Diseases of the Nervous System:

Part II

Neal G. Simon, Ph.D. Professor, Dept of Biological

Sciences Lehigh University

Mood Disorders: Medial Prefrontal Network & Amygdala

Price  &  Drevets  (2010)  

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

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      

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

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

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  

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  

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.    

PUTATIVE  BIOMARKERS  I  

§  P<0.001.   **  P<0.05.     ‡  P<0.01  

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  

PUTATIVE  BIOMARKERS  II  

§  P<0.001.   **  P<0.05.     ‡  P<0.01  

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  

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)  

What  Would  You  Do?  

Drug  Discovery  and  Development  

October  13,  2015    

Neal  G.  Simon,  Ph.D.  Professor  

Department  of  Biological  Sciences    

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  

US  FDA  

Drug Development Process

Drug Development Process

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  

II.  The  Research  &  Development  Landscape  

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  

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.  

R&D Cost Model per NME

Paul  et  al  (2010).  Nature  Rev  Drug  Discovery  

Private  &  Public  R&D  Spending  

III.  InnovaOon  and  TransformaOon  

 

InnovaOon  Models  and  TransformaOon  

Hu  et  al  (2007)  

Thank  you  for  your  Ome  and  adenOon