1. Organic Chemistry II 202 - DDB - 05 CAM
Aranesp
By Matthew Seidler ( )
Winter 2007
John Abbott College

2. Overview Benefits/Risks Competitors Personal Thoughts Introduction
What is it?
History
Structure/Chemistry
Benefits/Risks
Competitors
Personal Thoughts

3. Red Blood Cells Transport oxygen to various parts of the body
Oxygen = NP, Blood = P
Need a way to transport oxygen
Divide rapidly
When your body makes fewer RBCs, anemia develops

4. What exactly is Aranesp?
Darbepoetin alfa is a synthetic form of erythropoietin
Erythropoietin = produced by kidney, hormone that stimulates RBC production
Stimulates erythropoiesis (process by which erythrocytes (RBCs) are produced when oxygen is low (hypoxia)
Stimulates bone marrow to produce RBCs

5. When is oxygen supply lowered?
Exercise
High altitudes, etc

6. How EPO works
EPO binds to receptors (EpoR) in bone marrow to speed up mitosis of cells responsible for making RBCs
Oxygen in blood rises, EPO production slows down

7. EPO

8. Amgen, Inc. International Biotech company in California
The largest independent biotech firm, 15K staff members
As of 09/06, Amgen had eight FDA approved drugs (one of which was Aranesp)

9. Back to the drug…
09/01: approved by FDA for treatment in anemia in patients with chronic renal failure
Kidneys secrete erythropoetin, which stimulates RBC production
Patients w/ renal failure commonly suffer from anemia (lower RBC count)
06/01: approved by European Medicines Agency for the same treatments, but also for anemia patients undergoing chemotherapy
Chemotherapy affects rapidly dividing cells (I.e. RBCs)
You therefore need more erythropoetin in order to stimulate RBC production

10. Another Use
Patients who require a blood transfusion or have surgery where blood loss is expected, EPO is given in advance
If blood is lost in surgery…

11. How is it made?
Produced by recombinant DNA technology in modified Chinese hamster ovary cells
Differs from real erythropoietin (EPO) in that it has two more N-linked oligosaccharide chains
Why not just use real EPO?

12. Chemistry of the drug C815H1317N233O241S5
Ok, let’s draw it. IHD = 1/2(2*815+2…)
Molar mass = g/mol

13. Anemic Cancer Patients
01/07, Amgen wrote a letter that highlighted the results from a recent anemia of cancer trial, and warned doctors
They informed the FDA that control over the cancer was worse in patients on Aranesp (against those who weren’t on the drug)

14. What did the FDA say?
Released a public health advisory, in March 07, and a clinical alert for doctors about the use of erythropoeisis-stimulating agents such as epogen and darbepoeitin
Use caution when using these drugs in cancer patients
Lack of clinical evidence to support improvements in these situations

15. Risks Increases the risk of…
Cardiovascular problems (RBCs increases viscocity of blood)
Strokes
Hypertension
Congestive heart failure
Myocardial infarction (heart attack)
Seizures (why?)
Vascular thrombosis (clot inside blood vessel)
Edema (fluid collecting in cavities of body) (why?)
Side effects = fever, chest pains, nausea, etc

16. $10 000/ yr for drug (dialysis patient) $12 000/ yr for drug (chemo patient) Sales: $10 B in 2004

17. Abuse
Cross country skiers Larisa Lazutina & Olga Danilova of Russia and Johann Muhlegg of Spain

18. EPO as a blood doping agent
Used by healthy athletes to give a competitive advantage
Increases oxygen carrying capacity of the blood
Therefore, increases aerobic respiratory capacity of the muscles
Helps make more ATP

19. Continued
Useful for bicycle races (offsets decrease in RBC count that occurs over several races)
What happens if you OD?
The drug can produce so many RBCs that the blood thickens and strains the heart (I.e. during sleep when HR is low)

20. Competitors From Amgen: Epogen & Aranesp (Brand names)
There’s also Dynepo

21. Dynepo Pharmaceutical EPO under development by Shire Pharmaceuticals
Launched in Europe in 2006
Amgen patents prevent it from launching here
Instead of being made from cultured animal cells, it’s made from cultured human cells

22. Dynepo Has a true form of sialic acid & oligosaccharide residues
This makes it longer lasting than Amgen’s products (this is not confirmed yet…)
Undetectible in urine tests for EPO that is used on athletes

23. Personal Thoughts
Jehova’s Witnesses
Drug can be used for many things

24. QUESTIONS?