Evaluation of tolerability and antiepileptogenic efficacy of multitargeted drug combinations by a two-stage approach Wolfgang Löscher

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1 Evaluation of tolerability and antiepileptogenic efficacy of multitargeted drug combinations by a two-stage approach Wolfgang Löscher Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Germany

2 Multi-targeted drug combinations for antiepileptogenesis ( network pharmacology ) For anti-epileptogenesis, rational drug combinations targeting multiple targets in an epileptogenic network ( network pharmacology ) may be more effective than treatment with single, highly specific drugs (Löscher et al., Nature Rev. Drug Discov., 2013) Clinical translation of such a network approach (which is tested in preclinical models) would benefit from repurposing of drugs that are clinically available W. Löscher s group evaluates such novel multitargeted drug combinations in WP02 of the EPITARGET consortium

3 Multi-targeted approaches to prevent epilepsy 2013

4 Multi-targeted approaches to prevent epilepsy 2008

5 Tolerability and efficacy testing of drug combinations in rodents (Two-stage approach) Phase I (tolerability) 3-6 mice/drug Drug combinations (2-4 drugs) in nonepileptic mice (1-3 adm./d over 3-5 d) Tolerable Not tolerable Stage 1 (mice) Stage 2 (rats) Phase IIa (tolerabilty) 3-6 mice/drug Phase IIb (efficacy) ~20 mice/drug (depending on power analysis) Phase IIc (efficacy) ~20 rats/drug (depending on power analysis) Phase IId (efficacy) ~20 rats/drug (depending on power analysis) Tolerability and neuroprotection during latent phase after SE (i.h. kainate) Tolerable Not tolerable Lower doses Effects on neurodegeneration and SRS after SE (i.h. kainate, mice) Effective Not effective Other combination Effects on neurodegeneration and SRS after SE (i.h. kainate, rats) Effective Not effective Other combination Effects on neurodegeneration and SRS in rats with other epileptogenic brain insults (e.g., TBI)

6 Antiepileptogenic efficacy of levetiracetam and topiramate in mice Multimodal brain imaging MR imaging 2 days post-se (BBB/neurodegen.) PET imaging 7 days post-se (inflammation) MR imaging 37 days post-se (neurodegeneration) Kainate Latent period (5-7 days) Epilepsy with spontaneous recurrent electrographic and electroclinical (convulsive) seizures 0 1 week 4 weeks 12 weeks Treatment with either (1) LEV+TPM (2) Vehicle (3) LEV alone (4) Vehicle (5) TPM alone (6) Vehicle over 5 days t.i.d. (starting 6 h after kainate) in four separate experiments; each drug trial repeated at least once Video/EEG monitoring over one week Necropsy (brain histology/ immunohistology/ gene and protein expression analysis) Video/EEG monitoring over one week Necropsy (brain histology/ immunohistology)

7 Potential mechanisms of the favorable combination? No neuroprotective effect in the ih KA model in mice µpet and µmri imaging do not indicate any antiinflammatory, BBB-protective or neuroprotective effect of the LEV+TPM combination In a cooperation with Michael Johnson (Imperial College London), gene-regulatory network analysis is used to identify the potential therapeutic targets of the LEV+TPM combination in epileptic mice

8 Challenges/bottlenecks Testing high numbers of drug combinations for antiepileptogenesis is extremely laborious and timeconsuming The lack of reliable algorithms for EEG seizure detection adds to the problem As a consequence, testing of different doses per drug in a combination is hardly possible This may lead to false negative findings Next steps to move forward Continue drug combination testing by the two-stage approach Test most promising combination in a TBI model

9 Conclusions Using an algorithm based on clinical drug development, evaluation of various rationally chosen drug combinations in mice has identified an effective combination of two AEDs, levetiracetam and topiramate The disease-modifying mechanisms of this promising combination are currently being explored Based on our two-stage approach, the next step will be to study this combination in rats, preferably in a TBI model We expect that additional promising drug combinations will be identified soon All drugs are clinically approved, which should allow relatively rapid translation into clinical trials

10 The Hannover Epilepsy Research Team Alina Schidlitzki Marion Bankstahl Friederike Twele Kerstin Römermann Manuela Gernert Dave Bergin Wiebke Theilmann Lisa Welzel and other members of W. Löscher s group at the Department of Pharmacology, Toxicology and Pharmacy University of Veterinary Medicine Hannover, Germany Christopher Käufer Sebastian Meller Wolfgang Löscher The experiments of W. Löscher s group are supported by the German Research Foundation, the NIH/NINDS, the Marie Curie, EURIPIDES, and EPITARGET programs of the EU, and the Epilepsy Foundation of America Our studies are performed in cooperation with Pavel Klein (Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, USA)

11 Thank you! Wolfgang Löscher epixchange is a dissemination activity of the FP7 funded projects DESIRE, EpimiRNA, EPITARGET and EPISTOP. DESIRE, EpimiRNA, EPITARGET and EPISTOP are Collaboration Projects funded by the European Union's 7th Framework Programme under respectively grant agreement n , n , n , n