diseases of the nervous system: part ii - lehigh...
TRANSCRIPT
![Page 1: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/1.jpg)
Diseases of the Nervous System:
Part II
Neal G. Simon, Ph.D. Professor, Dept of Biological
Sciences Lehigh University
![Page 2: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/2.jpg)
Mood Disorders: Medial Prefrontal Network & Amygdala
Price & Drevets (2010)
![Page 3: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/3.jpg)
Alzheimer’s Disease
Ø An estimated 5.2 million Americans have Alzheimer's Disease
Ø 6th leading cause of death in the United States
Ø $226 billion: the direct costs of care in the United States in 2015
Ø In 2050: 14 million people will have AD
Ø In 2050: $1.1 trillion: direct costs
![Page 4: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/4.jpg)
Alzheimer’s Disease: Symptoms
Ø Memory loss that disrupts daily life
Ø Challenges in planning or problem solving
Ø Difficulty completing familiar tasks
Ø Confusion with time or place
Ø Trouble with visual images and spatial relationships
Ø New problems with words when speaking or writing
Ø Mood and personality changes
![Page 5: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/5.jpg)
Ø The cortex shrivels up, damaging areas involved in thinking, planning and remembering.
Ø Shrinkage is especially severe in
the hippocampus, an area of the cortex that plays a key role in formation of new memories.
Ø Ventricles (fluid-filled spaces
within the brain) grow larger.
The Alzheimer’s Brain: Gross Anatomical Changes
alz.org / braintour
![Page 6: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/6.jpg)
The Alzheimer’s Brain: Microscopic Changes
Ø Alzheimer's tissue has many fewer nerve cells and synapses than a healthy brain.
Ø PLAQUES, abnormal clusters
of protein fragments, build up between nerve cells.
Ø Dead and dying nerve cells contain TANGLES, which are made up of twisted strands of another protein.
alz.org / braintour
![Page 7: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/7.jpg)
TAU Tangles
A sec&on from the hippocampus of an Alzheimer’s disease pa&ent stained with a tau an&body (TNT1 – recognizes amino acids 2-‐18, see below). Note the classical triad of tau pathologies in AD, 1) neurofibrillary tangles (arrowheads), 2) neuropil threads (arrows), and 3) a neuri&c plaque (asterisk).
Alz.org; Kanaan
![Page 8: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/8.jpg)
Clinical & Biomarker Changes in Dominantly Inherited Alzheimer’s Disease
Bateman et al (2012)
Ø Amyloid Hypothesis: 3 genes can cause altered processing (APP, PSEN1, PSEN2)
Ø Compared Carriers & Non-‐Carriers (n =128)
Ø Clinical, CogniOve, Imaging, & Biochemical Assessments
Ø Normalized against parental age of onset
Ø Follows ADNI protocols and standards
![Page 9: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/9.jpg)
COGNITIVE MARKERS
Bateman et al., 2012
† Scores on the CDR-‐SOB range from 0 (cogni&ve normality) to 18 (maximal cogni&ve impairment).‡ P<0.01. § P<0.001. ¶ Scores on the Mini–Mental State Examina&on (MMSE) range from 0 (severe impairment) to 30 (no impairment). A score higher than 27 is considered normal. Scores on the Logical Memory subtest of the Wechsler Memory Scale–Revised range from 0 (no recall) to 25 (complete recall). ** P<0.05.
![Page 10: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/10.jpg)
PUTATIVE BIOMARKERS I
§ P<0.001. ** P<0.05. ‡ P<0.01
![Page 11: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/11.jpg)
Precuneus: § episodic memory, visual-‐spa&al abili&es, and motor ac&vity coordina&on strategies. self
percep&on, consciousness, and the execu&ve and working memory.
§ at rest, the highest metabolic rates, consuming more glucose than any other cortex
§ Part of Default Mode Network
thebrain.mcgill.ca
![Page 12: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/12.jpg)
PUTATIVE BIOMARKERS II
§ P<0.001. ** P<0.05. ‡ P<0.01
![Page 13: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/13.jpg)
Alzheimer’s Biomarkers: Comparison of Clinical CogniOve, Structural. Metabolic, & Biochemical Changes vs. EsOmated Expected Years for Symptom Onset
Bateman et al (2012)
Data shown are differences between mutaOon carriers and non-‐carriers
![Page 14: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/14.jpg)
Brain scans show evidence of Alzheimer’s disease 20 years before symptoms arise (far left), 10 years before (middle), and after the onset of symptoms (right). Beta amyloid, a protein associated with the disease, is more visible in people who develop the disease (top row) than in those who don’t. The more color in the scan, the more beta amyloid is present in the brain.
Predicting Alzheimer's Disease: Biomarkers
Bateman et al (2012)
![Page 15: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/15.jpg)
What Would You Do?
![Page 16: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/16.jpg)
Drug Discovery and Development
October 13, 2015
Neal G. Simon, Ph.D. Professor
Department of Biological Sciences
![Page 17: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/17.jpg)
Discovery and Preclinical Development
I. Background
II. The R&D Landscape
III. InnovaOon and TransformaOon
IV. Clinical Trials in CNS Drug Development
V. Drug Pricing
![Page 18: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/18.jpg)
US FDA
Drug Development Process
![Page 19: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/19.jpg)
Drug Development Process
![Page 20: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/20.jpg)
Biopharmaceutical Drug Development: Attrition
Drug Discovery
Pre-‐Clinical
5 years 1.5 years 6 years 2 years 2 years
Clinical Trials FDA Review Large Scale
Manufacturing/ Phase IV
IND Subm
ided
NDA
Sub
mided
250 Compounds 5 Compounds 10,000 Com-pound
s
1 FDA Approved
Drug
Quelle: Burrell Report Biotechnology Industry 2006
Phase I 20-‐100 Volunteers
Phase II 100-‐500 Volunteers
Phase III 1000-‐5000 Volunteers
![Page 21: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/21.jpg)
II. The Research & Development Landscape
![Page 22: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/22.jpg)
Sources: Congressional Budget Office (CBO). Research and development in the pharmaceu&cal industry. www.cbo.gov/sites/default/files/cbofiles/gpdocs/76xx/doc7615/10-‐02-‐drugr-‐d.pdf. Washington, DC: CBO; October 2006. Accessed March 2014. Pharmaceu&cal Research and Manufacturers of America (PhRMA). PhRMA annual membership survey, 1996-‐2014. Washington, DC: PhRMA; 2015
![Page 23: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/23.jpg)
![Page 24: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/24.jpg)
Source:Tugs Center for the Study of Drug Development (CSDD). Cost of developing a new drug. Briefing. Boston, Mass.: CSDD. Pubished November 2014. Accessed March 2015.
![Page 25: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/25.jpg)
R&D Cost Model per NME
Paul et al (2010). Nature Rev Drug Discovery
![Page 26: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/26.jpg)
Private & Public R&D Spending
![Page 27: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/27.jpg)
III. InnovaOon and TransformaOon
![Page 28: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/28.jpg)
InnovaOon Models and TransformaOon
Hu et al (2007)
![Page 29: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/29.jpg)
![Page 30: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/30.jpg)
![Page 31: Diseases of the Nervous System: Part II - Lehigh Universityinbios21/PDF/Fall2015/Simon_10142015.pdf · Diseases of the Nervous System: Part II Neal G. Simon, Ph.D. Professor, Dept](https://reader036.vdocuments.us/reader036/viewer/2022070611/5b1462b37f8b9a487c8ccd10/html5/thumbnails/31.jpg)
Thank you for your Ome and adenOon