Levetiracetam - Part 1

In part one of this two-part series, Dr. Neishay Ayub discusses the history of a novel anti-epileptic drug, levetiracetam. Show citations: Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsychiatr Dis Treat. 2008;4(3):507-523. doi:10.2147/ndt.s2937 Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond. CNS Drugs. 2016;30(11):1055-1077. doi:10.1007/s40263-016-0384-x Rogawski MA. Brivaracetam: a rational drug discovery success story. Br J Pharmacol. 2008;154(8):1555-1557. doi:10.1038/bjp.2008.221 Ulloa CM, Towfigh A, Safdieh J. Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures. Neuropsychiatr Dis Treat. 2009;5:467-476. doi:10.2147/ndt.s4844 Wu PP, Cao BR, Tian FY, Gao ZB. Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil. Neurosci Bull. 2024;40(5):594-608. doi:10.1007/s12264-023-01138-2 Mahmoud A, Tabassum S, Al Enazi S, et al. Amelioration of Levetiracetam-Induced Behavioral Side Effects by Pyridoxine. A Randomized Double Blind Controlled Study. Pediatr Neurol. 2021;119:15-21. doi:10.1016/j.pediatrneurol.2021.02.010 Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results. Epilepsy Behav. 2008;13(3):557-559. doi:10.1016/j.yebeh.2008.07.004 Romoli M, Perucca E, Sen A. Pyridoxine supplementation for levetiracetam-related neuropsychiatric adverse events: A systematic review. Epilepsy Behav. 2020;103(Pt A):106861. doi:10.1016/j.yebeh.2019.106861 Show transcript: Dr. Neishay Ayub: Hello, my name is Neishay Ayub, and today we are discussing the history of a novel anti-epileptic drug, levetiracetam. It's a story of a scientific dead end, a radical new testing method, and a mystery that took years to unravel. To set the scene, let's go back to 1974. The pharmaceutical company, UCB Pharma, was working on compounds to boost cognitive function. They were looking for a successor to their drug piracetam. During this research, levetiracetam was first synthesized, but the compound didn't show any significant brain-boosting effects. With no discernible purpose, it was filed away and largely forgotten. For nearly two decades, this medicine sat on a shelf an anonymous entry in a long list of failed drug candidates. The story could have ended there, but in the early 1990s, researchers took a different approach to drug discovery. Researchers screened their entire library of forgotten compounds against audiogenic seizure-susceptible mice. These are mice prone to seizures triggered by sound. Levetiracetam was incredibly ineffective in chronic epileptic mice. Interestingly, levetiracetam had previously failed traditional screening tests which was to prevent acute seizures in normal animals subjected to maximal electroshock or pentylenetetrazole. Levetiracetam was pushed forward to human clinical trials and was found to be efficacious in three placebo-controlled, randomized, blinded clinical trials for adults with refractory focal epilepsy. Two of the clinical trials reviewed levetiracetam three grams per day compared to placebo. They found the responder rate, i.e., 50% reduction in seizure frequency, was 39% to 42% for patients on three grams per day versus placebo at 10% to 16% when used as adjunctive therapy. One of these trials also used levetiracetam as monotherapy, noting a median percent reduction in focal seizure frequency of 73%, a responder rate of 59%, and 18% of patients achieving seizure freedom. In November 1999, the FDA gave its approval for adjunctive treatment of partial onset seizures. While levetiracetam was effective, how it worked was still unclear. It didn't affect the ion channels and neurotransmitter receptors that older, more traditional anti-epileptic drugs targeted. Eventually in 2004, scientists made another breakthrough. They identified the drug's primary molecular target, a protein called SV2A. This protein is involved in regulating the release of neurotransmitters. Instead of suppressing all neurologic activity, levetiracetam appears to bind to SV2A and selectively modulate neurotransmitter release in overactive seizing neurons. This precise mechanism is why it has such a favorable side effect profile. With the mystery solved and a novel mechanism understood, levetiracetam continues to be a popular anti-seizure medication to this day, and its use has been expanded. Further clinical trials led to FDA approvals for use in adult and pediatric patients with myoclonic epilepsy for myoclonic seizures as well as adult and pediatric patients with idiopathic generalized epilepsy for primary generalized tonic-clonic seizures. There is an off-label use for status epilepticus and seizure prophylaxis in TBI, in traumatic brain injury, subarachnoid hemorrhage, and neurosurgical cases. Formulations have also expanded to include tablets and liquid formulations for immediate release, extended-release tablets, and intravenous formulations. Today, with the original patent expired, generic versions are available, making this treatment accessible to millions. The journey of levetiracetam from an abandoned compound to a frontline treatment is a powerful reminder that in science, a failure might just be a success waiting to be tested in a different way.