Irish Sunday Post / Lars interview
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.
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.
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