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

Daclizumab§

IV, IM, SC THERAPIES

Glatiramer acetate

PEG IFNβ§

Mitoxantrone¶ 1 DMARDs Several clear risks: • age of subjects • underlying autoimmune disease severity • intensity of treatment (non-biologics and biologics) • use of corticosteroids • prior use (and length of use) of non-biologics Estimates of risk vary but 1.7 (CI 1.1-2.7) Most cases early (first 6 months) Anti-TNFa drugs most clearly implicated (some variation in risk) As data accumulates for other DMARDs – risks more obvious Rates for tofacitinib + MTX 5-8/100 PY

Risk of Clinical VZV in MS with Fingolimod and other DMT

Arvin AM, et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015 Jan;72(1):31-9.

Hepatitis B 179 subjects with resolved HBV receiving biological Rx (14 rituximab, 146 anti-TNFa, 19 other) . No virologic evidence for reactivation but transaminanses up Barone M, et al. Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection Hepatology. 2015 Jul;62(1):40-6.

Risk of reactivation greatest in HBsAg + subjects Small risk even in anti-HBsAg/anti-HBc positive Risk increases with combined Rx, MTX, corticosteroids Damage (clinical disease) most often occurs with reduced Rx Viral load up then Rx reduction leads to immune attack Nard FD, Todoerti M, Grosso V, Monti S, Breda S, Rossi S, Montecucco C, Caporali R. Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: Extending perspective from old to newer drugs. World J Hepatol. 2015 Mar 27;7(3):344-61.

HBsAg-Positive Subjects Receiving Chemo without Anti-HBV Prophylaxis Risk varies with underlying tumor • hematologic cancer (25%) vs. solid organ (4.4%) • among solid organ tumors hepatocellular (2.3%) colorectal (4.0%) lung (7.1%) breast (9%) gynecological (16.7%) urological (6.7%) head/neck cancer (0%) other (0%) Risk also varies with ChemoRx Regimen • schedule with Rituximab (40%) vs. no Rituximab (4.1%) Shih CA, Chen WC, Yu HC, Cheng JS, Lai KH, Hsu JT, Chen HC, Hsu PI. Risk of Severe Acute Exacerbation of Chronic HBV Infection Cancer Patients Who Underwent Chemotherapy and Did Not Receive Anti-Viral Prophylaxis. PLoS One. 2015 Aug 14;10(8):e0132426.

Risk of HBV Reactivation in HBsAg+ Patients Receiving Immuno-ablative Rx • Incidence of HBsAg+ ~10% in many Asian countries • 20-50% (73% in one study) with no prophylaxis - increases in serum HBV DNA (PCR) - increases in transanimases • Asymptomatic to fatal (progressive liver failure) • Pre-therapy testing rates low (17-31%) • Can occur at any cycle • Oral prophylaxis can reduce incidence by >70% (lamivudine, telbivudine, entecair,adefovir)

Pathophysiologic Mechanism?

www.pathpedia.com

www.pathpedia.com

Infected Hepatocytes Viral Load Serum DNA Cytotoxic T Cells

Chemotherapy

JC Virus and PML in MS DMTs multiple-sclerosis-research. blogspot.com

PML leads to multifocal demyelination of the white matter Reactivates during: - Immunosuppression (AIDS) or - Decreased CNS immunosurvelliance

Differential diagnosis of PML (vs MS) can be made based on: Clinically differentiating features between PML and MS Different features visualized on MRI of patients

In MS, PML is reported with: Natiluzimab (identified predisposing factor for development of PML) DMF Fingolimod PML, progressive multifocal leukoencephalopathy; JCV, John Cunningham virus; CNS, cerebral nervous system; AIDS, acquired immune deficiency syndrome; MS, multiple sclerosis

www.ajnr.org

Progressive Multifocal Leukoencephalopathy by the Total Number of MS Patients Treated 600 Dec 2014

517

500

475

400 343

300

298 242

200

Natalizumab Fingolimod DMF

201 159 124

100 0

79

0

July 2006

20000

40000

3

31

Jan 2010

60000

80000

100000

120000

4 140000

160000

Number of patients treated are estimates based on publicly available information

Cryptococcus species Encapsulated yeast Two common sp. – neoformans – gatti

Environment: – Soil, particularly associated with bird droppings – Eucalyptus trees

Cryptococcal meningitis Isolated cases reported in post-marketing 30.7 (95% CI: 11.3 – 66.8)

Fingolimod*

Among HIV– Leimann et al., 2008, Brazil Chen et al., 2011, Taiwan Pyrgos et al. 2013, (US, 1997-2009)

1.7 (95% CI: 1.5 – 2.0) 4.1 (95% CI: 3.8 – 4.4); hosp. due to CM 3.1 – 3.8 (hosp. due to CM)# Among HIV+

288 (95% CI: 237 – 348)

Leimann et al., 2008, Brazil

688 (95% CI: 625 – 757) hosp. due to CM

Chen et al., 2011, Taiwan Pyrgos et al. 2013, (US, 1997-2009)

2358 (2238-2482 ) hosp. due to CM#

* For fingolimod, reporting rates are presented # indicates range

Incidence rate (95% CI) /Hospitalizations due to CM (per million patient-years, MPY)1-4

The estimated reporting rate is higher than the incidence rate of hospitalizations due to CM for a non-HIV population but clearly below that in HIV+ population1

1. Novartis Data on File. Clinical Overview – Labelling Change (03-Feb-2015). 2. Pyrgos V et al. PLOS One. 2013;8:e56269.

3. Chen Y et al. Neuroepidemiology. 2011;36:79–84. 4. Leimann BC et al. Cad Saude Publica. 2008; 24(11): 2582–2592.

Crypotococcosis Unusual Manifestations

Tuberculosis Approximately 1/3 of world’s population positive Latent TB reactivates first 2-3 yrs or late (post 65 yo) Total life-time risk ~7-10%

Immunosuppression • hematologic malignancies • immuno-ablative therapies • HIV • anti-TNFa Rx • steroids • other DM drugs radiopaedia.org

Lahiri et al. Best Pract Res Clin Rheum 2015:29:290 Faulkner M. Expert Opinion Drug Safety 2015:14;1-12

Other Considerations as Biologics Applied to More Diverse Populations Histoplasmosis

Leishmaniasis (Visceral & Cutaneous)

Chagas Disease

Malaria (vivax, ovale, malariae)

Strongyloides stercoralis

Questions? organicfitness.com