Keppra: From adjunct therapy to monotherapy "Therapeutic efficiency" shown in retention study, comparison with carbamazepine
The licensing of novel therapeutic agents is usually a long process governed by stringent criteria, which is why graduating from "adjunct" to "monotherapy" status in just six years is a remarkable achievement. Levetiracetam (Keppra), an antiepileptic, is one of the few drugs with this distinction, according to Dr. Ley Sander, professor at University College London's Institute of Neurology. Speaking in a symposium organized by the Philippine Neurological Association and UCB Philippines, Sander traced the significant developments in the drug's short history and detailed its efficacy against epilepsy. Levetiracetam was launched in the Philippines in 2004 as an adjunct treatment for partial epilepsy among patients at least 16 years old. In 2006, it was licensed as adjunct therapy against partial seizures in children four years and older. This year, it was approved as adjunct therapy for myoclonic seizures in patients with juvenile myoclonic epilepsy 12 years and above. It was also formally launched as monotherapy for partial seizures in newly diagnosed epilepsy.
A drug's "therapeutic efficiency" can be demonstrated in a retention study, which looks into how well patients benefit from and tolerate a particular drug as well as how long they stay on it, said Sander. Long-term retention may therefore be considered a composite measure of tolerability and efficacy, and may even signify how likely it is for a drug to stay in the marketplace. Levetiracetam's high retention rate was shown in a retention study involving 811 patients treated with levetiracetam since 2000 at the National Hospital for Neurology in Queen Square, London, and other tertiary referral centers. The range of exposure was zero to 41 months, with a median duration of 16 months, and accumulated 1,083 patient-years. At last follow-up, 65 percent of patients were still maintained on the drug, "an amazingly high retention," nearly twice as high as the 35-percent retention rate shown with 36-month topiramate use, Sander noted. Ten percent discontinued with the treatment due to adverse events, while nine percent stopped due to a perceived lack of efficacy. Another nine percent discontinued because of adverse events and lack of efficacy. The total discontinuation rate resulting from adverse events was pegged at 19 percent. Eighteen percent experienced no seizures for more than six months (median, 11 months; mean, 12 months) while 29 percent experienced at least 50-percent reduction in seizures and 47 percent experienced lessened seizure severity or outright episode reduction. "It is very important that when you treat this sort of population, you always make clear that you are using a drug that can change seizure frequency, and can lead to changes in behavior," said Sander. When people are aware of this possibility, there is a better chance for the person to stay on the drug and derive its benefits, "and the drug doesn't get a bad name."
But the study that established levetiracetam's role in partial-epilepsy monotherapy is one that compared it with controlled-release carbamazepine in newly diagnosed epilepsy patients with partial-onset seizures. Carbamazepine is considered a standard comparator drug for its established efficacy. Its controlled-release form also offers better tolerance and easy titration. The study's primary objective was to show that levetiracetam 1,000 to 3,000 mg daily was not inferior to carbamazepine 400 to 1,200 mg daily in achieving a six-month seizure-free period among adults with newly diagnosed epilepsy. The phase-III randomized study lasted for 121 weeks and involved 579 patients. In terms of primary efficacy (seizure freedom for at least six months), both groups showed comparable rates (levetiracetam, 73 percent; carbamazepine, 72.8 percent), which, Sander said, satisfied the primary objective. One-year seizure freedom was also similar-56.6 percent for levetiracetam, 58.5 percent for carbamazepine. Most of the patients, whether they were on levetiracetam or carbamazepine, were shown to respond to the initial dose, a finding that mirrored the results of the Study of Standard versus New Antiepileptic Drugs (Marson AG, et al., Lancet 2007). The comparative efficacy of levetiracetam and carbamazepine was also confirmed in the intention-to-treat analysis, further proving levetiracetam's role in monotherapy, said Sander, adding that comparing levetiracetam against carbamazepine and producing the same results was clinically significant. Concluded Sander: "This is a very effective drug [at controlling seizures]. It's a broad-spectrum drug. It works as an add-on; it works as monotherapy. It has been shown that this is as good as standard, but it is a better drug because it has no autoinduction and there is no interaction described with this drug. It is well tolerated overall. At the moment, this is the most promising [antiepileptic drug] we have." M |
