Proliferation of Medications Explosion of new therapies have come to - PDF document

3/17/2017 Proliferation of Medications • Explosion of new therapies have come to market in past decade Novel Biologic Therapies for • Majority of these are in subspecialty Rheumatic Diseases: An Overview areas: – Oncology “One thing we rabbits know how to – ID (HIV, Hepatitis C, etc…) Jonathan Graf, MD Do is multiply….” Professor of Clinical Medicine, UCSF – Immuno ‐ therapeutics (Rheumatology, GI, Neurology, etc…) Division of Rheumatology San Francisco General Hospital Primary Care Update 2017 • How do those in general medicine fields keep up to date? Growing List of FDA approved Biologics Importance of Understanding Biologics for Rheumatic Diseases RA: Tocilizumab (anti ‐ IL6R) Ank Spondylitis/Psoriasis/Psoriatic Arthritis: • Their number has grown 2010 Secukinumab 2016 (anti IL17a) • The number of indications for their use has RA: Abatacept (CTLA4 Ig) Psoriatic arthritis: Ustekinumab (anti IL ‐ 12/23) grown 2005 2013 – Anti ‐ TNF therapies: rheumatoid arthritis, RA: Rituximab: depleting B cell psoriatic arthritis , spondyloarthritis, ANCA vasculitis: Antibody 2006 inflammatory bowel disease, juvenile idiopathic Rituximab 2012 arthritis, and others) RA: Anakinra: IL1 ‐ RA • They are now being used by patients with 2001 SLE: Belimumab chronic disease (anti ‐ BLyS) 2011 – Patients you will see in practice over many years (unlike oncology patients) Rheumatoid Arthritis: Anti ‐ TNFs Periodic fever syndromes : Etanercept 1998 CAPS, muckle wells, NOMID Infliximab 1999 • They are $$$$ expensive. One medication Canakinumab (anti ‐ IL1) 2009 (adalimumab/Humira) is the #1 selling drug Adalimumab 2002 Rilonacept (IL ‐ 1 TRAP) 2008 worldwide by sales since 2012 Certolizumab 2009 Golimumab 2009 1

3/17/2017 Overview of Today’s Talk Biologic Therapies • Anti ‐ TNF therapy in detail – Most commonly used in practice • What is meant by the term “Biologic Therapy”? • When anti ‐ TNF therapy for RA fails – Anti ‐ IL6 directed therapy (although there are other • Double meaning: options) – Large complex molecules (usually proteins or protein ‐ – Use this as example to show how indications are likely to based) that are synthesized by living cells increase beyond RA for biologics like this – Segue into discussion below: – Target a gene or protein and modify biologic responses • New small molecule “biological response modifiers” • Antibody ‐ antigen interactions • Cytokine ‐ receptor interactions (both ends) • Cell signaling proteins, inhibitors, or ligands • A lot of long ‐ worded medications that sound alike: “imabs, umabs.” Don’t fret – discuss general principles Conventional vs. biological medication Families of biological medications for comparison rheumatic diseases • Anti ‐ cytokine therapies Conventional medications Biological medications – Block pro ‐ inflammatory cytokines from binding their receptors • Larger complex molecules • Small molecules – Anti ‐ TNF, anti ‐ IL6, anti ‐ IL1, anti ‐ IL 12/23, anti ‐ IL 17 • Larger complex macromolecules: • Usually simple chemical structure usually peptides/proteins • Cell ‐ oriented therapies • Encoded genetically, transcribed, • Synthesized and purified from translated, and then post – Removal of or prevent activation and/or simple chemical reaction in lab translationally modified by living proliferation of cells implicated in disease cells • Structures can be identified = – Rituximab (B ‐ cells), abatacept (T ‐ cells) Often can be difficult to identify • easily manufacture generic full structure of complex molecules that biologically constructed modified by cells 2

3/17/2017 Biological therapy for rheumatoid Anti ‐ cytokine therapies arthritis • Pro ‐ inflammatory cytokines bind • Approaching two decades of to receptors on cells and mediate experience with first class of inflammatory responses from biological medications (anti ‐ TNF those cells medications) • Blockade of following cytokines significantly ameliorates these • Data have shown significant diseases benefits not only in treating – TNFa: RA, Psoriatic arthritis disease ‐ associated symptoms (PsA), psoriasis, ankylosing spondylitis, juv. arthritis, IBD – IL 17: Psoriasis and PsA • Significant prevention of joint – IL 12/23: Psoriasis and PsA erosion, narrowing, and – IL 6: RA, ?giant cell arteritis McInnes et al. JCI 2008 ultimately disability – IL 1: periodic fevers (?gout) Benefits of adding an anti-TNF medication to Biologic therapies for rheumatoid arthritis conventional therapy with methotrexate Klareskog et al. Lancet 2004. Tempo Trial • Anti-Tnf medications (5 total) – Etanercept (TNF decoy receptor fusion protein) – Infliximab, Adalimumab, certolizumab, golimumab (variations of anti-TNF antibodies or fragments) • B-cell depleting agents – Rituximab • T-cell costimulation inhibitors (receptor-ligand ) – Abatacept • Inhibitors of IL-6 signaling – Tocilizumab (anti Il-6 receptor antibody) • Il-1 Inhibitors (IL-1 cytokine receptor decoy) – Anakinra 3

3/17/2017 Tumor Necrosis Factor-a Biologic therapies for rheumatoid arthritis • Anti-Tnf medications (5 total) – Etanercept (TNF decoy receptor fusion protein) – Infliximab, Adalimumab, certolizumab, golimumab (variations of anti-TNF antibodies or fragments) • B-cell depleting agents – Rituximab • T-cell costimulation inhibitors (receptor-ligand ) – Abatacept • Where does it come from? • Inhibitors of IL-6 signaling – TNF genes located on chromosome 6 (MHC) – Tocilizumab (anti Il-6 receptor antibody) – Primarily Macrophage and Monocyte derived • Il-1 Inhibitors (IL-1 cytokine receptor decoy) – Anakinra – Some also produced in T Cells and Synoviocytes Natural Biological Effects of TNF TNF Effects: Good and the Bad GOOD BAD TNF ‐ alpha regulates biological • • TNF ‐ a binds membrane ‐ functions necessary for normal bound TNF receptors and inflammatory, immune, and mediates pro ‐ inflammatory tumor surveillance responses. processes implicated in inflammatory arthritis. – TNF ‐ alpha absolutely essential for granulomatous host defenses against intracellular bacteria (MTb, fungal infections, listeria) McInnes et al. JCI 2008 – Explains infection ‐ related toxicity profile of these medications 4

3/17/2017 Anti ‐ TNF medications Anti-TNF Family Anti ‐ Tnf medications – Etanercept (TNF receptor fusion protein) – Infliximab (anti ‐ TNF antibody) – Adalimumab (anti ‐ TNF antibody) – Certolizumab pegol (anti ‐ TNF Fab ‐ PEG) – Golimumab (anti ‐ TNF antibody) Etanercept Most of other anti ‐ TNF monoclonal Abs Practical issues to consider in patients on long Contraindications term anti-TNFs: Pharmacokinetics... • History of latent tuberculosis unless/until they have • Anti-TNF medications have long half lives completed an adequate courses of prophylactic therapy (Duration up for debate) • This is important for duration of the biologic effect • Active acute or chronic infections (HCV exception) • Also important in case someone develops a side effect or infection while on one of these medicines • Active or suspected malignancies. – Etanercept 4.25 days – Infliximab 8-12 days • Anti-TNFs are generally contraindicated in patients with – Adalimumab 14 days moderate or severe congestive heart failure (some have black box warning) • Many patients, especially those on IV therapy, (infliximab, rituxan, etc…) may not mention to their MD • History of demyelinating disease that they are on therapy 5

3/17/2017 Initiating and monitoring therapy Initiating Anti-TNF Therapy • Screening for active infections by history in all • Asses Latent TB status at baseline patients on active therapy – PPD or interferon release assay – Follow up CXR if necessary (I recommend CXRs on all – Hepatitis B (will be discussed shortly) high risk patients) • Initiate treatment for LTBI if necessary (I recommend holding therapy in high risk patients until they have completed a significant amount of their regimen) • If patients are being treated in our office, screen for illness (history, temperature and blood • Other intracellular organisms with latent infection: pressure) before infusions or injections – Consider coccidiomycosis and histoplasmosis in endemic regions before prescribing (should weigh into decision of risks/benefits) – Counsel patients to do the same if being treated at home and hold doses if ill. If truly sick – seek MD • Age appropriate cancer screening - good idea attention Infliximab and TB Anti-TNFs: Adverse Events Keane et al. N Engl J Med. 2001 Oct 11;345(15):1098-104 • Most common: Injection site reactions – Tend to wane over time and with use • Most serious: Increased risk of infections! (OR of 2.0 for serious infection in large meta analysis published in JAMA 2006) – Most common URIs – Problematic: mTB and other intracellular organisms for which TNF is necessary for immune containment • Increased malignancy risk: Controversial 56% Extra Pulmonary TB 24% Disseminated disease • May worsen symptoms of congestive heart Patients don’t make granulomas (atypical appearance) failure. Average onset 12 weeks after initiation (3 ‐ 4 th dose) 6