Lecture 11: Drug Discovery II

Question 1

Mutations in PCSK9 gene

Answer 1

-gain-of function variants = hypercholesterolemia
-12.1mmol/L = 465mg/dL (goal LDL< 130)
-nonsense mutation = extremely healthy

Question 2

PCSK9

Answer 2

-gene expressed in liver
-key in LDL regulation
-degraded by LDL-R
-blocks LDL-R recycling
=more LDL in blood?
-blocked by human mAb

Question 3

PCSK9 inhibitor tx

Answer 3

-mAb
-blocks LDL binding to LDL-R
-LDL-R recycled and takes more LDL out of blood
-add if LDL >70 and already on statin + ezetimibe
-failed to be blockbuster drug at this momen?

Question 5

Basics of biotech valuation

Answer 5

-company value = drug value = drug commercial potential
-company value = drug value + stock price
-determined by revenue forcasting and discounted cash flow analysis (DCF)

Question 6

Discounted cash flow formula

Answer 6

-

Question 8

Key points to consider for drug value evaluation

Answer 8

-does new drug offer advantage?
-where does drug fit in paradigm of unmet need? Used when and by who?
-what data needed for FDA approval and commercial success?
-how to set price?

Question 9

Problems associated with cardiovascular drug developmen

Answer 9

-long and big trials
-safety profile
-alt endpoint maybe not accepted
-may get approved for narrow pt population
-compete w other drugs
-payers may not want to pay for expensive drugs like biologics
-Repatha has a hazard ratio of 0.85 relative reduction in CV risk compared to statin, is it worth 100x more?