10th Antiepileptic Drug Trials Update: 2009
by Joyce Cramer, President, Epilepsy Therapy Project
Epilepsy experts discussed everything from animal models to predicting whether drugs would stop seizures to patient recruitment in clinical trials, during "Antiepileptic Drugs-10" the biennial conference devoted to clinical trials on antiepileptic drugs (held in Coral Gables, FL, on April 15-17, 2009). The conference was a lively review of mechanisms of action, types of preclinical and proof-of-principle clinical testing, through to thorny issues related to later stage clinical trials for regulatory approval. The following is a summary of the 2-day conference topics. A separate article reviews the 3rd day of the meeting: an intensive gallop through all most of the drugs, biologics, and devices in various stages of development as epilepsy therapies. Please register at http://professionals.epilepsy.com/page/mailinglist_signup.php to receive notices about other epilepsy conferences and news.
The increasing number of animal models with good correlation to human epilepsy, is bringing us to closer alignment with human phenotypes and genotypes. This is a risk-reducing feature that enhances development of new epilepsy therapies. The expansion from small molecules to peptides, viral vector transfer of peptides for treatment and genetic alteration of cells, direct delivery of molecules into brain, and devices to predict seizures and stimulate the brain to prevent events promise a revolution of treatment options in the next decade. Longstanding evidence that head injury creates a high risk for development of epilepsy has led to a recent surge of interest in preventive treatment for post-traumatic seizures. Approaches to neuroprotection and antiepileptogenesis are a high priority for epilepsy researchers.
Proof-of-Principle and Clinical Trial Endpoints
The photosensivity model is a classical approach to finding a signal for antiseizure activity. Although the number of patients who experience this effect is very small, sufficient numbers can be recruited to undergo repeated testing to evaluate new compounds. An advantage is that if the initial dose is too low, additional subjects may be tested until a response is seen, or the study is considered negative of a photosensitive response. If the dose is too high, causing adverse effects, repeat at a lower dose is possible, but with potential loss of efficacy.
Revision of the standard clinical trial endpoints (mean seizure reduction or 50% responder rate) to an endpoint of time to Nth seizure was based on analysis of completed trials. The FDA requirement for a placebo-control creates ethical constraints on monotherapy studies. The use of “historical controls," along with the requirements to match the populations between historical and new trials was discussed. The EMEA requirement to perform active comparator monotherapy trials results in the need for 2 types of trials, after completion of standard add-on therapy trials. A rationale to combine the add-on and monotherapy programs for a simplified approval. Russell Katz MD (FDA) was asked why epilepsy programs were prolonged by the need for multiple sequential trials when other therapeutic areas were not similarly constrained. It may be possible for FDA to convene a panel (internal or external) to consider the issues raised in this discussion.
Many of the estimated 700,000 people in the USA with treatment-resistant epilepsy may benefit from devices that stimulate the brain to prevent or abort seizures. The only currently approved device to reduce seizure frequency is the vagus nerve stimulator (Cyberonics) that provides a consistent stimulus to the brain. Unlike cardiovascular rhythms that should be consistent and organized, brain activity should be disorganized. Thus, the concept of stimulation of the brain is designed to maintain disorganization. Paradigms used in several devices were reviewed: Vagus Nerve Stimulation and deep brain stimulation use an open loop stimulation paradigm, where as the Responsive Neuro Stimulation system (Neuropace) uses a closed loop system based on detection and responsive stimulation. Other devices are planned to use a feedback loop for continuous control based on detection of all abnormal electrical activity. The SANTE study (Medtronic) assessed the effectiveness of an intercept system for anterior nucleus thalamus stimulation. The study showed 40% response rates for patients evaluated for more than a year. The key to peace and future devices is in recognition of an impending seizure before electrical synchrony is initiated. An alternative concept or approach is using cooling of the brain to reduce electrical activity. An advantage of hypothermia is that localization is not necessary. Ann Costello PhD, DMD (FDA) provided the FDA perspective on devices. She noted that future devices that combine drugs or biologics with devices will require thoughtful evaluation to determine the efficacy and safety off all components. The clinical trials needed for regulatory approval are similar to those used in drug studies.
What pediatric syndromes should be studied? The child neurologists' view of epilepsy often is based on age of onset. Historically, pediatric studies have focused on infantile spasms, Lennox Gastaut syndrome and childhood absence epilepsy. Recent evidence is that vigabatrin is useful for infantile spasms as a new treatment to ACTH for this disorder. Several drugs have been tested for efficacy in Lennox Gastaut Sydrome, the most recent being rufinamide. An NIH study comparing valproate, lamotrigine and ethosuximide surprised many clinicians and are showing superiority of ethosuximide. Unfortunately the mixture all types of seizures in pediatric syndromes suggests the need to group patients in other ways, such as age of onset, etiology, generalization process localization, comorbidities, and genetic mutations.
Is it worth the pharmaceutical companies' effort to obtain regulatory approval for treatments to be used only by small numbers of patients (orphan indications)? The challenges and usefulness of this approach include the continuing needs of the numerous treatment resistant patients. There are few shortcuts to obtaining an orphan indication: preclinical and early clinical studies remain the same, but clinical trials may be smaller. The technical challenges results in a seven-year exclusivity, but that is often eaten away during lengthy development and approval time frames. The avenues for success include partnership with nonprofits and the FDA.
The use of placebos in epilepsy trials is a concern because of the potential for harm to patients who might experience excessive seizures or dangerous tonic clonic seizures. Ethical concerns might differ in countries where only phenobarbital and phenytoin are available. The issue is whether there is equipoise on whether to treat or not to treat.
Geriatric epilepsy is on the rise, with the aging of the population. A link between epilepsy and Alzheimer's disease can be made through animal models. The neuroprotective effect of some epilepsy treatments may also be protective against the amyloid proteins seen in Alzheimer's dementia.
Formulations and delivery systems
Although neurologists and professional organizations have spoken out against mandatory substitution of generic for branded epilepsy treatments, the laws in many states allow pharmacists to make these changes without physician approval. Michael Privitera described the issue as indiscriminate substitution of generics with variable bioavailability. Frequent changing of generics results in inadequate blood levels, resulting in breakthrough seizures. The FDA goal of bioequivalence differs from therapeutic equivalence desired by doctors and patients.
Acute repetitive seizures (ARS) are clusters of seizures experienced by some patients. These events are less emergent than status epileptic but would benefit from treatment that increased seizure thresholds quickly. The benzodiazepines are classic treatments for rapid seizure control but usually are delivered only intravenously or intramuscularly. A new concept is the use of nasal sprays to deliver a benzodiazepine. It is assumed that this approach would be more acceptable to patients than the currently available rectal diazepam administration (Diastat, Valeant). However the studies of acute repetitive seizures are complicated by the need to find the uncommon patients who experience sufficient clusters. One approach to testing would be use of the Neurological Emergency Treatment Testing (NETT) program supported by NIH.
Patient recruitment in clinical trials
The number of patients appropriate for the typical clinical trial (minimum of four seizures per month) is decreasing for a variety of reasons. More patients may be controlled by the current medications or fewer patients are willing to enroll in trials. Jacqueline French noted that altered inclusion criteria might increase the number of people eligible for a moment, thereby shortening of clinical trials. Another approach is to perform studies globally, although this requires extensive assessment and training of all investigators and coordinators all over the world. Several recent clinical trials have demonstrated that sites differ in qualification and performance around the world. In addition, patient populations differ regionally, adding to the complexity of all clinical trials.
The recent FDA concern that antiepileptic drugs may be related to suicide it suicidality has brought into question the link between mood disorders and epilepsy as well as the impact of all antiepileptic drugs. There is a bidirectional relationship of epilepsy and suicidality. Of course, physicians should screen for mood disorders as well as suicidal ideation.
A separate article reviews the 3rd day of the meeting: an intensive gallop through most of the drugs, biologics, and devices in various stages of development as epilepsy therapies. See 2009 Pipeline Update.
Please register at http://professionals.epilepsy.com/page/mailinglist_signup.php to receive notices about the next epilepsy pipeline review and other information about new therapies.
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