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Agenda Item: 4-aminopyridine

DR. FEENEY: Thank you.

My purpose is to give a brief overview of the aminopyridines. Additionally, we have various specialists here today, who will also speak to their personal experience with the use of the aminopyridines, both 4-aminopyridine and diaminopyridine.

Dr. Sanders from Duke will later talk about the use of diaminopyridine in a rare disorder, -Eaton Syndrome and Dr. Bever from the University of Maryland will hopefully share his experience with the treatment of MS patients with both 4-aminopyridine and diaminopyridine. Then we also have three commercial sponsors, who will talk to you.

Again, my purpose is to provide a brief overview of both drugs, first for 4-aminopyridine . 4-aminopyridine is a potassium channel blocker that can be used to enhance the propagation of action potentials along injured axons and to enhance synaptic transmission. It has been used in patients with MS to improve neurologic function, as well as patients with chronic spinal cord injury.

4-aminopyridine is commercially available as a white to off-white crystalline powder. It is unstable at room temperature if exposed to light and humidity. Special care may be needed for handling bulk material because of potential toxicity if inhaled, absorbed through the skin or swallowed.

There are two reasonably sized controlled trials of 4-aminopyridine in the treatment of MS mentioned in the literature. This first one is published in detail, while details of the second study are not completely available. In this first study published in 1992, 70 MS patients with chronic stable deficits were treated for 12 weeks with 4-aminopyridine or placebo and then crossed over to the other treatment.

At the end of the study, there was a small but statistically significant benefit seen on the expanded disability status scale, a standard 10 point rating scale in MS studies. Also, while 10 4-aminopyridine patients improved by one full point on the EDSS, no placebo patients did so.

This one point change is generally considered to be clinically meaningful. The dose used in this study was 0.5 milligrams per kilogram per day, which for an average adult would be about 35 milligrams per day. We know that during the open label extension study, two of these patients went on to have convulsions.

A second larger study was performed, presumably following up on the positive results already seen. This second study enrolled 161 MS patients in a six week parallel trial. No difference was seen in the number of patients improving on the EDSS at the end of the study.

Approximately 20 percent of patients improved in both treatment arms. The dose that was used here was 45 milligrams per day of a slow release formulation. Several seizures were also seen in this study.

Now, chronic spinal cord injury can be in many ways analogous to stable MS and 4-aminopyridine has been used in spinal cord injury patients also. While this 26 patient crossover study found no difference on its specified primary outcome, a composite endpoint, there were trends in favor of the drug seen on a sensory scale, as well as a patient global assessment scale.

The dose that was used here was 35 milligrams per day, again, of the slow release formulation. Later today, hopefully, Dr. Ron Cohen can talk about a larger, 60 patient study that was performed also in spinal cord injury. Those results are not yet published in the literature.

Here you see the common adverse events that are seen with 4-aminopyridine and I think the same profile exists for diaminopyridine, although with diaminopyridine, you may see more of the abdominal pain and paresthesias predominating. But the two more serious concerns are listed here. One is a realized problem and one is a possible problem that really merits further evaluation before we can say much about it.

Seizures are the major concern with the use of 4-aminopyridine. In our literature search, we found a total exposure across all diagnostic categories of 409 individuals. That would include patients with spinal cord injury, MS, botulism, anything. The individuals were treated with different doses, ranging from 15 to a hundred milligrams per day. Likewise, they were treated with different formulations, varying from immediate release to slow release and peak blood levels would be expected to be lower with the slow release preparations.

But ignoring all those differences, we found six seizures for an overall risk of 1 in 68 for a risk of convulsions.

The QT interval on the electrocardiogram is directly related to potassium currents in the heart. It is strongly predicted that a potassium channel blocker, like 4-aminopyridine or diaminopyridine, would prolong the QT interval and put patients at risk for cardiac arrhythmias that could in some cases lead to sudden death.

While QT interval prolongation has not been reported with 4-aminopyridine or diaminopyridine, we are not sure that it has been adequately assessed in the experience to date. There are two reports that raise concern. Both are with diaminopyridine. The first is the report of a death attributed to MI in a middle-aged patient, newly exposed to diaminopyridine for -Eaton Syndrome.

Unfortunately, the details of that case are unavailable. The second case is that of an older woman with an inadvertent overdose of diaminopyridine. Initially, she had convulsions, but four days later, as she was recovering, she had an unexplained cardiac arrest. Fortunately, she was resuscitated and survived without sequelae.

Diaminopyridine is also a potassium channel blocker that can be used to enhance the propagation of action potentials along injured axons and to enhance synaptic transmission. It has been used in patients with MS to improve function, but its main use has been in the treatment of -Eaton Syndrome.

-Eaton is a rare disease, which can occur either spontaneously or in the setting of cancer, especially lung cancer. Antibodies are produced, which affect the calcium channels on presynaptic neurons. Synaptic transmission is reduced and patients experience muscle weakness and autonomic symptoms. Perhaps only 300 patients are affected in the United States at any given time.

Diaminopyridine is also commercially available as a white crystalline powder. Like 4-aminopyridine, it is also unstable at room temperature if exposed to light and humidity. In 1989, McEvoy, et al., published this report in The New England Journal. The authors enrolled 12 patients with -Eaton in a crossover trial with three day treatment periods. Not only did symptoms improve, but there was good electrophysiologic correlation with the doubling of compound muscle action potentials.

The dose that they used was a hundred milligrams per day. One of their 12 patients had a convulsion after ten months, but was able to continue successfully on a lower dose of the medication.

Donald Sanders, who is here today, recently reported on his ten year experience at Duke University treating Lambert-Eaton patients with diaminopyridine. Roughly half of his 40 patients returned to normal levels of functioning. In his report, Dr. Sanders mentioned an ongoing trial, which, hopefully, we will hear about more today.

Diaminopyridine, like 4-aminopyridine, has been studied in MS patients. Dr. Bever performed a 36 patient crossover study. Treatment periods were 30 days long, with a 30 day washout period. The dose used was a hundred milligrams per day. Favorable results on measures of leg strength were seen in the trial.

Paresthesias and abdominal pain, limited dosing in seven patients and one convulsion was recorded. So diaminopyridine, we have the same two safety concerns that were discussed for 4-aminopyridine; namely convulsions and QT prolongation. For diaminopyridine, we had a total exposure in the literature of 300 individuals.

Ignoring one convulsion that was in a patient with brain cancer and a convulsion attributed to theophylline toxicity, we found three other convulsions, which would leave a risk of about 1 in a hundred for convulsions.

It is because of the risk of convulsions and our concern about QT prolongation with both of the aminopyridines that the Division of Neuropharmacologic Drug Products believes these drugs should not be put on the compounding list at this time.

We believe that current experience with both of the drugs should allow for the accumulation of more data to hopefully improve their later safe use. And as the afternoon goes on, alternative distribution mechanisms that have been proposed will be discussed in more detail.

Thank you.

DR. JUHL: Thank you.

Are there questions on the presentation -- and, I guess, before I get to that, let me welcome Dr. Sid Gilman to the table. Dr. Gilman is the chairman of neurology at the University of Michigan and chair of the FDA Advisory Committee on the same topic.

Welcome, Sid.

Questions for Dr. Feeney?

MS. HOPE: I have one question. Do I understand correctly that there are two of these studies that use this slow release form?

DR. FEENEY: No, I am sure there -- I know there are more smaller studies that have used the slow release form.

MS. HOPE: And this was a commercially available slow release form so that I guess my relation to this is that if this were to go on this list, that then compounding pharmacies would not necessarily be compounding a slow release formulation that was comparable.

DR. FEENEY: That is correct. I would guess that most of the compounded product would be immediate release and Dr. Bever has studied the relationship between C-Max and convulsions. He may talk about that today. He believes that there is a relationship between the two and with the slow release formulation, there may actually be a lower C-Max and less of a risk.

DR. JUHL: Other questions of clarification?

[There was no response.]

Thank you. I am sure we will be calling on you again later.

Next is Dr. Chris Bever of the University of Maryland, professor of neurology.

DR. BEVER: Good afternoon. I have been asked by the staff to discuss our experience working with 4-aminopyridine.

DR. JUHL: By the way, those slides were handed out at lunch to the committee members. There should be a piece of paper that the first slide has Dr. Bever's name on it.

DR. BEVER: And it is my responsibility that they didn't get to you until lunch. So, I apologize for your not having more time to go over them.

I thought I should review just briefly some things about multiple sclerosis. I wasn't sure how much all the members of the panel knew about it.

There are about 250 to 350 thousand cases of multiple sclerosis in the United States. It is a disease that has its peak age of onset in the twenties and thirties. It generally does not significantly reduce life expectancy. So, it is a significant cause of neurologic disability, beginning in young adulthood.

It is a chronic inflammatory, demyelinating disease of the central nervous system. It can follow either a relapsing remitting or a slowly progressive course and it produces a wide range of neurologic symptoms, which relate to the location of lesions within the central nervous system.

Okay. There are treatments for multiple sclerosis and there has been quite a lot of interest in those treatments, but the newest treatments on the market, I would like to point out are preventative treatments, not restorative treatments. So, they do not offer symptomatic relief to patients with deficits from multiple sclerosis.

There are no treatments for some of the most common and disabling symptoms of multiple sclerosis, such as weakness and many patients have multiple symptoms and the available symptomatic treatments are generally effective only on one symptom.

The pathology of multiple sclerosis is one of inflammation with demyelination and accidental loss. Conductional abnormalities are produced by demyelination with swelling of action, potential propagation and blockade of actual potentials in some situations.

There is evidence that some deficits in MS patients are physiologic; that is, not anatomic loss, but physiologic derangement of nerve functioning. That comes primarily from studies of the effect of cooling and warming MS patients; that is, symptoms in some patients improve with cooling and they worsen when patients' core temperatures are elevated.

There are two mechanisms related to demyelination that are proposed for 4-aminopyridine in MS patients. The first is improving action potential duration amplitudes and velocities in demyelinated axons and the second is to increase transmitter release with reduced numbers of axons and synaptic endings.

There were a number of early studies of 4-aminopyridine in multiple sclerosis. The initial was an open label study that was done in the U.K. Then there were a series of partially controlled and partially blinded studies that were carried out by Floyd Davis and Dusan(?) Stephaski(?), at Rush Presbyterial Hospital in Chicago. In these studies, improvement was seen in a variety of deficits in MS patients. It did seem to vary from patient to patient. The side effects were relatively minor in a total of about 59 patients who were treated in these studies and the exposures were up to about one week.

The only side effects that were reported were paresthesias and dizziness. No serious adverse events.

That work led to the study, which has already been mentioned this morning by Chris Pulman and others in Amsterdam, which was a randomized, double blind, placebo controlled crossover design study, included 68 patients, who were treated for three months, no serious adverse events were reported in a 204 patient month exposure period and there was, as mentioned before, an improvement in overall disability scores in those patients.

This summarizes the side effects from those patients with dizziness being by far the most common paresthesias, fairly common gate problems, abdominal pain and anxiety, less commonly.

Responders from that trial were put into an open labeled safety study. There were 23 patients who went into that trial. Treatment durations were from 6 to 30 months. Most of the patients reported sustained improvement during that time. Two patients, as mentioned before, had grand mal tonicoclonic seizures. One patient was reported to have had a chemical hepatitis.

We were then approached by Elan Pharmaceutical Research Company to do a study, looking at pharmacokinetics and efficacy of 4-aminopyridine. This was looking at an immediate release formulation. We did a randomized, double blind, placebo controlled, concentration controlled, crossover over design trial in eight patients who were treated for up to 36 hours.

This study, again, was mentioned earlier in that we saw there was a relationship primarily between the area under the curve or total drug exposure and improvement of neurologic deficits. We also saw a single seizure in the patients whose drug levels were being monitored at the time of the seizure. So, we knew that the level was about 104 nanograms per ml. In general, in looking through the occurrence of adverse events and looking at the actual serum levels in those patients, there appeared to be a reasonable correlation between symptoms and peak levels.

DR. JUHL: Could I ask for a clarification on that point?


DR. JUHL: The people who experience seizures had high peak levels or the seizures occurred at the time you would expect --

DR. BEVER: The seizure occurred at the peak and a number of other side effects also occurred coincident with the peak or close to.

This formulation was then tested in an efficacy study that was carried out at the University of Rochester. It was a randomized, double blind, placebo controlled, crossover trial. Ten patients were treated for up to seven days with a slow release formulation that was developed by Elan and I believe that they will go into some detail on the issues related to developing that formulation later.
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