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Imatinib (Gleevec™)

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Imatinib (Gleevec™) Biologicals What Are They? When Did All of this Happen? There are Clear Benefits. Are there also Risks? Brian J Ward Research Institute of the McGill University Health Centre Global Health, Immunity & Infectious Diseases Grand Rounds – March 2016 Biologicals Biological therapy involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. National Cancer Institute (USA) What Effects Do Steroids Have on Immune Responses? This is your immune system on high dose steroids projects.accessatlanta.com • Suppress innate and adaptive responses • Shut down inflammatory responses in progress • Effects on neutrophils, macrophages & lymphocytes • Few problems because use typically short-term Virtually Every Cell and Pathway in Immune System ‘Target-able’ (Influenza Vaccination) Reed SG et al. Nature Medicine 2013 Nakaya HI et al. Nature Immunology 2011 Landscape - 2013 Antisense (30) Cell therapy (69) Gene Therapy (46) Monoclonal Antibodies (308) Recombinant Proteins (93) Vaccines (250) Other (81) http://www.phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf Therapeutic Category Drugs versus Biologics Patented Ibuprofen (Advil™) Generic Ibuprofen BioSimilars/BioSuperiors ? www.drugbank.ca Patented Etanercept (Enbrel™) BioSimilar Etanercept Etacept™ (India) Biologics in Cancer Therapy Therapeutic Categories • Hormonal Therapy • Monoclonal antibodies • Cytokine therapy • Classical vaccine strategies • Adoptive T-cell or dendritic cells transfer • Oncolytic virus therapy • Gene therapy • DNA oligonucleotide therapy • RNA oligonucleotide therapy FDA Approved Anti-Cancer Biologicals (2015) Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin®), ramucirumab (Cyramza®) Basal cell carcinoma: Vismodegib (Erivedge®), sonidegib (Odomzo®) Brain cancer: Bevacizumab (Avastin®), everolimus (Afinitor®) Breast cancer: Everolimus (Afinitor®), tamoxifen (Nolvadex), toremifene (Fareston®), Trastuzumab (Herceptin®), fulvestrant (Faslodex®), anastrozole (Arimidex®), exemestane (Aromasin®), lapatinib (Tykerb®), letrozole (Femara®), pertuzumab (Perjeta®), ado-trastuzumab emtansine (Kadcyla®), palbociclib (Ibrance®) Cervical cancer: Bevacizumab (Avastin®) Colorectal cancer: Cetuximab (Erbitux®), panitumumab (Vectibix®), bevacizumab (Avastin®), ziv-aflibercept (Zaltrap®), regorafenib (Stivarga®), ramucirumab (Cyramza®) Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec®) Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline® Depot) Head and neck cancer: Cetuximab (Erbitux®) Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec®), sunitinib (Sutent®), regorafenib (Stivarga®) Giant cell tumor of the bone: Denosumab (Xgeva®) Kaposi sarcoma: Alitretinoin (Panretin®) Kidney cancer: Bevacizumab (Avastin®), sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), temsirolimus (Torisel®), everolimus (Afinitor®), axitinib (Inlyta®), nivolumab (Opdivo®) Leukemia: Tretinoin (Vesanoid®), imatinib mesylate (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), rituximab (Rituxan®), alemtuzumab (Campath®), ofatumumab (Arzerra®), obinutuzumab (Gazyva®), ibrutinib (Imbruvica®), idelalisib (Zydelig®), blinatumomab (Blincyto®) Liver cancer: Sorafenib (Nexavar®) Lung cancer: Bevacizumab (Avastin®), crizotinib (Xalkori®), erlotinib (Tarceva®), gefitinib (Iressa®), afatinib dimaleate (Gilotrif®), ceritinib (LDK378/Zykadia™), ramucirumab (Cyramza®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), osimertinib (Tagrisso™), necitumumab (Portrazza™), alectinib (Alecensa®) Lymphoma: Ibritumomab tiuxetan (Zevalin®), denileukin diftitox (Ontak®), brentuximab vedotin (Adcetris®), rituximab (Rituxan®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), bortezomib (Velcade®), pralatrexate (Folotyn®), ibrutinib (Imbruvica®), siltuximab (Sylvant®), idelalisib (Zydelig®), belinostat (Beleodaq®) Melanoma: Ipilimumab (Yervoy®), vemurafenib (Zelboraf®), trametinib (Mekinist®), dabrafenib (Tafinlar®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), cobimetinib (Cotellic™) Multiple myeloma: Bortezomib (Velcade®), carfilzomib (Kyprolis®), panobinostat (Farydak®), daratumumab (Darzalex™), ixazomib citrate (Ninlaro®), elotuzumab (Empliciti™) Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec®), ruxolitinib phosphate (Jakafi®) Neuroblastoma: Dinutuximab (Unituxin™) Ovarian epithelial/fallopian tube/primary peritoneal cancers: Bevacizumab (Avastin®), olaparib (Lynparza™) Pancreatic cancer: Erlotinib (Tarceva®), everolimus (Afinitor®), sunitinib (Sutent®) Prostate cancer: Cabazitaxel (Jevtana®), enzalutamide (Xtandi®), abiraterone acetate (Zytiga®), radium 223 dichloride (Xofigo®) Soft tissue sarcoma: Pazopanib (Votrient®) Systemic mastocytosis: Imatinib mesylate (Gleevec®) Thyroid cancer: Cabozantinib (Cometriq®), vandetanib (Caprelsa®), sorafenib (Nexavar®), lenvatinib mesylate (Lenvima®) Top Anti-Cancer Rx in 2013 http://www.medscape.com/viewarticle/826649 Imatinib (Gleevec™) • Tyrosine kinase inhibitor • Targets bcr-abl (over-active kinase in Philadelphia Chromosome + CML) • Shuts down phosphorylation and either slows growth or kills (apoptosis) • Doubled 5-yr survival in CML patients • Licensed (in USA) in 2001) • Made the cover of Time Magazine • Patent ended 2015: extended ‘beta-crystal form’ to 2019 • Cost in 2001 ($30,000/yr) – same as interferon Rx • Novartis recouped development costs in 2 years • Price increased to $92,000/year in 2012 ($4.7B global sales) The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood 2013: 121: 4439–42. • Estimated ‘societal value’ of $143B at a cost to consumers of $14B • Gleevec sells for $200-$300/100 mg pill (generic at $2/pill) Bevacizumab (Avastin™) • Angiogenesis inhibitor • Humanized monoclonal antibody • Binds to and blocks vascular endothelial growth factor (VEGF-A) • First target – colorectal cancer • Licensed (in USA) in 2004 • Controversy regarding high cost for short-term benefit in several cancers • Also used for macular degeneration (at tiny doses - $40-$50) • Cost from $40,000-$55,000/yr (Canada & USA respectively) • Global sales in 2014 - $6.7B • 2012 (USA) sales fo ‘counterfeit ‘Avastin™’ manufactured in Egypt Counterfeits of cancer drug Avastin found in U.S". Reuters. February 15, 2012. • Several on-going attempts to make biosimilars (including in plants) Rituximab (Rituxan™) minimednews.wordpress.com • Chimeric monoclonal antibody against CD20 (expressed on surface of B cells) • Targets both healthy and pathologic B cells leading to B cell depletion • NK cells bind and B cells die by apoptosis • Hematologic malignancies (leukemias & lymphomas) • No activity against multiple myeloma • Increase in indications to target rheumatoid arthritis • Also other autoimmune conditions & multiple sclerosis • Cost from $160-$2450 per vial (USA) • Global sales in 2013 - $7.8B • Patent issued in 1998 and expired in 2015 • NextGen anti-CD20 - ocrelizumab (90-95% human) - ofatumumab (high-efficiency depletion) - obinutuzumab (improved ADCC) leading to B cell depletion Biologicals in Multiple Sclerosis Therapeutic Categories • Deplete B cells (anti-CD20: rituximab, ocrelizumab) • Directed against T cells - T cell mobility natiluzimab (anti-VLA4) fingolimod (SIP1 receptor ligand: blocks Tcm) - T cell proliferation (anti-CD25: daclizumab) • Depletes activated T & B cells (teriflunomide) • Targets cyto/chemokine pathways (DMF/BG12) • Depletes immune cells (anti-CD52: alemtuzumab) Current and future MS therapies ORAL THERAPIES Teriflunomide Fingolimod Laquinimod* Azathioprine† DMF Natalizumab Alemtuzumab‡ Ocrelizumab§ Beta-interferons § Glatiramer acetate IV, IM, SC THERAPIES Daclizumab § Mitoxantrone¶ PEG IFNβ <2005 2006 2008 2009 2010 2011 2012 2013 2014 2015+ Cyclophosphamide Methotrexate Mycofenolate Mofetil Dates are approximate as approval dates vary between different countries; for drugs beyond 2014, approval dates are estimated, based on current regulatory status. *Not yet approved by the FDA; negative opinion adopted by CHMP in January 2014, opinion being re-examined as of 21 February 2014. †Not currently approved by the EMA or FDA. ‡Approved by the EMA, rejected by the FDA in December 2013. §Not yet approved by FDA or EMA. ¶Not currently approved by the EMA Mechanism of Action of Fingolimod in MS • Oral anti-Multiple Sclerosis therapy • Binds to 4/5 S1P-Rs expressed o lymphocytes and cells in the CNS – S1P1 on lymphocytes, neural cells – S1P3 on all cells – S1P4 on lymphocytes Reversible retention of – S1P5 on CNS cells and NK cells naïve and central memory – lymphocytes in the lymph nodes Effector memory T cells not affected Crosses the BBB into the CNS Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J Exp Med 2005; 201:291 Mechanism of Action of Natalizumab in MS • Administered IV • Anti-VLA-4 humanised monoclonal antibody • Binds to the α4 chain of VLA-4 (α4-β1 integrin) • Prevents leukocytes adhesion & migration to CNS • Inhibits binding of lymphocytes to natural ligands - VCAM-1 (endothelium) - fibronectin - Osteopontin http://www.cvs.saude.sp.gov.br/up/Poster%204%20Lara.pdf Mechanism of Action of Alemtuzumab in MS B T CD52 CD52 • IV daily for 3-5 days/years for several years • Anti-CD52 humanised monoclonal antibody
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