UCSF-Led Research Drives Unique Clinical Trial of New Drug Candidate
In an unprecedented leap from lab to patients, a potential treatment for childhood epilepsy identified in experiments with zebrafish by UC San Francisco scientists was administered in a clinical trial to children with Dravet syndrome, a rare and devastating genetic form of epilepsy that can cause hundreds of seizures per day. The therapy tested in the small, compassionate-use trial, a drug known as lorcaserin (Belviq), significantly reduced the frequency of seizures in all five patients enrolled in the trial, and two of those children continue to take the drug with no increase in seizure activity.
The decision to evaluate lorcaserin as a Dravet therapy grew out of research in the UCSF laboratory of Scott C. Baraban, PhD, professor of neurological surgery, who has developed platforms with which hundreds of drug compounds can be rapidly assessed for effectiveness in zebrafish larvae that carry gene mutations paralleling those known to cause childhood epilepsy.
“This is the first time that scientists have taken a potential therapy discovered in a fish model directly into people in a clinical trial,” said Vicky Whittemore, PhD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH) that provided funding for the new study. “These findings suggest that it may be possible to treat neurological disorders caused by genetic mutations through an efficient and precision medicine–style approach.”
The clinical trial results, as well as the basic research leading up to the trial, are reported in the March 2017 issue of Brain.
Dravet Syndrome Caused by Gene Mutations
In children, Dravet syndrome is caused by mutations in a gene known as SCN1A, and the Baraban lab has previously shown that mutations in a corresponding zebrafish gene have similar effects: the fish larvae, which are no bigger than a human eyelash, have frequent spontaneous seizures and their brain waves during these events resemble those seen in human Dravet patients.
In a 2013 study that tested more than 300 compounds already approved for other uses by the Food and Drug Administration (FDA), Baraban’s research group found that clemizole, an antihistamine developed in the 1950s that has since fallen out of use, significantly reduced seizure activity and normalized brain waves in zebrafish carrying Dravet-like mutations.
But despite clemizole’s apparent effectiveness in the fish, the finding was puzzling, said Baraban, the William K. Bowes, Jr., Endowed Chair in Neuroscience Research and a member of the UCSF Weill Institute for Neurosciences. “There was no reason to believe that antihistamines could suppress seizures, and when we looked at all the other antihistamines in our library – about 40 or 50 drugs – none of them had anti-epileptic activity.”
These negative results led Baraban and colleagues to suspect that clemizole must be acting on a target other than histamine, which in addition to its well-known role in mucus production also acts as a neurotransmitter in the brain.
Binding Study in Search for Drug Candidate
Led by postdoctoral scholar Aliesha Griffin, PhD, the team used funds from UCSF’s Catalyst program to commission a binding study, a research technique that shows how drug molecules interact with a wide range of targets. This work revealed that clemizole also acts on certain receptors for the neurotransmitter serotonin, which made more sense, Baraban said, because these serotonin receptors are known to be involved in regulating the brain’s overall excitability and had previously been reported to exhibit antiepileptic actions.
Clemizole is currently unavailable in a clinical-grade formulation, so the team next began a search for other FDA-approved compounds that might act like clemizole on the serotonin receptors in question, and they identified both trazodone, often used as a sleep aid, and lorcaserin, which is prescribed as a weight-loss drug.
In experiments with zebrafish carrying the Dravet-like mutation, neither trazodone nor lorcaserin was as effective as clemizole in suppressing seizures, but the safety, commercial availability and side-effect profile of lorcaserin suggested it could be useful for children with Dravet who do not respond to therapies already in use, or who have developed resistance to antiepileptic drugs.
Kelly Knupp, MD, associate professor of pediatrics-neurology at the University of Colorado School of Medicine, agreed to lead a small compassionate-use, off-label trial of lorcaserin in five Dravet patients from 7 to 18 years old, all of whom experienced frequent seizures and were resistant to several existing drugs.
Results Among the Patients
As reported in Brain, one patient was initially seizure-free for three weeks, one was seizure-free for two weeks, and a third had one to two seizure-free days per week. All five patients exhibited a reduction in the total number of seizures. Generalized tonic-clonic seizures, which involve the whole body and can induce loss of consciousness, were significantly reduced in three patients, one of whom experienced a 90 percent reduction in these seizures with no need for additional medications. Lorcaserin was well-tolerated, with the most frequent side-effect being, as expected, a loss of appetite.
Given clemizole’s superior efficacy in zebrafish, however, Baraban has joined forces with Adam Renslo, PhD, associate professor of pharmaceutical chemistry in the UCSF School of Pharmacy, and with postdoctoral funding from the Dravet Syndrome Foundation, to begin to develop what he calls “clemologs,” newly designed compounds that will reduce clemizole’s affinity for histamine while preserving, or enhancing, its targeting of serotonin receptors.
Baraban is also making good progress on a project to create zebrafish models of all 70 gene mutations known to be involved in childhood epilepsy, and is continuing to screen new drugs.
“Thanks to the flexibility offered by zebrafish, we can do these things extremely rapidly. The NIH’s Epilepsy Therapy Screening Program, which was established forty years ago, screens approximately 200 drugs per year. We’ve screened more than 2,700 in the last three years alone, and are working at a pace of 100 drugs per month,” Baraban said. “Just because these are the few effective drugs we found doesn’t mean they’re the best possible drugs, so we’ll keep searching.”
Baraban, Griffin, and Knupp were joined in the research by UC Berkeley’s SoonGweong Hong, PhD, a postdoctoral fellow, and Luke P. Lee, PhD, the Arnold and Barbara Silverman Distinguished Professor of Bioengineering, Biophysics, Electrical Engineering, and Computer Science. In addition to funding from the NINDS (grant NS079214) and a UCSF Catalyst Award, Baraban’s work was supported by the Raymond and Beverly Sackler Center at UC Berkeley.
UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.