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TESTING A LEPTIN PRODUCT AS A NOVEL THERAPY FOR ALZHEIMER’S DISEASE

TESTING A LEPTIN PRODUCT AS A NOVEL THERAPY FOR ALZHEIMER’S DISEASE . J. Wesson Ashford, M.D., Ph.D. (1) Mark A. Smith, Ph.D. (2), G. Casadesus, Ph.D. (2), S.J. Greco, Ph.D. (3), J.M. Johnston, Ph.D. (3), N. Tezapsidis, Ph.D. (3)

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TESTING A LEPTIN PRODUCT AS A NOVEL THERAPY FOR ALZHEIMER’S DISEASE

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  1. TESTING A LEPTIN PRODUCT AS A NOVEL THERAPY FOR ALZHEIMER’S DISEASE • J. Wesson Ashford, M.D., Ph.D. (1) • Mark A. Smith, Ph.D. (2), • G. Casadesus, Ph.D. (2), • S.J. Greco, Ph.D. (3), • J.M. Johnston, Ph.D. (3), • N. Tezapsidis, Ph.D. (3)   (1) Stanford /VA Aging Clinical Research Center, VAPA-HCA, Palo Alto, CA USA  (2) Case Western Reserve University, Cleveland, OH, USA  (3) Neurotez, inc., Bridgewater, NJ, USA

  2. Disclosures Drs. Ashford and Tezapsidis are co-principal investigators on an NIH-funded SBIR to study the effects of Leptin in Alzheimer patients

  3. OVERVIEW Numerous factors (particularly age and APOE) are known to moderate the course of Alzheimer’s disease (AD), but the pathophysiology of AD causation is unknown. Serum Leptin levels appear to protect against cognitive decline in the elderly, and patients with AD have lower Leptin levels. Leptin injections in AD-transgenic mice protect against both the development of amyloid and tau pathology and reverse the cognitive impairments found in these animals. Therefore, Leptin may be a preventive therapy for AD

  4. ALZHEIMER’S DISEASE COURSE There is a prolonged period during which loss of cognitive function occurs. AAMI / MCI/ early AD -- DEMENTIA Ashford et al., 1995

  5. Ashford et al., 1998 J Neuropathol Exp Neurol.57:972

  6. Serum Leptin levels and cognition in the elderly Data: Satoris, Inc. In elderly, higher serum leptin appears to protect against cognitive decline (5 yr prospective study, 2,871 elders, Holden et al., 2009) Patients with AD have lower serum leptin levels compared to controls, independent of BMI (Power et al., 2001) AD 20 Leptin (ng/ml) 10 MiId Normal Severe Moderate 6

  7. In vitro: Leptin inhibits Ab production and stimulates Ab uptake Fewlass et al., 2004

  8. extra cellular intracellular APP is a transmembrane protein. It is first cleaved by one of two enzymes. Leptin receptors can activate JAK/STAT3, stimulate lipolysis, modulatng lipid raft composition, decreasing BACE activity Lipid raft (BACE) Fewlas et al., 2004

  9. In vitro Leptin is 270x more potent than Insulin in down-regulating tau phosphorylation Leptin, 4h Insulin, 4h IC50=46.9nM IC50=13mM Greco et al., (2008) BBRC

  10. Animal studies Chronic s.c. Leptin in Tg2576 reduces brain Ab Fewlass et al (2004) FASEB J

  11. Animal studies Leptin reduces phospho-tau in brain of TgCRND8 mouse Leptin reduces hippocampalAmyloid burden in TgCRND8 mouse

  12. Animal behavior studies

  13. Animal behavior studies Fear conditioning after 8 weeks leptin Greco et al., Manuscript submitted

  14. Summary of preclinical data High density of Leptin receptors in the hippocampus Leptin inhibits Ab production in neurons Leptin promotes ApoE-dependent Ab neuronal uptake Leptin inhibits tau phosphorylation Leptin (chronic application) reduces brain amyloid load in AD transgenic mice Leptin (acute and chronic application) improves memory in aged AD transgenic mice. The clinical and preclinical data provide compelling evidence to support a clinical trial of Leptin for AD

  15. Alzheimer’s Disease: Course, Pathology, Biomarkers Normal Pre- Symptomatic AD Mild Cognitive Impairment AD Clinical State None Amyloid Plaques, No Tangles Amyloid Plaques Few Tangles Amyloid Plaques Many Tangles Neuro pathology Normal tau Normal Ab tau? Ab? High tau Low Ab High tau Low Ab CSF Biomarkers Disease Progression

  16. Biomarkers for More Valid Alzheimer Diagnosis and Precise Measurement of Severity Lancet Neurol 2007; 6: 734–46

  17. Potential AD Biomarkers Blood, urine Aβ40? Aβ42? Neuritic threads? Most studies suggest not helpful Protein levels in blood – Proteomics, Leptin. Lower Leptin predicts MCI progression to dementia CSF: Aβ40? Aβ42? Others Aβ species? Possibly highly predictive CSF: tau, p-tau Assess active disease progression. Neuroimaging Structural (volumetric assessments) Functional (FDG-PET, SPECT) Specific protein imaging (PET)

  18. CSF in Alzheimer’s Disease, both MCI and Dementia patients: Low Aβ and High Tau Concentration (pg/mL) Aβ Tau Sunderland T, et al. JAMA. 2003;289:2094-2103.

  19. CSF of subjects with MCI progressing to AD has elevated tau, decreased β-amyloid The relative risk of progression to AD substantially increased in patients with MCI who had pathological concentrations of T-tau and A42 at baseline (hazard ratio 17·7, p0·0001). The association between pathological CSF and progression to Alzheimer’s disease was much stronger than, and independent of, established risk factors including age, sex, education, APOE genotype, and plasma homocysteine. Hansson et al., Lancet Neurology 2006

  20. ADNI Data – CSF ABeta, total tau

  21. Power Calculations for Reduction in Rate of Decline in AD for an Experimental Treatment Number needed per arm for 50% effect size (50% reduction over 1 yr in the rate of cognitive decline ) • ADAS-Cog 320 cases • MMSE 241 cases • hippocampal volume 21 cases • temporal horn volume 54 cases ----------------------------------------------------------------------------------------------------- CSF-tau – if level returns to normal in 12 weeks, - then only 6 cases (3+3) needed for statistics!! - plan 15 in each arm due to drop-outs, etc. Neurology 2003;60:253-260

  22. Numerous Leptin trials have been performed for several indications - no safety issues - AMGEN: obesity as a monotherapy, congenital obesity ROCHE: obesity as a monotherapy Amylin: obesity as a combination therapy with Symlin (amylin) Harvard U., Rockefeller U., Columbia U., NIH: obesity, hypothalamic amenorrhoea, lipodystrophies (i.e. aggressive anti-HIV therapies)

  23. Clinical Trials: Design A focused clinical trial, in a group of 45 early-stage AD (MCI range to very mild dementia) individuals pre-screened for low leptin, elevated CSF-tau, low CSF-Ab42, with APOE e4 genotype and MRI enrolled for a 12 week treatment period (15 on 5mg/d; 15 on 10 mg/d; 15 on placebo) with decreased CSF-tau as the primary outcome measure and cognitive function as a secondary outcome measure. Leading to a larger, multicenter, double-blind, placebo controlled trial, for 1 year (number of patients to be determined by pilot data). 1 2

  24. Summary Clinical Plan for Trial for Leptin Treatment in AD • Recruitment • Use of audience screening, genetic testing • Genetics • 45 APOE e4 patients • Baseline diagnosis • Amnesic MCI or mild dementia with AD • Baseline measures • Elevated CSF tau, decreased Ab • Drug administration • 3 groups - daily injections, placebo, 5, 10 mg SC • Outcome measures • Primary - CSF tau • Secondary – cognitive measures, other CSF/plasma measures

  25. Slides available at:www.medafile.com/leptin

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