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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 Grand Rounds – March 2016 Biologicals

Biological involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat .

National Institute (USA) What Effects Do Steroids Have on Immune Responses?

This is your 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 (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..ca Patented (Enbrel™)

BioSimilar Etanercept Etacept™ (India) Biologics in Cancer Therapy Therapeutic Categories

• Hormonal Therapy • Monoclonal antibodies • 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: (Herceptin®), (Cyramza®) Basal cell carcinoma: (Erivedge®), (Odomzo®) Brain cancer: (Avastin®), (Afinitor®) : Everolimus (Afinitor®), tamoxifen (Nolvadex), toremifene (Fareston®), Trastuzumab (Herceptin®), fulvestrant (Faslodex®), anastrozole (Arimidex®), exemestane (Aromasin®), (Tykerb®), letrozole (Femara®), (Perjeta®), ado- (Kadcyla®), (Ibrance®) Cervical cancer: Bevacizumab (Avastin®) : (Erbitux®), (Vectibix®), bevacizumab (Avastin®), ziv- (Zaltrap®), (Stivarga®), ramucirumab (Cyramza®) Dermatofibrosarcoma protuberans: mesylate (Gleevec®) Endocrine/neuroendocrine tumors: Lanreotide acetate (Somatuline® Depot) : Cetuximab (Erbitux®) Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec®), (Sutent®), regorafenib (Stivarga®) Giant cell tumor of the bone: (Xgeva®) Kaposi sarcoma: Alitretinoin (Panretin®) : Bevacizumab (Avastin®), (Nexavar®), sunitinib (Sutent®), (Votrient®), (Torisel®), everolimus (Afinitor®), (Inlyta®), (Opdivo®) : Tretinoin (Vesanoid®), imatinib mesylate (Gleevec®), (Sprycel®), (Tasigna®), (Bosulif®), (Rituxan®), (Campath®), (Arzerra®), (Gazyva®), (Imbruvica®), idelalisib (Zydelig®), (Blincyto®) : Sorafenib (Nexavar®) : Bevacizumab (Avastin®), (Xalkori®), (Tarceva®), (Iressa®), dimaleate (Gilotrif®), (LDK378/Zykadia™), ramucirumab (Cyramza®), nivolumab (Opdivo®), (Keytruda®), (Tagrisso™), (Portrazza™), (Alecensa®) : (Zevalin®), (Ontak®), (Adcetris®), rituximab (Rituxan®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), bortezomib (Velcade®), pralatrexate (Folotyn®), ibrutinib (Imbruvica®), (Sylvant®), idelalisib (Zydelig®), belinostat (Beleodaq®) : (Yervoy®), (Zelboraf®), (Mekinist®), (Tafinlar®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), (Cotellic™) Multiple myeloma: Bortezomib (Velcade®), carfilzomib (Kyprolis®), panobinostat (Farydak®), (Darzalex™), ixazomib citrate (Ninlaro®), (Empliciti™) Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec®), phosphate (Jakafi®) Neuroblastoma: (Unituxin™) Ovarian epithelial/fallopian tube/primary peritoneal : Bevacizumab (Avastin®), olaparib (Lynparza™) : 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: (Cometriq®), (Caprelsa®), sorafenib (Nexavar®), 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 + CML) • Shuts down phosphorylation and either slows growth or kills () • 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 Rx • 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 • 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 against CD20 (expressed on surface of B cells) • Targets both healthy and pathologic B cells leading to depletion • NK cells bind and B cells die by apoptosis

• Hematologic malignancies ( & ) • 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 - (90-95% ) - 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 - mobility natiluzimab (anti-VLA4)

fingolimod (SIP1 receptor ligand: blocks Tcm) - T cell proliferation (anti-CD25: ) • Depletes activated T & B cells (teriflunomide) • Targets cyto/chemokine pathways (DMF/BG12) • Depletes immune cells (anti-CD52: alemtuzumab) Current and future MS

ORAL THERAPIES Teriflunomide Fingolimod Laquinimod*

Azathioprine† DMF

Natalizumab Alemtuzumab‡ Ocrelizumab§ Beta-

§ 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 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 -

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 NK CD52 • CD52 on the surface of

T T and B lymphocytes CD52 reg NK cells Dendritic Cells, Monocytes & macrophages CD52 CD52 Some granulocytes

CD52 • Not on stem cells CD52 • Rapid depletion of CD52+ cells • Regulatory cells predominate

Speed of immune cell reconstitution varies by cell subtype Mechanism images adapted from: Linker RA et al. Trends Pharmacol Sci 2008 Biologicals in Rheumatology

• Rheumatic fever - anti-TNFa (, adalumimab, others) - anti-CD20 (rituximab, ocrelizumab)

• SLE - anti-TNF - anti-CD20 - anti-BAFF (BLyS)()

Postal M, Costallat LT, Appenzeller S. Biological therapy in systemic lupus erythematosus . Int J Rheumatol. 2012;2012:578641. Anti-TNFa Therapies

• Anti -TNFa initially tried in murine sepsis (1985) Beutler B, et al. "Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin.". Science 1985: 229 (4716): 869–71. • Ineffective in human sepsis • Transgenic mouse models suggested role in arthritis (1991) • First human trial reported in 1994 Elliott MJ, et al. "Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.". Lancet 1994: 344: 1105–10 • In 2016 - infliximab (Remicaide™) : mouse-human chimeric Mo Ab - (Humira™) : human Mo Ab - certolizumab (Cimzia™) : humanized Fab from mouse - (Simponi™) : human Mo Ab - etanercept (Enbrel™): TNFa receptor fused to IgG1 Fc • Other TNFa pathway inhibitors - pentoxifylline (muscle pain/vascular insufficiency – Trental™) - bupropion : (smoking cessation - Zyban™; depression – Wellbutrin™) - 5-HT2A agonist hallucinogens (eg: LSD) also inhibit TNFa

Biologicals in Dermatology Rapidly Expanding Therapeutic Options

Psoriasis/Psoriatic Arthritis • Anti-TNFa (infliximab, etanercept, adalimumab) • Anti-IL12/IL23 ()

Atopic Dermatitis • anti-IL4 receptor () • anti-IL5 () • blocks CD2-LFA3 binding (alefacept) • anti-CD11a (LFA-1 an ICAM-1 ligand)(efilizumab) • targeting other (IL13, IL21, IL31, TSLP) Ustekinumab (Stelara™)

• Human monoclonal antibody • Targets IL-12 and IL-23 via shared p40 subunit • Inhibits Th1 and Th17 signaling

• Major for in 2008 • Also useful in anti-TNFa-refractory Crohns and Ulcerative

• Licensed in 2010 – earned ~$300M • In first 6 months of 2103 ($717M) • Global markets for: Psoriasis drugs $3.5B Crohns/Ulcerative Colitis $4.2B

Schmidt C. Ustekinumab poised to enter the psoriasis Market. Nature Biotechnology 26, 1317 - 1318 (2008) Risks of Biologicals • Idiosyncratic effects - eg: fingolimod: SIP1 receptors have many functions • acute bradycardia due to effect on conduction • Predictable effects - Infectious • routine infections (new & reactivation) • opportunistic infections (new & reactivation) - neoplastic • skin cancers • hematologic malignancies - autoimmunity Local vs Systemic Adverse Events

Malignancy Infection Auto-Immunity

Kim WB et al. J Am Acad Dermatol. 2015 Aug;73(2):237-41. Adverse events resulting in withdrawal of biologic therapy for psoriasis in real-world clinical practice: A Canadian multicenter retrospective study. DMT and Infectious Diseases Risk

Hmmm … let’s see … When you mess with the immune systems (surprise, surprise) … you get more infections

thefoodduo.com Risk of High-Grade Infection with Anti-EGFR (cetuximab and panitumumab)

Funakoshi T et al. Cancer Treat Rev. 2014 Dec;40(10):1221-9. Experiments of Nature

Innate Acquired Humoral Cellular

All organisms Enteroviridae Almost all viruses Encapsulated bacteria Intracellular bacteria • S pneumoniae • mycobacteria • H influenzae • rickettsia spp • N meningitidis • S typhi Giardia lamblia • Listeria spp Many tissue protozoa • malaria spp • leishmania spp • Toxoplasma gondii Immune Experience Over Lifespan

Innate Antibody T cell Why Certain Infections?

• In $$$ countries, infections rare in young adults - except URTIs, UTIs and STIs - chronic infections (eg: Herpes, toxoplasma)

• Target population: 1) young or very old 2) ‘aggressive’ microbial environment

www.examiner.com • Most adults also have + + immunologic experience

(eg: lots of circulating TEM cells, good antibody titres)

Routine versus ‘Opportunistic’ Infections

Routine (vary by age) Opportunistic

• Upper Respiratory • Tuberculosis • Urinary Tract • JC Virus • Skin & soft tissue • Cryptococosis • Sexually-transmitted • Other mycobacteria • Pneumonia • Listeriosis • Varicella zoster • others …. • others …. The Degree of Immune Control Varies As T Cell Immunity Diminishes

• VZV & other Herpes viruses • Tuberculosis • Listeriosis • Non-tuberculosis mycobacteria • Cryptococcosis • Toxoplasmosis • JC Virus • others ….

Quantifying the Risk (Rheumatology)

Meta-Analysis of 106 trials of Standard DMARD & Biologics

Overall Risk of Serious Infection with Biological Rx OR 1.31 (1.09-1.58) for Standard Dose OR 0.93 (0.93-1.33) for Low Dose OR 1.9 (1.5-2.39) for High Dose

Risk lowest in males, previously untreated

Absolute risk (vs background rates) 6/1000 PY (STD Rx) 55/1000 PY (combined biological Rx)

Singh JA etal. Risk of serious infection in biological treatment of patients with Rheumatoid arthritis: a systemic review and meta-analysis. Lancet 2015:386:258 VZV and Biologics (In General)

Long history with corticosteroid use 2009 – RA subjects treated with >1 DMARDs www.shinglesexpert.org 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 + 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. 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 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: - (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, www.ajnr.org cerebral nervous system; AIDS, acquired immune deficiency syndrome; MS, multiple sclerosis Progressive Multifocal Leukoencephalopathy by the Total Number of MS Patients Treated

600

Dec 2014 517 500 475

400

343 300 298

242 200 201 Natalizumab 159 Fingolimod 124 DMF 100 79

31 3 4 Jan 2010 0 0 20000 40000 60000 80000 100000 120000 140000 160000

Number of patients treated are estimates based on publicly available information July 2006 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

Fingolimod* 30.7 (95% CI: 11.3 – 66.8)

Among HIV– Leimann et al., 2008, Brazil 1.7 (95% CI: 1.5 – 2.0) Chen et al., 2011, Taiwan 4.1 (95% CI: 3.8 – 4.4); hosp. due to CM

Pyrgos et al. 2013, 3.1 – 3.8 (hosp. due to CM)# (US, 1997-2009)

Among HIV+ Leimann et al., 2008, Brazil 288 (95% CI: 237 – 348)

Chen et al., 2011, Taiwan 688 (95% CI: 625 – 757) hosp. due to CM

Pyrgos et al. 2013, 2358 (2238-2482 ) hosp. due to CM# (US, 1997-2009)

* 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 3. Chen Y et al. Neuroepidemiology. 2011;36:79–84. (03-Feb-2015). 4. Leimann BC et al. Cad Saude Publica. 2008; 24(11): 2582–2592. 2. Pyrgos V et al. PLOS One. 2013;8:e56269. 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?

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