1:Epogen /Procrit

rErythropoetin
[FDA approval 1989]

Epo binds the Epo receptor (Epo R) on bone marrow erythroid progenitors, inducing proliferation, maturation, and differentiation of red blood cells (MOA)

For patients with anemia due to Dialysis/ Chronic Kidney Disease / Renal Failure / Chemo / HIV

Stimulates production of RBCs. Truly revolutionized treatment of anemia!

Epo: For patients on dialysis with anemia.

Procrit: For non-dialysis use only = Cancer, Chronic Kidney Disease, HIV (anemia due to AZT treatment); some blood transfusions

Sales of ~$2.4 B annually

Increases the risk of thromboembolic complications (Stroke)

GOOD OR BAD FOR CANCER? Epo has pleiotropic effects

Epo Doping

For patients with anemia due to Dialysis/ Chronic Kidney Disease / Renal Failure / Chemo

2 additional N-linked carbohydrate chains creates a longer lasting effect (3X greater that Epo), requires fewer injections - 1 shot every 3 weeks, rather than once/week

Glycoengineering increased half life from 8.5 to 25 hours (see below)

Sales of $2.8 B annually
increases the risk of stroke

Muehlegg, Lazutina stripped of gold medals
February 24, 2002

For Neutropenia: low WBC count febrile neutropenia (low WBC count with fever/ infection) due to chemo, BMT, AML.

G-CSFs are glycoprotein cytokine hormones that stimulate proliferation and growth of granulocytes, particularly neutrophils (WBCs) but also eosinophils, and basophils

A synthetic 'consensus' interferon based on the most common amino acid sequences in 12 natural interferons.

For patients with Chronic, non-responding, or relapsing hepatitis C viral (HCV) infection,

4 M Americans have Hepatitis C! -

3. Engerix-B/
Recombivax

Infection with HBV
Prevention of 1° liver cancer

New HepB Law (2005) for all Indiana 9th and 12th graders

Moderate-to-severe chronic plaque psoriasis

Suppresses overactive T lymphocytes found in autoimmune diseases
(more on this when we get to mABs)

Injected by physician (15 mg IM, into the muscle) once a week for a total of 12 doses.

Because Amevive reduces T-cell counts (important for fighting off infections, etc), T-cell levels are monitored closely after
MOA

SubQ every other day.

Sales of ~$118 M annually

Cancer: Metastatic renal cell carcinoma, and metastatic melanoma.

IL-2 activates lymphokine-activated killer (LAK) cells, NK cells that normally destroy tumor cells.

MOA: IL-2 activates the immune system in several ways, but the major one is to stimulate T cell and natural killer (NK) cell proliferation, increasing and activating these immune system cells to find and destroy cancer cells. (See figure) Sales of ~$92 M annually; MOA

PDGF is involved in developing protective tissue and skin after a wound or ulcer (a process called granulation; MOA)

Sales of $48 M annually

Thrombolytic:
Approved for treatment of AMI, cardiac ischemia, acute massive pulmonary embolism, and management of stroke.

CathFlo Activase: can be directly injected into an occluded central line catheter.

Converts plasminogen to plasmin, which activates fibrin, breaking down blood clot.

rTPA, tissue-plasminogen activator "+"

TNKase can be administered over five seconds in a single dose, fastest administration of any thrombolytic

Thrombolytic: TNKase is bioengineered with 3 amino acid substitutions from natural t-PA: T, N and K (Thr, Asp, Lys).

=Increased Fibrin Specificity
=Long Plasma Half-Life
=Greater Resistance to Plasminogen Activator Inhibitor-1

Investigate the Molecule

"An advanced lytic by design"

1,000 variants of rt-PA were evaluated, using site-directed mutagenesis

For management of cystic fibrosis in children 3 months - 5 years old. Inhalation Solution -

Pulmozyme hydrolyzes the DNA in sputum and airways of CF patients.

rHuman growth hormone (Somatropin; synthetic growth hormone)

[FDA approval 11/93]

What is a depot form?

Neutropin replaced Protropin [FDA approval October 1985; Genetech's first product];

Protropin stopped production in 2002

4a: Neutropin AQ: liquid formulation;
4b: Neutropin pen: same stuff, single use throw-away 'pen' injection

Diabetes: Used by over 3.5 million people in the U.S. every day

Rapid-acting 'mealtime' form

Annual revenues of ~$330 million.

July 25, 2003: FDA Approves Humatrope for Short Stature: (only the shortest 2-3% of children qualify).

rActivated Protein C.
[FDA approval 11/01]

Activated Protein C acts inside the blood vessel as an anticoagulant / antithrombotic - reduces blood clots; controls inflammation. Activated by thrombin.

Treatment of severe sepsis, a fast-moving, dramatic, and often fatal acute response to infection that claimed 215,000 lives each year (pre-Xigris)

Costs associated with treatment of sepsis are $17B annually in the US.

Increases the odds of survival by over 38% (efficacy somewhat disputed)

FDA approved Xigris in a split vote by a 20-member advisory panel; its efficacy is somewhat disputed.

Standard treatments for sepsis (antibiotics, blood pressure drugs) usually cost less than $50 per day, while Xigris costs $6,800 per treatment.

Worldwide sales of ~$100M annually.

About 10 million people in the US suffer from osteoporosis.

Black box warning: Forteo may promote bone cancer (osteosarcoma) by stimulation of osteoblasts.

Worldwide sales of ~$400M annually.

rGLP-1 (glucagon-like peptide-1) - "Exenatide"
[FDA Approval April 29, 2005]

Developed from Gila monster saliva! Patent 1995

Downside: twice a day injection, but "an appropriate option to consider when Type II patients cannot control their blood sugar using oral medications."

Upside: Steady, significant appetite suppression and weight loss in overweight diabetic patients

Amylin (San Diego) is the developer - Lilly is partner

Projected sales of $60 million 2005 and $190 million in 2006

rQuadrivalent HPV (human papilloma virus) types 6, 11, 16, 18
[FDA Approval 6/8/06]

L1 capsid protein of all 4 viruses made individually in yeast cells and combined into one vaccine.