdown to the suspension of Tysabri by the Food and Drug
Administration.
Lars Ekman: There was one confirmed case of the disease, progressive
multifocal leukoencephalopathy (PML), induced by a virus that
appeared in one of our patients.
Eamon Quinn: When did that come to your attention?
LE: It came to our attention after we announced the [results of] two-
year data.
The information came to Elan via Biogen. These adverse advents are
handled by Biogen. They have a specific process, and in the end, they
inform us, and that came to our attention after the release of our
two-year data.
EQ: How big was that study?
LE: Out of a total of 3,000 patients who had been treated.
So, that is one case out of 3,000 patients [in North America].
There was one patient who was confirmed and then there was another
one who is suspected. But we are not yet able to get any confirmation
on that patient because, in all honesty, they are not able to find
the virus or the right pathologies.
We do not know what that other case is. But we have one case.
EQ: Where is that case?
LE: We do not [disclose that] for confidentiality reasons . . . it is
somewhere in the western United States.
[The second case of PML was confirmed after the interview]
EQ: Were all 3,000 on the combo Tysabri and Avonex?
LE: Out of 3,000 of the total patient population that has been on
Tysabri, there is 558 who have been on this combo therapy. They have
been on the combo therapy for two years or more, between two and four
years.
EQ: This didn't appear before November, before the FDA approved
Tysabri?
LE: Oh no. You have to remember we had data on one year with very
strong efficacy [showing] outstanding results and safety features.
The two-year data also showed strong safety features.
It is important that you remember that every therapy has some severe
adverse advent. That you do have some adverse advents is an
integrated part of an effective therapy.
In Europe and the US, we have many thousands of patients with MS who
have today failed current treatments. And those patients will either
die or be crippled by their disease.
So what we are trying to do together with the FDA is two things. We
are trying to identify the prevalence, so we can tell the medical
community how frequent this is, what the risk is.
The second is how can you diagnose it and how can you treat it,
because if you have an adverse advent, you want to know what to look
out for.
Because you can then focus on whether this is a severe case of MS or
whether it is this PML situation. And if you find an adverse advent
how can you treat it.
EQ: What happened after February 17?
LE: We immediately forwarded the information to the FDA, and it
entered into the FDA system. We contacted the FDA with both a written
and a verbal communication. And in the week that followed, we
together with the FDA tried to gather more information about the
patient.
We discussed various actions. I have been 25 years in the industry
and I have never experienced a situation where you stop distributing
a drug for one patient.
EQ: Were you shocked by the decision?
LE: Last week [to Monday, February 28],we had a number of
conversations with the FDA, and I think that the political
environment and the sensitivity to the management of adverse advents
have changed drastically in the US at this point.
I think that the FDA had a desire to act promptly. We and the FDA,
said: ¡°Let's take the most conservative action we can think
of.¡± We
decided to stop dosing the patients in the trial, and temporarily to
suspend dosing the patients.
EQ: With combo or altogether?
LE: We discussed firstly only to do it with combo.
But we jointly decided, we said let's pause and then investigate all
patients so we know exactly what we are talking about.
EQ: And that decision was taken when?
LE: That decision was taken at the end of last week. I do not want to
go into the details.
We met both face-to-face and in various phone calls with the FDA many
times last week. We jointly decided that it was the right action to
take and that was then immediately executed.
EQ: You stopped the trial over the weekend, did you?
LE: Yes. That is correct. We thought to take the most ethical action
we can, because we are so convinced that this drug has exceptional
value for MS patients (and) Crohn's patients and also we as a company
wanted to take the high road. Let's take the most ethical action we
can in order to learn more.
It was also clear in the conversation with the FDA that this was a
matter of months.
Once we have the material we will jointly review it and decide when
we will bring the drug back to the market.
Bringing it back to the market would also [involve] bringing the
information that we have learned in this investigation. Then, we will
be able to write on the packages that the prevalence of this
phenomenon is such and such, and this is how you should diagnose it.
We would then have done everything possible to help the MS patients.
EQ: Were you surprised [following announcement of the two-year trial
on February 17] when you heard these results?
LE: I was personally informed two and half days after the
announcement. Our safety people got the signal about 36 hours after
the announcement. I was personally informed on the Sunday after the
announcement of the two-year data.
EQ: Sunday February 20?
LE: That is correct. We do not have the record when this information
came to Biogen.
We can only say when this information was forwarded into the Elan
system.
There is a defined operating procedure. You cannot just pass on
information. You have to go through a number of steps. You have to
validate the information. On February 17, we announced our two-year
data. I was personally informed on February 20.
EQ: How can it happen that a combo (therapy) has a reaction?
LE: In the one confirmed case, you cannot say with 100 per cent
certainty that it is combo alone. We think that it is related to
combo, but we don't know that.
If you have two immune modulators in combination, you may get an
effect that you can't predict using one drug by itself.
So, we do not know at all whether there is a causality between the
drug and this side-effect. All of these questions need to be
addressed.
EQ: And the other case?
LE: The other case was a patient of a similar age in their mid-
40s.The patient was on the dose for over two years and documented
itself in symptoms that suggested that it could be PML.
Then an investigation started doing all the necessary tests on the
brain and the cerebral spinal fluids.
EQ: The communication after February 17 up to last Monday. Is that a
normal time period?
LE: I think it is exceptionally fast. I think from the time when
companies notify when they have done their investigations and when
they have been to the FDA, in many cases, the turnaround time from
notification to action was about ten days. It is exceptionally fast.
Normally, you would have to have a much longer period to investigate
what is really happening. It is a difficult trade-off, because you
have to think of all those patients who are benefiting from the drug.
MS is a disease which can lead to disability and death. It is not an
easy decision. This is not a pain drug. This is a drug that prevents
a severely-disabling disease.
EQ: Can those 3,000 be put on another drug?
LE: It is too early to say how they are treated. They may be put on
Tysabri when it is reintroduced. We will talk to the FDA about when
it can be reintroduced. There will be a number of interactions with
the FDA in how we are going to manage these patients.
EQ: What happens now? Is the second case key to this process?
LE: No. Even if we have a third case, it is not key. What is key is
to go back into all the information we have. We have these brain
scans on the patients. Those scans will be reanalysed.
We will also be taking new scans on all the patients and we will be
doing a clinical work-up on each patient.
When all of that is done ,we will have a good understanding whether
there is another patient or whether this is a single case.
Together with the FDA, we will then be able to say how can we inform
the patients, how can we inform the physicians and when is the
appropriate time to bring the drug back to the patients.
We, as well as the FDA, have a desire to do so. The FDA on its
website took the unusual step of claiming that this was a very
important drug for the MS patient. It was eager to resolve this as
fast as possible.
I want to point out that the FDA has not suspended our licence to
market it. The FDA has not taken any legal action. We still have our
licence. This is by no means a legal action by the FDA.
EQ: Is it like the Alzheimer's setback of a few years before?
LE: No, it is not. That was a very, very different situation. This is
a drug which has been tested in patients for five years altogether.
It has gone through thousands of patients.
These are the biggest MS and Crohn's trials done ever in the history
of medicine.
They have all revealed exceptional results and have a strong safety
record.
EQ: Obviously, the FDA is not going to do something rash?
LE: What Kelly Martin [chief executive of Elan] told the market is
that our goal is to bring the drug back in the third quarter. That
remains our goal.
EQ: If the 3,000 test is suspended, talk me through what you need to
do to satisfy that everything is safe by the third quarter?
LE: The process is that we are having meetings with various experts
on this [PML] disease. We are conducting a programme with the FDA
which includes a new medical assessment of all the patients - all the
3,000 patients who have been treated with Tysabri.
EQ: Will Tysabri for use in Crohn's and rheumatoid arthritis be
delayed? You were to do a big trial on one for rheumatoid arthritis
this year?
LE: For Crohn's, we have done the last study. We are currently
analysing whether we can close that study and if so, we will have all
the data, and the Crohn's indication would not be affected at this
point.
We have already filed in Europe. The Europeans have all the
information they want and need.
Assuming we can close that trial - we are doing the bio-statistical
analysis as we speak - the Crohn's trial should be on track.
This specific trial has about 500 patients. In total, we will have
more than 1,200 patients on the Crohn's drug across Europe and the US.
We have previously said that we would aim to file, if the data
supports the filing, by mid-year. If we can close the trial, we would
be able to stick to that timeline.
EQ: And with rheumatoid arthritis, you were planning a robust trial?
LE:The Phase II study is being analysed right now. I do not have the
details myself. I assume we will have some delays.
I do not know whether it is three months or six months.
But I do not think that the basic facts have changed.
There will be a few months delay.
EQ: What are your feelings on the combo? Are the problems caused by
the combo [of Tysabri with Avonex]?
LE: I think it would be unprofessional to speculate on this one case.
We do not have the data to support that one way or another.
Source
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