Pgx Drug Discovery II

Question 1

Mutations in PCSK9 with Autosomal Dominant Hypercholesterolemia in Norway

Answer 1

• gain of function PCSK9 variant
• led to approximately a 465 mg/dL LDL level

Question 2

Frequent Nonsense Mutations in PCSK9 in Africa

Answer 2

• examples of Y142X and C679X
• led to approximately a 46, 61, and 63 mg/dL LDL level in men, women, and total

Question 3

Treatment Algorithm for PCSK9

Answer 3

PCSK9 is limited in use due to cost
- antibody is a biologic
- difficult to make
- also still in patent

Question 4

ICER Equation

Answer 4

Cost of Drug 2 - Cost of Drug 1 / QALY of Drug 2 - QALY of Drug 1

NOT USED IN THE US

Question 5

Discounted Cash Flow Analysis

Answer 5

Future Cash Flows x Time Value of Money = Total Value of Drug

Question 6

FUTURE MONEY IS ALWAYS LESS THAN CURRENT MONEY

Answer 6

FUTURE MONEY IS ALWAYS LESS THAN CURRENT MONEY

Question 7

How to calculate discounted cash flow

Answer 7

1. a 10% annual discount rate was often assume
   - this is not inflation
2. ratio of success of development of drug

Question 8

Key Points to Consider for Drug Evaluation

Answer 8

Does the new drug off any advantage to old drug?
- medical benefits, fewer side effects, easy to use

Where does this drug fit in the treatment alorgirthm of the unmet medical need? Which patient population would use this drug and at what point during treatment?

What data should clinical trials show to secure FDA approval and commercial success?

How to set the price of the drug so that payers will be willing to pay?

Question 9

Problems with Cardiovascular Drug Development

Answer 9

Trials may have to be very long and need thousands of patients

Safety profile of the drug needs to be excellent

Alternative endpoint may not be accepted

May only get approved for narrow patient population

Compete with many existing widely used drugs

Biologics might be significantly more expensive than small molecule drugs making payers less apt to pay