A description of Brivaracetam, a novel SV2A ligand, an anti-epileptic with greater potency and significantly reduced behavioural adverse effects compared to Levetiracetam .
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Brivaracetam
1. Brivaracetam:
A newer SV2A ligand
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist
Manipal Hospital, Bengaluru
2. Mechanism of Action of BRV
2
• BRV binds differently to SV2A
than LEV
• High affinity (15-30 times) and
selectivity to SV2A
• Does not inhibit high voltage-
activated Ca2+ channels or AMPA.
Nach Bialer and White 20101
Brivaracetam
Brivaracetam Levetiracetam
SV2A binding
affinity*
+++1
(0.05 µM)
+1
(1.6 µM)
HVA Ca2+
channel
current
no inhibition2
(inactive up to
1000 µM)
Inhibition3
(13.9 µM)
AMPA
receptor
antagonism
no inhibition4
(inactive up to
100 µM)
Inhibition5
(268 µM)
3. 33
Lipophilicity and brain permeability
Measured mouse brain permeability versus lipophilicity degree
diazepam
phenytoin
BRV
LEV
Nicolas JM, et al. Epilepsia. 2016;57:201–209
BRV brain permeability
is close to
benzodiazepines
and higher than for LEV.
4. 4
4
Predicted speed of entry in rhesus brain based on measures from SV2A
PET ligand displacement study in monkeys
Nicolas JM, et al. Epilepsia. 2016;57:201–209. SUV, standardised uptake values; TAC, time-activity curve
• The estimated displacement half-times were 6 minutes for BRV and 30
minutes for LEV, demonstrating faster SV2A occupancy for BRV
Lipophilicity and brain permeability
5. Kaplan-mier estimates for proportion of patients achieving sustained ≥50% responder
status (SRS) from the pooled efficacy population (N = 1,160), at day 1 was 18.1% with
BRV 100 mg/day and 19.4 % for 200 mg/day vs. 6. 7 % for placebo (p<0.001)
Day 7 this was sustained to 22% and 24.6 % for 100 and 200 mg/d vs. 9.2 % placebo
Early and Sustained Response
*Klein P. Epilepsia. 2017 Feb;58(2):e21-e25
Time to onset of sustained ≥50% responder status
6. Summary of BRV pharmacokinetics
6
• BRV has high selectivity and more affinity to SV2A receptors.
• Does not affect AMPA (less behavioral effects).
• High lipophilicity and permeability (rapid action).
• Faster brain distribution and SV2A occupancy.
• Does not interact with membrane transporters (including P-
glycoprotein and MRP-2).
• Potent and broad spectrum seizure suppression in different animal
models and has more pronounced antiepileptogenensis effects than
LEV in kindling model.
8. Primary efficacy outcome : ≥50% responder rate
8
• ≥ 50% responder rate from baseline was significant and greater
than placebo for all BRV dosages.
9. Secondary efficacy outcome : Median percent reduction in
POS frequency from baseline
9
• Median percent reduction in POS frequency from baseline was
similar for all BRV dosages and greater than placebo ( 17. 2%).
Elinor Ben-Menachem et al Neurology 87 July 19, 2016
12. Indian Contribution: >10% in pivotal study
• > 250 Indian subjects in 6 Briv (Phase II and III) studies
since 2006
12
N01252 (Phase III)
Global Patients : 399
Indian Patients : 90
N01358 ( Phase III)
Global Patients : 768
Indian Patients:33
N01254( supportive
phase III )
Global Patients : 480
Indian Patients:65
N01193 (Phase II)
Global Patients : 210
Indian Patients: 67
N01199 (Phase III
Extension)
Global Patients :667
Indian Patients:203
N01379 (Phase III
Extension)
Global Patients :627
Indian Patients:31Over 10 % of all
patients
Second biggest
contributor
13. N01252
• Phase III, double-blind, randomized, placebo controlled, fixed-
dose trial, conducted between September 2007 and February 2009.
• Patients were recruited from 88 sites in Poland, India, France,
Germany, Spain, Italy, Switzerland, Hungary, Finland, The
Netherlands, Belgium, and the United Kingdom.
Epilepsia. 2014;55(1):47–56 N01252
14. Primary efficacy outcome: Percent reduction in
seizure frequency per 28 days vs placebo
• Percent reduction of baseline adjusted POS
frequency/28 days versus placebo in India subset
analysis was numerically greater than global data.
10.2 9.2
20.5
36.7
42.8
48.7
BRV 20mg/day BRV 50mg/day BRV 100mg/day
Global Indian
N=99 n=22 N=99 n=22 N=100 n=23
Percentreductionofseizuresover
placebo(%)
15. Secondary efficacy outcome: ≥50% Responder rate
• Numerically greater ≥50% responder rates were seen in
three BRV groups compared to Placebo.
27.3 27.3 27.3
45.5
40.9
47.8
BRV 20mg/day BRV 50mg/day BRV 100mg/day
Global Indian
N=99 n=22 N=99 n=22 N=100 n=23
50%responderrate
16. N01252 Safety : India dataset
PBO
BRV
20mg 50mg 100mg BRV
Overall
(N=23) (N=22) (N=22) (N=23) (N=67)
n (%)
Subjects with at least 1 AE 7 (30.4) 9 (40.9) 8 (36.4) 10 (43.5) 27 (40.3)
Subjects with TE SAEs 2 (8.7) 0 1 (4.3) 1 (4.3) 2 (3.0)
TEAE in at least 2 subjects
General disorders and administration site conditions
Pyrexia 0 2 (9.1) 1 (4.5) 0 3 (4.5)
Infections and infestations
Nasopharyngitis 0 3 (13.6) 0 1 (4.3) 4 (6.0)
Nervous system disorders
Headache 0 3 (13.6) 4 (18.2) 1 (4.3) 8 (11.9)
Dizziness 0 2 (9.1) 1 (4.5) 0 3 (4.5)
Convulsion 0 2 (9.1) 0 0 2 (3.0)
Respiratory, thoracic and mediastinal disorders
Cough 0 1 (4.5) 0 2 (8.7) 3 (4.5)
AE=adverse event; BRV=brivaracetam; ITT=intent to treat; PBO=placebo
18. Pharmacokinetics: BRV vs LEV
18
LEV BRV
Absorption Rapid and complete, no food effect
Permeability BRV is more lipophilic than LEV, and therefore more permeable
Distribution Body water volume
Protein binding Negligible
Half-life 7 hours1 9 hours3
Metabolism Hydrolysis
Hydrolysis (1ary) + CYP2C19
(2ndary)3
IV dosing
infusion, in 100 mL
diluent1
Bolus, no diluent
infusion, in a compatible diluent3
Renal Impairment Dose reduction No dose reduction
Hepatic impairment
50% dose reduction in
severe HI
25% dose reduction in all grades
of HI
19. Concomitant use of BRV with LEV
191) Ryvlin P et al. Epilepsia 2014;55:47-56; 2) Biton V et al. Epilepsia 2014;55:57-66; 3) Klein P et al. Epilepsia 2015;**(*):1-9. 4) UCB, data
on file
Treatment
Clinical
benefit
Additional
safety concerns
LEV naïve Yes None
Previously failed
LEV
Yes None
Concomitant
LEV
No None
*A total of 152 patients were on
concomitant levetiracetam. Patients on
levetiracetam were excluded from one of
the 3 phase III clinical studies.1-3
20. ≥50% responder rate in subjects discontinuing LEV1
≥50% Responder Rate by LEV Status
20
• Concomitant LEV use was not permitted
• ITT population N=760
• p-value vs PBO
• 1Adapted from: Klein P et al. Epilepsia, 2015;56(12):1890–1898
• 2Brivaracetam SmPC. Available online at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003898/WC500200206.pdf. Last updated 25/01/2016. Last accessed 25/01/2016
96 28 26 23
Due to Insufficient
Efficacy
Due to
Adverse Event
≥50%ResponderRate(%)
For Any Reason
≥50%ResponderRate(%)
50.9
45.2
16.8
28.7 31.3
11.5
26.7
22.9 25.0
34.6
52.2
96 86
p<0.001
p=0.008
p=0.016 p=0.007
116 116 115 143 136 134
Efficacy of BRV is seen even in patients who have taken LEV earlier
Better efficacy was seen in patients who have discontinued LEV due to AE
Efficacy was also seen in patients who discontinued due to lack of efficacy of LEV.
n= n= n=
27..6
21. Switching from LEV to BRV owing to intolerable BAEs
21
• Phase IIIb, open-label, single-arm, prospective study
• Adults with benefit with LEV but experiencing intolerable BAEs
LEV 1000–3000 mg/day
Treatment period
(12 weeks open-label)
120
BRV 200 mg/day
(dose adjustment within
50–200 mg/day allowed)
−16
LEV to BRV switch
Retrospective baseline
(16 weeks)
Baseline
Treatment period
Entry into open-label LTFU study
Down-titration (4 weeks)
Drug-free (2–3 weeks)
BAE, behavioural adverse events
Key results
•27/29 (93.1%) had reduction in BAEs, no worsening of seizures
•18/29 (65 %) total abatement of BAEs
•Median time to resolution: 15 days after first BRV dose
•Improved HRQoL as indicated by a mean (SD) increase of 12.1
Yates SL, et al. Epilepsy Behav 2015;52:165−168
23. Patients were eligible for entry into the LTFU studies if the investigator believed
that a reasonable benefit could be expected from long-term BRV administration
Adults and children aged ≥16 years old, from phase IIb and phase III trials of
adjunctive BRV having POS uncontrolled on 1–3 AEDs.
Of 2,186 patients who received BRV, 2,051 (93.86%) patients completed their
core studies and continued in LTFU studies. The core studies were conducted
between May 2005 and May 2014.
Patients were recruited from Europe (1,055; 49.3%), North America (427;
19.5%), Asia Pacific/other countries (433; 19.8%), and Latin America (271;
12.4%).
Study design and Patient disposition
• Toledo M, et al. Epilepsia 2016;57:1139–1151
24. Long-term retention
24
1 year & 5 year retention rates was 79.8% & 54.4%,
maintained for >8 years
• Toledo M, et al. Epilepsia 2016;57:1139–1151
25. Median Reduction from Baseline (%)
25
• Baseline median POS frequency/28 days was 8.9
• Overall median percentage reduction from baseline in POS/28 days
Increased over time from 43.1%(1–3 months) to 77.0% (58–60 months)
• Toledo M, et al. Epilepsia 2016;57:1139–1151
26. ≥50% Responder Rate
26
• The percentage of patients with a ≥50% reduction in POS
frequency from baseline (≥50% responder rate) increased from
43.5% for 1–3 months to 71.0% at 58–60 months
• Toledo M, et al. Epilepsia 2016;57:1139–1151
27. Summary of TEAEs and most commonly reported TEAEs for BRV
modal dose groups 50–200 mg/day (safety population; N = 2,186)
27
• Toledo M, et al. Epilepsia 2016;57:1139–1151
29. Real world data of BRV
• Retrospective multicenter centre study involving university hospitals in
3 different German cities.
• At least 3 months of follow up.
• Responses were defined as 25%, 50% and 75% reduction in seizures
during follow up compared to 3 months baseline.
• All patients who were exposed to at least one dose of BRV were
included.
• Exclusion criteria: Lack of follow up
Epilepsia. 2017 Jul;58(7):1208-1216.
30. Baseline demographics
Characteristics
Total number of patients with at least 3 months of follow up 262
Mean age
<18 years
18-64 years
>65
40 ± 16 years
9
237
25
Focal epilepsy with or without secondarily generalized
Idiopathic (genetic) generalized epilepsy (IGE)
Symptomatic generalized epilepsy
Unclassified
87%
7%
3%
3%
Mean epilepsy duration 21.6 ± 14.7 years
Mean seizure frequency 25.0 ± 47.9
seizures per
month
Mean number of AEDs 2.4 ± 0.9
LEV (n = 133) mean dose 2,397 mg/day
31. Switching
• 245
133 133
LEV BRV
Mean dose = 2.4 g/day Mean dose = 168.6 mg/day
Most frequently prescribed drugs before initiation or switch to BRV
• Lamotrigine (n = 84, 32.1%, mean dose 363 mg)
• Lacosamide (n = 53, 20.2%, mean dose 347 mg)
• Valproate (n = 51, 19.5%, mean dose 1,392 mg)
• Zonisamide (n = 33, 12.6%, mean dose 326 mg)
• Oxcarbazepine (n = 26, 10%, mean dose 1,460 mg)
• Topiramate (n = 24, 9.2%, mean dose 308 mg)
32. Cumulative Retention Rate
32
Real world experience data in 262 patients show a retention rate of
75.8% at 6 months
Epilepsia. 2017 Jul;58(7):1208-1216.
34. Treatment-emergent adverse effects
• Intolerable TEAEs leading to discontinuation were
• Sedation: 8 pts.
• Dizziness: 8 pts.
• Mood change: 5 pts.
• Nausea or vomiting: 3 pts.
• Improvement of LEV-related adverse events was reported = 58.8%
• Nonpsychotic BAE improved = 57.1%
• Sedation improved = 70.8%
Epilepsia. 2017 Jul;58(7):1208-1216.
35. Key points from real world data
BRV in broad real world clinical use is a well-tolerated anticonvulsant drug with 50%
responder rates, similar to those observed in the regulatory trials even though 90% of the
patients included had previously been exposed to LEV.
Real World study data in 262 patients show a retention rate of 75.8% at 6 months
and 50 % percent responder rates of 40.5% & 15.3% seizure freedom for 6 months
Immediate switch from levetiracetam to brivaracetam at a 10:1 to 15:1 ratio is
feasible without titration
Switch can alleviate levetiracetam-induced behavioral adverse events
The main adverse events are somnolence, dizziness,and behavioural adverse
events
37. In total, 15 RCTs were included. All the studies contained a baseline and
treatment phase. The pooled OR of all newer AEDs vs placebo was 2.16
(95%CI: 1.82, 2.57) for responder rates, 1.54 (1.12, 2.10) for withdrawal rates, 1.67
(1.34, 2.08) for adverse effects.
Conclusions: The indirect comparisons suggested BRV, followed by RTG,
might be more effective than all other newer AEDs.
38. NNT - Comparison with other newer AEDs
Drug NNT
ESLICARBAMAZEPINE 5.88 (4.55, 8.33)
RETIGABINE 5.26 (3.85, 8.33)
LACOSAMIDE 6.25 (4.76, 9.09)
BRIVARACETAM 3.85 (2.56, 7.14)
PERAMPANEL 9.09 (4.17, 50.00)
38
• Number Needed to Treat
• Lower Number Needed to Treat (NNT )
better is the efficacy response
Gao L. et al . Epilepsy Research (2013) 103, 31—44
41. Comparing Safety and Efficacy of ‘‘Third-
Generation’’ Antiepileptic Drugs: Long-Term
Extension and Post-Marketing Treatment
Charlotte S. Kwok, Emily L. Johnson, Gregory L. Krauss
CNS Drugs : published online 4th Dec 2017
A review article highlighting the differences among the third
generation AEDs based on their clinical trial, long term
extension studies, and real world data.
42. Real world data : ≥50% responder rates at 1 & 2 yrs of exposure
≥50% responder rates at 1 and 2 years of exposure during adjunctive
treatment of POS: pooled extension studies for four new AEDs.
43. Retention rates at 1 and 2 years during adjunctive treatment
of POS from pooled extension studies for 4 new AEDs
AED antiepileptic drug, BRV brivaracetam, ESL eslicarbazepine acetate, LCM lacosamide, PER perampanel. † No 2-year extension study outcome data
available for ESL. *Retention data for BIA-2093-301 and BIA-2093-302 only
45. Indications
• Monotherapy in partial onset seizures with or without secondary
generalization in adults and children above 4 years of age.
• It can be used in patients who are LEV naïve or who have failed LEV
due to efficacy or tolerability reasons.
• Adjunctive therapy in partial onset seizures in adults and children.
46. Dosing : BRV is initiated without titration
• Gradual dose escalation is not required with BRV.
• Based on individual patient response, the dose may be
adjusted between 25 mg twice daily (50 mg/day) and
100 mg twice daily (200 mg/day).
• BRV offers a therapeutic dose on Day 1.
46
Brivaracetam [packageinsert]. Smyrna, GA: UCB, Inc.; March2016.
The recommended starting
dose of 100 mg/day
(50 mg twice daily) can be
initiated without titration
47. • Brivaracetam SmPC. Available online at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003898/WC500200206.pdf. Last updated 25/01/2016. Last accessed 25/01/2016
Administration
Instructions
• Oral tablets may be taken with or without food.
• No dose adjustment is needed in elderly patients
• Dose adjustments are not required for patients with renal
impairment.
• BRV is not recommended in ESRD patients on dialysis
• Maximum daily dose of 150 mg/day is recommended for
all stages of hepatic impairment. 50 mg/day starting dose
should be considered ( 25% reduction )
47
48. No significant drug interactions
48
Effects of BRV
• No significant effect on other AEDs, OCPs, other medications.
Effects on BRV
• Rifampicin : Strong hepatic enzyme inducer reduces BRV exposure by
45%. Therefore BRV dose may have to be doubled.
49. Summary
• Brivaracetam a newer SV2A ligand with high affinity and faster penetration.
• Effective from day 1 with no dose titration required to reach therapeutic dose.
• Selective effect on SV2A may explain less behavioral adverse effects.
• BRV is well-tolerated, with minimal drug interactions.
• Can be used in patients with hepatic and renal disease.
• Indicated as monotherapy in POS with or without generalization, in adults
and children > 4 years of age.
• Effective in LEV naïve patients and those who had previous exposure to LEV.
