Focusing on drugs under clinical trials

Shu Yi Hamide RezvaniSeyed Mohammad MotevalliMohammad OwaisEvan Atoni

Cancer NanotechnologyProf. Nie

Spring 2016

Drugs and Companies

• MEDI4736 AstraZeneca

• ABRAXANE Celgene

• Pertuzumab Roche

• DOX Plus Olaratumab Eli Lilly and Company

http://www.pmlive.com/top_pharma_list/global_revenues?SQ_DESIGN_NAME=2&#.VwcXsEfhs2_

Top 25 pharma companies by global sales

A Global Study to Assess the Effects of MEDI4736 Following Concurrent Chemoradiation in Patients With

Stage III Unresectable Non-Small Cell Lung Cancer (PACIFIC)

Brief Introduction MEDI4736 is a cancer drug on Phase III trial from AstraZeneca

For the treatment of non-small cell lung cancer (NSCLC) and other cancers

Directed against programmed cell death ligand 1 (PD-L1)

AZ is a British-Swedish multinational pharmaceutical company headquartered in

London, UK.

7th largest pharma company with operations in over 100 countries.

The combination therapy

To improve treatment outcomes, A variety of approaches for combining PD-1/PD-L1 pathway inhibitors with other therapeutic methods have been explored over the past few years in an effort to offer more feasible therapeutic options.

Combination therapy = MEDI4736 + Tremelimumab

MEDI4736 + Tremelimumab• MEDI4736, a monoclonal antibody that targets the

programmed cell death-1 ligand (PD-L1) expressed on tumor cells, and tremelimumab is a monoclonal antibody that inhibits cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) found on T cells. • Activation of both PD-L1 and CTLA-4 pathways blocks

the immune system and inhibits the generation of an immune response. • Tumor cells take advantage of this physiological process to

avoid immune detection and cell death. Inhibiting these proteins with MEDI4736 and tremelimumab restimulates the immune system to detect and destroy tumor cells.

Preventing PD-L1 from binding to its receptors on T-Cells (B7.1) may release the T-Cells from the Inhibitory effect of PD-L1

PD-L2 interactions should not be affected by PD-L1 interference• Studies suggest PD-L2 is a ligand primarily

expressed on normal tissues and immune cells and thus not affected

Adverse Events

Drug-related adverse events reported in Phase I & II are:• Fatigue (26 %)• Diarrhea (21 %)• Colitis (7 %).• Increased amylase (13 %).

Study Findings

Thus far..

Results demonstrate that the combination of MEDI4736 and tremelimumab has clinical activity in NSCLC(Non-Small Cell Lung Cancer) patients, including in patients who lack tumor expression of PD-L1. Out of 31 evaluable patients, 8 patients achieved a partial response and 11 patients had stable disease, while 3 out of 10 patients with PD-L1 negative tumors had a partial response.

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Safety and Efficacy Study of Abraxane as Maintenance Treatment After Abraxane Plus Carboplatin in 1st Line Stage IIIB / IV Squamous Cell Non-small Cell Lung Cancer (aboundsqm)

Celgene

• Celgene Corporation is an American biotechnology company that manufactures drug therapies for cancer and inflammatory disorders.• In 1986, Celgene, originally a unit of the Celanese

Corporation, was spun off as an independent company following the merger of Celanese Corporation with American Hoechst Corporation.

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Abroxane

• Protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel or nab-paclitaxel, is an injectable formulation of paclitaxel used to treat breast cancer, lung cancer and pancreatic cancer, among others. Paclitaxel destroys cancer cells by preventing the normal breakdown of microtubules during cell division. In this formulation, paclitaxel is bonded to albumin as a delivery vehicle.

• The active agent in ABRAXANE is paclitaxel, a microtubule inhibitor. The chemical name for paclitaxel is 5β,20-Epoxy- 1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

•  

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Chemical Structure

Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.91. It is highly lipophilic, insoluble in water, and melts at approximately 216°C to 217°C.The nomenclature for paclitaxel is structured on a tetracyclic 17-carbon (heptadecane) skeleton. There are a total of 11 stereocenters. The active stereoisomer is (−)-paclitaxel.

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Side Effects

• Blood and lymphatic system disorders: lymphopenia, febrile neutropenia• Skin and subcutaneous tissue disorders: nail disorder, pruritus• Nervous system disorders: peripheral motor neuropathy, paraesthesia• Gastrointestinal disorders: dyspepsia, abdominal pain, dysphagia• Investigations: blood alkaline phosphatase increased• Musculoskeletal and connective tissue disorders: back pain, pain in extremity,

musculoskeletal pain• Metabolic and nutrition disorders: dehydration• Infections and infestations: bronchitis, upper respiratory tract infection, urinary

tract infection• Vascular disorders: hypotension, hypertension• Eye disorders: vision blurred• Hepatobiliary disorders: hyperbilirubinaemia

A Safety and Efficacy Extension Study of Pertuzumab in Patients With Solid Tumors Previously Enrolled in a Hoffmann-La Roche-Sponsored

Pertuzumab Clinical Trial

Roche

• Roche was founded in 1896. It is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics.

• Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan.

Pertuzumab• Pertuzumab(trade name Perjeta) is a recombinant humanized monoclonal

antibody that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2). It consists of two heavy chains and two lights chains that have 448 and 214 residues respectively.

• Pertuzumab was developed at Genentech and is now owned by Roche which acquired Genentech in 2009.

Its application in Cancer • Breast cancer that is HER2 positive (HER2+) and has

metastasized (spread to other parts of the body). It is used in patients who have not been treated with anticancer drugs for metastatic disease.

• Breast cancer that is HER2+ and is locally advanced, inflammatory, or early-stage. It is used in patients who have a high risk that the cancer will metastasize or recur (come back). It is given as neoadjuvant therapy (to shrink the tumor before surgery).

Mechanism

• Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity(ADCC).

Mechanism

Pertuzumab

Side effects

• Left Ventricular Dysfunction

• Embryo-Fetal Toxicity

• Hypersensitivity Reactions/Anaphylaxis

A Study of Doxorubicin Plus Olaratumab (LY3012207) in Participants With Advanced or Metastatic Soft Tissue

Sarcoma (ANNOUNCE)

Eli Lilly and Company• American global pharmaceutical company

• located in Indianapolis, Indiana, in the United States.

• The company was founded in 1876 by Col. Eli Lilly, a pharmaceutical chemist.

• ImClone Systems Incorporated is a formerly independent biopharmaceutical company dedicated to developing biologic medicines in the area of oncology.

• It was founded in 1984 and has its corporate headquarters in Bridgewater, New Jersey and its research headquarters in New York City.

• On October 6, 2008, it accepted a $6.5 billion acquisition offer from Eli Lilly and Company, and became a fully owned subsidiary of Eli Lilly and Company on November 24, 2008.

• In 2014 the use of the ImClone brand name was retired and the former ImClone research and manufacturing sites were renamed Eli Lilly and Company.

Olaratumab

• Olaratumab (IMC-3G3; LY3012207) is a fully human IgG1 monoclonal antibody.• It can selectively binds human PDGFRα with high

affinity (Kd 40 pM), blocks PDGF-AA, PDGF-BB, and PDGF-CC (data not shown) binding, and induces receptor internalization.• It inhibits the proliferation and growth of a variety of

human tumor cell lines in vitro and in vivo.

Doxorubicine• An anthracycline antibiotic with

antineoplastic activity• Doxorubicin intercalates between base

pairs in the DNA helix, thereby preventing DNA replication and ultimately inhibiting protein synthesis.

• It inhibits topoisomerase II which results in an increased and stabilized cleavable enzyme-DNA linked complex during DNA replication and subsequently prevents the ligation of the nucleotide strand after double-strand breakage.

• Doxorubicin also forms oxygen free radicals resulting in cytotoxicity secondary to lipid peroxidation of cell membrane lipids; the formation of oxygen free radicals also contributes to the toxicity of the anthracycline antibiotics, namely the cardiac and cutaneous vascular effects.

Platelet-derived growth factor receptor alpha

• Embryonic development, cell proliferation, survival and chemotaxis.

• Promotes or inhibits cell proliferation and cell migration• Plays an important role in the differentiation of bone

marrow-derived mesenchymal stem cells

• Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate

• Plays a role in cell migration and chemotaxis in wound healing

The response depends on the

nature of the bound ligand and

is modulated by the formation

of heterodimers between

PDGFRA and PDGFRB

Targeting the α Receptor for Platelet-Derived Growth Factor as a Primary or Combination Therapy in a Preclinical Model of Prostate Cancer Skeletal Metastasis (Zoledronic acid and Olaratumab)

Side effects

• Hair thinning• Loss of fertility • Pain in the mouth, tummy (abdomen), bone, joints, or

area of the tumur• Loss of appetite• A rash, or red, dry itchy skin

Conclusion