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

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

Post on 22-Dec-2015




0 download

Embed Size (px)


  • Slide 1
  • The Importance of Clinical Trials: Getting New Therapies for Epilepsy on the Market Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center
  • Slide 2
  • 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
  • Slide 3
  • 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!
  • Slide 4
  • 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
  • Slide 5
  • 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
  • Slide 6
  • How do new therapies get on the market? The cost of developing a new drug is $800 million to 2 Billion and takes 12-15 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
  • Slide 7
  • Anti-seizure drugs All available therapies only treat symptoms of epilepsy (seizures) We now call drugs that only address seizure symptoms Anti-seizure drugs (ASDs) Most current clinical trials are for testing of ASDs. Almost every person with epilepsy takes at least one ASD
  • Slide 8
  • Ezogabine(Potiga TM ) Eslicarbazepine (Zebinix TM ) 1990 199520002005 201020152020 0 5 10 15 20 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 )
  • Slide 9
  • Dont take any of these red pills, and if that doesnt work, dont take any of the blue ones Sometimes, we feel Like this
  • Slide 10
  • 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
  • Slide 11
  • ASDs: 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
  • Slide 12
  • The evolution is coming: Compounds which are 2 nd or 3 rd generation derivatives of ASDs introduced before 1970 1 st Generation AED Carbamazepinee Tegretol TM Valproic Acid Depakote TM 2 nd Generation AED Oxcarbazepine Valrocemide (SPD493) Valnoctamide 3 rd Generation AED Eslicarbazepine Acetate (BIA 2-093) Phenobarbital T2000 Perucca et al, Lancet Neurol, 2007
  • Slide 13
  • 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
  • Slide 14
  • What s new in ASDs? (Approved or close to approval) One drug approved Revolutionary: Perampanel Two drugs in late trials Evolutionary Rikelta (brivaracetam) Stedesa (eslicarbazepine acetate)
  • Slide 15
  • 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
  • Slide 16
  • 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 -22.86 -32.13 (P=0.08) -39.48 (P=0.03) -40 -30 -20 -10 0 -50
  • Slide 17
  • 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 436.66.819.4 Most common (10%) Dizziness 1139.937.638.1 Sleepiness 6313.218.017.2 Irritability 355.07.514.2 Headache 5413.215.013.4 Fall386.69.812.7 Ataxia2406.011.9
  • Slide 18
  • OLD MECHANISM-MORE POWERFUL/SAFER Brivaracetam (Rikelta)Eslicarbazepine Acetate (Stedesa)
  • Slide 19
  • 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
  • Slide 20
  • 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 1665 y PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) 0 10 20 30 40 50 60 16.7% p = 0.047 32.0% p = 0.002 44.2% p = 0.001 55.8% % 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
  • Slide 21
  • Brivaracetam Adverse Events PBOBRV5BRV20BRV50 Patients (N)545052 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 AEs59507256 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)
  • Slide 22
  • 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
  • Slide 23
  • 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. 2009 Apr;65(4):448-56. TegretolDilantinCONTROL
  • Slide 24
  • 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
  • Slide 25
  • Other ASDs 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 Alzheimers disease)
  • Slide 26
  • 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
  • Slide 27
  • Truly Anti-Epileptic Approaches Anti-Inflammatory Treatments M-Tor Inhibitors Pre-treatment with an ASD or other therapy
  • Slide 28
  • Targeting Inflammation There is mounting


View more >