Guide
Another powerful tool for epilepsy treatment - the latest announcement on the official website of the National Medical Products Administration (NMPA) of China has officially approved the marketing of Brivaracetam tablets (hereinafter referred to as "Brivaracetam") for monotherapy and additive therapy of partial-onset seizures in patients aged 16 years and above.
Epilepsy treatment still needs to go further
Epilepsy is a group of chronic brain disorders with recurrent, episodic, and transient central nervous system dysfunction caused by abnormal overfiring of neurons in the brain. It is estimated that there are about 6.4 million people with active epilepsy in mainland China, and about 300,000 people with new epilepsy every year. Seizures place a heavy burden on patients, families, and society as a whole1.
Anti-seizure drugs (ASMs) are the most important and basic treatment for epilepsy and are the preferred treatment for most patients with epilepsy1. In the past few decades, with the continuous deepening of scientific research, many ASMs have appeared one after another, bringing good news to epilepsy patients, however, there is still an unmet need for epilepsy treatment, and one-third of epilepsy patients will still have uncontrollable seizures despite receiving ASMs treatment; Many patients with epilepsy are plagued by adverse effects of ASMs, poor adherence to treatment, or even termination of treatment, leading to an increased risk of death. Therefore, there is an urgent need for safer, effective, and well-tolerated innovative drugs to enhance seizure control, reduce side effects, and improve the overall quality of life of patients2,3.
Brivaracetam came into being, and it has added another weapon to the treatment of epilepsy in China
On August 27, 2021, the U.S. Food and Drug Administration (FDA) approved brimiracetam for the treatment of epilepsy patients with focal-onset seizures ≥ 1 month2. Now, this new drug has been approved for marketing in China, which will bring a new treatment option for Chinese epilepsy patients, and also provide new ideas and directions for the research and development of epilepsy drugs. As a third-generation ASMs, brivaracetam has performed well in terms of mechanism of action, clinical efficacy, safety and tolerability.
1. Mechanism innovation to accurately control seizures
The discovery of synaptic vesicle protein 2A (SV2A) has opened the door to the development of novel ASMs. SV2A is the most widely distributed subtype of synaptic vesicle protein 2 (SV2), with 12 intact transmembrane regions, which are present in almost all kinds of neurons and are widely distributed in the cerebral cortex, which is closely related to the release of neurotransmitters, endocrine exocytosis, and the maintenance of synaptic vesicle homeostasis4.
SV2A is a potential target for seizure control. Studies have shown that SV2A knockout mice are unable to grow and produce spontaneous seizures and die within 2-3 weeks of birth, while heterozygous SV2A knockout mice do not show spontaneous seizures. Alterations in SV2A protein expression and function were found in animal models of seizures and in brain tissue obtained from patients with epilepsy, suggesting that a decrease in SV2A protein expression/function contributes to the progression of epilepsy5.
Brimiracetam, as a more mature SV2A ligand, has a high affinity to bind to central SV2A with high selectivity, reduce the release of excitatory neurotransmitters, and regulate the balance of excitatory and inhibitory transmitters in the brain, thereby controlling seizures (Figure 1)3,6. Happily, spectra analysis of more than 55 targets, including receptors, enzymes, ion channels, and transporters, at concentrations of 10 uM (more than 100 times its affinity for SV2A) found that Brivaracetam precisely targeted the SV2A target without inhibiting high-pressure-activated (HVA) Ca2+ channels and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors3,6.
Figure 1. Brivaracetam innovates the mechanism of action3
2. No need for titration, rapid onset of effect, and the therapeutic dose will be reached on the first day
Titration of ASMs to the first therapeutic dose has traditionally been a common practice in the treatment of epilepsy, however, titration is often associated with increased seizure frequency, increased hospitalization, and subsequent increased healthcare costs compared to the maintenance phase of ASMs2. In a survey of 461 people with epilepsy from seven European countries, 51% of participants identified a reduction in titration as an important factor influencing treatment decisions2.
Brivaracetam does not require titration, can be started at the target dose from day 1, and has a rapid and sustained response2. 7,15.5%, 18.1%, and 19.4% of patients with 50 mg/day, 100 mg/day, and 200 mg/day of brizetam achieved a ≥50% response on day 1 (6.7% in the placebo group, P<0.001), respectively, and remained so throughout the study (through the entire treatment period to day 84).
A post-hoc analysis8 found that 79.8% and 81.0% of patients achieved a response of ≥75% on day 1 of brizemiracetam on day 1 (65.6% of patients in the placebo group at each dose <0.0001), 78.9% of patients in the two-dose group and 81.0% of patients who responded to ≥90% on day 1 of treatment in the two-dose group (65.1% of patients in the placebo group, P<0.0001 at each dose), and 100% on day 1 in the two-dose group The proportion of patients who responded was 5.1% and 4.0% (0.5% in the placebo group, P < 0.05 at each dose), respectively, and remained essentially unchanged by day 84. It can be seen that at the recommended starting dose, from the first day of treatment, bripiracetam can effectively reduce seizure frequency not only at the response level of ≥50%, but also at the more clinically meaningful response level of ≥75%, ≥90%, and 100%.
3. Evidence-based and effective
Brivaracetam has accumulated a wealth of evidence-based medical evidence as a shining star of a new generation of anti-seizure drugs. Among them, a pooled analysis of three pivotal Phase III, double-blind, randomized, placebo-controlled studies (NCT00490035, NCT00464269, and NCT01261325) of brimiracetam showed that9:
➤ The frequency of focal seizures (POS) per 28 days was reduced by 19.5% (P=0.001), 24.4% (P<0.001), and 24.0% (P<0.001) in the 50 mg/d, 100 mg/d, and 200 mg/d brimiracetam groups, respectively compared with placebo (Figure 2).
Figure 2. Percent reduction in POS frequency/28 days after baseline adjustment compared to placebo
➤ Compared with placebo (20.3%), the proportion of patients who responded to 50% ≥ brímiracetam at 50 mg/d, 100 mg/d, and 200 mg/d was significantly higher, with 34.2% (P=0.002), 39.5% (P<0.001), and 37.8% (P<0.001), respectively (Fig. 3).
Figure 3. Proportion of patients ≥ 50% responding
The study showed that the efficacy of brimiracetam in the treatment of POS was significantly better than that of the placebo group in all dose groups9. In addition, the Brimiracetam monotherapy registration clinical study10 has shown that bripiracetam monotherapy is as effective as add-on therapy in the recommended dose range of 50 to 200 mg/day.
Phase III study* in China (study code: QF-BRV-POS-301) – 179 patients aged 16-80 years with POS were randomized 1:1 to receive placebo or brimiracetam 200 mg/day (100 mg BID) plus therapy (n=90 in the brimiracetam group; n=89 in the placebo group, including 1 patient in the placebo group who did not take the drug) for 12 weeks. The results showed that the frequency of POS per 28 days in the brimiracetam 200mg/d group was significantly lower than that in the placebo group, which was reduced by 40.67% (F=18.97, P<0.0001), and the proportion of patients who responded ≥to 50% (48.9% vs. 23.9%, P=0.0006) and seizure-free rate (11.1% vs. 2.3%, P=0.0325) in the brimiracetam 200mg/d group were significantly better than those in the placebo group.
In summary, it can be seen that the efficacy of brimiracetam monotherapy/addition in the treatment of epilepsy focal seizures is certain, and the results of phase III studies in China are consistent with the results of foreign studies.
4. High retention rate, long-term care for patients
Treatment of ASMs is often chronic and lifelong, so it is important to maintain the safety, tolerability, and efficacy of the drug over time11. An 11-year, open-label follow-up study11 showed that brimiracetam was added to patients with POS or primary generalized epilepsy (PGS) safely and well-tolerated, with approximately half of patients still in the trial at year 4; Overall, 55.6% of patients with POS had a ≥50% reduction in seizure frequency compared to baseline, and efficacy outcomes improved with increasing time to brimiracetam exposure, with stable changes in the nine-year cohort.
Another pooled analysis12 showed that brimiracetam had a high retention rate with the addition of brimiracetam, with retention rates at 6, 12, 24, and 60 months of 91.0%, 79.8%, 68.1%, and 54.4%, respectively, in patients treated with brimiracetam 50 to 200 mg/day.
5. A safe choice to improve the overall quality of life
People with epilepsy often have psychiatric disorders and cognitive abnormalities, and it is important to note that many ASMs cause psychiatric side effects, such as ADHD and depression, and may increase the risk of suicide, in addition to the adverse effects of some ASMs on cognitive function. Side effects associated with ASMs are a significant determinant of quality of life in patients with epilepsy, even more important than controlling seizure frequency, and these potential side effects must be taken into account in the treatment of epilepsy13,14.
A systematic review14 showed that patients treated with brivaracetam had a lower incidence and severity of irritability and aggression. Another study15 showed that brivaracetam improved cognitive function in people with epilepsy, with improvement occurring at day 5 after treatment; After the use of brimiracetam, the attention and executive function of the patients were significantly improved (P=0.03), and the reaction time showed an improvement trend. It can be seen that brimiracetam is a trustworthy and safe choice for people with epilepsy, which can improve the overall quality of life of patients.
epilogue
Science and technology lead development, innovation drives the future. It is believed that with the approval of brivaracetam in China, it will further rewrite the status quo of epilepsy treatment in China, reshape the pattern of epilepsy treatment, and allow more epilepsy patients to return to normal life. *Research data are pending.
Bibliography:
1. Chinese Anti-Epilepsy Association. Clinical diagnosis and treatment guidelines-epilepsy fascicle (2023 revised edition)[M]. Beijing: People's Medical Publishing House, 2023.
2.Klein P, Bourikas D.Narrative Review of Brivaracetam: Preclinical Profile and Clinical Benefits in the Treatment of Patients with Epilepsy. Adv Ther. 2024 May 29.
3.Feyissa AM. Brivaracetam in the treatment of epilepsy: a review of clinical trial data. Neuropsychiatr Dis Treat. 2019 Sep 9;15:2587-2600.
4. Hu Mei, Liu Nan, Chen Yue, et al. Synthesis and clinical research progress of positron emission tomography agent based on synaptic vesicle protein 2A imaging[J].Chinese Journal of Modern Applied Pharmacy,2022,39(03):417-423.)
5.Russo E, Citraro R, Mula M. The preclinical discovery and development of brivaracetam for the treatment of focal epilepsy. Expert Opin Drug Discov. 2017 Nov; 12(11):1169-1178.
6.Gillard M, Fuks B, Leclercq K,et al. Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol. 2011 Aug 16; 664(1-3):36-44.
7.Klein P, Johnson ME, Schiemann J,et al. Time to onset of sustained ≥50% responder status in patients with focal (partial-onset) seizures in three phase III studies of adjunctive brivaracetam treatment. Epilepsia. 2017 Feb; 58(2):e21-e25.
8.Klein P, Laloyaux C, Elmoufti S,et al. Time course of 75%-100% efficacy response of adjunctive brivaracetam. Acta Neurol Scand. 2020 Aug; 142(2):175-180.
9.Ben-Menachem E, Mameniškienė R, Quarato PP, et al. Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies. Neurology. 2016; 87(3):314-323.
10.Schoemaker R, Wade JR, D'Souza J,et al. Evaluation of brivaracetam efficacy as monotherapy in adult patients with focal seizures. Epilepsy Res. 2017 Nov;137:95-100.
11.O'Brien TJ, Borghs S, He QJ,et al. Long-term safety, efficacy, and quality of life outcomes with adjunctive brivaracetam treatment at individualized doses in patients with epilepsy: An up to 11-year, open-label, follow-up trial. Epilepsia. 2020 Apr; 61(4):636-646.
12.Toledo M, Whitesides J, Schiemann J,et al. Safety, tolerability, and seizure control during long-term treatment with adjunctive brivaracetam for partial-onset seizures. Epilepsia. 2016 Jul; 57(7):1139-51.
13.Chen Y, Li W, Lu C,et al. Efficacy, tolerability and safety of add-on third-generation antiseizure medications in treating focal seizures worldwide: a network meta-analysis of randomised, placebo-controlled trials. EClinicalMedicine. 2024 Feb 28;70:102513.
14.Steinhoff BJ, Klein P, Klitgaard H, et al. Behavioral adverse events with brivaracetam, levetiracetam, perampanel, and topiramate: A systematic review. Epilepsy Behav. 2021 May;118:107939.
15.Witt JA, Elger CE, Helmstaedter C. Short-term and longer-term effects of brivaracetam on cognition and behavior in a naturalistic clinical setting-Preliminary data. Seizure. 2018 Nov;62:49-54.
Disclaimer: This platform aims to deliver more medical information to healthcare professionals. The content published on this platform should not be used as a substitute for professional medical guidance in any way, nor should it be regarded as diagnosis and treatment advice. If such information is used for purposes other than understanding medical information, the platform does not assume relevant responsibilities. This platform does not mean that it agrees with its descriptions and views on the published content. If copyright issues are involved, please contact us, and we will deal with it as soon as possible.
Yimaitong is a professional online doctor platform, and the mission of the platform is to "sense the pulse of the world's medicine and help China's clinical decision-making". Yimaitong has a series of products such as "Clinical Guidelines", "Medication Reference", "Medical Literature King", "Yizhiyuan", "eYantong" and "ePulse", which fully meet the needs of medical workers in clinical decision-making, obtaining new knowledge and improving scientific research efficiency.