1. What’s New in Epilepsy Therapy Research?
Evan Fertig, MD
Director JCMC Epilepsy Center
Director of Research
Northeast Regional Epilepsy Group

2. Outline Why is Epilepsy Research Important? What is a Clinical Trial?
Epilepsy Medications under Study at NEREG
New Surgical Approaches for Epilepsy
ESCLI
848
Ganaxolone

3. Case #1: Why Epilepsy Research is Important
Todd age 15
Grand mal seizures occur daily
Last MD told mom nothing else to do
He is on 2 anti-seizure medications with bad side effects, doing poorly in school
Second opintion. Names and ages were changed to protect the innocent
MD told him

4. More about Todd…
One of his medication is carbamazepine which is a sodium channel blocker
Video-EEG: Seizures coming from multiple areas of his brain
MRI Brain: Normal

5. We learn that… Seizures began 6 months with fever
Seizures occur more in the summer or with vigorous exercise (gym)
New genetic blood test sent: sodium channel mutation!

6. What’s Todd’s Diagnosis?
Dravet Syndrome
Caused by a genetic problem with a brain protein (sodium channel). This was not understood before!
Symptoms: Bad febrile seizures, then multiple sz types, worsens with sodium channel blockers
Last decade, researchers in France, had recognized that they had many patients with similar stories. Clinical research tests were done ad found that ….Appreciatin for this disorder has greatly increased, and genetic testing is availabe

7. And so what happened?
Carbamazepine is stopped (the sodium channel blocker), Atkins Diet (like the ketogenic diet) started.
Seizure free for 2 years
No side effects, doing very well in school
Clinical research for this condition identified that ….

8. Todd’s Success with Diet treatment!
Progress in Epilepsy Treatment Requires Teamwork between Patients an Researchers
Families agree to genetic testing (bloodwork)
Dravet Mutation Found!
Families with Dravet Mutation agree to participate in Diet Studies
Benefit Seen!
Todd’s Success with Diet treatment!

9. Key Points The better we understand the causes of epilepsy…
The better our treatments will be!
Clinical Research is the key but can’t happen without teamwork between patients, families, and MD’s

10. What is Epilepsy?
A disorder of spontaneously occurring unprovoked seizures (more than 2)
Seizures are electrical storms of brain cells that can cause many different symptoms

11. How do Neurons (Brain Cells) work?
Ion Channel
Sodium Channel: Excites!
Potassium, Choride Channel:
Rests!
Brain cells (so called neurons) are like telephone cables. Messages come in one side, travel down the wire, and then are released on the other side to talk to othe brain cells. On this other side there are special proteins called ion channels which help with the communication . There are multiple different types of ion channels. For now, since we just talked about todd, I want you to know that sodium channels excite other brain cells. Remember how I said sodium channel blockers made his epilepsy worse.

12. SEIZURE What causes Seizures? Brain Tumors, Scar tissue, etc.
So what causes seizures. Well something might irritate the receiving end of the neuron like a scar, etc. and cause the brain cell to fire too much. Or there might be a problem with the receiving end of the cells in the ion channels. For example, dravet mutation causes leaky sodium channels which causes to much firing and then seizures.
Ion Channel
Problems
Excessive firing
SEIZURE

13. How Do Seizure Medication Work?
Block release
Close Sodium Channels (CBZ)
Open Chloride Channels (gabapentin)
Talk about Todd on this slide. Leaky sodium channels. MAD diet is thought to stabize receptors
Excessive firing
SEIZURE

14. What are the Limits of Medical Therapy?
Trial and Error
Brain Side Effects
Body Side Effects
Trial and Error: Every pt is different. We don’t now until we try which will be the right receptors to open and right ones to block
Side effects: when you block too many neurotransmitters, channels- you disturb normal brain function and you get side effect. For example if too many NT are blocked you get sleepy and dizzy
1/3: New medication are not any better than old

15. Seizure Control
I discussed on the earlier slide drug resistant epilepsy, or seizures that are hard to controll with medicine, puts a person at higher risk for SUDEP. About 1/3 of people with epilepsy have drug resistant epilepsy. The definition of DRE is where seizures keep occuring despite 2 good trials of seizure medication. A good trial of a seizue medication means that an appropriate medication was used for the patient’s epilepsy and an appropriate dose was achieved. The medication failed because of persistent seizures and not side effects. For example, if the patient was still in the procress of increasing the medication to the target dose, and then had to stop it because of side effects, we wouldn’t call this a drug failure.
Also, there are many types of epilepsy, and not all doctors specialize in epilepsy. Different medications work for each type of epilepsy. Sometimes doctors, despite their best intentions, prescribe the wrong seizure medication for a patient’s epilepsy. For example, tegretol for absence seizures, which can make it worse.
So, a patient is only drug resistant only if they have tried two or more appropriate medications for their epilepsy and failed them because of persistent seizures.

16. How do We Move Forward? Basic Science Clinical Trials
FDA Approval-Medication available for public
So how does progress in research happen. Well new targets for treatment are identified from animal research or from clinical genetics studies like dravet syndrome. Researchers then find drugs which they suspect might help “hit this targets” and stop seizures. Then next step is to do clinical trials in patients to show they are safe and effective for epilepsy. If these trials are successful then the government (FDA) approves them for doctors to prescribe to the public

17. Clinical Trials What is a clinical trial?
Key terms (from Epilepsy Study Consortium)
Randomization and Control
Blinding
Placebo
CONSIDER ENROLLING IN EPILEPSY STUDY
From ESC: Clinical trials are carefully planned studies that will help determine important information about a new therapy. In a clinical trial, a new therapy will be used at predetermined doses, for a specific period of time, and the outcome of the therapy (usually seizure frequency and severity, and frequency of side effects) will be carefully measured. Clinical trials provide the information that will be needed for the FDA to make a decision whether the drug should be approved for use. Also, all the information that is included in the package insert will be determined from clinical trials and clinical research.
Randomization and control In a randomized trial, subjects are assigned to one of several possible therapies by chance. Randomization ensures that the outcome of the study has not been affected by bias. Each therapy option is called an arm of the study. Studies can have two to five arms. Sometimes the arms can consist of different doses of a single drug. In some trials arms can contain different drugs. Often, patients in one arm will have no change in treatment. These patients will act as the control, against which the other arms will be compared. A control is needed, because seizure frequency might change over time by chance, and it is important to be certain that any change is truly due to effect of the drug.
Blinding Sometimes, people will react differently if they know what treatment they are receiving. To prevent this, studies are often blinded, so that the subjects are not aware of which arm they have been randomized to. In a single-blind study, the doctor will know which arm the patient is on, but the subject will not. In a double-blind study, neither the doctor nor the subject will know. In any blinded trial, if an emergency occurs, the investigator will always be able to break the blind.
Placebo Often, if patients who receive a drug are going to be compared to patients who are not receiving the drug, those not receiving drug will get a sugar pill, or placebo. This is done to maintain the blind, so patients will not know which arm they have been randomized to. Although the idea of being randomized to a placebo is concerning to many, it should not be. Surprisingly, in almost every trial, patients in the placebo arm show some improvement. Also, most of the time, after the trial is over, every patient, even those randomized to the placebo group, will receive drug if they want it.

18. What Should I Know?
Previous safety record of study medication or device
Chance of getting it vs. placebo?
How long? What to expect at each visit?
Access to study agent after the trial?

19. What Are Some Promising New Medical Treatments under study at NEREG?
Emergency Treatment
Intranasal Midazolam
Everyday Treatment
Ganaxolone
Lacosamide (Vimpat)
Pregabalin (Lyrica)
YKB
Now I am going to shift gears and talk about some exciting research at NEREG. I have divided our medical treatment research into 2 catergories. One I call everyday treatments, or what doctors call maintainece treatments. These are treatments whih are taken everyday to help prevent seizures. On the other hand, emergency treatments are given when there are unexpected breakthoughs of seizure clusters or other seizure emergencies

20. Ganaxolone Neurosteroid GABA Partial epilepsy Twice a day pill
Derived natural hormone
New “mechanism of action”
GABA
Partial epilepsy
Twice a day pill

21. Ganaxolone (study 600) Effective Side Effects
20% reduction of seizure frequency on medication
25% of subjects were >50% responders
Side Effects
Safe in Animal Models
Safe in nearly 1000 patients to date
Dizziness and sleepiness are rare side effects

22. Ganaxolone vs. Placebo in the Adjunctive Treatment of Subjects with Partial Onset Seizures (POS)
Objective
How safe and effective is Ganaxolone in adults with POS with poorly controlled seizures?
Requirement
Age > 18, 3 AED, 3 or more sz per month
Study Procedure
Visits to Hackensack office. All medication, visits are provided for free + stipend
Explain about placebo

23. YKP3089 Unknown MOA Partial epilepsy Once a day pill GABA
Sodium Channel
Partial epilepsy
Once a day pill

24. YKP 3089 Effective Side Effects 1 early study
Significant of subjects were >50% responders. 70% reduction in GTC were seen.
Side Effects
Safe in Animal Models
Safe in nearly 400 patients to date
2 allergic reactions
2 case confusion

25. YKP vs. Placebo in the Adjunctive Treatment of Subjects with Partial Onset Seizures (POS)
Objective
How safe and effective is YPK3089 in adults with POS with poorly controlled seizures?
Requirement
Age > 18, 3 AED, 4 or more sz per month
Study Procedure
Visits to Hackensack office. All medication, visits are provided for free + stipend
Explain about placebo

26. Lacosamide (Vimpat) Studies
Why are we studying this medication when it is already available?
Learn how to use it better
Learn if it can be used safely in populations not included in original research

27. Cognitive and Behavioral Effects of Lacosamide (Vimpat) for POS
Cognitive and Behavioral Effects of Lacosamide (Vimpat) for POS. PI- Marcelo Lancman, MD
Objective
How does the new medicine Vimpat affect thinking (cognition) and mood (behavior)?
Requirement
Age > 18, English, 2 or more sz per month
Study Procedure
Visits to Hackensack office over 36 weeks. All medications, visits, and neuropsychological testing are provided for free plus stipend
Vimpat is a medication that you might have heard of. It was approved by the FDA for treatment of refractory partial epilepsy. Overall our experience with this medication has been very good. It seems like it is a very effective medication with relative few side effects. Dr. Lancman the head of our group is leading this study which is looking more closely on how this medication effects thinking and concentration (cognition) and mood

28. Lacosamide in Children. PI- Evan Fertig, MD
Objective
How safe and effective is this medication in children with partial and generalized seizures?
Requirement
Age > 1 mo to 18 years , 2 or more sz per month
Study Procedure
Visits to Hackensack office > 1 year. All medications, visitsare provided for free plus stipend
Vimpat is a medication that you might have heard of. It was approved by the FDA for treatment of refractory partial epilepsy. Overall our experience with this medication has been very good. It seems like it is a very effective medication with relative few side effects. Dr. Lancman the head of our group is leading this study which is looking more closely on how this medication effects thinking and concentration (cognition) and mood

29. Effect of Lyrica on Anxiety in POS
Objective
How safe and effective is Lyrica for Anxiety in Patients with poorly controlled POS?
Requirement
Age > 18, 1-2 AEDs, not presently treated for anxiety
Study Procedure
Visits to Hackensack office over 6 weeks. All medication, visits, travel free plus stipend
Lyrica is other medication you might of heard of. Researchers also know that it is helpful for patients who just have anxiety. We want to know if it also helps pts who have both epilepsy and anxiety, these frequently go together.

30. Completed Studies
New medications

31. Aptiom® (eslicarbazepine acetate)
Partial Onset Seizures
Once a day tablet
Carbamazepine (Tegretol) like medicine
Rash
Liver Abnormalities
Low blood sodium
U.S. Food and Drug Administration (FDA) approved Aptiom® (eslicarbazepine acetate) for adjunctive treatment of partial-onset seizures.  The FDA approved APTIOM without requiring scheduling and further review by the Drug Enforcement Administration (DEA).  APTIOM will be available in 200 mg, 400 mg, 600 mg, and 800 mg tablet strengths.  Sunovion plans to have APTIOM available in pharmacies in the first-half of 2014.
INDICATION AND IMPORTANT SAFETY INFORMATION
INDICATION
Aptiom® (eslicarbazepine acetate) is indicated as adjunctive treatment of partial-onset seizures. 
IMPORTANT SAFETY INFORMATION
APTIOM (eslicarbazepine acetate) is contraindicated in patients with a hypersensitivity to eslicarbazepine acetate or oxcarbazepine. 
Antiepileptic Drugs (AEDs), including APTIOM, increase the risk of suicidal thoughts or behavior. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.  Patients and caregivers should also be advised to be alert to these behavioral changes and to immediately report them to the healthcare provider.
Serious dermatalogic reactions, including Stevens-Johnson Syndrome (SJS), have been reported in association with APTIOM use.  Serious and sometime fatal dermatalogic reactions, including toxic epidermal necrolysis (TEN) and SJS, have been reported in patients using oxcarbazepine or carbamazepine which are chemically related to APTIOM.  Should a patient develop a dermatologic reaction while using APTIOM, discontinue APTIOM use unless it’s clearly not drug related. 
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking APTIOM.  DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement.  If this reaction is suspected, treatment with APTIOM should be discontinued. 
Rare cases of anaphylaxis and angioedema have been reported in patients taking APTIOM.  Anaphylaxis and angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions the drug should be discontinued.  Patients with a prior anaphylactic-type reaction after treatment with either oxcarbazepine or APTIOM should not be treated with APTIOM.
Clinically significant hyponatremia (sodium <125 mmol/L) can develop in patients taking APTIOM. In the controlled epilepsy trials, 1.0% (800 mg) and 1.5% (1200 mg) of patients treated with APTIOM had at least one serum sodium level value less than 125 mEq/L, compared to none on placebo.  These effects were dose related and generally appeared within the first 8 weeks of treatment (as early as after 3 days). Measurement of serum sodium and chloride levels should be considered during maintenance treatment with APTIOM, particularly if the patient is receiving other medications known to decrease serum sodium levels. 
APTIOM causes dose-dependent increases in the following events (dizziness, disturbance in gait and coordination, somnolence, fatigue, cognitive dysfunction, and visual changes) compared to placebo. These events were more often serious in APTIOM treated patients than placebo.   For dizziness, disturbance in gait and coordination, and visual changes, there may be an increased risk of these adverse reactions in patients 60 years of age and older compared to younger adults.  The incidence of dizziness and diplopia were greater with concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine.
As with all AEDs, APTIOM should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus.
Hepatic effects, ranging from mild to moderate elevations in transaminases (>3 times the upper limit of normal) to rare cases with concomitant elevations of total bilirubin (>2 times the upper limit of normal) have been reported with APTIOM use.  Baseline evaluations of liver laboratory tests are recommended.  APTIOM should be discontinued in patients with jaundice or other evidence of significant liver injury.  
Dose-dependent decreases in serum T3 and T4 (free and total) values have been observed in patients taking APTIOM.  These changes were not associated with other abnormal thyroid function tests suggesting hypothyroidism.  Abnormal thyroid function tests should be clinically evaluated.
The most frequently reported adverse reactions in patients receiving APTIOM at doses of 800 or 1200 mg (≥4% and ≥2% greater than placebo) were dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision and tremor.
When APTIOM and carbamazepine are taken concomitantly, the dose of APTIOM or carbamazepine may need to be adjusted based on efficacy and tolerability.  For patients taking other enzyme inducing AEDs (i.e. phenobarbital, phenytoin and primidone) higher doses of APTIOM may be needed.  
A dose reduction is recommended in patients with moderate and severe renal impairment (i.e., creatinine clearance <50 mL/min). 
Dose adjustments are not required in patients with mild to moderate hepatic impairment.  Use of APTIOM in patients with severe hepatic impairment has not been studied, and use in these patients is not recommended. 
Concomitant use of APTIOM and oral contraceptives containing ethinylestradiol and levonorgestrel is associated with lower plasma levels of these hormones.  Patients should use additional or alternative non-hormonal birth control during APTIOM treatment and after discontinuation of APTIOM for one menstrual cycle, or until otherwise instructed.

32. Emergency Treatment Rectal Diastat Clinically proven Hard to give
Social Stigma
Can’t self administer
Now I will shift gears and talk about emergency treatments. Diastat is a very good option but unfortunately it is our only one. It is clinically proven through research to work, but for bigger kids, teens, and adults it has limiatations. It is hard to give, since it is harder to undress a bigger person, that takes time. It may also leak out of the rectum. Teens and adults might not like getting disrobed in public. Also it can’t be self-administered

33. Intranasal Midazolam Easy to give Preferred route
Can be self-administered or given by caretaker
Under study
We are doing a study with an emergency treatment called midazolam (versed) which is given in the nose. Advantages are: Efficacy and Side Effects unknown

34. Intranasal Midazolam (IM)
Objective
How safe and effective IM for Seizure Clusters?
Requirement
Age 14-22, Seizure Clusters
Study Procedure
One visit to Hackensack Hospital for test dose then follow up visits. Travel and meds are free
Explain about placebo

35. What are the Limits of Surgical Therapy? What’s on the Horizon?

36. When Do We Consider Resective Epilepsy Surgery?
Partial Epilepsy
Treatment Resistant Epilepsy
Failure to become seizure free after > 2 adequate trials of 2 AEDs used appropriately
Intolerable adverse effects of AEDs?

37. Why?
Rate of Seizure Freedom with continued trials of Sz med is low (5%)
Potential for injury with uncontrolled epilepsy over a lifetime is high!
Rate of Seizure Control with Resective Epilepsy Surgery is in comparison is high (30-80%) with a low complication rate
Reduction or Elimination of Sz med is frequently possible

38. How does Epilepsy surgery work?
Brain Tumors, Scar tissue, etc.
Excessive firing
SEIZURE

39. Epilepsy Surgery And can it be taken out safely?

40. Rates of Surgical Success*
Temporal Lobectomy %
“Lesion” Resection %
“Non-Lesional” Resection %
Medical Management %
Disabiling- greater than auras
* Absence of Disabling Seizures

41. What are the Limits of Surgical Therapy?
Small risk: bleeding and infection
Not effective for all seizures types
Not effective if seizures are come from more than one location
Not possible if seizures arise from critical brain tissue (hand area)

42. Visualase Laser Treatment Evaluation is same as for epilepsy surgery
No need for open brain
operation
A Study to Prospectively Evaluate the Effects of MR-guided Laser Ablation of Epileptogenic Foci in Patients with Treatment Resistant Partial Epilepsy
To prospectively collect information from patients who have received MR-guided Laser Ablation of epileptogenic foci, to assess clinical and neuropsychological outcomes following the procedure.

43. Visualase Implant Probe inserted in OR Transferred to MRI Treatment
Laser Treatment
MRI monitors safety of Laser Rx real-time
Follow up
Probe Removed
Patient can leave same day

44. Neuromodulatory Treatments
Device implanted to alter instead of destroy brain tissue
Range of treatment possible: Electrical, Cooling, local medications
Limit body/brain side effects
Improve brain function?
Already have been studies in paralyzed individuals improving motor function, and memory in rats

45. NeuroPace Implant Device under skull Leads to seizure focus Treatment
Detects seizure
Electrical treatment delivered
Follow up
MD reviews
Fine tunes treatment

46. What will Epilepsy Care Look Like in Future?
Personalized Medical Choices based on genetics
Truly Anti-epileptic therapy
Treatment directed right at the seizure focus

47. Conclusion
In most cases, seizures can be well controlled with medications with minimal side effects
The correct diagnosis to guide treatment is essential
Epilepsy is more than just seizures, and the treatment may require a team approach

48. Conclusion
Some cases are more difficult to control, and treatment with diet therapy or surgery may be used, or clinical trials may be an option

49. Please Contact Us for More Information!
Director of Research Evan Fertig, MD
Clinical Research Coordinator Munazza Malik, MD (201)