Presentation on theme: "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."— Presentation transcript:
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 (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 co- principal investigators on an NIH- funded SBIR to study the effects of Leptin in Alzheimer patients
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 OVERVIEW
AAMI / MCI/ early AD -- DEMENTIA ALZHEIMER’S DISEASE COURSE Ashford et al., 1995 There is a prolonged period during which loss of cognitive function occurs.
Ashford et al., 1998 J Neuropathol Exp Neurol.57:972
Serum Leptin levels and cognition in the elderly 6 MiId Moderate Normal Severe 10 20 Leptin (ng/ml) Data: Satoris, Inc. AD 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)
7 Fewlass et al., 2004 In vitro: Leptin inhibits A production and stimulates A uptake
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 intracellularextra cellular Fewlas et al., 2004 (BACE) Lipid raft
Leptin, 4hInsulin, 4h IC50=46.9nM IC50=13 M In vitro Leptin is 270x more potent than Insulin in down-regulating tau phosphorylation Greco et al., (2008) BBRC 9
Chronic s.c. Leptin in Tg2576 reduces brain A Fewlass et al (2004) FASEB J 10 Animal studies
11 Leptin reduces hippocampal Amyloid burden in TgCRND8 mouse Leptin reduces phospho-tau in brain of TgCRND8 mouse Animal studies
Fear conditioning after 8 weeks leptin 13 Greco et al., Manuscript submitted Animal behavior studies
Summary of preclinical data High density of Leptin receptors in the hippocampus Leptin inhibits A production in neurons Leptin promotes ApoE-dependent A 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 Disease Progression Normal tau Normal A tau? A High tau Low A High tau Low A CSFBiomarkers NoneAmyloidPlaques, No Tangles AmyloidPlaques Few Tangles AmyloidPlaques Many Tangles Neuropathology NormalPre-SymptomaticADMildCognitiveImpairmentAD ClinicalState
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 AβAβTau Concentration (pg/mL) Sunderland T, et al. JAMA. 2003;289:2094-2103.
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
Power Calculations for Reduction in Rate of Decline in AD for an Experimental Treatment 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 Number needed per arm for 50% effect size (50% reduction over 1 yr in the rate of cognitive decline )
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)
Clinical Trials: Design 23 1 2 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-A with APOE 4 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).
Summary Clinical Plan for Trial for Leptin Treatment in AD Recruitment Use of audience screening, genetic testing Genetics 45 APOE 4 patients Baseline diagnosis Amnesic MCI or mild dementia with AD Baseline measures Elevated CSF tau, decreased A Drug administration 3 groups - daily injections, placebo, 5, 10 mg SC Outcome measures Primary - CSF tau Secondary – cognitive measures, other CSF/plasma measures