Center for Drug Evaluation and Research




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There was improvement in quantitative measures in all the ten patients, who were studied in this and there were no serious adverse events. We enrolled 22 patients who participated in pharmacokinetic studies of the slow released formulation in an open label safety study. And the treatment exposure in those 22 patients ranged from 6 to 42 months. There were a total of 52 patient years of experience in this group. There was long term efficacy in 16 -- that is, greater than two years of efficacy in 16 of the patients.

There was one grand mal seizure, which occurred after the patient had been treated for 24 months. Now, it was mentioned before that the major side effect of 4-aminopyridine is seizures. There is in vitro evidence suggesting that aminopyridine treatment increases both inhibitory and excitatory transmitter release in hippocampal neurons and in other areas.

That is likely to be the underlying basis of epileptogenesis. Seizure induction is a dose-related effect in animals. The early experience with this was in an outbreak of botulism poisoning in Birmingham, England. 4-AP was given intravenously and two patients in that group had seizures and drug levels at the time were estimated in the range of 35 to 90 nanograms per ml in one patient or 140 to 475 in the other.

There have also been cases reported by poison control in New York. A couple of these were reported in the literature and in one a drug level was available and it was 136 nanograms per ml.

In the concentration controlled trial that I already mentioned, the level in the patient, who had a seizure was 104 nanograms per ml. In the Dutch open labeled study, which I mentioned before, there were two seizures, but serum levels were not available in those patients. It has already been mentioned that there was a U.S. multi-center trial, which has not been fully reported. Three patients in that study had seizures.

The drug levels coincident with those seizures were 47, 7 and 140 nanograms per ml with the 140 nanograms per ml apparently related to an accidental overdose. There are also many anecdotal reports of seizures in patients taking various forms of 4-aminopyridine and I guess to clarify from the compounding pharmacies, you can get either an immediate release formulation or you can get what is called the slow release formulation, which is basically 4-AP, mixed with carboxymethyl cellulose.

I guess I could add at this point as an anecdote that in our open label safety study, we had to terminate treatment last summer and 11 of those patients continued or were switched over to compounded slow release 4-aminopyridine and one of those patients had a seizure last fall after about three months on treatment. This is somebody who had not had a seizure in over three years of treatment with the other slow release formulation and then was rechallenged and had another seizure after several weeks on treatment and that patient has now been stopped.

Another patient, who I think Ron Cohen will mention, is currently in the hospital in Frederick, after presenting in status epilepticus. So, we had a rather disappointing experience in our patient group switching them over to the compounded drug.

In conclusion, epipletogenesis, I think, is the most serious toxicity that has been demonstrated. Seizures appear to be serum concentration related, but it is important to realize that the seizure threshold appears to vary quite widely from individual to individual. The toxic, the therapeutic margin, may be very narrow in some individuals. The overall risk of seizures in MS patients, who are appropriately dosed and carefully monitored, is probably under 5 percent, which is comparable to the risk that was found with beta seron(?) treatment, which is a currently approved treatment for MS.

Then the last transparency, 4-AP may produce a modest improvement in some symptoms in some MS patients. For patients with no alternative treatments, these improvements may be highly valued. The efficacy of 4-AP in MS has not been proven in a large, well-designed trial.

I would be happy to take questions.

DR. JUHL: Questions of clarification?

Dr. Gilman, Dr. Katz.

DR. GILMAN: Chris, can you give us some anecdotal idea of what these patients were like on drug? They improved on the functional scales, but what does this really mean translated to the individual patient? Was the patient able to walk on drug and not previously able to walk? Or was walking greatly improved so the quality of life was improved? What did it do?

DR. BEVER: Okay. I used the term "modest" in the slide because we are not seeing the Lazarus effect, where a patient is non-ambulatory and you give them this drug and they are walking. We have had one patient like that and Andrew Goodman has had one patient like that. But those are patients, who were sort of poised on the brink of just having lost a function and if you gave them back 10 percent, they would be able to do much more.

Typical would be improvement in strength and improvement in fatiguability and endurance. For those of you who don't deal with MS patients a lot, although we speak of this as a disease, a neurologic disease, one of the most disabling symptoms is the fatigue that goes along with the neurologic impairment that patients have. I think if you talk to a broad range of patients, who have been on this drug, that would be the main thing that people would report to you; that is, the woman who is at home is able to do more housework, is able to get up the steps.

We have an example of a patient here, who could walk with assistance around the house and on 4-AP was able to walk in the neighborhood and get out and just in many cases be able to do a full day's worth of activity; whereas, they couldn't without this drug.

DR. LIEBMAN: For your patients who needed a compounded medication, who compounded it? Do you know?

DR. BEVER: I do not direct patients to a particular compounding pharmacist and I can't tell you which pharmacist provided this drug. I have a list of about a dozen pharmacies and I tell patients to call them and find out what their prices are for what they need and go where the price is best. But maybe that is bad advice in retrospect.

DR. JUHL: Dr. Katz was next and then Dr. Sellers.

DR. KATZ: I am interested in your conclusion that the seizures are concentration related. I am just not clear on what you mean. Apparently, seizures occurred at the concentrations from 30 to 140 or thereabouts. I am just wondering how you come to that conclusion or what you mean by it in some sense.

DR. BEVER: Okay. My thinking is that a given patient has a threshold level above which they will have a seizure and that if your drug level is below that, they will not, but that the level at which you can induce a seizure varies from patient to patient and the reason -- I mean, this makes sense to me in terms of MS because we have a disease, which is randomly causing inflammatory lesions in the brain. Some of those lesions are going to be closer to cortex in some patients than lesions are in others.

There are actually a couple of anecdotal cases of people, who had been doing well on 4-aminopyridine, who had seizures and we did on one of our patients and another patient that I am aware of had MRI scans, which showed that they had cortical lesions at the time of the -- that were new, basically, found after the seizure occurred and were not present on earlier MRI scans, although we don't know exactly --

DR. KATZ: So, you think there is an interaction between disease location and propensity to have a seizure with treatment? In other words, you have to have a near cortical lesion to have a seizure with this?

DR. BEVER: Well, no. We can make a seizure in a normal person. So, it can't be just that simple. But I think that if somebody has cortical lesions, that probably increases the likelihood of their having seizures.

But I think -- I mean, really what you want is good, titrating up people to when they have a seizure so that I could say the threshold in you was this level and in me was some other level, we don't have data like that.

DR. SELLERS: You are touching on my question there.

Monitoring of the drug level, how routine is that and what is the availability of having levels done at a lab across the country? I mean, is it something that you have set up in your practice or --

DR. BEVER: Okay. The levels that were done in some of our studies were carried out in the School of Pharmacy at the University of Maryland. Jim Leslie set up an assay. That was done during the period of the concentration control trial and for some time after that. As far as I know right now, the only levels are from Elan and I am not sure of that. There may be another source for them. They can be done, but usually the turnaround time is in a matter of days. It took a lot of logistical support in order to get levels back in three hours, which is what we required for the concentration control trial.

DR. SELLERS: It appears that we are looking at a drug that may have a narrow therapeutic index and in that case, it would most likely require routine monitoring of levels.

DR. BEVER: Well, we have thought about that. The problem is that you have some people who had a seizure at 104 nanograms per ml and somebody who also had a seizure at 44 nanograms per ml. So, I am not sure that therapeutic --

DR. SELLERS: Well, you were mentioning titrating the dose based on levels or based on therapeutic response to the drug?

DR. BEVER: Yes. Practically speaking, we would look at therapeutic response in patients and that is how we titrate it.

MR. TRISSEL: I believe you mentioned that you had several patients in your study who dropped out for some reason that was unspecified and you referred them to a compounding pharmacy. Was there no effort to get the Elan product donated for off-study use for these patients to continue them on?

DR. BEVER: WE went through a rather long and protected negotiation, which ended up in my getting an IND number so that we can do that, but it never occurred. We never got drug.

DR. RODRIGUEZ: How useful it was in cases where a patient had seizure, let's say, to try to prevent the seizure? I am talking about other -- in other words, epileptogenic control. Did you try that in some of the patients that you tried to titrate?

DR. BEVER: Okay. I guess the question is if a patient had seizure on 4-AP, would it be useful to put them on an anti-epileptic drug and then put them back on 4-AP. I guess there are two different aspects to that question. The first aspect is it has been tried, not by us. There is a practitioner in New York City, who has prescribed 4-aminopyridine quite widely and he had enough seizures so that he started putting people on concomitant treatment with anticonvulsants, but from anecdotal reports that I have obtained, he still had patients having seizures, even though they were on anticonvulsants at the same time.

The second issue is that we have actually reported a couple of cases where patients were given carbomazopine for trigeminal neuralgia while they were getting 4-aminopyridine and the patients reported to us without us prompting them at all, I promise, that they saw a decrease in efficacy. Theoretically, if you give a sodium channel blocker, that can undo some of the beneficial effects of the potassium channel blocker.

So, we may be somewhat limited in the drugs that can be used along 4-AP to try to do this. Depacote, valproic acid would be one that has been suggested. That is the situation with the use of anticonvulsants right now.

DR. GILMAN: I would like to follow-up on Dr. Katz's question. I think the advent of seizures in any particular patient is the major concern here with respect to safety. So, the question is, first, do you know whether there is a higher frequency of seizures in MS patients compared to any other group that has tried all this medication?

DR. BEVER: Again, I can't speak in detail about the spinal cord injury studies, which I only know sort of superficially, but my understanding is that they have not had seizures in the spinal cord injury group --

DR. GILMAN: In Lambert-Eaton.

DR. BEVER: In Lambert-Eaton, I am less sure about. Dr. Sanders is here. He can --

DR. GILMAN: I have a communication that I will tell you about in detail later from one of the people at the Mayo Clinic, who did the -- who reported on the 1989 study in Lambert-Eaton Syndrome. They believed that seizures were very rare, as long as you keep the dose under 25 milligrams per day -- sorry -- four times a day. They believe that the blood level, in fact, is key. The question is whether there is a bigger variation in MS patients than in Lambert-Eaton.

DR. BEVER: Okay. Now, they are working with 3,4-diaminopyridine.

DR. KATZ: Yes, I know, and it is slightly different.

DR. BEVER: Our study was mentioned. We had one seizure out of 36 patients, who were each exposed for a month.

So, anyway, to get back to your question, I think that there probably is some difference in the frequency of seizures in different patient populations and I think, again, we are reviewing the evidence in MS. We came up with a number, something under 5 percent, 3 to 5 percent, something in that range. I think that is higher than has been reported in spinal cord injury.

DR. JUHL: Dr. Katz.

DR. KATZ: Yes. I just wanted to make a comment about whether or not an event is rare, as you suggest it might be with 3,4-diaminopyridine in the Lambert-Eaton patient. "Rare," I guess, is in the mind of the beholder. I don't know what the size of the cohort is that -- even though you showed me that -- what the size of the cohort is, but if you have 50 patients, let's say, even if they have that many, and you don't see a seizure, it could still be fairly common and it might have been missed.

So, I just -- sort of as a word to the wise. I guess we will hear about that.

DR. MC BURNEY: Dr. Bever, the patients now that are on the medication, they are receiving it through an IND from a drug company?

DR. BEVER: No. The patients -- I had a group of patients who were in an open label safety study. The open label safety study was terminated by the sponsor. I applied for an IND in order to try to continue to be able to provide the drug to them outside that safety study. We were never successful and I got the IND, but I never actually got the drug.

So, those patients were given the option of going on the compounded drug and that group of 11 patients is the one that I mentioned, where we have had a couple of seizures.

DR. JUHL: When you say you couldn't get the drug, you know, the drug product from the sponsor, the same product?

DR. BEVER: Right. We needed to get the drug from Elan. That is what we were trying --

DR. JUHL: The drug product, the final formulation.

DR. BEVER: Right. And we were never able to get that.

DR. MC BURNEY: And that company is no longer carrying out the studies?

DR. BEVER: No. Elan is still the manufacturer of the study. They licensed the drug to Acorda and Ron Cohen will be talking to you later as a representative of that company.

DR. MC BURNEY: Thank you.

DR. JUHL: Other questions of clarification?

[There was no response.]

Thank you very much.

We will now move to Multiple sclerosis. Sharon Hamm, who is a senior vice president, Research and Development Technical Operations for Elan, to talk about formulation issues related to 4-aminopyridine.

Again, that handout was given to you during lunch, I believe.

MS. HAMM: Good afternoon.

I am Sharon Hamm of Elan Corporation. Elan is a leading provider of drug delivery technology. As a pharmacist, I understand both the art and the interest in compounding prescriptions.
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