1 / 25

Gene G. Kinney, Ph.D. Prothena Biosciences

Of Mice and Men: How Temporal and Other Biological Factors Affect Interpretability of Animal Models March 1, 2013. Gene G. Kinney, Ph.D. Prothena Biosciences. American Society for Experimental NeuroTherapeutics | 15 th Annual Meeting. Type of Financial Relationship

aaron
Download Presentation

Gene G. Kinney, Ph.D. Prothena Biosciences

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Of Mice and Men: How Temporal and Other Biological Factors Affect Interpretability of Animal ModelsMarch 1, 2013 Gene G. Kinney, Ph.D. Prothena Biosciences American Society for Experimental NeuroTherapeutics | 15thAnnual Meeting

  2. Type of Financial Relationship • Former employee and current shareholder (Elan and Bristol-Myers Squibb) • Current employee and shareholder Disclosure Name of Commercial Interest Bristol-Myers Squibb; Merck & Co.; Elan Pharmaceuticals; Janssen Alzheimer Immunotherapy Prothena Biosciences, Inc. American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

  3. Learning Objectives Using animal models of Alzheimer’s disease and anti-Aβ immunotherapy as a case study, illustrate: The strengths and limitations of animal model results for predicting clinical efficacy The importance of iterative translation during clinical development ≠ http://3.bp.blogspot.com/-8mjLTwgy_3w/UG2cW1Da9VI/AAAAAAAAEME/Mw3nTKKAWoA/s1600/dementia_83248459.jpg American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

  4. Exemplifying the obvious • In a “modestly aggressive” mouse model of AD (PDAPP) the average age for onset of pathology is ~12 months of age* • The average lifespan of a PDAPP mouse is ~18-32 mos §Traditionally a differential diagnosis based on dementia. Recent move to more biologically-based definitions. * some deficits generally attributable to soluble Aβ aggregates are observed pre-pathology http://ars.els-cdn.com/content/image/1-s2.0-S0924977X02001037-gr1.jpg Most cases of Alzheimer’s disease are diagnosed§ at age ≥ 65 yrswith a median survival of 4-8 years post-diagnosis It is generally believed that Alzheimer’s disease pathology can begin ≥ 20 yrsprior to diagnosis

  5. Alzheimer’s disease biology • First identified in 1907 by Alois Alzheimer based on post-mortem evaluation of demented patients • Extracellular plaques and intracellular tangles; but cause or consequence? Alois Alzheimer Auguste D Production inhibitors Immunotherapeutics Clearance enhancers Anti-aggregate and “plaque buster” Amyloid β plaques Tau Kinase inhibitors (phosphorylation) Microtubule stabilization tangles Brunden et al., Nature Reviews Drug Discovery 8, 783-793 (October 2009)

  6. Development of the PDAPP mouse model enabled initial immunotherapy studies • Focus on pathological contributions to disease • Development of the first plaque forming mouse model was enabling for the testing of putative therapeutic approaches designed to be “disease modifying” Plaque formation Non-Tg PDAPP Loss of synaptic integrity Loss of neuronal integrity Games et al., Nature, 373:523, 1995

  7. Anti-Aβ immunotherapy: Background • Anti-Aβ immunotherapy proposed as a therapeutic approach for the removal of Aβ from the CNS (Schenk et al, Nature, 400:173, 1999) Vehicle Immunized Reductions in dystrophic neurites and astrogliosis also observed following immunization UTC = untreated controls SAP = immunization with serum amyloid P PDAPP mice immunized between 6 wks and 13 mos

  8. Translational aspects of anti-Aβ immunotherapy

  9. Anti-Aβ immunotherapy: Background • Elan/Wyeth anti-Aβ vaccine (AN-1792) demonstrated activity on some endpoints in clinical trials • Reduction of senile plaque and cognitive benefit on NTB

  10. Anti-Aβ immunotherapy: Background • AN-1792 trials were discontinued following reports of meningoencephalitis in ~6% of the active treatment group • T-cell mediated response to the self-antigen is a likely cause

  11. Translational aspects of anti-Aβ immunotherapy

  12. Next generation approaches include passive and active immunization Schenk, Nature Reviews Neuroscience 3, 824-828 (October 2002)

  13. Median Aβ burden values following passive immunization: 6 mo treatment TY11/15 10.23% 3D6 0.69% PDAPP mice (N>30/group) treated with 3 or 10mg/kg/week at 12-18 months of age • Similar effects on: • Neuritic dystrophy • Brain Aβ levels (ELISA) Seubert et al., Neurodegenerative Dis, 5:65, 2008

  14. The discovery of the Pittsburgh Compound-B (PiB) tracer allowed for PET imaging of amyloid deposition in AD patients

  15. Bapineuzumab decreases amyloid burden in human subjects using [11C] PiB PET imaging • N=28 patients with mild to moderate AD • Randomized to intravenous bapineuzumab (N=20) or placebo (N=8) in three ascending dose cohorts (0.5, 1.0, or 2.0 mg/kg) Rinne JO et al., Lancet Neurol., 9:363, 2010

  16. MRI observations consistent with transient edemic events were observed following Bapineuzumab treatment • 69-year-old APOE ε4 homozygote Female • Treated with bapineuzumab 1.0 mg/kg IV. Remained asymptomatic despite the appearance of multiple areas of ARIA evident on MRI. Patient was redosed at 0.5 mg/kg and followed for over 2 years without recurrence of ARIA Salloway, S. et al. Neurology 2009;73:2061-2070 • Reported by Salloway et al., 2009 (Phase 2 data) • Anti-Aβedemic events appear sensitive to Bapineuzumab dose and APOE ε4gene dose • Events were transient in some cases and did not recur following redosing in a limited data set

  17. Clinical evidence suggests that ARIA may be related to Aβ mobilization

  18. Translational aspects of anti-Aβ immunotherapy

  19. Preclinical studies designed to further understand the biology of ARIA Vascular Aβ Normal Zago et al., Alz. & Dement., In Press The brain capillary network appears to be involved in antibody induced amyloid removal Aβdeposition on brain vasculature may impair vessel integrity, recovery following removal of vascular Aβ Key proteins involved in resolution of edemic events may be modulated during the process of immunotherapy induced clearance of Aβ

  20. More work to do How is the disease defined? • Dementia, Pathology, mix? • Spatial reference learning / memory; Episodic memory Staging of disease • MMSE; ADAS-Cog; CDR-SB etc.

  21. Even more work to do How do key aspects of intervention therapy translate? • Dementia, Pathology, mix? • Spatial reference learning / memory; Episodic memory • MMSE; ADAS-Cog; CDR-SB etc.

  22. 1mAmp 1mAmp 120s 2s 120s 2s 30s Training (Day 1) Context Shock Contextual Fear Conditioning has been developed as a sensitive functional cognitive measure Comery et al., J. Neurosci. 2005;25:8898-8902

  23. Common Clinical Assessment Tools http://www.mdanderson.org/publications/conquest/issues/2008-fall/old-drugs-new-possibilities-conquest-fall-2008-old-drugs-new-possibilities.html http://ginny-livingwithlyme.blogspot.com/2012/10/spinal-tap-3.html http://www.nimh.nih.gov/images/pubs/neuro-pet.jpg

  24. Summary • Although many (if not most) human diseases cannot be fully recapitulated by animal models, key aspects of the disease process are reproduced • Key breakthroughs in biological understanding of the disease processes • Useful models for testing interventional therapy • Animal models are most effectively utilized when there is a full understanding of the limitations around the translation of the models to human disease • How is “efficacy” defined both pre-clinically and clinically • Clinical trial design limitations must be considered • Heterogeneity of human subjects • Limitations around invasive endpoint assessment • Potential disconnect between “biological” and “pathological” disease definitions • Clinical development will often result in unpredicted findings necessitating iterative translational approaches • AN-1792 immunization in AD patients resulted in meningoencephalitis in ~6% of the active treatment group • New approaches to avoid Aβ directed T-cell responses are being tested clinically (passive and active immunization) • Reports of radiologically identified edemic events following passive immunization have led to additional preclinical studies using the PDAPP mouse model

  25. Elan Pharmaceuticals / Prothena Biosciences/ Janssen AI Robin Barbour Bob Brashear Manuel Buttini Ming Chen Dora Games Henry Grajeda Michael Grundman Terry Guido Stefan Heylen Karen Khan Mike Lee Enchi Liu Ruth Motter Dale Schenk Sally Schroeter Peter Seubert Eric Yuen Wagner Zago Wyeth / Pfizer Davinder Gill Steven Jacobsen Tom Comery MenelasPangalos Acknowledgements

More Related