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Emerging therapies in Lennox-Gastaut Syndrome


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Tracy Dixon-Salazar, PhD presents on emerging therapies in LGS

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Emerging therapies in Lennox-Gastaut Syndrome

  2. 2. Tracy Dixon-Salazar, PhD Director of Research & Strategy Emerging Therapies & Clinical Trials in LGS
  3. 3. Overview 1. Introduction 2. New therapies i. Novel targets ii. Re-purposing iii. Re-visiting iv. Concept of precision therapies
  4. 4. Many types of clinical Trails in childhood epilepsy exist 0 2 4 6 8 10 12 14 16 Partial epilepsy No.ofRCTs GTC LGS Infantile spasms JME Absence Neo- natal SMEI Updated from NICE HTA newer AEDs 2005
  5. 5. 13 trails done in LGS • Cochrane review 2013 Hancock & Cross • 13 RCTs, 9 available – Cinromide N=56 2-17 yrs (7.5) – Felbamate N=73 4-36 yrs (13) – TRH N=98 ? – Lamotrigine N=169 3-25yrs (9) – Lamotrigine N=20 – Topiramate N=98 2-42yrs (11.2) – Rufinamide N=139 4-30 yrs – Clobazam N=68 – Clobazam N=217 2-60 yrs
  6. 6. Conclusions: Cochrane review of LGS Trials done • Optimum treatment for Lennox-Gastaut syndrome remains uncertain • No study has shown any drug to be highly efficacious in treatment of LGS • Lamotrigine, topiramate, felbamate and rufinamide may be helpful as add on therapy • Evidence base for one therapy over another limited; each patient needs to be considered individually, taking into account potential benefit of each therapy vs risk of adverse effects Hancock E, Cross H. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev 2013;CD003277.
  7. 7. LGS first line therapy – expert opinion Wheless et al, J Child Neurol 2005;20s1:s1-56
  8. 8. Cross, Auvin, Falip. Striano, Arzimanoglou 2017 submitted
  9. 9. Expectations of treatment and treatment response in epilepsy • Common disorder vs. rare disorder treatment • Treatment aim is seizure freedom; >50% reduction in seizures is considered successful • Achieved with the first drug in 70% • Achieved with the second drug in a further 10- 20%
  10. 10. New in treatment - Drugs i. Novel targets a. Neuronal synapse b. Other sites ii. Re-purposing drugs used in other diseases iii. Re-visiting drugs used for other epilepsies or abandoned in the past
  11. 11. Site of action of AEDs at the neuronal synapse Bialer & White; Nature Reviews Drug Discovery 2010: 68-82 •Consider a new drug which acts on a different site •Consider synergism
  12. 12. New sites of action • Perampanel – post-synaptic AMPA receptors • Cannabidiol – endocannabinoid system
  13. 13. Perampanel - highly selective, non-competitive, post-synaptic AMPA receptor antagonist Redrawn and adapted from [2] and [3].1Hanada et al. Epilepsia 2011;52:1331–1340; 2Rogawski MA, Löscher W. Nat Rev Neurosci 2004;5:553–564; 3Rogawski MA. Epilepsy Currents 2011;11:56–63. 13 Post-synaptic neuron Pre-synaptic neuron Inhibitory interneuron Post-synaptic excitability AMPA receptor Glutamate NMDA receptor
  14. 14. % of patients achieving ≥50% reduction from baseline in seizure frequency/28 days *P<0.05 vs placebo **P<0.005 vs placeboN=45 N=21 N=13 N=44 N=20 ITT population: studies 304,305 &306, pooled. Double-blind phase 1Data on file, Eisai Inc; 2Rosenfeld et al. 2012 CNS; 3ISE Table 14.2. 2.2 Responder rate 14 Responderrate(%) Overall Population1 N=1478 Adolescents (306)2 N=60 Adolescents (304 & 305)2 N=83 Adolescents (Pooled)3 N=143 N=441 N=180 N=172 N=431 N=254 N=14 N=21 N13 N=12 N=31 N=32 N=20 Adolescents * * * * * Krauss GL et al. Neurology 2012;78(18):1408--1415; French JA et al. Neurology 2012;79:589–596: French JA et al. Epilepsia. Epub 20 Aug 2012; 4Krauss GL et al. Epilepsia. Epub 20 Aug 2012.
  15. 15. Perampanel • It works • Even seizure freedom • Even 2mg can be helpful • Prevention of evolution to bilateral convulsive • Long half-life • Introduce very slowly Side effects • Aggression can prevent ongoing use • Dizziness to be expected • Can see overshoot • Interaction with other drugs – exacerbates lamotrigine side-effects Positive results
  16. 16. Cannabis • One of the most widely used recreational and medicinal drugs worldwide. – ~150 million people smoking cannabis daily (WHO) • Likely the first non-food plant cultivated by humans (~8000 BC) • Best known for its psychoactive constituent, Δ9- tetrahydrocannabinol (‘THC’).
  17. 17. Two major cannabinoids THC • analgesic, anti-spasmodic, anti-tremor, anti- inflammatory, appetite stimulant and anti-emetic properties CBD • Anti-inflammatory, anti- convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. • Lacks the psychotomimetic and psychotropic effects of THC • May alleviate some of the potentially unwanted side- effects of THC.
  18. 18. The endocannabinoid system • First described in the late 1980s/early 1990s • Endogenous ligands, receptors, synthetic and degradation enzymes • Cannabinoid receptors: – cell surface receptors – present on a wide variety of cell types. – two CBR types: • CB1: • CB2: • Endocannabinoids: • anandamide • 2-arachidonoyl glycerol • Numerous synthetic ligands for CB1Rs and CB2Rs have also been developed Anandamide 2-arachidonoyl glycerol (2-AG) Courtesy of Dr Ben Whalley
  19. 19. Cannabidiol in childhood epilepsy • 214 patients across 11 sites • safety & tolerability 167 • Adverse events 79% • 137 efficacy analysis Dravet N=32 49% responders, 3% SF LGS N=30 37% responders, 3% SF Lancet Neurology e-pub ahead of print 15th December 2015
  20. 20. Conclusion: cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Lancet Neurology 2016;15:270- 8 Safety analysis (N=162) Somnolence 41 (25%) Decreased appetite 31 (19%) Diarrhoea 31 (19%) Fatigue 21 (13%) Convuslsion 18 (11%) Increased appetite 14 (9%) Status epilepticus 13 (8%) Lethargy 12 (7%) Weight increased 12 (7%) Weight decreased 10 (6%)
  21. 21. AED interaction; clobazam 13/25 children CBD 2— 25mg/kg/day Mass General Hospital, Boston Norclobazam increased in 12/13 Side effects 10/13 • Drowsiness 6 • Ataxia 2 • Irritability 2 • Restless sleep 1 • Urinary retention 1 • Tremor 1 • Loss of appetite 1 Geffrey et al, Epilepsia, 56(8):1246–1251, 2015
  22. 22. Cannabidiol in LGS; RCT
  23. 23. Where are we now with cannabinoids? Efficacy • 50% responders, 3% seizure free – Devinsky, Lancet Neurology 2015 – Friedman, NEJM 2015 Emerging experience • Side-effects – Somnolence – Decreased appetite – Diarrhoea – Tremor • Interaction with clobazam – Geffrey, Epilepsia 2015 • Abnormal liver function • Up to 25-50 mg/kg/day • Tolerance
  24. 24. Neonatal epileptic encephalopathies 1 month 4 months0 1 year 6 months Epilepsy limited to females with mental retardation PCDH19 Early onset epileptic encephalopathy STXBP1, CDKL5, ARX, PLCB1, SLC25A22, SPTN1, SLC19A3 Early myoclonic encephalopathy Infantile epileptic encephalopathies KCNQ2 encephalopathy Epilepsy in infancy with migrating focal seizures SCN1A, KCNT1, PLCB1 Dravet syndrome SCN1A West syndrome CDKL5 in girls ARX in boys Copy Number Variants 8% Genetic basis of the Early Infantile Epileptic Encephalopathies Slide courtesy of Prof Helen Cross
  25. 25. Repurposing & precision therapies & re-visiting Loss of function mutations Gain of function mutations • SCN2A and SCN8A • Use sodium channel blockers – High dose phenytoin and carbazepine • SCN1A – Avoid sodium channel blockers – CBD – Revisting ‘old’ drugs
  26. 26. SCN1A and LGS - re-visiting fenfluramine • High doses used for obesity, heart valve thickening, taken off market • Effective for self-induced/photosensitive seizures – Boel, Neuropediatrics 1996 • Effective in Dravet syndrome – Ceulemans, Epilepsia 2012 • Mechanism uncertain: stimulates serotonin; 5HT2A agonist • Randomised placebo control trial for LGS in Europe and US
  27. 27. SCN1A and LGS - re-visiting fenfluramine
  28. 28. Summary • Treatment options for LGS continue to expand – Perampanel, Epidiolex (CBD), Fenfluramine trials – Other drugs in earlier stages of development – Using specific drugs to treat specific genetic forms of epilepsy continues to progress
  29. 29. Thank you!
  30. 30. Fenfluramine (ZX008) LGS Phase 3 Study L G S F a m i l y & P r o f e s s i o n a l C o n f e r e n c e : E m e r g i n g T h e r a p i e s & C l i n i c a l T r i a l s D r . K e l l y K n u p p N o v e m b e r 2 0 1 7
  31. 31. 31 Background: Fenfluramine in Epilepsy & LGS • Timeline: – Early 1980’s – initial case reports on potential utility for epilepsy – 2012- Reported effectiveness in a cohort of DS patients in Belgium – 2016 – Zogenix Initiates Phase III DS Program – 2016 – AES poster presentation – Pilot LGS Open-Label Study • Median 50% reduction in Major Motor Seizure Frequency – 54% with > 50% reduction • The most common treatment-emergent AEs reported: – Decreased appetite (n=3; 23%) – Decreased alertness/fatigue (n=3; 23%) – Insomnia (n=2; 15%) – 2017 – Zogenix to Initiate Phase III LGS Study
  32. 32. 32 ZX008 LGS Phase III: Study Design • Part 1 – Placebo Controlled • Part 2 – Open Label Long-Term Safety 12 Months All on Active Study Drug Baseline 4 weeks Titration 2 weeks Maintenance 12 weeks Transition to Part 2 or Taper 2 weeks Randomize Placebo ZX008 0.8 mg/kg/d ZX008 0.2 mg/kg/d
  33. 33. 33 ZX008 LGS Phase III: Key Inclusion Criteria • Male or female, age 2 to 35 years • Diagnosis of Lennox-Gastaut syndrome, where seizures that result in drops are not completely controlled by current antiepileptic treatments (Add-on Treatment) – If on Ketogenic Diet or VNS therapy, must be stable for 4 weeks prior to screening • Subjects must meet all of the following 4 criteria: – Onset of seizures at 11 years of age or younger – Multiple seizure types, including countable motor seizures that result in drops – Abnormal cognitive development – Characteristic EEG Pattern consistent with LGS • Seizure Frequency Prior to Screening – must have had at least 8 drop seizures in the last 4 weeks prior to inclusion • parent/guardian report to investigator or investigator medical notes
  34. 34. 34 ZX008 LGS Phase III: Key Exclusion Criteria • Subject only has drop seizures in clusters, where individual seizures cannot be counted reliably. • Current or past history of cardiovascular or cerebrovascular disease or pulmonary hypertension • Positive result on urine tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at the Screening Visit • Subject does not have a reliable caregiver who can provide seizure diary information throughout the study.
  35. 35. 35 Study Site Locations - 2017 Phillips Tacoma, WA Zupanc Orange Co, CA Perry Fort Worth, TX Laux Chicago, IL Thiele Boston, MA Marsh Philadelphia, PA Sullivan San Francisco, CA Devinsky Livingston, NJ Miller Miami, FLTalwar Tucson, AZ Connolly Vancouver, BC Joshi Aurora, CO Sweney Salt Lake City, UT Smith St. Paul, MN Davis Orlando, FL Flamini Atlanta, GA Burdette Grand Rapids, MI Renfroe Gulf Breeze, FL Expected to be open by end of the year
  36. 36. 36 Additional Information • If you are interested in participating or would like more information: – – will be posted soon –Contact Betty Quarles, Associate Director, Clinical Operations • 510-550-8308 • •
  37. 37. Inside the LGS Brain Brenda Porter MD, PhD
  38. 38. LEFT RIGHT NOT Seizure Background
  39. 39. Tonic Seizure
  40. 40. Atonic Seizure
  41. 41. Three Patients all LGS • Etiology: All different, one had encephalitis at 3 months with prolonged status epilepticus. One has a mutation in the SCN2A gene. One has no known cause. • They all have seizures that are called generalized, that means both sides of the brain seem to have simultaneous discharges. • This is a key feature of LGS-generalize EEG abnormalities.
  42. 42. Hemispheric synchrony
  43. 43. Corpus Callosotomy
  44. 44. Decrease in Drop Seizures Following CC • Graham D Graham D et al. 2017
  45. 45. Development • Adults do not develop LGS. • Infants and young children develop LGS. – There often is a progression of seizure types with age. – Young infants will have focal or infantile spasms then go on to develop the key generalized seizures of LGS, Tonic and Atonic seizures. – Why does the developing brain develop this aberrant synchrony?
  46. 46. Multiple Etiologies • Genetic-25-50% • Lesion Genetic- 10-20% • Lesion injury (early in life)-25% • Somehow a change in the brain, often the cortex that is present early in life and possibly only on one side can cause the whole brain or at least both sides to have a discharge simultaneously.
  47. 47. Hemispheric synchrony
  48. 48. Conceptualizing Lennox–Gastaut syndrome as a secondary network epilepsy Archer et al 201
  49. 49. Take home points • LGS is due to a usurping of the normal networks that develop in childhood. Abnormalities in the cortex in one or many sites can drive the aberrant connections. The network becomes “to linked” and that causes seizures and cognitive problems.
  50. 50. So what to do? • If there is a cortical driver take it out. – Clear from TS and focal developmental disorders and the first patient I showed with encephalitis you can find cortical drivers in the network and removing them can improve seizures and (cognition?). • Earlier you take it out the better (probably) • What about manipulating the network? A work in progress?
  51. 51. Network Modulation • Electrical-Deep Brain Stimulation- Unclear still what target though the thalamus is the most often targeted site. • Genetic- There are at least 40 companies currently in phase 1-2 trials for gene replacement. Though rare in brain disorders, at least 2 are showing success.
  52. 52. Epilepsy Team • Neurologists • Nurses Neurosurgeons Dieticians • Neurodiagnostic Technologist • Genetic Counselor • Study Coordinators