Two Birds, One Stone
Dr. Wilner: An entire day of the meeting was devoted to the presence of comorbidities with epilepsy, such as bipolar disorder, neuropathic pain, and migraines. How does that figure into drug development?
Dr. Rogawski: The first day of the meeting was focused on conditions described as overlapping with epilepsy. By this term, I think the organizers of the meeting meant that they are conditions with underlying pathophysiologies similar to epilepsy, and for which we know AEDs may be useful. Such conditions as bipolar disorder, neuropathic pain, and migraine all fall into this category. AEDs are frequently used and are effective for these conditions.
A scientific base of information suggests that in several cases, particularly in the case of neuropathic pain and migraine, there may be underlying pathophysiologic similarities. In addition, some of these conditions may be comorbid with epilepsy. For example, patients with migraine have a higher incidence of epilepsy, and patients with epilepsy have a higher incidence of migraine. Similarly, depression is a common comorbidity of epilepsy.
There are many similarities between these conditions, and therefore, when drugs are developed for epilepsy, they are often applied to these other conditions. Because we have a variety of valid animal models that seem to be predictive of efficacy in human epilepsy, development usually progresses from the creation of a drug for epilepsy to use in these other disorders. Preclinical animal models are not as well validated for these overlapping conditions, in terms of predicting efficacy. But once the drugs are developed for epilepsy, they are usually tried in patients with these other conditions, and in some cases they have been found to be effective. This has led to widespread use of the agents for these other conditions.
Sometimes the manufacturer is willing to carry out clinical trials, submit them to the regulatory authorities, and obtain labeling for the other indications. In other cases, the AEDs are used off-label by clinicians.
Dr. Wilner: You are saying that the crossover to these comorbid conditions occurs rather late in the drug development phase -- that this is not generally considered in the laboratory?
Dr. Rogawski: Traditionally, this has been the case. The drugs have been developed initially for epilepsy, and then later on were discovered to be useful for these other conditions after they had been introduced into the market. However, I think drug developers are now attempting to assess the potential of their pipeline agents for these other conditions, recognizing that this may tilt the economics toward a more favorable direction; if their pipeline drug has a potential utility for some of these other conditions, it may have a larger market.
For example, migraine is a much larger market than epilepsy. Somewhere on the order of 35-37 million Americans have migraines, whereas only about 1 million have epilepsy. If a drug can be shown to be useful in these other overlapping conditions, it can enhance the economics.
Dr. Wilner: At the meeting, I noticed an undercurrent of concern that the pharmaceutical companies have become less interested in developing drugs for epilepsy. Is that true, and if so, what is the plan to remedy that situation?
Dr. Rogawski: That is absolutely correct. Big Pharma has moved away from AED development. I don't think any large pharmaceutical companies have major programs in epilepsy right now. We learned at the meeting that Pfizer does have an AED in the pipeline, and that was good news; but overall, large pharmaceutical companies are not addressing the epilepsy market.
I think the large pharmaceutical companies have misperceived the market opportunity. They believe that the market is saturated with generic drugs, and that it would be very difficult for them to recoup their investment and make what they consider to be an adequate profit in this market.
However, history has shown that AEDs can be highly profitable, and in fact be blockbusters. This was the case with many of the last generation of new AEDs, such as lamotrigine, topiramate, gabapentin, and pregabalin, which all did very well in the marketplace. There is no reason to believe that a new agent could not have this same degree of market success.
Dr. Wilner: Given that the unmet need is still quite large, a drug that really worked would definitely have blockbuster potential.
Dr. Rogawski: Absolutely. Even a drug that provides important, but incremental, advances can do very well in the marketplace. Such a drug does not have to be the magic bullet, but a drug that provides an advantage over the currently available medications would do very, very well in the marketplace.
For example, a drug with less teratogenicity than the currently available drugs would fill an important need. We are not confident that any of the currently marketed AEDs is free of effects on the fetus. If we had an effective agent that could be prescribed with greater confidence to women of reproductive age who have epilepsy, that would be a very successful AED.
As you know, epilepsy affects both sexes equally, which means that 50% of patients with epilepsy are women. Epilepsy often arises at the time of puberty, and physicians are often faced with the prospect of prescribing a drug for a young woman who may become pregnant. To put a young woman on an antiepileptic drug is a very difficult decision, given this potential teratogenicity risk. That is just one example of the kind of incremental advance that could be a game-changer and would make for a very profitable drug for a pharmaceutical company.