Cetuximab and Rituximab

8/10/2019 Cetuximab and Rituximab

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Cetuximab and RituximabGroup 6Introduction MounikaCetuximab Vidhi

Market Analysis of Cetuximab AnirbanRituximab & Market Analysis of Rituximab

JayshilMode of Action & Adverse Effects ofRituximab- John


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IntroductionMonoclonal antibodies are monospecific antibodies made by

identical immune cells that are all clones of a unique parent cell.Monoclonal antibody are used to specifically bind to target cells orproteins. This may then stimulate the patient's immune system toattack those cells.Cetuximab : chimeric monoclonal IgG antibody with a high affinityfor the Epidermal Growth Factor Receptor given by intravenousinfusionGeneric Name: Cetuximab Brand Name: ErbituxFDA label uses Head and neck cancer, in combination with radiation therapy. Metastatic colorectal cancerOff label uses: Head and neck cancer, with platinum-based therapy; as

combination therapy Pancreatic cancerDOSAGE FORMS AND STRENGTHS---------------------

100 mg/50 mL, single-use vial


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Rituximab Chimeric monoclonal antibody against the protein CD20, found on

the surface of immune system B cells.Rituximab destroys B cells and is therefore used to treat diseasesGeneric Name : rituximab.Brand Name : RituxanFDA label uses

Non-Hodgkins Lymphoma (NHL)

Chronic Lymphocytic Leukemia (CLL)Rheumatoid Arthritis (RA)

.-USE IN SPECIFIC POPULATIONS----------------------- Pregnancy: Administer Erbitux to a pregnant woman only if the

potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Discontinue nursing during and for 60 days


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Off Label uses Autoimmune diseases

DOSAGE FORMS AND STRENGTHS--- --------------- 100 mg/10 mL and 500 mg/50 mL solution in a single -use vial

USE IN SPECIFIC POPULATIONS Pregnancy: Limited human data; B -cell lymphocytopenia occurredin infants exposed in utero Nursing Mothers: Caution should be exercised when administeredto a nursing woman


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Structure of Cetuximab


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ec an sm o ac on an s eeffects:

Storage and handling:

It is a sterile, injectable liquid containing no preservatives.

Store vials under refrigeration at 2 C to 8 C (36 F to 46 F). Donot freeze.

Increased particulate formation may occur at temperatures at orbelow 0 C.


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Cetuximab Mechanism of Action The EGFR (HER1, c-ErbB-1) is a transmembrane glycoprotein

It is constitutively expressed in normal epithelial tissues

Over-Expression of EGFRs is detected in many human cancersincluding head, neck, colon and rectum

Cetuximab binds specifically to the EGFR on both normaland tumor cells, and competitively inhibits the bindingof epidermal growth factor (EGF) and other ligands, such astransforming growth factor-alpha

Binding of cetuximab to the EGFR blocks phosphorylation andactivation of receptor-associated kinases, resulting in inhibition ofcell growth, induction of apoptosis, decreased matrixmetalloproteinase and vascular endothelial growthfactor production.


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KRAS, is a protein that in humans is encoded by theKRAS gene. The protein product of the normal KRAS geneperforms an essential function in normal tissue signaling, andthe mutation of a KRAS gene is an essential step in thedevelopment of many cancers .

If the KRAS protein is mutated, cetuximab has beenfound not to work, because the mutated KRAS genedownstream is causing the problem by continuously sending agrowth signal (the KRAS protein) and this mutated gene nowdoes not respond to the EGFR receptor.

Therefore, before cetuximab is used, the standard ofcare is that the KRAS gene in the cancer cells is tested formutation. If KRAS is normal (wild type), cetuximab might work.

Contind.


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Side effects:The following are the adverse reactions of cetuximab: Infusion reactions Cardiopulmonary arrest

Pulmonary toxicity Dermatologic toxicity Hypomagnesemia and Electrolyte Abnormalities

The most common adverse reactions

include cutaneous adverse reactions (including rash, pruritus,and nail changes), headache, diarrhea, and infection.

Source: https://sites.google.com/site/doseitrighttech/mabs Source: http://www.biology.iupui.edu/biocourses/Biol540/6secondwavequestionCSS.html


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Market Analysis of CetuximabIn 2009-2012 , the market volume of monoclonal antibody grewat a CAGR of 13%

Between 2013-2017 , Chinese monoclonal antibody market willboost at the rate of 35%, partaking 21.5% of the globalmonoclonal antibody market in 2017 (9.5% in 2012)

Cetuximab sales ignited worldwide revenue to more than $2billion in 2009 .


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Net Sales by products

Dollar in million 2012 2011 2010

Erbitux 702 691 662

According to BRISTOL-MYERS SQUIBB COMPANY , Data

exclusivity in U.S. expires in 2016 and no patent exists thatexclusively claim cetuximab, the active ingredient in Erbitux .The company's rights to commercialize cetuximab terminate in2018.


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Rituximab Rituximab, Rituxan antibody is a genetically

engineered chimeric IgG1 anti-CD20 MAb , is abreakthrough MAb for cancer, rheumatoid arthritis, anda wide range of immunologic illnesses.

Rituximab is a major blockbuster bio-pharma drug -first successful antibody against cancer

Rituximab was developed by IDECPharmaceuticals under the name IDEC-C2B8 currentlyco-marketed by Biogen Idec and Genentech in theU.S.

Rituximab received its initial FDA approval for


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Structure of Retuximab


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FDA - Rituxan is medicine used to treat:

1) Non- Hodgkins Lymphoma (NHL) - are diverse group ofblood cancers, derived from lymphocytes, a type of white bloodcell

2) Chronic Lymphocytic Leukemia (CLL) - Most commontype of leukemia in adults. Leukemias are cancers of the whiteblood cells (leukocytes). CLL affects B cell lymphocytes.

3) Rheumatoid Arthritis (RA)- Rheumatoid arthritis (RA) is achronic, systemic inflammatory disorder that primarily affects

joints

4) Granulomatosis with Polyangiitis (GPA) & MicroscopicPolyangiitis (MPA) - It is a form of vasculitis (inflammation ofblood vessels) that affects small- and medium-size vessels in

many organs


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Production of Rituximab

Chimeric Anti-CD20 Antibody is cultured inmammalian cell in a suspension culture withantibiotic gentamycin.

It is purified by affinity and ion exchangechromatography .

Final process involves inactivation and removalof Viruses.

Final product is preservative free and availablein single use vial.

Stored at 2C to 8C (36 to 46F)


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Structure of Rituximab

Used in treating B cell malignancies. The most effective strategy

for treating NHL is the combination of Rituximab and CHOP

chemotherapy.

CD20 Found to be binding with CD20 of pre-B and Mature B-

Cells at Bp35.

Fab domain binds to CD20 Antigen

Fc domain recruits immune effector functions.


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ADCC Ab-Fc with CD16 anti-tumor activity and Activation of

Natural Killer Cells. Lenalidomide and NHL and CLL. (Lue w v MD , Peter

Schafer et all) The most obvious interpretation of these findings is that NK

cells are mediating ADCC of rituximab-coated target cells.

However, there are alternative explanations. For example,NK cells are activated and produce IFN when they come incontact with rituximab-coated target cells.

This IFN could have direct anti-tumor effects on themalignant cells, or could be activating other immune

effector cells that could contribute to ADCC. Lenalidomide (Revlimid is approved for the treatment

of transfusion-dependent patients with anemia due to low-or intermediate-1-risk MDS associated with a del 5qcytogenetic abnormality with or without additional

cytogenetic abnormalities, and in combination

withdexamethasone is for the treatment of multiple


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Induction of Apoptosis

Found in NHL. Intrinsic and extrinsic pathway Intrinsic: originates at mitochondria The extrinsic pathway:TNFR family neurotransmitters glutamate

and dopamine cytosolic domain-death domainand initiation of apoptotic cascade

Cross linking of CD20 with murine antibodies induced apoptosis. (Shan D,Ledbetter JA et all Blood 1998, 91. 1644.52 ) P18 and tyrosine kinase Caspases


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Complement Activation

What is complement? Complement consists of a group of serum proteins that activates inflammation,

destroys cells and participates in opsonisation. Complement can be activated by anumber of different foreign molecules.

Cascading proteins from C1 to C9 Classical Pathway and Alternative Pathway.

Lectin mannose pathway Complement Activation Determines the

Therapeutic Activity of Rituximab In Vivo NicolaDi Gaetano*, Elena Cittera*, et all.

Non, athmyic and knockout C1

Song time.


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Adverse reactions:

InfusionRelatedEventsImmunologicEventsRetreatmentEventsHemolyticEventsCardiacEvents


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Market Even after 14 years on the market, Rituxan continues to

grow.

At US$6.6 billion worldwide in 2010 sales , rituximab is thelargest revenue-producing biologic.

The Rheumatoid Arthritis Drug Market Will ExperienceModest Growth as Sales Increase from $11.1 Billion in 2011to $15.2 Billion in 2021 (Decision Resources, one of theworlds leading research and advisory firms )

The non-Hodgkin lymphoma (NHL) market will be worth$9.2 billion by 2020 (according to new research byReportsnReports).


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Biosimilar Development Rituxan's patent expiration is around the corner : 2013 in

Europe and 2018 in the U.S.

Sandoz, the generic subsidiary of Novartis (NYSE:NVS),is conducting a phase 3 trial for its compound GP2013, abiosimilar version of Rituxan

Pfizer's (NYSE:PFE) biosimilar compound is PF-05280586. The company is running phase 1 and2 trials for RA patients and phase 1 trial for patients with

CD20 positive NHL.

Teva Pharmaceutical in joint venture withSwitzerland's Lonza Group developing TL011. Teva hascompleted phase 1 and 2 trials for RA and is running a

phase 1 for lymphoma patients.


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Complex biosimilar developmentProcess

Biosimilar development is not for the faint-hearted, asbarriers to introducing these large and complexbiomolecules range from significant technical difficulties ,potential regulatory issues, surfacing submarine patents.

Samsung has halted clinical development for thebiosimilar due to safety requirements issues in Europe andthe US

Teva Pharmaceuticals has suspended its phase III trial forits biosimilar version (TL011),considering to meet therequirements from FDA and EMA


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India leading the way

Reditux , the worlds first biosimilar MAb for rituximab ,wasdeveloped by the Indian generic manufacturer, Dr ReddysLab.

It is launched in 2007 with a price of approximately 50%less than the originator. Within 3 years of launch ofReditux, the number of patients receiving this therapyincreased more than six-fold in India

In 2013,Intas Pharmaceuticals launched Mabtas inIndia with a view to make Non-Hodgkin's Lymphoma (NHL)treatment cost-effective. Mabtas is a biosimilar version ofRituximab.

Not able to entre EU market yet due to strict regulations


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References: Lenalidomide Strongly Enhances Natural Killer (NK) Cell Mediated

Antibody-Dependent Cellular Cytotoxicity (ADCC) of RituximabTreated Non- Hodkins Lymphoma Cell Lines In Vitro. Lei Wu, MD1,Peter Schafer, PhD1,*, George Muller, PhD1,*, David Stirling,PhD1,* and J. Blake Bartlett, PhD1,*

http://www.sec.gov/Archives/edgar/data/14272/000119312513061678/d450621d10k.htm

Emerging drugs to treat squamous cell carcinomas of the head andneck-Christopher Fung and Jennifer R Grandis

https://sites.google.com/site/doseitrighttech/mabs http://www.sec.gov/Archives/edgar/data/14272/0001193125130616

78/d450621d10k.htm

Emerging drugs to treat squamous cell carcinomas of the head andneck-Christopher Fung and Jennifer R Grandis

http://www.biology.iupui.edu/biocourses/Biol540/6secondwavequestionCSS.html

Complement Activation Determines the Therapeutic Activity of

Rituximab In Vivo 1 Nicola Di Gaetano*, Elena Cittera*, Rachele Nota*, Annunciata


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References: Zaina P Qureshi,Jametta S Magwood,Sarveshwari Singh,Charles L

Bennett. Rituximab and biosimilars equivalence and

reciprocity,2013 Sandozs bio similar rituximab on track, Generic and bio similar

initiative,2013 http://www.gabionline.net/Biosimilars/News/Sandoz-s-biosimilar-

rituximab-on-track Amgen starts phase III trial for biosimilar rituximab,2014, Generic

and bio similar initiative http://www.gabionline.net/Biosimilars/News/Amgen-starts-phase-III-

trial-for-biosimilar-rituximab Patient access to rituximab in emerging markets, Generic and bio

similar initiative http://www.gabionline.net/layout/set/print/Biosimilars/Research/Pati

ent-access-to-rituximab-in-emerging-markets The Non-Hodgkin's Lymphoma Drug Market Will Nearly Double to

More Than $10 Billion by 2022,2013,Market Watch http://www.marketwatch.com/story/the-non-hodgkins-lymphoma-

drug-market-will-nearly-double-to-more-than-10-billion-by-2022-2013-10-28


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Cetuximab and Rituximab

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