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 Immune-mediated Inflammatory Diseases Initiation Susceptibility Triggers Accelerants Innate Immune responses Adaptive Inflammation (TNF, IL-1, IL-6, IL-17, IL-23, IL-18, IL-15, Others) Damage / Destruction / Symptoms (RA, SLE, PsA, IBD, AS, MS) DM, CHF, Alzheimer's, Transplant, Sepsis, Allergy, Vasculitis, ASO, HIV Evolution of BIOLOGICS for IMIDS (USA-Approved partial list) Infliximab Adalimumab Golimumab Gold D-Penicillamine Etanercept Certolizumab 1940s 1950s 1960s 1970s 1980s 1990s 2000sAnakinra* Leflunomide Rituximab Hydroxychloroquine Methotrexate Abatacept Corticosteroids Auranofin Azathioprine Tocilizumab Ustikinumab Belimumab Natalizumab Canakinumab Rilonacept Tofacitinib Molecules in development RA (ACR 2014) Compound Phase 1 Phase 2a Phase 2b Phase 3 Approved Kinase inhibitors Tofacitinib (JAK 3/1/2) Fostamatinib (syk) Baricitinib (JAK 1/2) VX-509 (JAK 3/1) GLPG0634 (JAK 1) ASP015K (JAK 1/3) IL-6 inhibitors Sarilumab (anti-IL-6R mAb) Sirukumab Olokizumab ALX-0061 (anti-IL-6R nanobody) IL-17 inhibitors Ixekizumab Secukinumab Brodalumab (anti-IL-17R mAb) SUSPENDED Molecules in development RA (ACR 2014) Compound Phase 1 Phase 2a Phase 2b Phase 3 Targeted B cell therapies NNC0109-0012 (anti-IL-20 mAb) Ocaratuzumab (anti-CD20 mAb) Tabalumab (anti-BAFF/Blys mAb) SUSPENDED Atacicept SBI-087 Biosimilar GP2013 (rituximab) Other molecules PPARγ agonist IFNα kinoid vaccination NNC141-0100 (anti-NKG2a mAb) NNC0114-0005 (anti-IL-21 mAb) Ozoralizumab (ATN-103) Vagal Nerve Stimulation Dekavil (F8-IL-10) GnRH antagonist IV Staph protein A Tregalizumab (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 Addition of Warning Information in Anti-TNFα Labels Over Time Data collected during clinical trials and postmarketing surveillance Legionella Listeria Leukemia Pediatric malignancy Invasive fungal infections HBV HSTCL Hepatotoxicity Exposure CHF Malignancies Tuberculosis Neurologic Events Hematologic Events Sepsis Infections Hypersensitivity 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 FDA web site. Available at: http://www.fda.gov. ENBREL® (etanercept) Prescribing Information, Immunex Corporation. REMICADE® (infliximab) Prescribing Information, Centocor Ortho Biotech, Inc. HUMIRA® (adalimumab) Prescribing Information, Abbott Laboratories. SIMPONI™ (golimumab) Prescribing information, Centocor Ortho Biotech, Inc. CIMZIA® (certolizumab pegol) Prescribing Information, UCB Inc. 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 Data Problems 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 Molecular Structures of TNF-α InhibitorsHuman recombinant receptor/Fc fusion protein Humanized Fab’ fragment Human recombinant Chimeric antibodies monoclonal Receptor VL VH antibody CL CH1 Constant 2 CDR Fc Constant 3 PEG PEG Infliximab Adalimumab Golimumab Etanercept IgG1 IgG1 IgG1 IgG1 Certolizumab Mouse Human CDR=Complementarity-determining region PEG=Polyethylene glycol Structural differences not indicative of differences in efficacy or safety Adapted from Tracey D et al. Pharmacol Ther. 2008;117:244-279. 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 •Retrospective series Infection 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-α inhibitor 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 American College of Rheumatology 2015 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 IRAP - anakinra Dubois E et al. Br J Clin Pharmacol. 71:5, 639-641. 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 Mesenchymal cells, Monocytes/ Endothelial cells fibroblasts/ macrophages synoviocytes T-cell activation T cell differentiation IL-6 Hepatocytes TH17 Acute-phase response Maturation of Hepcidin, CRP megakaryocytes ↓ CYP450 B-cells Osteoclast activation Bone resorption Thrombocytosis Auto-antibodies (RF) Hyper-γ-globulinemia Adapted from 1 Firestein GS. Nature. 2003; 423:356-361. 2 Smolen JS, et al. Nat Rev Drug Disc. 2003; 2:473-488. IMNL-SCT-019940 Targeting Inflammatory Pathways: IL-6 as an Example Ahmed, et al. Mol Cancer Ther. 2007;6:2386-2390 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 Sirukumab IL-6 Target the Jansen ligand Sarilumab (Reg Olokizumab Sanofi) UCB (& Tocilizumab)\ Clazakizumab ALX0061 BMS IL-6R gp130 Cell Surface P JAK P STAT Tofacitinib STAT P STAT Baricitinib P GLPG0634 VX-509 STAT ⇌ P STAT Nucleus P Transcription 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 <350, VL - ND 50% enrolled I. To examine the effects of systemic IL-6 inhibition on the pathogenesis of immune failure and inflammation in treated HIV infection. II. To examine the effect of systemic IL-6 inhibition on indices of cardiovascular risk in treated HIV-1 infection. III. To examine the effects of systemic IL-6 inhibition on the inflammatory transcriptome and plasma metabolomes in treated HIV-1 infection. 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 Nal Engl J Med Volume 363(8):711-723 August 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. pembrolizumab Topalian SL et al. N Engl J Med 2012;366:2443-2454 exhaustion or senescence ? COULD THERE BE BENEFICIAL EFFECTS OF IMMUNOLOGIC EXHAUSTION? 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 Conclusion • 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 Immune Phenotypes of Cancer and Protracted Infection. CANCER INFECTIONS Hotchkiss RS, Moldawer LL. N Engl J Med 2014;371:380- 383. IL-17 based drugs • Secukinimab Novartis ABA head to head TNF- IR - – ongoing in Ps PsA,SpA **** uveitis • Ixekizumab Lily anti-IL17A –