The Importance of Clinical Trials: Getting New Therapies for Epilepsy on the Market Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center

The first randomized controlled trial: Lind ’ s treatise on scurvey Six groups (2 patients/group): – 2pts : a quart of cider a day – 2pts: elixir of vitriol – 2 pts: vinegar – 2 pts: seawater – 2pts: mixture of garlic, mustard, spices – 2pts: oranges and lemons Group receiving oranges and lemons fit for duty in 6 days and began to tend the other patients

Why do we do clinical trials? The American Public looks to its government for assurance that therapies developed to treat diseases are both SAFE and EFFECTIVE The Food and Drug Administration (FDA) is charged with ensuring that safety and effectiveness are proven before a drug is put on pharmacy shelves, or before a device is marketed They are also responsible for LABELING drugs so that the public is aware of risks and benefits There are very strict rules that govern the conduct of clinical trials to determine safety and efficacy (effectiveness) Without clinical trials, no new therapy would be marketed!

The course of drug development Pre-Clinical testing 10,000 Compounds Phase I – Testing in about 100 normal volunteers – Developer needs to get approval from FDA in the form of an NDA (new drug application) Phase II/III – Tests to determine if therapy is safe and effective 250 Get to Animal Testing 10 Reach Human Trials

The course of drug development Phase II/III (continued) – For a drug, at least 2 trials, (usually as add-on, i.e. new drug added on to existing therapy) with a control group (usually placebo(sugar pill)) Drug must be better than “placebo” Can see how frequent dose-related side effects are compared to placebo – It is essential to make these trials as safe and patient-friendly as possible

How do new therapies get on the market? The cost of developing a new drug is $800 million to 2 Billion and takes years Most drugs and devices (even if the idea comes from research labs or the National Institutes of Health (NIH) will be tested by companies that eventually will sell the product Private sector companies need to partner with clinical researchers and doctors to perform good trials People with epilepsy must enroll in trials in order for drugs to obtain approval from FDA

Anti-seizure drugs All available therapies only treat symptoms of epilepsy (seizures) We now call drugs that only address seizure symptoms “Anti-seizure drugs” (ASD’s) Most current clinical trials are for testing of ASD’s. – Almost every person with epilepsy takes at least one ASD

Ezogabine(Potiga TM ) Eslicarbazepine (Zebinix TM ) Felbamate Vigabatrin (Sabril TM ) Zonisamide (Zonegran TM ) Lamotrigine (Lamictal TM ) Perampanel (Fycompa TM ) Gabapentin (Neurontin TM ) Topiramate (Topamax TM ) Oxcarbazepine (Trileptal TM ) Tiagabine (Gabitril TM ) Pregabalin (Lyrica TM ) Clobazam (Onfi TM ) Rufinamide (Banzel TM ) Year Number of AEDs Timeline: ASD approvals by FDA since 1990 Brivaracetam (Rikelta TM ) Levetiracetam (Keppra TM ) Lacosamide (Vimpat TM ) Not approved (Felbatol TM )

“Don’t take any of these red pills, and if that doesn’t work, don’t take any of the blue ones” Sometimes, we feel Like this…

DO WE NEED MORE NEW ANTISEIZURE DRUGS? Problem with current ASDs: – Seizure control Newly diagnosed well treated Still 40% with therapy resistance New ASDs over last 20 years have not substantially changed this equation! – Safety/tolerability Some new (and old) ASDs still have important safety and tolerability problems

ASD’s: How do we make progress? Revolutionary Drugs – Drugs that work with new mechanisms never tried before – Expectation: They will control seizures that existing drugs can ’ t control Evolutionary Drugs – Improve on existing drugs – Expectation: We can eliminate some of the problems/side effects of good drugs, without reducing their effect on seizures

The evolution is coming: Compounds which are 2 nd or 3 rd generation derivatives of ASDs introduced before st Generation AED Carbamazepinee Tegretol TM Valproic Acid Depakote TM 2 nd Generation AED Oxcarbazepine Valrocemide (SPD–493) Valnoctamide 3 rd Generation AED Eslicarbazepine Acetate (BIA 2-093) Phenobarbital T2000 Perucca et al, Lancet Neurol, 2007

Compounds which are second generation derivatives of AEDs introduced after 1990 GabapentinLevetiracetam Pregabalin Brivaracetam (ucb 34714) Precursor CNS Drug Piracetam 1 st Generation AED 2 nd Generation AED Perucca et al, Lancet Neurol, 2007

What ’ s “new” in ASD’s? (Approved or close to approval) One drug approved – Revolutionary: Perampanel Two drugs in late trials – Evolutionary Rikelta (brivaracetam) Stedesa (eslicarbazepine acetate)

Perampanel First ASD to work on excitation rather than inhibition or stabilization of membranes – “take away the kindling” rather than putting a blanket on the fire Inhibits excitatory chemical in the brain (AMPA) Approved for add-on treatment in partial onset seizures (adults) October 2012

Placebo (n=119) Perampanel 8 mg/day (n=132) Perampanel 12 mg/day (n=130) Perampanel : Percent reduction in seizure frequency during maintenance phase Median % change in seizure frequency (P=0.08) (P=0.03)

Treatment-emergent side effects (add-on) TEAEs, treatment-emergent adverse events PlaceboPerampanel Treatment emergent Side effects % N (n=121) 8 mg (n=133) 12 mg (n=134) TEAEs leading to study or study drug withdrawal Most common (≥10%) Dizziness Sleepiness Irritability Headache Fall Ataxia

OLD MECHANISM-MORE POWERFUL/SAFER Brivaracetam (Rikelta)Eslicarbazepine Acetate (Stedesa)

BRIVARACETAM (Rikelta) Works in a similar way in the brain as Levetiracetam (Keppra TM ) but much stronger in animal models Also other activity that Keppra does not have (sodium channel blocking) Keppra causes irritability/depression in some patients- unknown if Rikelta will have improved tolerability profile FDA trials underway. First study very positive, second study unclear, third trial underway First approval will be for add-on therapy for partial seizures. Other uses (eg for generalized seizures) will be explored later

Efficacy of Brivaracetam (5, 20 and 50 mg/day) Add-on Treatment in Refractory Partial-Onset Epilepsy SEIZURE-FREEDOM RATES RESPONDER RATES ITT population: n=208; 110M, 98F; age range 16–65 y PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) % p = % p = % p = % % Respondents PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) 0 10 % Patients 1.9% 1/54 8.0% 4/50 7.7% 4/52 7.7% 4/52

Brivaracetam Adverse Events PBOBRV5BRV20BRV50 Patients (N) Permanent study drug discontinuation 2 (3.7)3 (6.0)1 (1.9)0 Patients with ≥1 AE, n (%)29 (53.7) 26 (52.0) 29 (55.8) 28 (53.8) Total AEs AEs reported in ≥ 5% patients Headache Somnolence Influenza Dizziness Neutropenia Fatigue 4 (7.4) 3 (5.6) 1 (1.9) 2 (3.7) 4 (8.0) 1 (2.0) 4 (8.0) 1 (2.0) 4 (8.0) 0 2 (3.8) 3 (5.8) 0 2 (3.8) 1 (1.9) 3 (5.8) 1 (1.9) 4 (7.7) 0 3 (5.8)

Why do we need a better Carbamazepine? Effective drug but… – Speeds metabolism through the liver, causing: Need for dose adjustment of other drugs that are taken simultaneously Changes (reduction) in levels of vitamins, hormones Increase in cholesterol levels, lipid levels Reduction in sodium (salt) levels in the blood that can lead to problems

Change in Cholesterol after removal of Tegretol or Dilantin (First to second blood draw) Mintzer S. et al Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann Neurol Apr;65(4): TegretolDilantinCONTROL

Eslicarbazepine Acetate A “ third generation ” Carbamazepine (Tegretol TM ) Improves on second generation (Trileptal TM ) – Less effect on sodium – Smoother release may produce less side effects – Does not have the same impact on the liver Hopefully will work equally as well Already approved in Europe as “Zebenix”. Will be marketed in US as “Stedesa”. FDA has accepted the submission

Other ASD’s in development Revolutionary: – YKP 5089 (mechanism unknown) – Ganaxolone (Neurosteroid-type positive allosteric modulation at GABA A receptor sites) – Huperzine (Naturally occurring plant alkaloid also being explored for use in Alzheimer’s disease)

Is That All There is a desperate need for – Drugs that prevent epilepsy – Drugs that modify or treat underlying disease True antiepileptic drug – Drugs that address co-morbidities such as cognitive disturbance, mood disorder, anxiety

Truly Anti-Epileptic Approaches Anti-Inflammatory Treatments M-Tor Inhibitors Pre-treatment with an ASD or other therapy

Targeting Inflammation There is mounting evidence that inflammation plays an active role epilepsy Inflammation is clearly evident in brain tissue removed from patients with epilepsy. New paradigm: If we can target inflammation, we may be able to impact a key common mechanism and reverse the underlying cause of seizures. 28 Vezzani A, French J, Bartfai T, and Baram T. The Role of Inflammation in Epilepsy. Nature Reviews Neurology 2011 Jan;7(1):31-40

What is the conclusion? If successful, this would be the first anti-epilepsy therapy that would actually target the abnormality rather than just masking seizures A trial of VX-765 is underway It is likely that other anti- inflammatory treatments will follow 29

M-Tor Inhibitors Mammalian target of rapamycin (mTOR) signaling pathway regulates how brain cells grow, differentiate and multiply. Genetic defects in the pathway can cause diseases such as Tuberous sclerosis, and cortical dysplasia (both causes of epilepsy) In Animal models, M-Tor inhibitors can prevent or reverse epilepsy caused by these illnesses Galanopoulou AS, Gorter JA, Cepeda C. Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target.

Clinical Trial of M-Tor Inhibitor Everolimus A clinical trial of Everolimus (an M-Tor inhibitor) was performed in children with TS and giant cell astrocytomas. – It appeared that seizures were also improved New trial in children/adults with TS and resistant seizures Franz DN et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet Jan 12;381(9861):

Pre-Treatment: Tuberous sclerosis-Treatment with vigabatrin prior to development of epilepsy Jóźwiak et al Eur J Paediatr Neurol Sep;15(5): Standard Care N=31 Patients with Epilepsy N=22 (71%) Patients without Epilepsy N=9 (29%) Patients with intellectual Disability N=15 (48%) Patients with Normal IQ N=7 (23%) Patients with intellectual Disability N=0 Patients with Normal IQ N=7 (23%) Vigabatrin Rx N=14 Patients with Epileptiform EEG N=10 (71%) Patients with Normal EEG N=4 (29%) Patients with Epilepsy N=6 (42%) Patients without Epilepsy N=4 (29%) Patients with Epilepsy N=0 Patients without Epilepsy N=4 (29%) Patients with intellectual Disability N=2 (14%) Patients with intellectual Disability N=0 Patients with Normal IQ N=4 (29%) Patients with Normal IQ N=4 (29%) Patients with intellectual Disability N=0 Patients with Normal IQ N=4 (29%) 8 pts (58%) without epilepsy and 12 pts (87%) with nl IQ

Typical Randomized Controlled Trials vs Real Life Restricted ages No other medical Problems No psychiatric disease No pregnancy

What we don’t know What we know What We Know after Regulatory Trials

What do we know about AEDs at time of approval? How the drug works in difficult to control seizures (proof that drug is better than placebo) Side effects when used at titration rates and doses employed in trials, over short term Safety in ,000 subjects Drug interactions

What don ’ t we know about AEDs at time of approval? How the drug works in other types of epilepsy How the drug works in newly diagnosed patients Comparative data vs new or old AEDs Impact at different ages – Pediatric – Elderly Best dose, titration schedule Some safety issues (including long-term) How well the drug works by itself Pregnancy effects

After Approval After approval we need “comparative effectiveness” studies – Determine which drugs will benefit which people – Unlikely that “one size fits all” This is where government trials are needed – National Institutes of Health – Patient-Centered Outcome Research Institute (PCORI)

The Epilepsy Study Consortium Sponsored by Epilepsy Therapy Project and FACES Group of Epilepsy Centers who work together to write protocols, bring better drugs forward, Maintain the focus of drug development on helping people with epilepsy, NOT commercial concerns of pharmaceutical companies!

The future Need active pipeline with good compounds moving through Need better trial designs – Shorten placebo period? – Weed out effective drugs from non-effective – Improve risk-benefit Need patients to volunteer for clinical trials!