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 Disclosures Drs. Ashford and Tezapsidis are coprincipal investigators on an NIHfunded SBIR to study the effects of Leptin in Alzheimer patients 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 ALZHEIMER’S DISEASE COURSE Estimate MMSE as a function of time MMSE score 30 25 20 15 10 There is a prolonged period during which loss of cognitive function occurs. 5 0 -10 -8 -6 -4 -2 0 2 4 6 8 10 Estimated years into illness AAMI / MCI/ early AD -- DEMENTIA Ashford et al., 1995 Ashford et al., 1998 J Neuropathol Exp Neurol.57:972 Serum Leptin levels and cognition in the elderly AD 20 Severe Moderate MiId 10 Normal Patients with AD have lower serum leptin levels compared to controls, independent of BMI (Power et al., 2001) Data: Satoris, Inc. Leptin (ng/ml) In elderly, higher serum leptin appears to protect against cognitive decline (5 yr prospective study, 2,871 elders, Holden et al., 2009) 6 In vitro: Leptin inhibits Ab production and stimulates Ab uptake 7 Fewlass et al., 2004 extra cellular APP is a transmembrane protein. It is first cleaved by one of two enzymes. intracellular Lipid raft (BACE) Fewlas et al., 2004 Leptin receptors can activate JAK/STAT3, stimulate lipolysis, modulatng lipid raft composition, decreasing BACE activity In vitro Leptin is 270x more potent than Insulin in down-regulating tau phosphorylation Leptin, 4h IC50=46.9nM Greco et al., (2008) BBRC Insulin, 4h IC50=13mM 9 Animal studies Chronic s.c. Leptin in Tg2576 reduces brain Ab Fewlass et al (2004) FASEB J 10 Animal studies Leptin reduces hippocampal Amyloid burden in TgCRND8 mouse Leptin reduces phospho-tau in brain of TgCRND8 mouse 11 Animal behavior studies 12 Animal behavior studies Fear conditioning after 8 weeks leptin Greco et al., Manuscript submitted 13 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 14 Alzheimer’s Disease: Course, Pathology, Biomarkers Clinical State Neuro pathology CSF Biomarkers Normal PreSymptomatic AD None Amyloid Plaques, No Tangles Normal tau Normal Ab tau? Ab? Mild Cognitive Impairment AD Amyloid Amyloid Plaques Plaques Few Tangles Many Tangles High tau Low Ab Disease Progression High tau Low Ab Biomarkers for More Valid Alzheimer Diagnosis and Precise Measurement of Severity Lancet Neurol 2007; 6: 734–46 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) CSF in Alzheimer’s Disease, both MCI and Dementia patients: Low Aβ and High Tau AD Patients Control Patients Concentration (pg/mL) 700 600 500 400 300 200 100 0 Aβ Sunderland T, et al. JAMA. 2003;289:2094-2103. Tau 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 Ttau 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 ADNI Data – CSF ABeta, total tau 220 Abeta(1-42) 200 180 33 160 34 44 140 120 100 Normal MCI Mild AD 140 130 Tau (total) 120 110 33 100 34 90 44 80 70 60 Normal MCI Mild AD 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 MMSE hippocampal volume temporal horn volume 320 cases 241 cases 21 cases 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 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) 22 Clinical Trials: Design 1 2 A focused clinical trial, in a group of 45 earlystage 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). 23 Summary Clinical Plan for Trial for Leptin Treatment in AD Recruitment Use of audience screening, genetic testing Genetics 45 APOE e4 patients Baseline diagnosis Baseline measures Elevated CSF tau, decreased Ab Drug administration Amnesic MCI or mild dementia with AD 3 groups - daily injections, placebo, 5, 10 mg SC Outcome measures Primary - CSF tau Secondary – cognitive measures, other CSF/plasma measures Slides available at: www.medafile.com/leptin