1. Acetyl Hexapeptide-8 for Treatment of Blepharospasm Codrin Lungu, MD Medical Neurology, NINDS, NIH

2. Disclosures The study substance is provided by BCN Peptides inc. under a CTA with NIH. Study supported with intramural NIH funds None of the investigators have any relevant conflicts of interest or any financial interests in this project

3. Background Blepharospasm is a focal dystonia, involving primarily or exclusively the orbicularis oculi. Botulinum neurotoxin (BoNT) injection remains the mainstay of therapy BoNT therapy is associated with significant discomfort, and has a duration of action of 3 months, requiring frequent treatments emedicine Hallett M, Neurotoxininstitute

4. BoNT action Willis B et al, Angew Chem Int Ed Engl. 2008

5. BoNT action Willis B et al, Angew Chem Int Ed Engl. 2008

6. Acetyl Hexapeptide-8 Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2 Small molecule, competitively inhibits SNAP25, skin penetrance Showed efficacy in cosmetic applications – wrinkle reduction Blanes-Mira C et al, Int J Cosmet Sci. 2002

7. Design and Challenges Most patients are being successfully treated with BoNT Limited outcome measures First medical use

8. Design and Challenges Most patients are being successfully treated with BoNT Recruitment challenge Ethical challenge BoNT is a proven effective therapy Need to perform a blinded placebo controlled trial

9. Design Focus on duration of action Enrolling patients with primary blepharospasm, receiving successful BoNT therapy at 3 months intervals Visit1: initial evaluation, BoNT injection within 24hrsMonthly visits, clinical measures of severityThe study ends when patients reach the baseline severity scoresResume BoNT therapy

10. Clinical Measures Ramasamy B et al, J Neuroophthalmol. 2007 Jankovic J et al, Mov Disord. 2008

11. Outcomes Primary: time to return to baseline JBRS Duration to return to baseline (BoNT injection) Proportion of patients Secondary: JBRS and DBS scores at endpoints Simulated data

12. Current Status Active enrollment, patient no. 19 enrolled 03/02. Target for appropriate power 22, ceiling 44 6 patients completed the study No withdrawals, no complications, no unexpected problems Projected blind break 08/2010

13. Challenges and Lessons Unable to perform a head-to-head study with the proven effective therapy at this time, the substance is being tested as an adjunct. Need to limit inclusion to patients receiving BoNT at regular intervals (same 3 month interval for all patients) Limitations and variability in the scales used – started using blinded video evaluation Intrinsic variation of BoNT response No prior knowledge of expected effect on blepharospasm, dose needed, delivery – follow-up studies planned