Anti-Seizure Drugs: Discovery and Development Roger J. Porter,

Transcription

1 Anti-seizure Drugs: Discovery and Development 1 M.D. onsultant Adjunct Professor of Pharmacology, USUHS Adjunct Professor of Neurology, Univ. of Pennsylvania Former Deputy Head, R&D, Wyeth-Ayerst Research Former Deputy Director, NINDS, NIH onflict of interest statement and disclaimer MD MD, has, at one time or another, worked with 80-90% of companies that have developed or plan to develop anti-seizure drugs Advice provided in this lecture is an overview of drug development some individual compounds may require different approaches than are recommended here - RJP 2 Anti-seizure drugs vs. anti-epileptic drugs (AEDs) Seizures vs. the epilepsies 3 1

2 I. The discovery of anti-seizure drugs 4 First anti-seizure drug potassium bromide (Sir harles Locock, 1857) Toxic: dermatitis, psychosis 5 Second anti-seizure drug phenobarbital (Hauptmann, 1912) Toxicity: less than bromides Efficacy: better than bromides Almost 50 other barbiturates marketed in first 35 years of the 20th century 6 2

3 Phenobarbital HN 2 H 5 H N H 7 Third anti-seizure drug (other than barbiturate derivatives) phenytoin (Putnam and Merritt, 1937) 8 Figure 74. Experimental Equipment Used for Testing Electroshock Thresholds 9in Diphenylhydantion Development (from Putnam and Merritt, 1937) 3

4 The discovery of phenytoin by Merritt and Putnam (1937) 1. Established that an effective AED need not be sedative 2. Demonstrated the value of systematic laboratory testing to search for AEDs 3. Encouraged the search for AEDs with selective anti-seizure action 4. pened a new era of study of structure-activity relationships 5. Provided a new tool for basic investigations of neurophysiological and neurochemical basis of seizures 10 Swinyard, 1982 Early concepts in the discovery of anti-seizure drugs Two principal effects of anti-seizure drugs: Elevation of threshold for seizure discharge Reduction of spread of seizure discharge Experimental methods for determining activity: Subcutaneous Pentylenetetrazol (scmet; scptz) Maximal Electroshock (MES) 11 Experimental seizures in mice (p.o.) MES ScPTZ Phenobarbital Phenytoin 9 N/E Ethosuximide N/E 193 (130 i.p.) Valproic acid (149 i.p.) 12 4

5 Disadvantages of MES and ScPTZ: 1. ld tests 2. Mechanisms obscure 13 The challenge of newer tests: Validation 14 ERA antiepileptic drugs marketed Diones Succinimides Barbiturates & Desoxybarbiturates Hydantoins 15 5

6 H H 5 6 H 5 H 5 6 NH NH HN Phenobarbital HN Phenytoin H 3 H 3 H 3 H 2 H 3 N H 3 NH 16 Trimethadione H 2 Ethosuximide ERA Big slowdown in anti-seizure drug discovery in the United States Important exceptions: arbamazepine Diazepam Valproate 17 Major anti-seizure drugs in use pre Phenobarbital 1912 Phenytoin 1938 Primidone 1954 Ethosuximide 1960 arbamazepine 1974 Valproic acid 1978 (+ Benzos) 6

7 NINDS, NIH Anticonvulsant Screening Program (ASP) Started in 1975 by Harvey Kupferberg, Kiffin Penry and Ewart Swinyard NINDS contract to Univ. of Utah to screen compounds ompounds are accepted from all sources More than 30,000 have been screened to date 19 ASP receipt of test substance active Identification (MES & scptz) inactive Quantification active 6 Hz test inactive Differentiation Advanced Studies Stop testing 20 Proconvulsant Potential Drug-drug Interaction Studies Mechanistic Studies Axonal transmission Does the anticonvulsant screening program (ASP) find new drugs? Some of the models still in use date to the 1940 s Answer: The ASP has identified compounds with 18 different mechanisms of action in the past 3.5 decades The ASP has revolutionized drug therapy in the past 3.5 decades Patients are treated today with a very different array of drugs than in

8 Discovery of anti-seizure drugs: Serendipity Screening Rational development 22 New strategies for rational AED development Potentiating inhibition Reducing excitation Modifying ion channels Modifying presynaptic mechanisms But screening has, thus far, proven more effective than rational development 23 New anti-seizure drugs since 1990: almost all from screening Felbamate 1993 Gabapentin 1994 Lamotrigine 1996 Fosphenytoin 1996 Topiramate 1997 Tiagabine 1999 Levetiracetam 2000 Zonisamide 2000 xcarbazepine 2005 Pregabalin 2008 Lacosamide, Rufinamide, Stiripentol 2011 Retigabine (Esogabine) 8

9 II. The clinical development of anti-seizure drugs 25 Ideal product profile Effective in refractory patients Minimal adverse effects ffers once daily dosing Interacts minimally with other drugs an be easily titrated Works via a logical mechanism of action (?) 26 A major issue There is scarcely a substance in the world capable of passing through the gullet of man that has not at one time or another enjoyed the reputation of being antiepileptic. Edward Sieveking,

10 linical study of the Lennox-Gastaut syndrome drug treated group (real clinical trial from the 1980s!) Percent hange 28 Worsened Improved % Improved % Worsened Patient Number linical study of the Lennox-Gastaut syndrome placebo treatment (same trial!) Percent hange 29 Worsened Improved % Improved % Worsened Patient Number Topics not discussed here: Safety studies in-vivo and in-vitro Drug supply and formulation Drug metabolism Regulatory processes (except IND and NDA) 30 10

11 IND Investigational New Drug (application) Results of all preclinical work hemical structure Mechanism of action (if known) Adverse effects in animal studies How the compound will be manufactured linical plan and first protocol My apologies for only using the US regulatory nomenclature for EU, for example, please go to 31 Drug product flow Discovery Development Lead Finding IND Track Phase I Phase II Phase III Registration NDA IND 32 Phase I First stage of drug development 33 11

12 Phase I studies 1) The first 2-3 studies in humans 2) Phase I is sometimes (incorrectly) used to describe the linical Pharmacology studies which are performed throughout the entire period of the drug s development 34 Typical phase I studies 1) Single Ascending Dose (SAD) - (First study in humans) 2) Multiple Ascending Dose (MAD) ) Effect of food (Prelim) 4) Effect of age and/or gender (Prelim) 35 linical pharmacology two fundamentals: Pharmacodynamics what the drug does to the body Toxicity Efficacy Pharmacokinetics what the body does to the drug 36 12

13 Aims of phase I studies Pharmacodynamics: To define the acute and subacute tolerability and toxicity of the drug at various exposure levels in humans To define, inasmuch as possible, the desired action of the drug (efficacy) Pharmacokinetics: To collect pharmacokinetic information and to correlate this information with both the toxicity and the desired action of the drug All this in intensive studies, in-house, with small no s of volunteers 37 Issues in determining tolerability and toxicity Toxicity Evaluations Include: Duration Intensity Degree of reversibility All as a function of dose and duration of dosing Usually in normal human volunteers The MTD is usually sought 38 Evaluating the desired pharmacodynamic efficacy effect in phase I 39 Efficacy evaluation requires a specific response (can be a surrogate); The response is expected from the mechanism of action (if known) of the drug; Ideally the response is both: 1) Predictive of the therapeutic effect and 2) Readily assessable Rarely happens in epilepsy until Phase II 13

14 Determining the pharmacokinetic profile (ADME) Pharmacokinetic Information can provide data on: Absorption (w/wo food) Distribution Metabolism (expected metabolites may already be identified) Elimination Relationship of above to dose (linearity) 40 Summary: aims of the phase I program To provide information for the rational design of Phase II dose-response trials-specifically: Selection of doses for optimal dose response Development of a safety monitoring strategy ptimization of dosing in relation to meals 41 Phase II proof of principle Does the drug work in human disease? Under what circumstances does the drug work? How can we get an early assessment on whether to expend large sums of money on Phase II and especially Phase III? Proof of principle in seizure disorders continues to be difficult and expensive 42 14

15 Unfortunately, for most seizure types, no shortcut has been found that provides reliable preliminary efficacy An expensive, randomized, blinded, controlled clinical trial is the only sure way to ascertain whether a drug is efficacious 43 Some clinical trial considerations in epilepsy Preclinical predictions The patients Seizure type Patient seizure frequency oncomitant medications and drug interactions The dose(s) to be tested Study designs 44 Some preclinical factors in choosing compounds for clinical development Efficacy in animal models PK/Bioavailability Safety profile Drug interaction data 45 15

16 Some clinical trial considerations in epilepsy Preclinical predictions The patients Seizure type Patient seizure frequency oncomitant medications and drug interactions The dose(s) to be tested Study designs 46 The first important concept in the design of clinical trials in the epilepsies: Many different syndromes are included in the epilepsies, and Meaningful data cannot be collected from an undifferentiated group of persons with epilepsy 47 Type of seizure Determines choice of medication in the clinic Is used to segregate patients for clinical trials 48 16

17 49 Two kinds of seizures Partial seizures - seizures which begin in a localized part of the brain Simple partial seizures omplex partial seizures Partial seizures secondarily generalized Generalized seizures - seizures which begin without evidence of a localized onset Generalized tonic-clonic (grand mal) seizures Absence (petit mal) seizures Tonic seizures Atonic seizures lonic and myoclonic seizures Infantile spasms From Porter and Meldrum, 2012 linical trials of partial seizures 50 Advantages: 1. Attacks relatively easily recorded 2. Patients are common 3. Many uncontrolled patients (including adults) 4. orrelates with animal models Disadvantages: 1. onsiderable within-group heterogeneity 2. Low seizure frequency may require a long trial Some clinical trial considerations in epilepsy Preclinical predictions The patients Seizure type Patient seizure frequency oncomitant medications and drug interactions The dose(s) to be tested Study designs 51 17

18 Seizure frequency of patients to be studied Must be sufficiently high that a new compound will have a measurable effect If the seizure frequency is low, the investigator may compensate with either: a) A larger number of patients b) A longer period of observation 52 Some clinical trial considerations in epilepsy Preclinical predictions The patients Seizure type Patient seizure frequency oncomitant medications and drug interactions The dose(s) to be tested Study designs 53 Drug interactions: Must be defined before performing a definitive clinical trial Did the new drug work by increasing the level of other concomitant medications? 54 18

19 Some clinical trial considerations in epilepsy Preclinical predictions The patients Seizure type Patient seizure frequency oncomitant medications and drug interactions The dose(s) to be tested Study designs 55 The doses of the test compound to be evaluated in the clinical trials: ften receives inadequate attention Not all doses will be effective Best plan when possible - is to include the maximal tolerated dose (MTD) 56 Why emphasize the maximum tolerated dose (MTD) in humans 1) Safety We need to know what the dose-limiting adverse effects are in humans, i.e., what actually happens at the MTD 57 Is this dose-related toxicity safe or is it dangerous? - Good signs N&V, dizziness, ataxia, headache, drowsiness - Bad signs EKG abnormalities, liver function abnormalities Remember that, in clinical practice, a few physicians prescribing higher-than-recommended doses will quickly expose the dose-limiting adverse effects! The effort to find the MTD should begin in Phase I But the MTD in patients is much more reliable 19

20 Why emphasize the maximum tolerated dose (MTD) in humans? (2) 2) Efficacy Test at least one dose in the controlled trials near the MTD to assure that you are not overly optimistic about the drug s efficacy A big error is to limit either Phase I or Phase II studies to coverage in animal safety studies Another big error is to assume that the efficacious exposure in animals will correctly predict the required efficacious exposure in humans; Don t believe it If you conduct a controlled study with no adverse effects at any tested dose, you run the substantial risk of having no efficacy at any dose a waste of millions of dollars Finally Don t let the regulatory agencies stop you from getting the MTD data they may not know it, but they need this information as much as does the sponsor! 58 Some clinical trial considerations in epilepsy Preclinical predictions The patients Seizure type Patient seizure frequency oncomitant medications and drug interactions The dose(s) to be tested Study designs retigabine as an example 59 Retigabine (Ezogabine) A potassium channel opener F H N NH 2 H N 60 20

21 Study 202 design (phase IIA) pen label Retigabine Maximally Tolerated Dose Retigabine Monotherapy (2 weeks) Standard AED 75% 50% 25% 61 Baseline Phase (2-3 weeks) Titration Phase (4 to 7 weeks) Start Retigabine mg bid or tid (increased every 1-2 weeks by mg) Maintenance Phase (2 weeks) Tapering Background AED (3 weeks) Modified from Porter, et al., onclusions from phase IIA pen-label study of retigabine: Dose-Related Safety of retigabine is generally good for the class The doses range between 400 and 1600 mg/d in patients with epilepsy (1200 mg/day is near the MTD) TID better than BID Minimal drug interactions will not require dose adjustment (For the 4 drugs tested) Efficacy, observed in some refractory patients, remains to be demonstrated in controlled clinical trials Proof-of-concept study (phase IIB) Retigabine study 205: 63 Phase IIB, randomized double-blind, study Refractory partial-onset seizures secondary generalization Stable dose of 1 or 2 AEDs 4 partial-onset seizures/month No 30-day seizure free period 3 doses of retigabine 600, 900, and 1200 mg/day Primary outcomes (FDA required) hange in monthly total partial-seizure frequency Secondary outcome (EMEA required) Responder rate ( 50% reduction seizure frequency) Porter, et al.,

22 Standard AEDs Randomization Study 205 design Phase IIB Retigabine 1200 mg/day (1100 mg/day) (1000 mg/day) Retigabine 900 mg/day (800 mg/day) (700 mg/day) Retigabine 600 mg/day (500 mg/day) (400 mg/day) Placebo Baseline Phase (8 weeks) Titration Phase Maintenance Phase (8 weeks) (8 weeks) 16-Week Double-Blind Phase Start Retigabine 300 mg/day (increase by 150 mg/day every week) 64 From Porter et al., 2007 Retigabine study 205, cont.: 6 months duration (2 months maintenance) 399 patients randomized 215 patients entered the long-term extension (Study 212) 65 Study 205: reduction in partial seizure frequency (ITT) 50 Median Reduction in Total Monthly Partial Seizure Frequency (%) % Placebo (n=96) 23.4% 600 mg/d (n=99) 29.3% 900 mg/d (n=95) 35.2% 1200 mg/d (n=106) Retigabine 66 ITT: p<0.001 for overall difference across all treatment arms, and p=0.047 for overall difference across retigabine 600, 900, and 1200 mg/d (closed-test procedure for dose response) 22

23 Study 205: responder rate 50% reduction in total partial seizure frequency 67 Patients (%) % Placebo (n=96) a p= and b p=0.016 versusplacebo 23.2% 600 mg/d (n=99) 31.6% a 31.6%b 900 mg/d (n=95) Retigabine 1200 mg/d (n=106) 68 Study 205: treatment emergent adverse events (incidence >10%) Incidence (%) Placebo (n = 96) 600 mg/day (n = 99) Retigabine 900 mg/day (n = 95) 1200 mg/day (n = 106) NS-related Somnolence 6.3* onfusion 5.2* Dizziness 4.2* Tremor 2.1* Amnesia 1.0* Thinking abnormal 0* Vertigo Speech disorder (dysphasia) 0* ther Headache Asthenia P<0.05 versus the combined retigabine groups Study 205: discontinuation due to adverse events occurred mainly during titration verall During titration During maintenance 29.2% 27.4% Patients (%) % 12.5% 17.0% 14.0% 20.0% 18.9% 10 0 Placebo (n = 96) 1.0% 3.0% 600 mg/day (n = 100) 1.1% 900 mg/day (n = 95) 1.8% 1200 mg/day (n = 106) 69 Retigabine 23

24 70 Study 205: conclusions Adjunctive retigabine therapy significantly reduces seizure frequency in patients with refractory partial-onset seizures Linear dose response Effective doses: 900 and 1200 mg/day Proportion of patients with seizure reduction increased with continued treatment Well tolerated up to 1200 mg/day Most common adverse events were NS related Discontinuations were more frequent during the titration phase No clinically relevant adverse effects Hepatic, renal, or thyroid function ardiovascular risk Study 212: Long-term safety open label pen-label extension of study 205 All study 205 patients titrated or tapered to 900 mg/day Those not tolerating 900 mg/day underwent 3-week tapering phase Primary outcome Safety and tolerability of long-term adjunctive treatment Secondary outcomes Preliminary efficacy in long-term adjunctive treatment 71 Phase III Follows a successful phase II program onfirms efficacy in additional controlled studies Generates safety data in a larger number of patients 72 24

25 Retigabine phase III The RESTRE trials: overview Pair of Phase III studies with similar design to the 205 Phase IIB Study: RESTRE 1: Retigabine 1200 mg/day vs. placebo RESTRE 2: Retigabine 600 and 900 mg/day vs. placebo See Brodie et al., and French et al., for these Phase III Studies RESTRE 1 & 2, together with Study 205, formed the core studies for regulatory submission and approval of retigabine in Europe and in the United States 73 Primary efficacy endpoints Phase III FDA Submission Median reduction in total partial-seizure frequency per 28 days from baseline to the end of the doubleblind period EMEA* Submission Proportion of responders (>50% reduction in seizure frequency per 28 days comparing maintenance period to baseline) 74 *EMEA = European Medicines Evaluation Agency Lecture summary In spite of the large number of new anti-seizure drugs introduced since 1990, many unmet needs remain Many patients continue to have adverse effects from their medications Refractory seizures are still an issue in 20-30% of patients 75 25

26 Lecture summary (2) The discovery and development of new anti-seizure drugs presents huge challenges both for patients and for the pharmaceutical industry 1. The expense and the complexity of the process is daunting 2. The return on the outlay is not guaranteed 3. Industry currently sees NS in general as a difficult area for investment 76 Lecture summary (3) But we cannot give up! Discovery Development Lead Finding IND Track Phase I Phase II Phase III Registration 77 IND NDA References Brodie MJ, Lerche H, Gil-Nagel A, Elger, Hall S, Shin P, Mansbach H, Nohria V: Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy, Neurology 75: , 2010 French JA, Abou-Khalil BW, Leroy RF, Yacubian EM, Shin P, Hall S, Mansbach H, Nohria, V: Randomized double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy, Neurology 76: , 2011 Porter RJ, Partiot A, Sachdeo R, Nohria V, Alves WM: Randomized, multicenter dose-ranging trial of retigabine for partial-onset seizures, Neurology, 68: , 2007 Porter, RJ, Baulac, M and Nohria, V: linical development of drugs for epilepsy: A review of approaches in the United States and Europe, Epilepsy Research, 89: , 2010 Porter RJ, Burdette DE, Gil-Nagel A, Hall ST, White R, Shaikh S, DeRossett SE: Retigabine as adjunctive therapy in adults with partial-onset seizures: Integrated analysis of three pivotal controlled trials, Epilepsy Research 101: , 2012 Porter RJ & Meldrum BS: Antiseizure Drugs, In Katzung BG (Ed): Basic and linical Pharmacology, 12 th Edition, Lange/McGraw-Hill, New York, 2012, Putnam TJ and Merritt HH: Experimental determination of the anticonvulsant properties of some phenyl derivatives, Science 85: , 1937 Swinyard EA: Introduction, In Antiepileptic Drugs (2 nd Ed), Woodbury, Penry and Pippinger (eds), Raven Press,

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