H. Steve White, Ph.D., D. Sci. Anticonvulsant Drug Development Program

1. Using Toxicology and Toxicokinetics to Better Predict Therapeutic Index (of Anti-seizure Drugs)March 1, 2013 H. Steve White, Ph.D., D. Sci. Anticonvulsant Drug Development Program Dept. Pharmacology and Toxicology University of Utah Salt Lake City, UT American Society for Experimental NeuroTherapeutics | 15thAnnual Meeting

2. Scientific Advisory Board Consultant Sponsored research & consultant Scientific co-founder Vimpat Speakers Bureau Senior Research Advisor Disclosure Upsher-Smith Laboratories Insero Health Janssen Pharmaceuticals NeuroAdjuvants, Inc. UCB Pharma Citizen’s United for Research in Epilepsy American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

3. Disclosure I’m NOT a Toxicologist! American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

4. Learning Objectives Discuss the approach used in the early identification of anti-seizure drug activity and toxicity. Gain a greater understanding of the tolerability issues associated with chronic use of anti-seizure drugs Discuss the utility and limitations of standard rodent behavioral tests in predicting human tolerability to anti-seizure drugs American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

5. IND Objectives: Pharmacology • Provide rationale for human benefit • Employ animal data to extrapolate projected doses or blood concentrations that will be efficacious in humans • Identification of unintended actions that may impact safety • Estimate THERAPEUTIC INDEX from Pharmacology/Toxicology data

6. Therapeutic Index • The ratio of the dose that produces the desired therapeutic effect (ED50) to the dose that produces a toxic effect (TD50).

7. Current Era of AED Discovery • Ushered in by Merritt and Putnam in 1938 with the discovery of phenytoin • Employs well-characterized animal seizure models • Goal is to provide sufficient Proof-of-Concept efficacy data to support an Investigational New Drug Application

9. Existing Rodent Seizure and Epilepsy Models Find Drugs Felbamate Fosphenytoin Gabapentin Lamotrigine Lacosamide Levetiracetam Oxcarbazepine Perampanel Pregabalin Rufinamide(Lennox-Gastaut Syndrome) Stiripentol(Dravet Syndrome) Tiagabine Topiramate Vigabatrin(Infantile Spasms) Zonisamide Importantly, many new drugs have been introduced for the treatment of epilepsy that have benefited adult and pediatric patients! Further,

10. Brivaracetam(binds SV2A & blocks voltage-gated Na+ channels) 2-deoxy-glucose (inhibits glycolysis) Ganaxolone(neurosteroid) Huperzine A (NMDA antagonist) ICA-105665(Kv7.2/7.3 activator) NAX 810-2 (galanin-based neuropeptide) Propylisopropylacetamide(VPA analog) Tonabersat(presumed gap junction inhibitor) YKP-3089 (broad-spectrum AED) Also: http://www.epilepsy.com/etp/pipeline_new_therapies More AEDs in the Pipeline* http://boston.com/travel/getaways/us/ hawaii/articles/ 2007/12/02/shooting_the_tube/ Image kindly provided by Professor Harold Wolf *Presented at Eleventh Eilat Conference (April 6-10, 2012)

11. Perceived Efficacy of AEDs Slide courtesy of Jacqueline French, MD

12. Pharmacology of Valproic Acid (VPA) ;

13. Relationship between human AED plasma (Css) and rat MES ED50 values Bialer et al., Epilepsy & Behavior, 5: 866-872, 2004.

14. So what’s the PROBLEM??

15. There are still many patients with uncontrolled epilepsy!! Mohanraj & Brodie, 2005 • Many patients can only achieve seizure control at a substantial cost to their quality of life!

16. Perceived Adverse Events of AEDs Slide courtesy of Jacqueline French, MD

17. Could these adverse events be predicted from animal studies ??

18. Predicting human AEs using rodent testing: General behavior

19. Animal Models of Hyperlocomotion: AccuScan SuperFlex (IITC, Inc.) (Smith et al., unpublished)

20. Predicting human AEs using rodent testing: anxiety, depression, mood

21. Animal Models of Depression Porsolt Forced Swim Test (rats or mice) Tail Suspension Test (mice)

22. Animal Models of Anxiety Disorders Light-Dark Box (mice or rats) AccuScan SuperFlex (IITC, Inc.) Novelty Induced Hypophagia (rats or mice) Elevated plus maze (rats) (Dulawa & Hen, 2005)

23. Predicting human AEs using rodent testing: Cognition

24. Assessing Cognitive Decline In-vitro: Long-Term Potentiation In-vivo: Morris Water Maze

25. Phenytoin and Carbamazepine, but not Valproate, attenuate TBS-induced LTP in area CA1

26. Valproic Acid Displays Cognitive Impairment in Morris Water Maze

27. Single Dose Phenytoin and Valproic Acid Produce Impairment in Morris Water Maze * p<0.05

28. Given all of the available behavioral and cognitive tests why are we not better at predicting CNS tolerability issues?

29. Issues associated with rodent behavior and cognitive testing Extensive behavioral and cognitive testing not routinely conducted. The degree to which results from rodent testing translates to humans is not known. Behavioral and cognitive testing is often done after acute dosing in neurologically intact animals. Rodent testing is conducted following mono-therapy; patients with refractory epilepsy are often taking multiple anti-seizure drugs. Naïve, neurologically intact rodents don’t display comorbidities.

30. Epilepsy as a spectrum disorder • Up to half of all epilepsy patients have some form of cognitive or psychiatric condition. • The cognitive symptoms often include impairments in attention, executive function, and memory. • Cognitive symptoms do not universally disappear once seizures are well controlled. • Pharmacology: the double-edged sword: • Anticonvulsants may exacerbate cognitive dysfunction. • Nootropics may lower seizure thresholds. Jensen. Epilepsy as a spectrum disorder: Implications from novel clinical and basic neuroscience. Epilepsia (2011) vol. 52 Suppl 1 pp. 1-6

31. Neuropsychiatric Comorbidities of Epilepsy: Major Depressive Disorder: Most frequent psychiatric comorbidity (35-55%) in people with epilepsy (PWE). Anxiety Disorder: Second most frequent (10-35%) psychiatric comorbidity in PWE. Bipolar Disorder: Intermittant episodes of mania and depression (12%).

32. Adult Patient with Epilepsy Long-term epilepsy (altered neuronal substrate) Often taking multiple AEDs Treatment is chronic Hepatically induced Often displays co-morbidities Mice and Rats Neurologically intact Pharmacologically naïve Treatment is acute Non-induced No known co-morbidities How comparable are the drug evaluation studies: human vs. rodent?

33. Summary • There are animal models that could aid in the assessment of drug-induced ataxia, incoordination, sedation and cognitive impairment. • Perceived adverse events may be the result of the therapy and/or the attendant comorbidity. • Modification of current approach may yield more informative data for predicting chronic adverse events in the person with epilepsy.

34. Acknowledgements University of Utah Karen Wilcox, Ph.D. Peter West, Ph.D. Gerald Saunders Anitha Alex, Ph.D. Misty Smith, Ph.D. Anticonvulsant Screening Project, NINDS, NIH John Kehne, Ph.D. Jeff Jiang, Ph.D. Tracy Chen, Ph.D. Taek Oh, Ph.D. Funding NINDS, NIH Contract HHSN271201100029C

36. BDZ, benzodiazepines; CBZ, carbamazepine; ESM, ethosuximide; EZG, ezogabine; FBM, felbamate; GBP, gabapentin; LCM, lacosamide; LTG, lamotrigine; LVT, levetiracetam; OxCBZ, oxcarbazepine; PB, phenobarbital; PGB, pregabalin; TGB, tiagabine; TPM, topiramate; VPA, valproic acid; VGB, vigabatrin; ZNS, zonisamide *PB, TGB, and VGB block clonic seizures induced by sc PTZ but are inactive against generalized absence seizures and may exacerbate spike wave seizures. amodels of spike-wave seizures not routinely employed in initial evaluation of investigational drugs ;