The billion dollar pill: special considerations

Question 1

What is the difference between small molecule drugs and biologic drugs?

Answer 1

1. small molecule drugs have a lower molecular weight than biologics
2. small molecule drugs are made via chemical synthesis whereas biologic drugs are made via live cells
3. making small molecule drugs requires fewer critical steps than biologic drugs
4. small molecule drugs are more easily characterized than biologic drugs
5. small molecule drugs are made relatively pure whereas biologic drugs are not
6. small molecule drugs are usually not immunogenic while biologic drugs usually are immunogenic

Question 2

Why are biologic drugs extracted as heterogenous mixtures?

Answer 2

Since they are extracted from organisms, the serum may contain other molecules too.

Question 3

What are the advantages of nucleic acid based therapeutics?

Answer 3

1. It is easy to design
2. It has high specificity so there is a low chance of off target binding and thus side effects
3. There is intervention from the top. If the DNA coding for the faulty protein is blocked, then no proteins are produced

Question 4

Why are nucleic acid based therapeutics transported in a vector?

Answer 4

So that it doesn’t get degraded before it reached the nucleus

Question 5

How does gene therapy work?

Answer 5

A gene is delivered through a vector into the nucleus. This allows for the translation of target proteins to achieve a therapeutic effect.

Question 6

How does Chimeric antigen receptor technology work against cancer?

Answer 6

1. T cells are extracted from the patient’s’ blood
2. The cells are engineered to recognise cancer cells
3. The cells are replicated and reintroduced into the blood.
4. This allows cancerous cells to be killed by the immune system

Question 7

Why is chimeric antigen receptor theory not always effective?

Answer 7

Because you need to identify the specific antigen that prevents immune cells from recognising them as cancer cells

Question 8

How do mRNA vaccines work?

Answer 8

1. The viral protein encoded by the mRNA is translated
2. This stimulates the host immune response, allowing for immunity

Question 9

What are the ways DNA binding agents stop cancer progression?

Answer 9

1. Alkylaton: Alkyl groups bind to DNA strands
2. Transition metal binding
3. Intercalators: bind to planar regions by pi-pi stacking
4. Groove binders
   all of these prevent DNA from being replicated, so the cancer cell can’t divide

Question 10

What are the ways in which non-DNA binding agents can stop progression of cancer?

Answer 10

1. Inhibit cell cycle enzymes to interfere with the replication process eg: topoisomerase inhibitors, HDAC inhibitor, mitotic inhibitor
2. Interfere with precursor molecules essential for DNA replication eg: DFHR inhibitor, 5-Fluorouracil, Thioguanine

Question 11

What are the limitations of chemotherapy?

Answer 11

1. There are significant off target effects
2. Some agents are carcinogenic
3. The drug acts of other rapidly dividing cells of the body eg: gastrointestinal cells (causes gastric), hair follicles (hair loss0, and immune cells

Question 12

How does molecular targeted therapy work?

Answer 12

If there is a specific target unique to the cancer, molecular therapy targets that thing to stop the cancer

eg: targeting oncogenes as they are specific to cancer formation

Question 13

What does the BCR-ABL translocation cause?

Answer 13

Chronic myelogenic leukemia

Question 14

How does the enzyme inhibitor work for CML caused by the BCR-ABL translocation?

Answer 14

Since Abl codes for an enzyme which causes the cell to proliferate, the inhibitor arrests enzyme activity and prevents this from happening

eg: gleevac, which prevents autophosphorylation of the enzyme

Question 15

What are the 2 types of protein therapeutics?

Answer 15

1. Ligands
2. Antibodies

Question 16

What are the special considerations for biologic drugs?

Answer 16

1. Metabolism studies are not required (because the amide bonds are easily cleaved by proteases)
2. Genotoxicity studies are not required
3. Carcinogenicity studies are generally not needed, except for growth factors and immunosuppressive agents

Question 17

Why is it important for drug companies to study how biologics change when they undergo glycosylation, amidation, oxidation etc?

Answer 17

If the drug needs to go into an organelle, the cell attaches signal peptides to it to allow the drug to enter

Question 18

What does NCE stand for?

Answer 18

New Chemical Entity

Question 19

What does BLA stand for?

Answer 19

Biologic license application

Question 20

Why might nucleic acid drugs be better than protein drugs?

Answer 20

1. They won’t undergo post translational modification
2. There won’t be issues with differences in conformation

Question 21

When are cancer drugs given special considerations?

Answer 21

1. Life threatening with high death rates
2. Existing therapies have limited effectiveness
3. Need new agents expeditiously
4. Clinical dose levels are close to adverse effect levels

Question 22

What exemptions are given to cancer drugs?

Answer 22

1. No need to measure observed adverse effect level
2. Requires embryo-fetal toxicity studies, but not toxicity to the mother
3. Genotoxicity and carcinogenicity testing is not required

Question 23

What is an orphan drug?

Answer 23

A drug needed for the treatment of a rare disease