Organic Chemistry II 202 - DDB - 05

CAM

Aranesp

By Matthew Seidler (0588687)

Winter 2007

John Abbott College

Overview

• 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)• Hypertension

• 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?