L6 - AD therapeutics

Question 0

Drug trial phases:

Answer 0

• Pre-clinical - pharmacological profile & toxicity (animal species; >2; 2-3y)
• Phase I - safety & pharmacodynamics (healthy volunteers or subjects with indications; 1000; 2-3y)
• Phase IV - ongoing safety monitoring (s w indications; >1000; 1-5y)

Question 1

Expected number of AD patients by 2040

Answer 1

• 115 million

Question 2

Average costs involved in launching a new drug on the market:

Answer 2

• out of pocket: ca. $300mln to pass pre-clinical; $873mln from start to end
• capitalized cost per launch: $1,778mln

Question 3

APP Swedish mutation

Answer 3

… makes APP a more favored substrate for beta-secretase cleavage, thereby increasing the flux of APP down the beta-gamma-secretase cleavage pathway…

Question 4

PSEN 1 & 2 mutation effects:

Answer 4

… mutations in PS 1 & 2 alter gamma-secretase cleavage and promote the overproduction of A-beta42.

Question 5

ApoE4 effects:

Answer 5

(presumed)

• competes with a-beta for clearance through the low-density-lipoprotein-related protein receptor
• enhances aggregation and fibrillogenesis of extracellular A-beta
• may be worse at its roles in lipid metabolism and repair mechanisms than ApoE3 or ApoE2

Question 6

Drugs currently used in AD:

Answer 6

• Donepezil (Aricept): all stages
• Rivastigmine (Exelon): mild to moderate
• Galantamine (Reminyl): mild to moderate

Question 7

Adverse effects to the common AD drugs:

Answer 7

• nausea, vomiting, diarrhea, weight loss, loss of appetite, muscle weakness

Question 8

Memantine (Axura, Memox)

Answer 8

• used for moderate to severe AD
• protects from excitotoxicity
• reduces psychiatric symptoms
• adverse effects: dizziness, headache, constipation, confusion

Question 9

The main types of drugs in current use for AD

Answer 9

Acetylcholinesterase inhibitors and NMDA antagonists

Question 10

Metal chelators in AD

Answer 10

Zn and Cu

- PBT2 entered Phase II

Question 11

Active vs passive immunization in AD

Answer 11

Active - injection with full or partial a-beta together with adjuvant (B cells will produce antibody against a-beta)

Passive - injection with full antibody against a-beta

Question 12

Three A-beta immunization effector mechanisms:

Answer 12

• catalytic dissolution by the antibody
• Fc-receptor-mediated phagocytosis
• peripheral sink