Thursday, November 24, 2016

Brivaracetam 2

On February 19, the US Food and Drug Administration (FDA) approved brivaracetam (Briviact®) for the adjunctive treatment of partial-onset seizures in patients 16 years and older.  Brivaracetam is the first antiepileptic drug (AED) for partial seizures approved by the FDA since the 2013 approval of eslicarbazepine (Aptiom®). It joins 16 other AEDs approved since 1993, most with indications for the treatment of partial seizures.

Brivaracetam has a high affinity for selectively binding to synaptic vesicle protein 2A (SV2A), which is the mechanism of action proposed for the familiar AED levetiracetam (Keppra®). SV2A, located in presynaptic membranes, regulates the calcium-dependent exocytosis of neurotransmitters into the synaptic cleft.  The AED binding of SV2A decreases the release of excitatory neurotransmitters and controls seizures by resetting the balance from excitation to inhibition. The affinity for its target is 15-30 times greater with brivaracetam than with levetiracetam, resulting in a dose approximately 10 times lower.

In a meta-analysis of six randomized, placebo-controlled, single- or double-blind trials, brivaracetam was administered to 1715 of 2399 participants.[3] The increase in 50% responders (patients with a decrease in seizures from baseline of at least 50%) was nearly twice as high with brivaracetam as with placebo (relative risk [RR], 1.79), and the increase in seizure-free patients was nearly five times as high (RR, 4.74). The most common adverse events were irritability, fatigue, somnolence, and dizziness. The effect of brivaracetam on seizure control was diminished in patients already taking levetiracetam (RR, 0.88) and in those already taking other AEDs (RR, 1.99). This decrease could be related to similarities in the mechanisms of action of brivaracetam and levetiracetam.

Both brivaracetam and levetiracetam have similar chemical structures and mechanisms of action, but their effects have not been compared in head-to-head trials. A meta-analysis and indirect comparison of the two drugs that involved 13 trials suggested that brivaracetam might not be superior to its older congener; the difference in efficacy was not significantly different between the two drugs, and the incidence of dizziness was higher with brivaracetam than levetiracetam.

However, one small (n=29), open-label, prospective study suggested that, in patients who switched from levetiracetam to brivaracetam because of behavioral adverse events, quality of life improved and there was no loss of seizure control.  Because it is a new AED, the long-term efficacy and safety of brivaracetam are not known.


A new drug for seizure control is always welcome. Brivaracetam is a second-generation SV2A ligand, modeled on the successful antiseizure drug levetiracetam. As with many new AEDs, it is unclear whether brivaracetam represents a therapeutic advance or simply a viable alternative for patients who do not achieve seizure control or who suffer intolerable effects with other treatments. It is unlikely that double-blind, randomized controlled trials of brivaracetam and levetiracetam will be conducted in the foreseeable future. Given that both drugs have similar mechanisms of action, their combination will probably not be advantageous. As experience with brivaracetam grows, close observation might reveal which patients are more likely to respond to brivaracetam and which are more likely to respond to levetiracetam in terms of efficacy, tolerability, or safety. A differential response could unveil subtle differences in mechanisms of action between brivaracetam and levetiracetam, and offer insight into the pathophysiology of each patient's epilepsy.

http://www.medscape.com/viewarticle/869575

3 comments:

  1. Yates SL, Fakhoury T, Liang W, Eckhardt K, Borghs S, D'Souza J. An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Epilepsy Behav. 2015 Nov;52(Pt A):165-8.

    Abstract
    We evaluated nonpsychotic behavioral adverse events (BAEs) in patients receiving levetiracetam (LEV) who switched to brivaracetam (BRV). Patients ≥16 years of age, receiving 2-3 antiepileptic drugs (AEDs), including LEV 1-3g/day, and experiencing BAEs within 16 weeks of LEV treatment initiation, enrolled in an open-label Phase 3b study (NCT01653262) comprising a ≤1-week screening period, an immediate switch from LEV to BRV 200mg/day (without titration), and a 12-week treatment period. The percentages of patients with investigator-assessed clinically meaningful reduction in BAEs, shift in maximum BAE intensity, and change in health-related quality of life (HRQoL) (Patient-Weighted Quality of Life in Epilepsy Inventory-Form 31 [QOLIE-31-P]) were assessed. Of 29 patients enrolled, 26 (89.7%) completed the study. At the end of the treatment period, 27/29 (93.1%) patients switched to BRV had clinically meaningful reductions in BAEs. Physicians reported a reduction in the maximum intensity of primary BAEs in 27/29 (93.1%) patients. Mean change from baseline to Week 12 in QOLIE-31-P total score was 12.1, indicating improved HRQoL. During the treatment period, 23/29 (79.3%) patients reported treatment-emergent adverse events (TEAEs). One patient reported a serious TEAE (suicidal ideation and suicide attempt). Two patients discontinued BRV because of TEAEs. Findings from this small study suggest that patients experiencing BAEs associated with LEV may benefit from switching to BRV.

    ReplyDelete
  2. Ma J, Huang S, You C. Adjunctive brivaracetam for patients with refractory partial seizures: A meta-analysis of randomized placebo-controlled trials. Epilepsy Res. 2015 Aug;114:59-65.

    Abstract
    OBJECTIVE:
    To evaluate the clinical efficacy and safety of the newer antiepileptic drug (AED), brivaracetam (BRV), as adjunctive therapy for adults with refractory partial seizures.
    METHODS:
    Randomized-controlled trials (RCTs) of BRV in the treatment of refractory partial seizure were systematically reviewed and quantified using fixed- or random-effects meta-analysis. 50% responder rate, seizure free rate and adverse events in the treatment period were analyzed as outcomes for measuring efficacy and safety. Pooled effects of risk ratio (RR) and 95% confidence interval (CI) were derived from meta-analysis implemented in RevMan 5.2.
    RESULTS:
    Five RCTs were identified for inclusion, and included a total of 1639 patients. The pooled RR of BRV vs. placebo as adjunctive therapy for adults with refractory partial seizure was 1.80 (95% CI 1.43-2.26, P < 0.00001) for 50% responder rates, 4.11 (95% CI 1.39-12.21, P = 0.01) for seizure free rates, 1.08 (95% CI 0.73-1.59; P = 0.70) for withdrawal rates. There was no evidence of a statistically significant association between the use of BRV and most adverse events, except somnolence (RR 1.63, 95% CI 1.08-2.45, P = 0.02) and fatigue (RR 2.05, 95% CI 1.19-3.53, P = 0.009).
    CONCLUSION:
    This study confirmed significant effects of BRV as adjunctive treatment of refractory partial seizures. This study also demonstrated the good tolerability profile of adjunctive BRV for patients with epilepsy. Further large clinical and pharmacovigilance studies are needed to investigate the long-term efficacy and safety of BRV and, furthermore, to suggest an optimal BRV dosage for clinical use.

    ReplyDelete
  3. Wood MD, Gillard M. Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. Epilepsia. 2016 Dec 24. doi: 10.1111/epi.13638. [Epub ahead of print]

    Abstract
    OBJECTIVE:
    Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV.
    METHODS:
    Radioligand binding studies were carried out using [3 H]BRV and [3 H]LEV. Studies were performed in membranes from both recombinant cells expressing human SV2A protein and human brain tissue.
    RESULTS:
    The modulator increased the binding of both radioligands but by different mechanisms. For [3 H]BRV, the increase was driven mainly by an increase in affinity, whereas for [3 H]LEV, the increase was due to an increase in the number of apparent binding sites. Kinetic studies confirmed this differential effect.
    SIGNIFICANCE:
    These studies suggest that LEV and BRV may act at different binding sites or interact with different conformational states of the SV2A protein. It is possible that some of the pharmacologic differences between BRV and LEV could be due to different interactions with the SV2A protein.

    ReplyDelete