Biologics Risks and Benefits of Treating

Inflammation

Leonard H Calabrese Professor of Medicine

RJ Fasenmyer Chair of Clinical Immunology

Cleveland Clinic Lerner College of Medicine

Cleveland Clinic

Disclosures

• LH Calabrese, C Calabrese

• COI managed by the Cleveland Clinic Innovation Management & Conflict of Interest Program http://cc-clcoirpt51.cc.ad.cchs.net/COIProd.

- Consultant Pfizer Jansen Sanofi GSK Roche- Speaker Genentech, Abbive, Jansen, BMS, Crescendo

Flow of Immunity with Age

The Effect of HIV Infection and Its Treatment on Inflammation and Immunosenescence

Deeks SG et al, Annu Rev Med. 2011. 62:141-55

Damage / Destruction / Symptoms(RA, SLE, PsA, IBD, AS, MS)

Inflammation(TNF, IL-1, IL-6, IL-17,

IL-23, IL-18, IL-15, Others)

Immune-mediated Inflammatory DiseasesInitiation

SusceptibilityTriggersAccelerants

Immune responses AdaptiveInnate

DM, CHF, Alzheimer's, Transplant, Sepsis, Allergy, Vasculitis, ASO, HIV

Evolution of BIOLOGICS for IMIDS(USA-Approved partial list)

1940s

Gold

Hydroxychloroquine Corticosteroids

Etanercept

1950s 1960s 1970s 1980s 1990s 2000s

D-Penicillamine

Methotrexate Auranofin Azathioprine

InfliximabAdalimumab Golimumab Certolizumab

Anakinra* LeflunomideRituximabAbataceptTocilizumabUstikinumabBelimumabNatalizumabCanakinumabRilonaceptTofacitinib

Molecules in development RA (ACR 2014)

Compound Phase 1 Phase 2a Phase 2b Phase 3 Approved

Kinase inhibitorsTofacitinib (JAK 3/1/2)Fostamatinib (syk)Baricitinib (JAK 1/2)VX-509 (JAK 3/1)GLPG0634 (JAK 1)ASP015K (JAK 1/3)IL-6 inhibitorsSarilumab (anti-IL-6R mAb)Sirukumab

OlokizumabALX-0061 (anti-IL-6R nanobody)

IL-17 inhibitorsIxekizumabSecukinumabBrodalumab (anti-IL-17R mAb) SUSPENDED

Molecules in development RA (ACR 2014)

Compound Phase 1 Phase 2a Phase 2b Phase 3Targeted B cell therapiesNNC0109-0012 (anti-IL-20 mAb)Ocaratuzumab (anti-CD20 mAb)Tabalumab (anti-BAFF/Blys mAb) SUSPENDEDAtaciceptSBI-087Biosimilar GP2013 (rituximab)Other moleculesPPARγ agonistIFNα kinoid vaccinationNNC141-0100 (anti-NKG2a mAb)NNC0114-0005 (anti-IL-21 mAb)Ozoralizumab (ATN-103)Vagal Nerve StimulationDekavil (F8-IL-10)GnRH antagonistIV Staph protein ATregalizumab (anti-CD-4 mAb)Mavrilimumab (anti-GM-CSFRα)CCX354-L2 (chemokine inhibitor)

ARG098 (intra-articular anti-FAS IgM mAb)

Candidate molecules/pathways

• TNF• IL-6• IL-1 targeting• Anti T cell therapies• Others IL17, GM-CSF, IL12/23

http://www.absolutelyfengshui.com/images/yin-yang-symbol.jpghttp://www.absolutelyfengshui.com/images/yin-yang-symbol.jpg

ListeriaLegionella

Addition of Warning Information in Anti-TNFαLabels Over Time

ENBREL® (etanercept) Prescribing Information, Immunex Corporation.HUMIRA® (adalimumab) Prescribing Information, Abbott Laboratories.

CIMZIA® (certolizumab pegol) Prescribing Information, UCB Inc.

FDA web site. Available at: http://www.fda.gov. REMICADE® (infliximab) Prescribing Information, Centocor Ortho Biotech, Inc.SIMPONI™ (golimumab) Prescribing information, Centocor Ortho Biotech, Inc.

Data collected during clinical trials and postmarketing surveillance

Expo

sure

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Hematologic Events

InfectionsSepsis

Hypersensitivity

Neurologic EventsTuberculosisMalignancies

CHF

Hepatotoxicity

HSTCLHBV

Pediatric malignancyLeukemia

Invasive fungal infections

Determining Toxicity of Drugs in Clinical Trials – Tools and Limitations

• Events- Infections – routine, opportunistic - Non infectious complications

• Autoimmune – cytopenias, SLE, MS • Malignancy, Cardiovascular disease• Infusion reactions, hypersensitivity

• Frequency- Common 1/100- Rare 1/1000- Extremely rare 1/10,000

Problems with Analyzing Toxicity from RCT

• Short duration

• High drop out rate in placebo group

• Not powered for AEs- Rule of three (3000 subjects for a 95%

CI of 1/1000)

Registry and / or Observational DataProblems Interpreting Data

• Confounding by indication (“channeling”)• Variation in selection of comparator drug

cohort• Variations in duration of follow-up• Confounding by indication• Difficulty in controlling for bias• Assumptions of hazard function over time• Voluntary reporting in “post marketing”

i.e. Med watch

Mouse Human

CDR=Complementarity-determining regionPEG=Polyethylene glycol

Chimeric monoclonal

antibody

CDR

InfliximabIgG1

Human recombinant antibodies

AdalimumabIgG1

Humanized Fab’ fragment

EtanerceptIgG1

Human recombinant receptor/Fc fusion protein

Fc

Receptor

Constant 2

Constant 3

Molecular Structures of TNF-αInhibitors

PEG PEG

Certolizumab

VL VH

CL

CH1

GolimumabIgG1

Adapted from Tracey D et al. Pharmacol Ther. 2008;117:244-279.

Structural differences not indicative of differences in efficacy or safety

Differences among approved agents

• PK • Cellular toxicity (apoptosis, C mediated,

reverse signaling ) - CRTZ- ETN

• Immunoregulatory• Immunogenicity

Differential toxicity profiles

• Infections- Bacterial mycobacterial fungal- Viral – HBV VZV- opportunistic

• Autoimmunity• Malignancy – NHL?• Congestive failure• Demyelinating diseases• OTHERS: liver, cytopenias

The Use of anti-TNF in HIV+ patients w/rheumatic disease

American College of Rheumatology 2015

•Retrospective seriesInfection Rate in HIV Patients Who Received TNF-α Inhibitor Therapy for Concomitant Autoimmune Diseases

BACKGROUND:Few HIV-infected patients have been treated with tumor necrosis factor (TNF) -α inhibitor therapy for autoimmune diseases refractory to conventional therapies. Evidence supporting the safety of TNF-αinhibitor therapy in HIV-infected individuals is limited and based on isolated case reports and small series.

26 cases with no untoward toxicity when clinically and virologically controlled

IL1 signaling

• IL1 alpha and beta, IRAP, IL18, IL33• IL1 beta – IL1type 1receptor• Produced by cells of hematopoetic and

non-hematopoetic lineage in response to external and internal danger signals

• Pleotropic activites similar to TNF but augments T cell proliferation and IL2 production

Dubois E et al. Br J Clin Pharmacol. 71:5, 639-641.

IRAP - anakinra

IL1 and inflammation

Canakinumab Anti-inflammatory Thrombosis Outcomes Study

CANTOS Study NCT101327846

• Phase III DBPCT RTC• Primary endpoint: Time to 1st CV event 36

months• 152 centers- 17,200 patients• Intervention: quarterly infusions of

canakinumab

IL-6 is Produced by Multiple Cell Types and Is Associated with Numerous Biologic

Activities1,2

Monocytes/macrophages

T-cell activationT cell differentiation

TH17

Endothelial cells Mesenchymal cells,fibroblasts/

synoviocytes

Hepatocytes

Acute-phase responseHepcidin, CRP

↓ CYP450Maturation ofmegakaryocytes

Thrombocytosis

Osteoclast activationBone resorption

B-cells

Hyper-γ-globulinemiaAuto-antibodies (RF)

Adapted from 1 Firestein GS. Nature. 2003; 423:356-361. 2 Smolen JS, et al. Nat Rev Drug Disc. 2003; 2:473-488.

IL-6

Targeting Inflammatory Pathways: IL-6 as an ExampleAhmed, et al. Mol Cancer Ther. 2007;6:2386-2390

gp130

Nucleus

⇌

Transcription

JAK PP

IL-6

IL-6R

Cell Surface

Sarilumab (Reg Sanofi)

(& Tocilizumab)\

Sirukumab JansenOlokizumab UCBClazakizumab BMS

TofacitinibBaricitinibGLPG0634VX-509

STAT

STAT P

P

STAT

STAT P

P

STAT

Target the ligand

Currently (February 2013), tocilizumab is approved by the EMA and FDA for use in RA, and tofacitinib is approved by the FDA for use in RA

IMNL-SCT-019940

ALX0061

Additional safety signals

• Infections - bacterial• Cytopenias 1-2% no correlation with IE• Lipids – significance ?• Lower GI perforations in patients with

previous history of diverticulitis• Liver – moderate increase in LFTs ; no

SAE

Effects of IL-6 blockade in Treated HIV Infection CD4

T cell directed therapies

T cell directed therapies

• Abatacept (CTLA4-Ig) approved RA in trials vasculitis, other IMIDS

• Belatacept –approved anti-rejection therapy

• Anti CTLA4 – ipilimumab approved various cancers

• Anti-PD1 –Nivolumab

Immune checkpoints regulate different components in the evolution of an

immune response.

WHY DO WE NEED THEM???

Original Article

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

F. Stephen Hodi, M.D., Steven J. O'Day, M.D., David F. McDermott, M.D., et alN Engl J MedVolume 363(8):711-723August 19, 2010

Activity of Anti–Programmed Death 1 (PD-1) Antibody (Nivolumab) in Patients with Treatment-Refractory Melanoma, Non–Small-Cell Lung Cancer, or Renal-Cell Cancer.

Topalian SL et al. N Engl J Med 2012;366:2443-2454

pembrolizumab

exhaustion or senescence ?

COULD THERE BE BENEFICIAL EFFECTS OF IMMUNOLOGIC EXHAUSTION?

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCJ7dwrSV-sYCFcvUgAodn_kO2g&url=http://www.natural-homeremedies.com/the-top-symptoms-of-exhaustion/&ei=XYq1Vd66PMupgwSf87vQDQ&bvm=bv.98717601,d.eXY&psig=AFQjCNFOXf0AcB0GvzQm383rKeKOu_OUtw&ust=1438047141623953http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCJ7dwrSV-sYCFcvUgAodn_kO2g&url=http://www.natural-homeremedies.com/the-top-symptoms-of-exhaustion/&ei=XYq1Vd66PMupgwSf87vQDQ&bvm=bv.98717601,d.eXY&psig=AFQjCNFOXf0AcB0GvzQm383rKeKOu_OUtw&ust=1438047141623953

Expression of classical markers of immune development that occur with aging

Multiple co-stimulatory and inhibitory interactions regulate T cell responses

Realities of Biologic Therapies in Inflammation

and aging

Clinical Immunologists

• Therapeutic armamentarium for IMIDS is rich

• Many/any of these agents can be re-purposed for anti- aging strategies

• The no harm principle is of paramount importance and predictors for such calculations are often flawed

Conclusion

Immune Phenotypes of Cancer and Protracted Infection.

Hotchkiss RS, Moldawer LL. N Engl J Med 2014;371:380-383.

CANCER INFECTIONS

IL-17 based drugs

• Secukinimab Novartis ABA head to head TNF-IR - – ongoing in Ps PsA,SpA **** uveitis

• Ixekizumab Lily anti-IL17A – Ps PsA ? RA• Broadalumab Amgen Ps PSA • ALX-0761 (Ablynx) Bispecific nanobody IL17

A&F -- phase 1• ABT-122 (ABBVIE) IL17 & TNF• RA• UNLIKELY TO MOVE IN RA or IBD –Ps and

PsA, SpA hopeful

IL12/23 Ustekinumab PsAPS1 & 2

• The US Food and Drug Administration (FDA) and European Union (EU) have approved the interleukin (IL) 12/23 inhibitor ustekinumab (Stelara, Janssen Biotech) for adults with active psoriatic arthritis who have not responded adequately to previous nonbiological disease-modifying antirheumatic drug therapy,

• Arthritis-enthesitis-dactlyitis,skin, x-ray

• Ann Rheum Dis. 2014 Jan 3. doi: 10.1136/annrheumdis-2013-204248. [Epub ahead of print]

• Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS).

• Poddubnyy D1, Hermann KG, Callhoff J, Listing J, Sieper J.

http://reference.medscape.com/drug/stelara-ustekinumab-345050http://www.ncbi.nlm.nih.gov/pubmed?term=Hermann%20KG%5BAuthor%5D&cauthor=true&cauthor_uid=24389297http://www.ncbi.nlm.nih.gov/pubmed?term=Poddubnyy%20D%5BAuthor%5D&cauthor=true&cauthor_uid=24389297http://www.ncbi.nlm.nih.gov/pubmed?term=Hermann%20KG%5BAuthor%5D&cauthor=true&cauthor_uid=24389297http://www.ncbi.nlm.nih.gov/pubmed?term=Callhoff%20J%5BAuthor%5D&cauthor=true&cauthor_uid=24389297http://www.ncbi.nlm.nih.gov/pubmed?term=Listing%20J%5BAuthor%5D&cauthor=true&cauthor_uid=24389297http://www.ncbi.nlm.nih.gov/pubmed?term=Sieper%20J%5BAuthor%5D&cauthor=true&cauthor_uid=24389297

The Human Kinome

518 protein kinases• 8 major groups• 90 tyrosine kinases• 30 families of tyrosine kinases• Critical for signal transduction

• 4 JAKsIs it possible to generate a pharmacologically useful tyrosine kinase inhibitor?

• Most bind in ATP-binding site

Is it possible to develop drugs that block ATP?

Mechanism of Action of Orencia- Abatacept

With AbataceptIV or SQ

Abatacept

DCT

Orencia® (abatacept) PI.

PHASE 3

Interleukins in RA Family1,2 Cell Source*1 Role in RA2

IL-1 (IL-1-α, IL-1β, IL-1RN, IL-18)

Macrophages, monocytes, lymphocytes, DCs, fibroblasts, Kupffer cells, keratinocytes, osteoblasts, neutrophils, synovial lining cells

Bone matrix degradation; increased synovial fibroblast kinase, MMP, iNOS, PG release; increased monocyte cytokine, ROI; osteoclast activation, endothelial cell adhesion molecule expression

IL-2 (IL-7, IL-2RA, IL-4, IL-15, IL-21)

CD4+, CD8+ T cells, DCs, NK, NKT, T,B, Th2, mast, skeletal muscle cells, myeloid precursors, basophils, eosinophils, monocytes, keratinocytes

Growth and proliferation factors for progenitor and mature cells, and a role in lineage-specific cell differentiation. Stimulates Th2 cell development, activates T cells, has role in the differentiation, survival, and activation of NK cells; promotes proliferation and expansion of CD4 and CD8 clones; involved in cell-mediated and humoral responses1

IL-10 T and B cells, monocytes, macrophages, NK cells, and DCs

Attenuates the activated immune system by inhibiting antigen presentation and release of proinflammatory cytokines1

IL-12 (IL-23) Macrophages, activated DCs T1 and T17 cell expansion, perhaps also role in breach of tolerance2; mediators of inflammatory disorders.1

IL-6 Endothelial cells, fibroblasts, monocytes/ macrophages

Mediator of acute phase response; signals through a cell-surface type cytokine receptor complex consisting of IL-6R chain and L6ST1

IL-17 (IL- 17A to F)

Th17, CD8+, NK, NKT, T cells, neutrophils

Propagation of joint inflammation, cartilage destruction and bone erosion3; acts on cells involved in autoimmunity, inflammation, and tumors, and may play a role in skeletal tissue destruction and inflammatory processes in RA1

Chemokines (IL-8)

Monocytes, macrophages, neutrophils, lymphocytes, synovial cells, hepatocytes

Perhaps involved in early-onset RA1

IL-322 Epithelial cells, monocytes, synovial fibroblasts

Macrophage cytokine, prostaglandin and matrix metalloproteinase release

1. Magyari L et al. World J Orthop. 2014;5(4):516-536.2. McInnes IA, Schett G. Nat Rev Immunol. 2007;7:429-440.3. Moon YM et al. Arthritis Res Therap. 2012;14:R246.

*DCs = Dendritic cells; NK = Natural killer cells; NKT = Natural killer T cells; PG = ProstaglandROI = Reactive oxygen intermediate

46

Other Cytokines in RA1Family Cell Source Role in RA

GM-CSF* Macrophages, T cells, mast cells, NK cells, endothelial cells and fibroblasts2

Bioactivity in rodent models, but true role in RA is unknown.1 Acts in a paracrine fashion to recruit circulating neutrophils, monocytes, and lymphocytes to enhance host defense

TNF Monocytes, T, B cells, NK cells, PMNs, mast cells, osteoblasts, synovialfibroblasts

Activates monocytes, prostaglandin and cytokine release; increased macrophages priming, apoptosis and oxidative burst; T-cell apoptosis, clonal regulation and TCR dysfunction; decreased fibroblast proliferation and collagen synthesis; increased MMP and cytokine release and endothelial cell adhesion molecule expression, cytokine release

RANKL T cells, stromal cells, osteoblasts Stimulates bone resorption via osteoclast maturation and modulates interaction of T cell with DC

Oncostatin M

Monocytes, activated T cells Megakaryocyte differentiation, increased synovial TIMP, acute-phase reactants and cytokine release, increased neuroendocrine effects and corticosteroid release; decreased monocyte TNF release and IL-1 effector function

TGF-β Synovial fibroblasts, monocytes, T cells, platelets

Initial activation then suppression of inflammatory reactions, wound repair, matrix maintenance, fibrosis; early macrophage activation then suppression; increased early phase leukocyte chemoattractant, gelatinase and integrin expression; decreased iNOS expression

BMP family Epithelial cells, synovial fibroblasts, endothelial cells, macrophages

Regulates chemotaxis, mitosis, and differentiation during chondrogenesis and osteogenesis; tissue morphogenesis

PDGF Platelets, macrophages, endothelial cells, synovial fibroblasts

Autocrine or paracrine growth factor; wound healing

FGF family Synovial fibroblasts, monocytes Growth and differentiation of mesenchymal, epithelial, and neuroectodermal cells

MIF Macrophages, activated T cells, synovial fibroblasts

Increased macrophage activity, T cell activation, fibroblast proliferation

47

*GM-CSF = Granulocyte-macrophage colony-stimulating growth factor; TNF = Tumor necrosis factor; RANKL = Receptor activator of nuclear factor kB ligand; TGF-β = Transforming growth factor-beta; BMP = Bone morphogenetic protein;PDGF = Platelet-derived growth factor; FGF = Fibroblast growth factor; MIF = Macrophage migration inhibitory factor; MMP = Matrix metalloproteinase; TCR = T-cell receptor; iNOS = Inducible nitric-oxide synthase

1. McInnes IA et al. Nat Rev Immunol. 2007;7:429-440.

2. Shi Y et al. Cell Res. 2006;16:126-133.

Biologics �Risks and Benefits of Treating Inflammation �DisclosuresFlow of Immunity with Age The Effect of HIV Infection and Its Treatment on Inflammation and ImmunosenescenceImmune-mediated Inflammatory DiseasesEvolution of BIOLOGICS for IMIDS� (USA-Approved partial list)Molecules in development RA (ACR 2014)Molecules in development RA (ACR 2014)Candidate molecules/pathwaysAddition of Warning Information in Anti-TNF Labels Over TimeDetermining Toxicity of Drugs in Clinical Trials – Tools and LimitationsProblems with Analyzing Toxicity from RCTRegistry and / or Observational Data�Problems Interpreting DataMolecular Structures of TNF-α InhibitorsDifferences among approved agents�Differential toxicity profiles��The Use of anti-TNF in HIV+ patients w/rheumatic diseaseIL1 signalingDianummer 20IL1 and inflammationCanakinumab Anti-inflammatory Thrombosis Outcomes Study�CANTOS Study �NCT101327846IL-6 is Produced by Multiple Cell Types and Is Associated with Numerous Biologic Activities1,2Targeting Inflammatory Pathways: IL-6 as an ExampleAdditional safety signalsEffects of IL-6 blockade in Treated HIV Infection �CD4