Convegno Regionale SIN SNO Lazio. Dai trial alla pratica clinica: novità in terapia dell epilessia

Transcription

1 Convegno Regionale SIN SNO Lazio Dai trial alla pratica clinica: novità in terapia dell epilessia Roma, 24 Novembre 2017

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3 Response to optimally used AED therapy Initial monotherapy Seizure-free:50% Altern. monotherapy Seizure-free:15% First add-on therapy Seizure-free:10% Other add-on therapy Seizure-free: 5% Perucca 1998; Brodie e Kwan 2000, 2010; Schiller e Najjar 2008

4 Possible determinants of antiepileptic drug resistance in human and experimental epilepsies Etiology Epilepsy severity Morphological (network) alterations Worsening epilepsy patterns Drug related factors (e.g,, tolerance) Psychiatric comorbidities RESPONSE TO ANTIEPILEPTIC DRUGS Alterations in glial functions Drug-target alterations Inflammatory processes Alterations in drug efflux transporters Genetic factors Modified from Schmidt D & Schachter SC, BMJ 2014

5 Therapeutic approaches for epilepsy Pharmacological approach AEDs Other Non-Pharmacological approach Resective surgery VNS DBS RNS Neurostimulation Stereotactic approaches Radiosurgery Thermocoagulation Non-pharmacological, non-surgical approaches Botanicals, nutrition, etc.

6 The modern approach to the management of refractory epilepsy Reconsider diagnosis and drug selection, exclude pseudo-refractory epilepsy Consider eligibility for surgery at an early stage Optimize combination therapy targeted therapies? Consider non pharmacological measures Address comorbidities

7 Treating epilepsy in 2017: the bright side Two thirds of pts achieve seizure freedom with available AEDs, usually with little o no side effects Available AEDs differ in efficacy spectrum, side effects and impact on comordities opportunities to tailor treatment choices Good knowledge how to combine AEDs more effectively in difficult-to-treat pts There have been advances in identifying pts eligible for epilepsy surgery

8 Treating epilepsy in 2017: the dark side About one third of pts are drug-resistant (the same as in the 40s) None if the existing AEDs is ideal in terms of ease of use and tolerability Currently available AEDs suppress symptoms but do not affect the underlying disease Using the best an armamentarium of 25 AEDs is a challenge and the risk of suboptimal use is significant

9 Chronological development of antiepileptic drugs Golyala A & Kwan P. Seizure 2017

10 Antiepileptic drugs (AEDs) available in Europe until 2017 Generation First Acetazolamide Carbamazepina Clobazam Clonazepam Diazepam Ethosuximide Phenitoin Phenobarbital Lorazepam Primidon Valproate Second Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Tiagabine Topiramate Vigabatrin Zonisamide Third Rufinamide Stiripentol Lacosamide Eslicarbazepine Retigabine Perampanel Brivaracetam

11 Mechanisms of AEDS: target synaptic neurotransmission Mechanism AED Site of action AE property Sodium channel blockers Phenytoin Carbamazepine Oxcarbazepine Eslicarbazepine Lamotrigine Lacosamide Presynaptic axon, voltage-gated sodium channels Blockade of highfrequency action potentials neurotransmitter release Neuronal Cachannel binding Gabapentin Pregabalin Multiple sites -- Vescicle release Levetiracetam Brivaracetam Presynaptic bouton (SV2A and 2 ) Presinaptic transmission GABA degradation blockade Vigabatrin Presynaptic bouton Presynaptic GABA pool GABA reuptake blockade Tiagabin Synaptic cleft/surround GABA [C] in synaptic cleft GABAA modulation Phenobarbital Benzodiazepines Postsynaptic GABA receptors post-synaptic Cl influx via GABAAR Modified from Schulze-Bonhage A., Ex. Opin. On Pharmacoth. 2017

12 Mechanisms of AEDS: target synaptic neurotransmission Mechanism AED Site of action AE property Antiglutamatergic Perampanel Postsynaptic AMPA receptor Na+ /Ca2+ influx via AMPA rec. Antiglutamatergic Felbamate Postsynaptic NMDA rec Na+ /Ca2+ influx via NMDA rec Neuronal hyperpolarization Regigabine Ezogabine Postsynaptic voltagegated K+ channels (KCNQ2) K+ efflux by M- current activatio Multiple mech./unspecified Valproate Topiramate Zonisamide Modified from Schulze-Bonhage A., Ex. Opin. On Pharmacoth. 2017

13 Mechanisms of AEDS: target synaptic neurotransmission Drug Mech. of action Absorption (bioavaib. %) Protein binding (%) Half life Metabolism & elimination Indications Lacosamide Low inactivation of sodium channel Rapid (95 100) <15 13 Hepatic metabolism Partial onset Eslicarbazepine acetate Sodium-channel blockade Rapid (90) Glucuronidation, Partial onset renal excretion Perampanel Non-competitive AMPA- receptor antagonist Rapid (100) Glucuronidation, feces, urine Partial onset PGTCS Brivaracetam Binds to SV2A receptor Rapid (100) < Renal excretion Partial onset Golyala A & Kwan P. Seizure 2017

14 N previous AEDs N Pts Responder rate (%) 1 AED N = AEDs AEDs Holtkamp et al., Acta Neurol Scand 2016

15 N=113 pts with partial seizures (4 szs/month), 1-4 AEDs, median of used AEDs = 3 (0-7) Seizure freedom >6 months = 26.2%, median dose = 100 mg/die (50-300) Seizure freedom in 15/36 pts (41.7%) receiving LCM as first add on

16 N = 571; 45.5% seizure-free, 70% responders

17 Seizure freedom according to antiepileptic drug schedule N = 707

18 LCM with/without Na channels blockers AEDs Post-hoc exploratory analysis SCB+ Pooled data pivotal trials II/III phases (N=1308) SCB+ 82% SCB- 18% SCB- Sakè et al, CNS Drugs 2010

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21 N = % in frequency of SG seizures in patients treated for at least 2 years (N=141)

22 Conclusions Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE Classification of evidence This study provides Class I evidence that adjunctive PER reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE

23 Seizure freedom: 4.9% placebo vs 23,5% perampanel

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25 Steinhoff BJ, Hamer H, Trinka E, Schulze-Bonhage A, Bien C, Mayer T, Baumgartner C, Lerche H, Noachtar SA A multicentre survey of clinical experiences with perampanel in real life in Germany and Austria. Epilepsy Res 2014;108: N=281

26 N = 464 pts Higher % of seizure-free patients in the group receiving 2 concomitant AEDs at onset vs those receiving >2 concomitant AEDs (10.4% vs 5.1%) Similar result for responders: 32.8% vs 23.2% Villanueva V et al., Epilepsy Research 2016

27 N =1478

28 N =768

29 N = 1160 Ben-Menachem E et al., Neurology 2016

30 N262 patients, retention rate of 75.8% at 6 months 50% responder rates of 40.5% (15.3% seizurefree) for 6 months Immediate switch from LEV to BRV at a 10:1 to 15:1 ratio Reduction of LEV-induced behavioral adverse events Main adverse events: somnolence, dizziness, behavioral disorders

31 BRV: adverse events Steinig I et al., Epilepsia 2017

32 Brief overview of 3 rd generation AEDs in clinical practice Drug Strength Weakness Eslicarbazepine acetate Lacosamide Perampanel Good effectiveness Good safety profile Single dose Use in elderly Good effectiveness Good safety profile Monotherapy i.v. formulation (SE) Use in elderly Synergy with VPA e LEV? Good effectiveness Good safety profile Single dose Wide spectrum (IGE) Use in elderly Available as add-on only Limited prescription (PT) Side effects in combination with other SCB Not completely known spectrum Available as add-on only Some interactions Possible worsening seizures Psychiatric side effects Brivaracetam Good effectiveness Good safety profile Rapid action Wide spectrum Use in elderly i.v. formulation (SE) Available as add-on only Delay in marketing Psychiatric side effects Lack of real life experience in Italy

33 Therapy for epilepsy beyond AEDs Immunomodulation (steroids, IVIG, monoclonal Ab) Multiple pathways acting compound (ketogenic diet) Autoimmune epilepsies Glut1 deficiency syndromes Multiple, poorly known, mechanisms drugs (cannabis) mtor pathways (Everolimus) Tuberous sclerosis

34 Cannabis: state of art

35 Pharmacology of cannabinoids in treatment of epilepsy Gaston TE Friedman D, Epilepsy and Behav 2017

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37 Non-pharmacological approach in drug-resistant epilepsy Resective surgery in selected patients (e.g. MTLE, dysplasia) Neuromodulation (VNS, DBS, RNS) Stereotactic approaches (radiosurgery, thermocoagulation) Other (e.g. MR-guided focused ultrasound MRI-guided laser interstitial thermal therapy)

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39 Overview of the pathophysiology of epileptogenesis Clossen BL, Reddy DS. Biochimica et Biophysica Acta 2017

40 Selected compounds currently under clinical investigation Developmental approach Name of compound Mechanism of action Mechanisms of action similar to those of marketed AEDs Ganaxolone Allopregnanolone (SAGE-547) Selurampanel (BGG492) ICA YKP3089 (cenobamate) GABA receptor modulator GABAA receptor modulator Compet. Antagonist AMPA/kainate rec Selective opener of neuronal Kv7 K ch. Novel mechanisms of action Beprodone Huperzine A Agonist of the melatonin type 3 rec. Inhibitor of AChE receptor Repurposed compounds which were initially developed for treatment of other diseases Everolimus Fenfluramine Nalutozan Pitolisant Quinidine Valnoctamide Verapamil Selective inhibitor of mtor path. Serotonin reuptake inhibitor Nonazapirone 5-HT1A partial agonist Histamine 3 receptor antagonist Partial antagonist of KCNT1 GABAA receptor agonist Inhibitor of P-glycoprotein Unknown mechanisms of action JNJ Multiple, unknown Golyala A & Kwan P. Seizure 2017

41 Novel therapeutic approaches for disease-modification of epileptogenesis mtor pathway Neuroinflammation Neurosteroids Neuropeptides Adenosine pathway Stem cell therapy Interruption of JAK-STAT pathway Epigenetic inhibition of epileptogenesis Ketogenic diet inhibition of epileptogenesis

42 Progress report on new antiepileptic drugs EILAT XIII Adenosine Allopregnanolone Injection (SAGE-547) Bumetanide and Its Derivatives Cannabidiol Cannabidivarin 2-Deoxy-D-Glucose Everolimus Fenfluramine HCl (ZX008) FV-082 Ganaxolone Huperzine A (BIS-001) Minocycline NAX OP-2198 SAGE-217 SAGE-689 Valnoctamide and sec-butylpropylacetamide Bialer M et al.,. Epilepsia 2017

43 Conclusions New AEDs have provided incremental progress in controlling epileptic seizures Recent AEDs with synaptic targets have improved tolerability more than efficacy Drugs in the pipeline also address extrasynaptic mechanisms Ongoing drug development focused on modulation of additional pathways relevant for epileptogenesis and disease progression First available drugs interfering with disease specific mechanisms of epileptogenesis (mtor inhibitors)