Proliferation of Medications Explosion of new therapies have - PDF document

4/12/19 Proliferation of Medications • Explosion of new therapies have Biological Agents for Rheumatic come to market in past decade Diseases: A Primary Care Primer 2019 • Majority of these are in subspecialty areas: – Oncology “One thing we rabbits know how to Jonathan Graf, MD – ID (HIV, Hepatitis C, etc…) Do is multiply….” – Immuno-therapeutics (Rheumatology, Professor of Clinical Medicine, UCSF GI, Neurology, etc…) Division of Rheumatology Zuckerberg San Francisco General • 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 & ixekizumab 2017 (anti-IL 17), guselkumab & • The number of indications for their use has RA: Abatacept (CTLA4 Ig) tildrakizumab (anti-iL23) 2018 grown 2005 Ustekinumab (anti IL- – Anti-TNF therapies: rheumatoid arthritis, RA: Rituximab: depleting B cell 12/23) 2013 psoriatic arthritis , spondyloarthritis, inflammatory bowel disease, juvenile idiopathic Antibody 2006 arthritis, and others) ANCA vasculitis: Rituximab 2012 RA: Anakinra: IL1-RA • They are now being used by patients with 2001 chronic disease SLE: Belimumab – Patients you will see in practice over many years (anti-BLyS) 2011 (unlike oncology patients) Rheumatoid Arthritis: Anti-TNFs Periodic fever syndromes : Etanercept 1998 CAPS, muckle wells, NOMID They are $$$$ expensive. One medication Infliximab 1999 • 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

4/12/19 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 Biological medications Conventional 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 cells proliferation of cells implicated in disease • 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

4/12/19 Biological therapy for rheumatoid Anti-cytokine therapies arthritis • Approaching two decades of • Pro-inflammatory cytokines bind 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 + new “biosimilars”) – Etanercept (TNF decoy receptor fusion protein) – Infliximab, Adalimumab, certolizumab, golimumab (variations of anti-TNF antibodies or fragments) – Biosimilars • B-cell depleting agents – Rituximab • T-cell costimulation inhibitors (receptor-ligand ) – Abatacept • Inhibitors of IL-6 signaling – Tocilizumab and others (anti Il-6 receptor antibody) • Il-1 Inhibitors (interfere with IL1 activity) – Anakinra, Canakinumab, and others 3

4/12/19 Anti-TNF Family Anti-Tnf medications – Etanercept (TNF receptor fusion protein) • Because of structural & manufacturing complexities, these biological products are considered as similar, but – Infliximab (anti-TNF antibody) not generic equivalents of parent biologics – Adalimumab (anti-TNF antibody) – Certolizumab pegol (anti-TNF Fab-PEG) • FDA definition: Highly similar to the reference product without clinically meaningful differences in safety, purity and – Golimumab (anti-TNF antibody) potency – Biosimilars (new) • Somewhat more streamlined process of providing analytical, pharmakokenetic/dynamic, and toxicity data • Extrapolation allowed Tumor Necrosis Factor-a FDA approved biosimilars as of 11/17 • Where does it come from? – TNF genes located on chromosome 6 (MHC) – Primarily Macrophage and Monocyte derived – Some also produced in T Cells and Synoviocytes 4

4/12/19 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 Anti-TNF Family Anti-TNF medications 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 5

4/12/19 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 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 high risk patients) – Hepatitis B (will be discussed shortly) • 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 – Counsel patients to do the same if being treated at risks/benefits) home and hold doses if ill. If truly sick – seek MD • Age appropriate cancer screening - good idea attention 6