Advanced Pharmaceutical Advanced Pharmaceutical Biotechnology Phar571Biotechnology Phar571

Lec. 2Lec. 2

Dr. Yara Al TallJUST / Faculty of Pharmacy

Pharmaceuticals and Biotechnology- Pharmaceuticals and Biotechnology- Benefits of CombinationBenefits of Combination

When the two disciplines- pharmaceuticals and biotechnology- come together, they result in many advantages for humankind in terms of healthcare.

This is possible through Pharmacogenomics (derived from 'pharmacology' and 'genomics') which refers to the study of how the genetic inheritance affects individual human body's response to drugs.

Biopharmaceutical drugs aim at designing and producing drugs that are adapted to each person’s genetic makeup.

Thus pharmaceutical biotechnology companies may develop tailor-made medicines for maximum therapeutic effects.

Also, biotechnology drugs can be given to the patients in appropriate dosages as the doctor would know the patient’s genetics and how the body processes and metabolizes a medicine.

One more benefit of pharmaceutical biotechnology is in the form of better vaccines. Biotech companies design and produce safer vaccines by organisms that are transformed through genetic engineering. These biotech vaccines minimize the risks of infection.

Pharmaceutical Biotechnology ProductsPharmaceutical Biotechnology Products

The common pharmaceutical biotechnology products:

1.Antibodies - Antibodies are proteins that are produced by white blood cells and are used by the immune system to identify bacteria, viruses, and other foreign substances and to fight them off. In the recent years, monoclonal antibodies are one

of the most exciting developments in biotechnology pharmaceuticals.

2. Proteins - Proteins made of amino acids are large, complex molecules that do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs.

TransportHemoglobinCarries O2

DefenseAntibody

Fights Viruses

EnzymeProteaseDegrades Protein

SupportKeratin

Forms Hair and Nails

MotionActin

Contracts MusclesRegulationInsulinControls Blood Glucose

Proteins do most of the work in Proteins do most of the work in the cellthe cell

Protein biotechnology is emerging as one of the key technologies of the future for understanding the development of many diseases like cancer or sickle cell anemia.

3. Recombinant DNA Products - Recombinant Deoxyribonucleic Acid is the genetically engineered DNA created by recombining fragments of DNA from different organisms.

Some of the Recombinant DNA Products include:A. Recombinant DNA VaccinesB. Recombinant DNA DrugsC. Recombinant DNA EnzymesD. Recombinant DNA Growth HormoneE. Recombinant DNA InsulinF. Recombinant DNA ProteinsG. Recombinant DNA Yeast

Biotech's First Wave: Recombinant DNA Biotech's First Wave: Recombinant DNA DrugsDrugs

In this section we will focus mainly on Drug Biotech companies (started as biotech firms) rather than the "Big Pharma" companies (Pfizer, J&J, Merck, Abbott, Bayer, Roche, etc) - many of which license biotech drugs and may even have developed a few of their own (Lilly is an exception).

The following is a list for many of the best rDNA drugs on the market today classified according to their companies:

The best rDNA drugs on the market todayThe best rDNA drugs on the market today

1. Amgen: A. Epogen/Procrit: This drug produces rErythropoetin.

  Epo binds the Epo receptor (Epo R) on bone

marrow erythroid progenitors, inducing proliferation, maturation, and differentiation of red blood cells.

Figure 1. Erythropoietin (Epo) binds its receptor (Epo R) on the surface of red blood cell progenitors in the bone marrow.It causes proliferation, maturation, and differentiation, thereby preventing or correcting anemia. Epo may also bind Epo R expressed on the surface of cancer cells and may elicit tumor growth via cell proliferation, protection from apoptosis, and/or angiogenesis. [Note: figure adapted from Brower, V. (2003) Nat. Med. 9:1439.]

why Epogen/Procrit are prescribed and what they do in the body?

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 Zidovudine treatment AZT); some blood transfusions.

B. Aranesp This drug also produces rErythropoetin.

Uses: For patients with anemia due to Dialysis/

Chronic Kidney Disease / Renal Failure / Chemo

It has a longer lasting effect (3X greater that Epo), requires fewer injections - 1 shot every 3 weeks, rather than once/week.

C. Neulasta rGranulocyte colony-stimulating factor (G-CSF)

G-CSFs are glycoprotein cytokine hormones that stimulate proliferation and growth of granulocytes (A type of WBC filled with microscopic granules that are little sacs containing enzymes)

Uses: For Neutropenia: low WBC count febrile neutropenia

(low WBC count with fever/ infection) due to chemo, bone marrow transplant (BMT), Acute myeloid leukemia (AML).

D. Infergen: rInterferon alpha.

Question: What are interferons? Interferons (IFNs) are proteins made and

released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.

"No one knows exactly how interferons work”!

UsesInfergen is used for patients with Chronic,

non-responding, or relapsing hepatitis C viral (HCV) infection.

2. Biogen This is another biotech company which has

released the following drugs:

A. Avonex

It is rInterferon beta-1a: it "Calms" or down-regulates the immune system

Made in Chinese hamster ovary (CHO) cells.

Uses:Treatment of relapsing forms of Multiple

Sclerosis (MS). Slows the progression of MS by regulating the body's immune response against myelin.

Given as an IM injection once per week.

Q. Anyone knows Multiple Sclerosis بلصتلالتصلب ?بلصتلالمتعدد

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System (CNS) -brain and spinal cord.

It is a disease of the "white matter" tissue. The white matter is made up of nerve fibers which are responsible for transmitting communication signals both internally within the CNS and between the CNS and the nerves supplying rest of the body.

For more information on Multiple Sclerosis, please have a look at the following website:

http://www.youtube.com/watch?v=qgySDmRRzxY&feature=player_embedded

B. Intron A It is rInterferon alpha-2b

Uses: Over 20 indications!i. Malignant melanomaii. Non-Hodgkin's lymphoma iii. Hairy cell leukemiaiv. Kaposi's sarcomav. Chronic hepatitis B (HBV)vi. Chronic hepatitis C (HCV)

Sales exceeding

$440 million in !

three years

3. Engerix-B/Recombivax: They are a rHepatitis B vaccine

Uses: Infection with HBV prevention of 1° liver cancer.

The global HBV market exceeds $1 billion dollars annually. It will grow as more countries adopt WHO recommendations for the vaccination of newborns, teenagers, healthcare workers and other at-risk populations. "

4. Amevive:

It is a protein which blocks the growth of T-cells, and acts as an immunosuppressant. The exact mechanism of action is complicated, however, the T-cell activity is weakened, which reduces the symptoms of psoriasis and the inflammation that is involved in it.

Uses: Moderate-to-severe chronic plaque psoriasis Suppresses overactive T lymphocytes found in

autoimmune diseases

3. Chiron ( a Novartis partnership)A. Betaseron: It is rInterferon beta-1b.

Uses: Multiple Sclerosis: Significantly delays the

progression of secondary MS, including relapsing-remitting MS.

25

B. Proleukin It is Interleukin-2 - IL-2

Uses: Cancer: Metastatic renal cell

carcinoma, and metastatic melanoma.

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

26

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.

27

28

C. Regranex: It is rPlatelet-derived growth factor (PDGF).

Uses: Treatment of diabetic foot ulcers.

PDGF is a cytokine (growth factor) that stimulates skin cell and blood vessel production

29

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

>>>>> However, FDA has concluded that patients who use three or more tubes of Regranex experience a five-fold increase in the risk of cancer death compared to patients who do not use the drug.

30

4. GenentechA. CathFlo Activase: It is rTPA, tissue-plasminogen activator.

Uses: Thrombolytic: Approved for treatment

of acute myocardial infarction (AMI), cardiac ischemia, acute massive pulmonary embolism, and management of stroke.

31

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

Clot dissolution

32***FDP: FIBRIN DEGRADATION PRODUCTS

B. TNKase rTPA, tissue-plasminogen activator TNKase can be administered over five

seconds in a single dose, fastest administration of any thrombolytic

Uses: Thrombolytic: TNKase is bioengineered

with 3 amino acid substitutions from natural TPA: T, N and K (Thr, Asp, Lys).

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

Inhibitor-1 33

34

C. Pulmozyme It is a rDeoxyribonuclease

I (rhDNase)

Uses: 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.

35

MOA:

In CF patients, lungs and airways become clogged with mucous containing high concentrations of extracellular DNA released by degenerating leukocytes (neutrophils).

* Watch this!http://www.pulmozyme.com/how-pz-

works.jsp 36

D. Neutropin It is a rHuman growth hormone

(Somatropin; synthetic growth hormone)

Uses: Treatment of GHD (growth hormone

deficiency) in children and in adults Identical to pituitary-derived hGH. Also

indicated for growth failure associated with chronic renal insufficiency (CRI) prior to kidney transplantation, and short stature associated with Turner syndrome. 37

5. The 5th company is: Eli Lilly: A. Humulin: It is rInsulin

Uses: Diabetes: Used by over 3.5 million

people in the U.S. every day

Worldwide revenues of $2.5 B annually

38

1: Humulin pens 2: Humalog: Humalog is the brand name of

insulin lispro which is a rapid-acting insulin.

3: Humalog Mix (Biphasic insulin) Rapid acting + longer acting insulin : mixture of insulin lispro and insulin lispro protamine.

39

Rapid-actingLispro (Humalog ®) Eli lilly Start < 15 min.

Peak 30-60min

Aspart (Novorapid®) Novo Nordisk

Short-acting(Regular: identical to human insulin= unmodified)

Humulin ® R Eli lilly Start 30-60 min.Peak 4 hr Novolin® R Novo Nordisk

Intermediate-acting

(Isophane insulin: insulin+protamine+zinc

Humulin ® N Eli lilly Start 1.5 hrsPeak 7 hr

Novolin® N Novo Nordisk

Long-acting

Humulin® U: withdrawn from market

Eli lilly Start 1 hr. Peakless

Glargine (Lantus®) cannot be combined with other insulins

Sanofi-Aventis

Detemir (Levemir®) Novo Nordisk

41

B. Humatrope rHuman growth hormone (hGH) (Somatropin)

Uses: For Somatropin Deficiency Syndrome

(SDS) in adults and GHD in children due to hypopituitarism, a pituitary tumor or other pituitary disorder, or Turner Syndrome.

42

C. Xigris It is rActivated Protein C.

Activated Protein C acts inside the blood vessel as an anticoagulant/antithrombotic -

reduces blood clots; controls inflammation. Activated by thrombin.

43

Uses: Treatment of severe sepsis, a fast-

moving, dramatic, and often fatal acute response to infection that claimed 215,000 lives each year (pre-Xigris)

44

D. Forteo It is rParathyroid hormone.

Uses: Treatment of osteoporosis in women

and men - Anabolic Therapy: stimulates new bone formation, osteoblasts, bone mineral density (BMD) and bone strength.

45

E. Byetta It is rGLP-1 (glucagon-like peptide-1)

Uses: Type II Diabetes: regulates glucose

homeostasis and enhances glucose-dependent insulin secretion.

46

Byetta is an incretin mimetic similar to GLP-1, an incretin hormone that increases insulin release & decreases glucagon secretion from the pancreas; increases satiety/ fullness

47

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

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

48

6. Merck

One drug from Merck : Gardasil: It is rQuadrivalent HPV (human

papilloma virus) types 6, 11, 16, 18

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

49

Uses:

First Cancer Vaccine: Approved for the immunization of:

children aged 9 to 15 years adult females aged 16 to 26 years

Used for the prevention of cervical cancer, high-grade cervical dysplasia (abnormality in development), and warts caused by HPVs types 6, 11, 16 and 18

50

Virtually 100% effective in protecting against the HPV-16 and HPV-18 strains.

-ve: The wholesale price for Gardasil will be $120 per dose; $360 for all three doses.

51