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What’s New In Antiepileptic Drugs

What’s New In Antiepileptic Drugs . Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center. ANTIEPILEPTIC DRUG DEVELOPMENT. Retigabine. Rufinamide Lacosamide Brivaracetam. ?. 20. Pregabalin. Zonisamide. Levetiracetam. Oxcarbazepine. Tiagabine. 15. Fosphenytoin. Topiramate.

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What’s New In Antiepileptic Drugs

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  1. What’s New In Antiepileptic Drugs Jacqueline A. French, M.D. NYU Comprehensive Epilepsy Center

  2. ANTIEPILEPTIC DRUG DEVELOPMENT Retigabine Rufinamide Lacosamide Brivaracetam ? 20 Pregabalin Zonisamide Levetiracetam Oxcarbazepine Tiagabine 15 Fosphenytoin Topiramate Lamotrigine Gabapentin Number of Licensed Antiepileptic Drugs 10 Felbamate Sodium Valproate Carbamazepine Benzodiazepines Ethosuximide 5 Phenytoin Primidone Phenobarbital Bromide 0 2000 1840 1860 1880 1900 1920 1940 1960 1980 Calendar Year

  3. SINCE 1998 20 Pregabalin 10 Zonisamide Levetiracetam Number of Licensed Antiepileptic Drugs Oxcarbazepine Tiagabine Topiramate Fosphenytoin 5 Lamotrigine Gabapentin Felbamate 0 1990 2000 Calendar Year

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

  5. 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

  6. Compounds which are second or third generation derivatives of AEDs introduced before 1970 CarbamazepineeTegretol TM 1st Generation AED Valproic Acid Depakote TM Phenobarbital 2nd Generation AED Valrocemide (SPD–493) Oxcarbazepine T2000 Valnoctamide 3rd Generation AED Eslicarbazepine Acetate (BIA 2-093) Licarbazepine (MHD) Perucca et al, Lancet Neurol, 2007

  7. Compounds which are second generation derivatives of AEDs introduced after 1990 Precursor CNS Drug Piracetam 1st Generation AED Gabapentin Lamotrigine Levetiracetam 2nd Generation AED XP-13512 JZP-4 Seletracetam (ucb 44212) Brivaracetam (ucb 34714) Pregabalin Perucca et al, Lancet Neurol, 2007

  8. What’s new this year? • Two new drugs to be approved • Revolutionary • Vimpat (lacosamide) • Inovelon (rufinamide) • Four drugs in late trials • Evolutionary • Rikelta (brivaracetam) • Eslicarbazepine • Revolutionary: • Carisbamate • Retigabine

  9. What’s new this year? • Many drugs off/going off patent (going generic) • Neurontin (gabapentin) • Lamictal (lamotrigine) • Topamax (topiramate) • Trileptal (oxcarbazepine) • Keppra (levetiracetam)

  10. What’s new this year? • Two new trial designs endorsed by FDA • “Withdrawal to monotherapy”: Speed approval for monotherapy • “Time to Nth seizure”: Create more “patient-friendly trials

  11. DRUGS THAT WORK IN NEW WAYS lacosamide rufinamide retigabine

  12. Lacosamide (RIKELTATM) • Works on sodium channels, like Carbamazepine (Tegretol TM) and Phenytoin (DilantinTM) • However, It selectively enhances slow inactivation of sodium channels, whereas the older drugs work on fast inactivation • Approved in Europe, expected to be approved in US by December 2008

  13. Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy:50%Responder Rates (n=418) 41%* 38%* 33% (* P<0.05 vs PL) % Patients 22% Placebo LCS 200mg LCS 400mg LCS 600mg Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

  14. Lacosamide Treatment-emergent adverse events (%) leading to discontinuation in at least 5% of patients in any treatment group Percentages are based on the number of patients in the randomized dose group who received at least one dose of trial medication. Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

  15. RUFINAMIDE (INOVELONTM) • Also works on sodium channels with new mechanism • Approved in Europe for treatment of a severe form of epilepsy (Lennox-Gastaut syndrome) • “Orphan drug” • In Front of FDA for Lennox-Gastaut and Partial seizures

  16. Rufinamide Lennox-Gastaut Responder Rate: Tonic-Atonic Seizure Frequency P=0.0003 P=0.002 P=0.006 % of Subjects ≥75% ≥50% ≥25% Seizure Reduction

  17. Rufinamide AEs With Incidence ≥3% vs Placebo: All Treated Subjects With Epilepsy (Double-blind Only)

  18. What we don’t know LEVEL OF KNOWLEDGE AT TIME OF APPROVAL What we know

  19. 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 1500-15,000 subjects • Drug interactions

  20. 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

  21. Retigabine • Works on a NEW channel that other drugs don’t work on (Potassium channel) • Defect in potassium channel linked to one inherited form of epilepsy (benign neonatal seizures) • Trials completed, ready to submit to FDA for approval

  22. Patients with >50% Seizure Reduction in Overall Treatment Period(Titration + Maintenance) Study 302 Study 301 % Patients 179 181 178 152 153 600 900 Placebo 1200 RTG Placebo RTG Intent-to-treat *p<0.005 **p<0.001

  23. Retigabine 1200 mg/day vs Placebo: Most Common Adverse Events (>10% incidence)

  24. Discontinuations Due to Adverse Events *Dose-related

  25. OLD MECHANISM-MORE POWERFUL/SAFER Brivaracetam Eslicarbazepine Acetate

  26. BRIVARACETAM • Similar mechanism to Levetiracetam (KeppraTM) but much stronger in animal models • Also has sodium channel blocking activity • FDA trials underway

  27. Genetic Absence Epilepsy Rats from Strasbourg Levetiracetam Values given are means ± S.D. (n=8)

  28. Genetic Absence Epilepsy Rats from Strasbourg seletracetam Values given are means ± S.D. (n=8)

  29. Efficacy of Brivaracetam (5, 20 and 50 mg/day) Add-on Treatment in Refractory Partial-Onset Epilepsy RESPONDER RATES SEIZURE-FREEDOM RATES p = 0.001 55.8% 60 10 8.0% 4/50 7.7% 4/52 7.7% 4/52 p = 0.002 44.2% 50 p = 0.047 32.0% 40 % Patients % Respondents 30 16.7% 20 1.9% 1/54 10 0 0 PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) ITT population: n=208; 110M, 98F; age range 16–65 y

  30. Brivaracetam Adverse Events

  31. Eslicarbazepine • A “third generation” Carbamazepine (TegretolTM) • Improves on second generation (TrileptalTM) • Less effect on sodium • Smoother release may produce less side effects • Hopefully will work equally as well • Ready to submit to FDA

  32. Many Drugs going off Patent • This allows multiple (generic) companies to make the drug, in addition to the brand manufacturer • At same dose, two formulations must be within (80%-125%) of amount in brand, with 90% assurance. • Different generic brands could be either high or low • If a physician does not check the “do not substitute” box, insurance companies are at liberty to switch patients to generic

  33. Brand TRx as Percent of Total Molecule Generic Erosion Prescription Source: WKH PHAST TRX and Sales data factored by Verispan PDDA Note: Celexa included as a reference of typical generic erosion

  34. Many Drugs going off Patent • Generics may be very good and close to the brand; The problem is that EACH TIME a new prescription is filled, it can be filled with a different company’s generic, which could be high or low.

  35. No well performed blinded studies to assess risk from switching between generics • Excipients and colorants may be different, leading to potential for allergic reactions • Dissolution properties may vary • Risks of generics should be weighed against cost benefits1 1Epilepsy Foundation. Statement on substitution of generic antiepileptic drugs.

  36. Changing to Generic (or to Brand) • Baseline levels • Check level again when stable on new preparation • Ideally limit changes between different generic manufacturers • Report suspected problems (preferably with documentation) to FDA MedWatch (http://www.fda.gov/medwatch/)!

  37. The Epilepsy Study Consortium • Sponsored by Epilepsy Therapy Development 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 comercial concerns of pharmaceutical companies!

  38. 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 • Acceptance by FDA of 2 new trial designs will speed good therapies

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