Organic Chemistry II 202 - DDB - 05 CAM Aranesp By Matthew Seidler (0588687) Winter 2007 John Abbott College

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

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

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

When is oxygen supply lowered? Exercise High altitudes, etc

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

EPO

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)

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

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…

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?

Chemistry of the drug C815H1317N233O241S5 Ok, let’s draw it. IHD = 1/2(2*815+2…) Molar mass = 18396.1 g/mol

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)

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

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

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

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

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

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)

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

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

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

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

QUESTIONS?