Therapeutic Class Overview Immunomodulators INTRODUCTION Immunomodulators treat a wide variety of conditions, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), plaque psoriasis (PsO), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), hidradenitis suppurativa (HS), and uveitis (UV), as well as several less common conditions. T cells, B cells, and cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) play a key role in the inflammatory and immune process (Choy et al 2001). This has led to the development of biologic agents to target these areas. The Food and Drug Administration (FDA) has currently approved 5 originator TNF inhibitors: Cimzia (certolizumab), Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab), and Simponi/Simponi Aria (golimumab), as well as 7 biosimilar TNF inhibitors: Amjevita (adalimumab-atto), Erelzi (etanercept-szzs), Hyrimoz (adalimumab-adaz), Inflectra (infliximab-dyyb), Renflexis (infliximab-abda), Cyltezo (adalimumab-adbm), and Ixifi (infliximab-qbtx). Other agents targeting different cells and cytokines are also FDA- approved for RA treatment. These include Orencia (abatacept), which inhibits CD28-B7 mediated costimulation of the T-cell; Rituxan (rituximab), which targets CD20, a molecule that is found on the surface of B-cells; Actemra (tocilizumab) and Kevzara (sarilumab), which have activity directed against the IL-6 receptor; and Kineret (anakinra), which targets the IL-1 receptor. Of these agents, one biosimilar product has been approved: Truxima (rituximab- abbs). Oral agents on the market, Xeljanz and Xeljanz XR (tofacitinib) and Olumiant (baricitinib), target Janus- associated kinase (JAK) pathways. By inhibiting the JAK pathway, the ability of cytokines to produce inflammation is reduced. Other immunomodulators include Ilaris (canakinumab), which binds to the IL-1ß receptor and is approved to treat JIA; and Entyvio (vedolizumab), which binds to the α4β7 integrin and is approved to treat CD and UC. Otezla (apremilast), an oral, small-molecule phosphodiesterase 4 (PDE-4) inhibitor, and Stelara (ustekinumab), which targets the IL-12 and IL-23 cytokines, are each approved for the treatment of PsA and PsO; Stelara is additionally indicated for the treatment of CD. Cosentyx (secukinumab) and Taltz (ixekizumab) bind and neutralize IL-17A and are indicated for the treatment of PsO and PsA; Cosentyx is additionally indicated to treat PsA and AS. Siliq (brodalumab), an IL-17 receptor antagonist, as well as Tremfya (guselkumab) and Ilumya (tildrakizumab-asmn), both IL-23 antagonists, are indicated for selected patients with PsO. Certain rare conditions for which immunomodulators are indicated are mentioned in this review but are not discussed in detail; these include: o Ilaris for the treatment of 1) cryopyrin-associated periodic syndromes (CAPS), specifically the subtypes familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS); 2) TNF receptor associated periodic syndrome (TRAPS); 3) hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD); and 4) familial Mediterranean fever (FMF) o Kineret for the treatment of CAPS, specifically neonatal-onset multisystem inflammatory disease (NOMID) o Actemra for giant cell arteritis (GCA) and cytokine release syndrome (CRS). Rituxan is also approved for non–Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), granulomatosis with polyangiitis (GPA) (Wegener’s granulomatosis) and microscopic polyangiitis (MPA), and pemphigus vulgaris. These indications will not be discussed in this review. Tysabri (natalizumab), an integrin receptor antagonist, is indicated for multiple sclerosis and CD for patients who have had an inadequate response to, or are unable to tolerate conventional therapies and TNF inhibitors; it is not included as a drug product in this review (Tysabri prescribing information 2018). Arcalyst (rilonacept), an interleukin-1 blocker indicated for CAPS, is also not included in this review (Arcalyst prescribing information 2016). Although FDA-approved, the launch plans for the biosimilar drugs Amjevita (adalimumab-atto), Erelzi (etanercept- szzs), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz), Ixifi (infliximab-qbtx), and Truxima (rituximab-abbs) are pending and may be delayed; therefore, these agents are not currently included in this review. The manufacturer of Ixifi to date does not have plans to launch Ixifi in the United States. Medispan Classes: Antineoplastic-Monoclonal Antibodies, Antipsoriatics, Antirheumatic-Enzyme Inhibitors, Anti-TNF- Alpha-Monoclonal Antibodies, Integrin Receptor Antagonists, Interleukin-1 Receptor Antagonists, Interleukin-1beta Receptor Inhibitors, Interleukin-6 Receptor Inhibitors, PDE-4 Inhibitors, Selective Costimulation Modulators, Soluble Tumor Necrosis Factor Receptor Agents, Tumor Necrosis Factor Alpha Blockers Data as February 14, 2019 SS-U/JA-U Page 1 of 63 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. Table 1. Medications Included Within Class Review Biosimilar or Drug Manufacturer FDA Approval Date Generic Type of Agent Availability Actemra Human monoclonal antibody Genentech 01/08/2010 - (tocilizumab) targeting the IL-6 receptor Cimzia UCB 04/22/2008 - TNFα inhibitor (certolizumab) Cosentyx Human monoclonal antibody Novartis 01/21/2015 - (secukinumab) to IL-17A Enbrel sTNFR fusion protein, TNFα Amgen 11/02/1998 -* (etanercept) inhibitor Takeda Entyvio Human monoclonal antibody Pharmaceuticals 05/20/2014 - (vedolizumab) binds to the α4β7 integrin America, Inc. Humira AbbVie 12/31/2002 -* TNFα inhibitor (adalimumab) Ilaris Human monoclonal antibody Novartis 06/17/2009 - (canakinumab) that binds to IL-1ß Ilumya Sun Pharma Human monoclonal antibody (tildrakizumab- 03/20/2018 - Global to IL-23 asmn) Inflectra Celltrion/ 04/05/2016 N/A† TNFα inhibitor (infliximab-dyyb) Hospira/Pfizer Kevzara Sanofi Genzyme Human monoclonal antibody 05/22/2017 - (sarilumab) Regeneron targeting IL-6 receptor Kineret Swedish Orphan 11/14/2001 - IL-1 receptor antagonist (anakinra) Biovitrum Olumiant Small molecule Janus kinase Eli Lilly 05/31/2018 - (baricitinib) (JAK) inhibitor Orencia Bristol Myers sCTLA-4-Ig recombinant 12/23/2005 - (abatacept) Squibb fusion protein Small-molecule Otezla Celgene 03/21/2014 - phosphodiesterase 4 (apremilast) Corporation inhibitor Remicade Janssen Biotech 8/24/1998 -† TNFα inhibitor (infliximab) Renflexis Merck 04/21/2017 N/A† TNFα inhibitor (infliximab-abda) Rituxan Anti-CD20 monoclonal Genentech 11/26/1997 -* (rituximab) antibody Human monoclonal antibody Siliq Valeant 02/15/2017 - directed against the IL-17 (brodalumab) receptor A (IL-17RA) Simponi/ 04/24/2009 and Simponi Aria Janssen Biotech - TNFα inhibitor 07/18/2013 (golimumab) Human monoclonal antibody Stelara Janssen Biotech 09/25/2009 - targeting the IL-12 and IL-23 (ustekinumab) cytokines Taltz Human monoclonal antibody Eli Lilly 03/22/2016 - (ixekizumab) to IL-17A Tremfya Human monoclonal antibody Janssen Biotech 07/13/2017 - (guselkumab) to IL-23 cytokine Xeljanz / Xeljanz 11/06/2012 and Small molecule Janus kinase Pfizer - XR (tofacitinib) 02/23/2016 (JAK) inhibitor Data as February 14, 2019 SS-U/JA-U Page 2 of 63 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. *Erelzi (etanercept-szzs) has been FDA-approved as a biosimilar to Enbrel (etanercept). Amjevita (adalimumab-atto), Cyltezo (adalimumab-adbm), and Hyrimoz (adalimumab-adaz) have been FDA-approved as biosimilars to and Humira (adalimumab). Truxima (rituximab-abbs) has been FDA-approved as a biosimilar to Rituxan (rituximab), but only carries an indication for the treatment of adult patients with NHL.The specific launch dates for these products are pending and may be delayed. Further information on Erelzi, Amjevita, Cyltezo, Hyrimoz, and Truxima will be included in this review after these products have launched. †Inflectra (infliximab-dyyb), Renflexis (infliximab-abda), and Ixifi (infliximab-qbtx) have been FDA-approved as biosimilar agents to Remicade (infliximab), however, they are not FDA-approved as interchangeable biologics. (Drugs@FDA, 2019; Prescribing information: Actemra, 2018; Cimzia, 2018; Cosentyx, 2018; Enbrel, 2018; Entyvio, 2018; Humira, 2019; Ilaris, 2016; Ilumya 2018; Inflectra, 2018; Kevzara, 2018; Kineret, 2018; Olumiant 2018; Orencia, 2017; Otezla, 2017; Remicade, 2018; Renflexis, 2017; Rituxan, 2019; Siliq, 2017; Simponi, 2018; Simponi Aria, 2018; Stelara, 2018; Taltz, 2019; Tremfya, 2019; Xeljanz/Xeljanz XR, 2018) Information on indications, mechanism of action, pharmacokinetics, dosing, and safety has been obtained from the prescribing information for the individual products, except where noted otherwise. Data as February 14, 2019 SS-U/JA-U Page 3 of 63 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. INDICATIONS Table 2. Food and Drug Administration Approved Indications (see footnotes for less common indications: CAPS, CRS, FMF, GCA, HIDS/MKD, and TRAPS) Systemic Polyarticular Plaque Rheumatoid Crohn’s Juvenile Juvenile Psoriatic Ankylosing Hidradenitis Psoriasis Ulcerative Uveitis Drug Arthritis Disease Idiopathic Idiopathic