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Neurotrophins Promises Neuroprotection, Neuro-restoration NGF, BDNF, Nerturin Limitations Poor bio-availability in target organ following systemic peripheral delivery Undesirable side effects from non-targeted central delivery, e.g. generalized sprouting promoting inappropriate connections, neuralgia Solutions Localized (chronic) central delivery to affected region(s) Surgical implants for localized infusion (GDNF) Targeted delivery Gene therapy (Tuczyinski 2004) via implantation of genetically modified fibroblasts; CERE-110 – viral delivery of NGF (recruiting P2, n=50 end May 2012) CERE-120 (AAV2-Neurturin) - P2 (Dec 2008): Failed on 1o endpoint (efficacy in motor function at 12 mo), may have benefit at 18 mo. OLE in progress
Immunotherapy targeting Ab for AD Ab peptide active immunizationFormerly theexclusivedomain ofsmall moleculePotential ofbiologics for RxofNeurodegenerative disease Anti-Ab mAb passivePhagocytosis immunizationof plaquetriggered byantibodyopsonization ofamyloid
Initial Results of Immunotherapy: Active &Passive Immunotherapy targeting Ab Preclinical Observations Induces clearance of plaques, improvement in synaptic density, reduces gliosis Efficacy in behavioral testing Multiple potential mechanisms: antibody induced plaque phagocytosis, peripheral sink Clinical observations with AN1792 Plaque clearance and reduced plaque associated neuropathology Significant effect on NTB P2 trial halted due to meningioencephalitis in subset of patients Attributable to T-cell epitopes in full length Ab peptide Epitope mapping of responders combined with pre-clinical studies suggests safer follow-on approaches
Antibody Response in AN1792 treated AD Patients is Specific to the Amino Terminus of Ab • No reaction to APP • Binds to plaques • Adsorbable by linear peptideM. Lee et al, Ann Neurol 2005
Preclinical Endpoints Effected By Immunotherapy with3D6, the Murine Precursor of BapineuzumabNeuritic 3D6: Very similar to AN1792-induceddystrophy antibodies Binds amino-terminus of Ab, but not APPAstrogliosis Recognizes both plaques and soluble forms of AbNeutralizatio Chronic efficacy testing in PDAPP mousen of model of ADneurotoxic Treatment and prevention models, followingAb species chronic therapyVascular Positive on broad spectrum of efficacy end-pointsAmyloid
Principles of Drug Development Exemplified inAb Targeted Immunotherapy Access to target organ CNS:Plasma exposure of drug Target engagement Biological readout of drug activity Translational medicine Preclinical clinical observation
Access of drug to target organ 10000 7500 cpm/gm tissue• Peak accumulation of binding occurred ~14 d post injection and remains stable up to 27 5000 days 2500• Accumulation continues even as antibody serum levels drop over two weeks 0 The 125I-3D6 tHippocampus in Cortexbrain than in the serum Cerebellum 1/2 is longer 2 7 the 14 21 27 2 7 14 21 27 2 7 14 21 27 Day post-injection Bard et al., 2010“Unique Brain PK Properties of 3D6 and Bapineuzumab Depend on Cerebral Amyloid Load in PDAPP Transgenic Mice” P4-406, ICAD 2010
Target Engagement Elevation of plasma Ab via prolongation of t1/2 Seubert et al (2007), Neurodegenerative Dis. 5:65-71; Gray et al. (2007) Neuroreport 18: 293 Mobilization of deposited central Ab Pre-clinical: dose dependent increased vascular Ab, microhemorrhage Wilcock 2004) J Neuroinflammation 1:24 Racke (2005)J Neurosci 25:629 Schroeter (2008) J Neurosci 28:6787 Clinical: Vasogenic edema/ ARIA Sperling (2012) The Lancet: DOI 10.1016/S1474-4422(12)70015-7
Clinical translation of pre-clinicalObservations 1. Ab ImmunizedReductio PDAPP Micen of Ab Schenk, D. (1999) Nature 400:173amyloid 2. AN 1792 (A-beta)pathology Immunized patients Nicoll, J et al. (2006) J. Exp. Neurol. &in brain Exp. Neur. 65:1040 3. Bapineuzumab Treated patient Rinne, JO (2010) Lancet Neurol. 9:363
A proliferation of biologics in preclinical discovery for neurodegenerative disease Immunotherapy Engineered BiologicsImmunotherap (mAbs, Fc-Fusions, etc.)y AD (Ab Tau, BACE); PD (a-Syn);TargetedDelivery viaEngineeredBiologics
Tau ImmunotherapyEfficacy on taupathology andbehavior end-points followingactive andpassive Rxtargeting PHFtau epitope inFTD mousemodelSub-cellularlocalization ofinternalizedAntibody inbrain slicemodel
Case by case opportunities employing TargetedDelivery Antagonist antibody targeting BACE, a traditional small molecule target
Anti-BACE immunotherapyAnti-BACEmAb IC50 ~3 nMCentralreduction ofAb followingperipheraladministration in mice(brain) andprimate(CSF) at 30or 100 mg/Kg Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y, Heise CE, Hoyte K, Luk W, Lu Y et al. 2011. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Science translational medicine 3: 84ra43.
Brain:Plasma of non-targeted anti- BACEAtwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y, Heise CE, Hoyte K, Luk W, Lu Y et al. 2011. A therapeuticantibody targeting BACE1 inhibits amyloid-beta production in vivo. Science translational medicine 3: 84ra43.
Pharmacokinetics considerations oftargeted delivery of antibodiesCNS and • Order of magnitude dropperipheral in plasma concentrationexpression ofcarrier of drug by 2h following IVmediated administration attributabletransport to uptake via peripheraltargets e.g. TfR insulin receptorand InsRcontributes to • mAb Volume ofrapid clearance distribution ~ plasmaof mAb from volumecirculation, witht1/2 ~ small • Transport receptormolecules targeted mAb volume of Boado, R.J., Hui, E. K. W., Lu,J. Z., and Pardridge, W. M. (2009b). AGT- 181: Expressionin CHO cells and pharmacokinetics, safety, and plasma distribution ~ small iduronidase enzyme activity in Rhesus monkeys.). Biotechnol. 144, 135-141. molecule
Challenges Associated with TargetedDelivery for CNS indications Advantages of Traditional mAbs Bi-specific targeting modalities, e.g. Long t1/2 BACE IV-transfusion, infrequent dosing Scalable manufacture of bi-specific (monthly) mAb PK Advantages Negated by transport Cost of Goods: receptor targeted delivery Hu eq dose BACE/TfR = 1.75g/70kg; More Frequent dosing depending Tysabri: 300 mg IV, q4 wks upon: Humira: 40-160 mg IV, qw – q4 wk Target:Ligand stoichiometry demands Dosing interval BACE/TfR? for desired pharmacologic outcome Monthly = 21g/person/yr Pharmacodynamic effect if target engagement may allow less frequent Bimonthly = 42g/person/yr dosing 300 person 1 yr P2 trial = 12.6 kg drug product
Antibody TechnologiesCMC, timeline to IND, and cost considerations
Growth of Antibody TherapeuticsNelson AL, Dhimolea E, Reichert JM. 2010. Development trends for human monoclonal antibody therapeutics.Nature reviews Drug discovery 9: 767-774.