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NOVEL ANTIEPILEPTIC DRUGS
Amr Hassan M.D.,FEBN Associate professor of Neurology - Cairo University
Antiepileptic drug development
eslicarbazepine Perampanel Retigabine Rufinamide Vigabatrin
20 Lacosamide Pregabalin Zonisamide Levetiracetam Levetiracetam Tiagabine Oxcarbazepine 15 Topiramate Fosphenytoin Lamotrigine Gabapentin 10 Felbamate Sodium Valproate Carbamazepine Ethosuximide Benzodiazepines 5 Phenytoin Phenobarbital Primidone
Bromide Number of Licensed Antiepileptic Antiepileptic Drugs ofLicensed Number 0 1840 1860 1880 1900 1920 1940 1960 1980 2000 Calendar Year 2 Do we need more new epilepsy drugs?
Seizure control New drugs Safety/tolerability
Compliance OD dosing, XR formula
ARS and SE Rapid drug delivery
Detection and New Devices Prediction of seizures How do we make progress?
Evolutionary Drugs • Improve on existing drugs
Revolutionary Drugs • Drugs that work with new mechanisms never tried before
4 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 5 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 6 Brivaracetam (BRV)
Company: UCB
Approval Status: Approved February 2016
7 Brivaracetam (BRV): Mechanism of Action
Brivaracetam
Inhibitory synapse Excitatory synapse
8 Brivaracetam (BRV)
• A novel high-affinity synaptic vesicle protein 2A (SV2A) ligand. • Also displays inhibitory activity at neuronal voltage- dependent sodium channels. • Adjunctive treatment of adults with POS.
1.Kenda et al. J Med Chem 2004;47:530–549 2.Zona et al. Epilepsy Res 2010;8846–54 9
Brivaracetam (BRV): (Briviact)
10 Brivaracetam (BRV) Levetiracetam
• Company: Aprecia Pharmaceuticals Company
• Approval Status: Approved August 2015
• a 3D printed drug product
12 ZipDose Technology using 3D printing: How it’s made
13 Levetiracetam (Spritam)
14 Topiramate Extended-Release Formulation
Company: Upsher-Smith Laboratories
Approval Status: Approved March 2014
Specific Treatments:
• Partial onset and primary generalized tonic-clonic seizures
• Lennox-Gastaut Syndrome
15 Topiramate Extended-Release Formulation (Qudexy XR )
16 Eslicarbazepine Acetate (Aptiom)
• Company: Sunovion Pharmaceuticals
• Approval Status: Approved November 2013
• Indications:
Partial-onset seizures
17 Eslicarbazepine Acetate : Mechanism of Action
Eslicarbazepine
Inhibitory synapse Excitatory synapse
18 Oxcarbazepine extended release
• Company: Supernus Pharmaceuticals
• Approval Status: Approved October 2012
• Indications:
Partial seizures in adults and in children 6 years to 17 years of age
19 Oxcarbazepine extended release (Oxtellar XR )
20 Perampanel
• Company: Eisai Inc.
• Approval Status: Approved October 2012
• Indications:
Partial-onset seizures
21 Perampanel
Perampanel
Inhibitory synapse Excitatory synapse
22 Perampanel (Fycompa®)
23 Perampanel (Fycompa®)
•Serious Psychiatric Changes •Behavioral Changes •Homicidal Or Suicidal Thoughts. Ezogabine = Retigabine
• Company: Valeant Pharmaceuticals
• Approval Status: Approved June 2011
• Indications: Partial-onset seizures
25 Retigabine: Mechanism of Action
Retigabine
Retigabine
Inhibitory synapse Excitatory synapse
26 Ezogabine = Retigabine (Potiga)
27 Rufinamide
• Company: Eisai Medical Research Inc.
• Approval Status: Approved November 2008
• Specific treatments: Lennox-Gastaut Syndrome
28 Rufinamide
29 Rufinamide: Mechanism of Action
Rufinamide
Inhibitory synapse Excitatory synapse
30 Rufinamide (Banzel)
31 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 32 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 33 Seletracetam(SEL)
34 Selurampanel
• Phase II.
• a competitive antagonist of the AMPA and kainate receptors.
• It has also been studied in the acute treatment of migraine(some pain relief, but with a relatively high rate of side effects
35 Bumetanide
NKCC1 inhibition
Neonatal seizures
36 Cannabidiol (Epidiolex)
March 14, 216 (GLOBE NEWSWIRE)
Dravet syndrome
37 Stiripentol (Diacomit)
Company: Laboratoires Biocodex
Approval Status: Not FDA approved
Specific treatments: Dravet syndrome
Stiripentol increases GABAergic activity.
It enhances central GABA neurotransmission through a barbiturate-like effect.
38
Ganaxolone
PCDH 19 female pediatric epilepsy
39 PCDH 19 female pediatric epilepsy
• Serious and rare epileptic syndrome.
• An inherited mutation of the protocadherin 19 (PCDH19) gene (X chromosome).
• Early-onset cluster seizures, cognitive and sensory impairment and behavioral disturbances.
40 IV Ganaxolone
April 15, 2016
Status epilepticus
41 Synthetic Huperzine A
• Company:Biscayne ph
• Derived from Chinese plant Chinese club moss • AchEI • Phase II 2016 CPS • Phase II 2017 Dravet syndrome
42 AED vs AEG
AED AED VS AEG AEG
43
Gene expression
Signaling pathways Epigenetics
(ICER) BDNF REST cAMP response miRNA element JAK-STAT mTOR (CREB) Gene expression
Signaling pathways Epigenetics
(ICER) BDNF REST cAMP response miRNA element JAK-STAT mTOR (CREB)
AEG Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 52 52 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 53 53 IV Carbamazepine (Carnexiv)
• Company: Lundbeck • Approval Status: Approved October 2016 • Lundbeck plans to make Carnexiv commercially available in the United States in early 2017.
54 Intrabuccal midazolam (epistatus)
55 Diazepam rectal gel (Diastat)
56 Diazepam auto-injector Diazepam auto-injector
58 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 59 59 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 60 60 Inhaled alprazolam
• Originator Alexza Pharmaceuticals
• Mechanism of Action GABA A receptor agonists
• Phase II
61 Staccato technology
62 Transdermal CBD gel ZYN002
63 Transdermal cannabidiol (CBD) gel
64 Intranasal midazolam
65 Intranasal Diazepam(Neurelis)
66 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 67 67 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 68 68 Triheptanoin in GLUT1 deficiency
GDD •
Epilepsy • Movement • disorders
69 Triheptanoin in GLUT1 deficiency
70 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 71 71 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 72 72 Responsive Neurostimulation
• FDA Approved
November 2013
• Adjunctive treatment for adults with medically refractory partial seizures Epilepsy Alarm Bed Seizure Detection
Anti-Suffocation Pillows
Watches
Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 77 77 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 78 78 Trigeminal nerve stimulation (TNS)
79 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 80 80 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 81 81 Eslicarbazepine acetate chemical structure
IV Lacosamide
IV Levetiracetam
Levetiracetam: Mechanism of action
Levetiracetam
Inhibitory synapse Excitatory synapse
85 Epilepsy’s new pipeline therapeutics
Marketed New Drugs Under Trial
New route Marketed (Enhanced Drug Under Trial Delivery)
Dietary Supplement Marketed New Therapeutic Devices Under Trial
New in Egyptian Market 86 86 DO WE NEED MORE NEW EPILEPSY DRUGS?
Seizure control New drugs Safety/tolerability
Compliance OD dosing, XR formula
ARS and SE Rapid drug delivery
Detection and New Devices Prediction of seizures Overcoming challenges !!
88
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