Transcript AIC Plenary Lecture
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 co principal investigators on an NIH funded 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
30 25 20 15 10 5 0 -10 There is a prolonged period during which loss of cognitive function occurs.
-8 -6 -4 -2 0 2 4
Estimated years into illness
6 8 10
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
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)
20 10 Data: Satoris, Inc.
AD 6
In vitro
: Leptin inhibits A
b
production and stimulates A
b
uptake Fewlass et al., 2004 7
extra cellular
APP is a transmembrane protein. It is first cleaved by one of two enzymes.
intracellular
Lipid raft (BACE) Leptin receptors can activate JAK/STAT3, stimulate lipolysis, modulatng lipid raft composition, decreasing BACE activity Fewlas et al., 2004
In vitro
Leptin is 270x more potent than Insulin in down-regulating tau phosphorylation Leptin, 4h Insulin, 4h IC50= 46.9nM
Greco et al., (2008) BBRC IC50= 13
m
M 9
Animal studies Chronic s.c. Leptin in Tg2576 reduces brain A
b
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 A
b
production in neurons Leptin promotes ApoE-dependent A
b
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
Clinical State
Alzheimer’s Disease: Course, Pathology, Biomarkers
Neuro pathology Normal None Pre Symptomatic AD Mild Cognitive Impairment AD Amyloid Plaques, No Tangles Amyloid Plaques Few Tangles Amyloid Plaques Many Tangles CSF Biomarkers Normal tau Normal A
b
tau?
A
b?
High tau Low A
b
High tau Low A
b
Disease Progression
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 700 600 500 400 300 200 100 0
A β Sunderland T, et al. JAMA. 2003;289:2094-2103.
Control Patients
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 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
ADNI Data – CSF ABeta, total tau
220 200 180 160 140 120 100 33 34 44 Normal MCI Mild AD 140 130 120 110 100 90 80 70 60 33 34 44 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 320 cases 241 cases 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
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
1 2
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-A outcome measure.
b42,
with APOE
e
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 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 e 4 patients
Baseline diagnosis
Amnesic MCI or mild dementia with AD
Baseline measures
Elevated CSF tau, decreased A b
Drug administration
3 groups - daily injections, placebo, 5, 10 mg SC
Outcome measures
Primary - CSF tau Secondary – cognitive measures, other CSF/plasma measures