Lecture #10

Question 1

Mutations in PCSK9 gene causes

Answer 1

autosomal dominant hypercholesterolemia
these pts with hypercholesterolemia carry gain-of-function PCSK9 variants
want desirable value of LDL < 130 mg/dL

Question 2

Individuals with PCSK9 nonsense mutations

Answer 2

are extremely healthy
loss of function stop codon mutation

Question 3

increase in PCSK9

Answer 3

leads to a decrease in LDL-R proteins –> increase in LDL-C

Question 4

Blocking PCSK9

Answer 4

use a fully human monoclonal antibody against PCSK9 to block the PCSK9/LDL-R interaction
LDL-R recycling is restored, increased LDL-R concentration

Question 5

PCSK9 failed to be

Answer 5

a blockbuster drug because it is only used for a very narrow pt population
also extremely high cost

Question 6

The basics of biotech valuation

Answer 6

company value = drug value = drug’s commercial potential

Question 7

Drug’s commercial potential

Answer 7

–> revenue forcasting –> peak sale + years of peak sales

Question 8

Discounted cash flow analysis

Answer 8

–> future cash flows * time value of money = total value of drug

Question 9

Stock price

Answer 9

–> total value of company/total shares outstanding

Question 10

Future money is always

Answer 10

less than past/current money

Question 11

Key points to consider for drug value evaluation

Answer 11

does this new drug offer any advantage compared to existing drugs?
where does this drug fit in the treatment paradigm of the unmet medical need? which pt population would use this drug and at which point during their treatment?
what data should clincial trials show to secure FDA approval and commerical success?
how to set the price of the drug so that payers would be willing to pay?

Question 12

Problems associated with cardiovascular drug (or in general non-cancer drug) development

Answer 12

trials may have to be very long and need many thousands of pts
safety profile of the drug needs to be excellent
alternative endpoint may not be accepted; lowering LDL (short) vs reductions in atherosclerotic cardiovascular events (medium), or reducing mortality (extremely long)
may only get approved for a very narrow pt population
compete with many existing widely used drugs
biologics might be signigicantly more expensive than small molecules and payers may not want to pay