1. CREB & The Development Of Novel Memory Enhancers Tim Tully Chief Science Officer Dart Neuroscience LLC

2. 76543210 0 20 40 60 80 100 10x spaced 10x massed 1x RETENTION TIME (day) PERFORMANCE INDEX Long-Term Memory In The Fruit Fly Tully et al (1994)

3. PERFORMANCE INDEX TIME (days) hs-dCREB2-r massed spaced 0 20 40 60 80 100 -20 1 35 7 CREB Repressor Blocks LTM Yin et al (1994) See also: Bourtchouladze et al (1994)

4. 0 10 20 30 40 50 control CREB-a 1x 10x spaced 7-DAY MEMORY TRAINING SESSIONS CREB Activator Enhances Memory Yin etal. (1995)

5. dCREB2 Homologs Olson etal (2005) GENESEER

6. Drug Screen For Enhancers of CREB ATP cAMP AMP AC PDE PKA Ca/CaM CRE CREB luciferase nucleus forskolin neuroblastoma cell HT-0712

7. 0 10 20 30 40 50 60 Memory Score Vehicle 0.1mg/kg HT0712 (60’ after) * 8 8 88 Memory Enhancement In Normal, Young Mice 2 Trials 5 Trials

8. Paired-Associate Memory In Elderly Macaque 0 5 10 15 20 25 30 vehicle Training Days to Criterion 1 mg/kg10 mg/kg 100 mg/kg

9. Mouse Model Of Rubinstein-Taybi Syndrome wild-type (sib) CBP +/- mice Oike etal (1999)

10. 15-min Training Facilitation Of LTM In RTS Model VehicleHT0712 (0.1 mg/kg) * wt CBP +/- 80 70 60 50 40 30 20 10 0 -10 Memory Score Bourtchouladze etal (2003)

11. Facilitation Of Rehabilitation After Stroke Post-stroke motor recovery Day 0 0.5 1.0 1.5 0 1 2 3 4 5 6 7 8 9 10 11 vehicle HT-0712 (0.15 mg/kg ) MacDonald et al. (2007) Neurorehabil. Neural Repair 6: 486.

12. Cognitive Rehabilitation After Traumatic Brain Injury Hallam etal (2010) unpublished.

13. Cognitive Rehab Generalizes Hallam etal (2010) unpublished.

14. Clinical Safety Phase 1 (single rising dose) 42 healthy young and elderly exposed (405 mg max dose) no serious adverse events Phase 1 (repeat dose) 24 healthy young and elderly exposed (135 mg max dose) no serious adverse events Phase 1 (interaction with warfarin) 21 elderly exposed (45 mg dose) no serious adverse events Phase 2a (28 daily doses) 55 elderly with AAMI (90 mg max dose) no serious adverse events

15. ProjectResearch Pre- Clinical Phase IPhase IIPhase III PDE4 GalR3 MAO-B GABA-A Novel GLYT1 Drug Development Pipeline HT-2157 BackUp Back-ups HT-1067 BackUp Back-ups Hits Screening HT-4313 HT-0712 Screening Hits

16. Acknowlegements Ken Johns CEO Phil PereraCMO Anne DanksDirector, Preclinical Development Alan Kaplan Director, Chemistry Tim TullyFounder, x-CSO Lila DavachiNYU Emmanuel DeCampTJU Jeff KleimUF-Gainesville Collaborators

17. HT-0712 Facilitates Motor Rehab After TBI Hallam etal (2010) unpublished.

18. HT-0712 Facilitates Cognitive Rehab After TBI Hallam etal (2010) unpublished.

19. Drug Alone Does Not Facilitate Hallam etal (2010) unpublished.

20. MEMORY RETENTION 0 1 3 5 24 TIME (hr) STM MTM ARM LTM observed No Measures Of Long-Term Memory In The Clinic… clinical measures of dementia

21. 7-Day WordRecall In Humans With AAMI