PIPELINE PLUS
Biologics Will Pump Up the Vasculitis Market Chris Fellner
V
asculitis (also known as angiitis and arteritis) is a group of heterogeneous disorders characterized by inflammation and necrosis of the blood vessels, including the veins, arteries, and capillaries. Several forms of vasculitis exist, and their clinical characteristics can differ substantially in terms of symptoms, severity, and duration of disease, depending on the organs and the types of blood vessels that are involved.1–3 The exact cause of vasculitis remains unknown, but factors that appear to trigger the disease include an individual’s genetic makeup, infections (such as hepatitis B and C), blood cancers, immune system diseases (such as rheumatoid arthritis and scleroderma), and reactions to certain drugs.2 The various types of vasculitis are grouped according to the size of the blood vessels they affect. Large-vessel vasculitis includes Behçet’s disease, Takayasu’s arteritis, giant cell arteritis (also known as temporal arteritis), and polymyalgia rheumatica; vasculitis affecting medium-size vessels includes Kawasaki’s disease, polyarteritis nodosa, and Buerger’s disease (thromboangiitis obliterans); and small-vessel vasculitis includes immunoglobulin A vasculitis, cryoglobulinemia vasculitis, and hypersensitivity vasculitis. The various types of vasculitic disease are listed in Table 1.1 The main goal of treating vasculitis is to reduce inflammation in the affected blood vessels. The prescription medications most commonly used to treat vasculitis include corticosteroids (such Chris Fellner is a medical writer and the Editor of PTCommunity.com.
as prednisone, prednisolone, and methylprednisolone) and cytotoxic drugs (such as azathioprine, methotrexate, and cyclophosphamide). Corticosteroids help to reduce inflammation in blood vessels, and cytotoxic medications kill the immunesystem cells that cause inflammation.1,5 All of these drugs, however, are used off-label in patients with vasculitis.4 In April 2011, the biologic therapy rituximab (Rituxan, Biogen Idec/Genentech) became the first and only FDA-approved treatment for vasculitis. Specifically, rituximab is indicated in combination with glucocorticoids for patients with Wegener’s granulomatosis (a rare disorder that causes vasculitis) or microscopic polyangiitis (a type of vasculitis affecting the small blood vessels).6 Rituximab is a genetically engineered chimeric murine/ human monoclonal immunoglobulin G1 (IgG1) kappa antibody directed against CD20 antigens expressed on the surface of pre-B and mature B lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis.7 Table 2 lists the leading vasculitis treatments in use in the United States.4 On the horizon, six biologics are in latestage development as potential vasculitis therapies (Table 3). All offer novel mechanisms of action.4 Abatacept (Orencia, Bristol-Myers Squibb/Ono Pharmaceuticals) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) linked to the modified Fc portion of human IgG1. It is approved in the U.S. for the treatment of adult rheumatoid arthritis and juvenile idiopathic
arthritis.8,9 In addition, the drug is in phase 3 development globally for granulomatosis with polyangiitis (GPA) and in phase 2 development for large-vessel vasculitis and Behçet’s disease.4 Apremilast (Otezla, Celgene) is an oral, small-molecule phosphodiesterase 4 (PDE4) inhibitor indicated for the treatment of psoriatic arthritis and psoriasis.10 By inhibiting PDE4, apremilast increases intracellular levels of cyclic adenosine monophosphate, which in turn modulates the expression of inflammatory cytokines.10,11 It is the only drug in late-stage development for the treatment of Behçet’s disease and the only oral formulation under development in the vasculitis pipeline.4 Belimumab (Benlysta, GlaxoSmithKline) is a human IgG1 gamma monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as B-cell activating factor). By binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. It is indicated for use in adults with active, autoantibody-positive, systemic lupus erythematosus.12 Belimumab is the only drug in late-stage development for microscopic polyangiitis. It is also under development for GPA.4 Infliximab (Remicade, Janssen Biotech) is a chimeric IgG1 kappa monoclonal antibody specific for human tumor necrosis factor (TNF)-alpha. It neutralizes the biologic activity of TNFalpha by binding with high affinity to the soluble and transmembrane forms of TNF-alpha and inhibits binding of
Table 1 Types of Vasculitis 1 Primary Blood Vessel Involvement Large Vessels • • • • •
Behçet’s disease Cogan’s syndrome Giant cell arteritis (temporal arteritis) Polymyalgia rheumatica Takayasu’s arteritis (aortic arch syndrome)
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Medium Vessels • Buerger’s disease (thromboangiitis) • Central nervous system vasculitis • Kawasaki’s disease (mucocutaneous lymph node disease) • Polyarteritis nodosa
Small Vessels • ChurgStrauss syndrome (eosinophilic granulo matosis with polyangiitis) • Cryoglobulinemia vasculitis • Immunoglobulin A vasculitis • Hypersensitivity vasculitis (allergic vasculitis, cutaneous vasculitis, leukocytoclastic vasculitis) • Microscopic polyangiitis
PIPELINE PLUS TNF-alpha with its receptors. TNF-alpha induces proinflammatory cytokines, such as interleukin (IL)-1 and IL-6; enhances leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes; activates neutrophil and eosinophil functional activity; and induces acute-phase reactants and other liver proteins, as well as tissue-degrading enzymes produced by synoviocytes and/ or chondrocytes. Infliximab is in phase 3 clinical development for the treatment of Kawasaki’s disease in the U.S.4 Mepolizumab (Nucala, GlaxoSmithKline) is a humanized IL-5 antagonist monoclonal antibody produced by recombinant DNA technology. IL-5 is the major cytokine responsible for the growth, differentiation, recruitment, activation, and survival of eosinophils in inflammation. Mepolizumab is being developed as a treatment for eosinophilic GPA (eGPA, also known as Churg-Strauss syndrome) and, if approved, would be the only drug with that indication in the vasculitis arena. It is the most expensive pipeline biologic, with an expected treatment cost of approximately $71,600 in the U.S. (see Table 3).4 Tocilizumab (Actemra, Genentech/ Roche) is a recombinant humanized antihuman IL-6 receptor monoclonal antibody of the IgG1 kappa subclass. IL-6 is a proinflammatory cytokine produced by a variety of cell types, including T and
Table 2 Leading Treatments for Vasculitis in the U.S. (2015) 4 Drug Name Brands
Therapeutic Class
Indication(s)
Immunosuppressive antimetabolite
Vasculitis
Alkylating agent
Vasculitis
IgG human antibody
KD, LVV
Folic acid analog; anti neoplastic/antimetabolite
Vasculitis
Mycophenolate mofetil CellCept, Myfortic, generics
IMPDH inhibitor
Vasculitis
Prednisone, prednisolone, methylprednisolone Numerous generics
Glucocorticoids
Vasculitis
CD-20 protein inhibitor
MPA, WG
Azathioprine Imuran, Imurel, generics Cyclophosphamide Endoxan, Cytoxan, generics Immunoglobulin (IV) Numerous brands, including Privigen, Kiovig, Gammagard Methotrexate Numerous generics
Rituximab* Rituxan (Biogen Idec/Genentech)
*Only rituximab is approved by the Food and Drug Administration for the treatment of patients with vasculitis. IgG = immunoglobulin G; IMPDH = inosine monophosphate dehydrogenase; IV = intravenous; KD = Kawasaki’s disease; LVV = large-vessel vasculitis; MPA = microscopic polyangiitis; WG = Wegener’s granulomatosis.
B cells, lymphocytes, monocytes, and fibroblasts. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors and has been shown to inhibit IL-6–mediated signaling through those receptors. Tocilizumab is the only drug in late-stage development for largevessel vasculitis (i.e., giant cell arteritis and Takayasu’s arteritis).4
The vasculitis market in the U.S. is expected to grow at an annual rate of 3.8% during the decade between 2014 and 2024, reaching sales of $316 million. Key drivers of market growth will include the launch of mepolizumab for eGPA in 2018; the launch of tocilizumab for large-vessel vasculitis in 2019; and the launch of abatacept for microscopic polyangiitis and GPA in 2020 (see
Table 3 Late-Stage Vasculitis Pipeline as of December 2015 4 Product Name Company
Therapeutic Class
Targeted Indication(s)
Developmental Stage(s)
Selective co-stimulating modulator (inhibits T cell activation)
BD, GPA, MPA†
Phase 2 (BD) Phase 3 (GPA)
$41,642
2020 (GPA)
PDE4 inhibitor
BD
Phase 3
$6,220
2018
Belimumab (Benlysta) GlaxoSmithKline
BLyS-specific inhibitor
GPA, MPA
Phase 3
$50,190
2018 (GPA, MPA)
Infliximab (Remicade) Janssen Biotech
TNF inhibitor
KD
Phase 3
$17,180
2016
Mepolizumab (Nucala) GlaxoSmithKline
IL-5 antagonist
eGPA
Phase 3
$71,617
2018
Tocilizumab (Actemra) Genentech/Roche
Anti–IL-6 monoclonal antibody
GCA, TA
Phase 3
$19,728
2019 (LVV)
Abatacept (Orencia) Bristol-Myers Squibb/Ono Pharmaceuticals Apremilast (Otezla) Celgene
Expected U.S. Expected U.S. Treatment Cost Launch Date
†Abatacept is expected to be used off-label for MPA. BD = Behçet’s disease; BLyS = B lymphocyte stimulator; eGPA = eosinophilic granulomatosis with polyangiitis; GCA = giant cell arteritis; GPA = granulomatosis with polyangiitis; IL-1 = interleukin 1 family; IL-5 = interleukin 5 family; IL-6 = interleukin 6 family; IL-6R = interleukin 6 receptor; KD = Kawasaki’s disease; LVV = largevessel vasculitis; MPA = microscopic polyangiitis; PDE4 = phosphodiesterase 4; TA = Takayasu’s arteritis; TNF = tumor necrosis factor.
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PIPELINE PLUS Table 3). At the same time, the launch of biosimilars (adalimumab in 2016, rituximab and infliximab in 2018, abatacept and tocilizumab in 2019, and belimumab in 2023) will cut into the sales of major brands.4
REFERENCES 1.
National Heart, Lung, and Blood Institute. Types of vasculitis. September 23, 2014. Available at: www.nhlbi.nih.gov/health/ health-topics/topics/vas/types. Accessed February 8, 2016. 2. Mayo Clinic. Vasculitis: definition. October 8, 2014. Available at: www.mayoclinic.org/diseases-conditions/vasculitis/basics/definition/con-20026049. Accessed February 8, 2016. 3. Gross WL, Trabandt A. Vasculitis: aims of therapy diagnosis and evaluation of vasculitis. Rheumatology 2000;39:245–252. 4. Annis A. OpportunityAnalyzer: Vasculitis––Opportunity Analysis and Forecast to 2024. New York, New York: GlobalData; January 2016. 5. Mayo Clinic. Vasculitis: treatment and drugs. October 8, 2014. Available at: www. mayoclinic.org/diseases-conditions/vasculitis/basics/treatment/con-20026049. Accessed February 9, 2016. 6. Food and Drug Administration. FDA approves Rituxan to treat two rare disorders. April 19, 2011. Available at: www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm251946.htm. Accessed February 10, 2016. 7. Rituxan (rituximab for injection) prescribing information. South San Francisco, California: Genentech, Inc.; August 2014. Available at: www.gene.com/download/pdf/rituxan_prescribing.pdf. Accessed February 10, 2016. 8. McCoy KD, Le Gros G. The role of CTLA-4 in the regulation of T cell immune re sponses. Immunol Cell Biol 1999;77:1–10. 9. Orencia (abatacept for injection) prescribing information. Princeton, New Jersey: Bristol-Myers Squibb Company; June 2015. Available at: http://packageinserts. bms.com/pi/pi_orencia.pdf. Accessed February 10, 2016. 10. Otezla (apremilast tablets) prescribing information. Summit, New Jersey: Celgene Corporation; December 2015. Available at: www.otezla.com/otezla-prescribing-information.pdf. Accessed February 10, 2016. 11. Celgene Corporation. Apremilast Palace program demonstrates robust and consistent statistically significant clinical benefit across three pivotal phase III studies (PALACE-1, 2 & 3) in psoriatic arthritis. September 6, 2012. Available at: http://ir.celgene. com/releasedetail.cfm?ReleaseID=795548. Accessed February 10, 2016. 12. Benlysta (belimumab for injection) prescribing information. Research Triangle Park, North Carolina: GlaxoSmithKline; November 2015. Available at: www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENLYSTA-PIMG.PDF. Accessed February 10, 2016. n
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Biologics Will Pump Up the Vasculitis Market Chris Fellner
V
asculitis (also known as angiitis and arteritis) is a group of heterogeneous disorders characterized by inflammation and necrosis of the blood vessels, including the veins, arteries, and capillaries. Several forms of vasculitis exist, and their clinical characteristics can differ substantially in terms of symptoms, severity, and duration of disease, depending on the organs and the types of blood vessels that are involved.1–3 The exact cause of vasculitis remains unknown, but factors that appear to trigger the disease include an individual’s genetic makeup, infections (such as hepatitis B and C), blood cancers, immune system diseases (such as rheumatoid arthritis and scleroderma), and reactions to certain drugs.2 The various types of vasculitis are grouped according to the size of the blood vessels they affect. Large-vessel vasculitis includes Behçet’s disease, Takayasu’s arteritis, giant cell arteritis (also known as temporal arteritis), and polymyalgia rheumatica; vasculitis affecting medium-size vessels includes Kawasaki’s disease, polyarteritis nodosa, and Buerger’s disease (thromboangiitis obliterans); and small-vessel vasculitis includes immunoglobulin A vasculitis, cryoglobulinemia vasculitis, and hypersensitivity vasculitis. The various types of vasculitic disease are listed in Table 1.1 The main goal of treating vasculitis is to reduce inflammation in the affected blood vessels. The prescription medications most commonly used to treat vasculitis include corticosteroids (such Chris Fellner is a medical writer and the Editor of PTCommunity.com.
as prednisone, prednisolone, and methylprednisolone) and cytotoxic drugs (such as azathioprine, methotrexate, and cyclophosphamide). Corticosteroids help to reduce inflammation in blood vessels, and cytotoxic medications kill the immunesystem cells that cause inflammation.1,5 All of these drugs, however, are used off-label in patients with vasculitis.4 In April 2011, the biologic therapy rituximab (Rituxan, Biogen Idec/Genentech) became the first and only FDA-approved treatment for vasculitis. Specifically, rituximab is indicated in combination with glucocorticoids for patients with Wegener’s granulomatosis (a rare disorder that causes vasculitis) or microscopic polyangiitis (a type of vasculitis affecting the small blood vessels).6 Rituximab is a genetically engineered chimeric murine/ human monoclonal immunoglobulin G1 (IgG1) kappa antibody directed against CD20 antigens expressed on the surface of pre-B and mature B lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis.7 Table 2 lists the leading vasculitis treatments in use in the United States.4 On the horizon, six biologics are in latestage development as potential vasculitis therapies (Table 3). All offer novel mechanisms of action.4 Abatacept (Orencia, Bristol-Myers Squibb/Ono Pharmaceuticals) is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) linked to the modified Fc portion of human IgG1. It is approved in the U.S. for the treatment of adult rheumatoid arthritis and juvenile idiopathic
arthritis.8,9 In addition, the drug is in phase 3 development globally for granulomatosis with polyangiitis (GPA) and in phase 2 development for large-vessel vasculitis and Behçet’s disease.4 Apremilast (Otezla, Celgene) is an oral, small-molecule phosphodiesterase 4 (PDE4) inhibitor indicated for the treatment of psoriatic arthritis and psoriasis.10 By inhibiting PDE4, apremilast increases intracellular levels of cyclic adenosine monophosphate, which in turn modulates the expression of inflammatory cytokines.10,11 It is the only drug in late-stage development for the treatment of Behçet’s disease and the only oral formulation under development in the vasculitis pipeline.4 Belimumab (Benlysta, GlaxoSmithKline) is a human IgG1 gamma monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as B-cell activating factor). By binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. It is indicated for use in adults with active, autoantibody-positive, systemic lupus erythematosus.12 Belimumab is the only drug in late-stage development for microscopic polyangiitis. It is also under development for GPA.4 Infliximab (Remicade, Janssen Biotech) is a chimeric IgG1 kappa monoclonal antibody specific for human tumor necrosis factor (TNF)-alpha. It neutralizes the biologic activity of TNFalpha by binding with high affinity to the soluble and transmembrane forms of TNF-alpha and inhibits binding of
Table 1 Types of Vasculitis 1 Primary Blood Vessel Involvement Large Vessels • • • • •
Behçet’s disease Cogan’s syndrome Giant cell arteritis (temporal arteritis) Polymyalgia rheumatica Takayasu’s arteritis (aortic arch syndrome)
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Medium Vessels • Buerger’s disease (thromboangiitis) • Central nervous system vasculitis • Kawasaki’s disease (mucocutaneous lymph node disease) • Polyarteritis nodosa
Small Vessels • ChurgStrauss syndrome (eosinophilic granulo matosis with polyangiitis) • Cryoglobulinemia vasculitis • Immunoglobulin A vasculitis • Hypersensitivity vasculitis (allergic vasculitis, cutaneous vasculitis, leukocytoclastic vasculitis) • Microscopic polyangiitis
PIPELINE PLUS TNF-alpha with its receptors. TNF-alpha induces proinflammatory cytokines, such as interleukin (IL)-1 and IL-6; enhances leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes; activates neutrophil and eosinophil functional activity; and induces acute-phase reactants and other liver proteins, as well as tissue-degrading enzymes produced by synoviocytes and/ or chondrocytes. Infliximab is in phase 3 clinical development for the treatment of Kawasaki’s disease in the U.S.4 Mepolizumab (Nucala, GlaxoSmithKline) is a humanized IL-5 antagonist monoclonal antibody produced by recombinant DNA technology. IL-5 is the major cytokine responsible for the growth, differentiation, recruitment, activation, and survival of eosinophils in inflammation. Mepolizumab is being developed as a treatment for eosinophilic GPA (eGPA, also known as Churg-Strauss syndrome) and, if approved, would be the only drug with that indication in the vasculitis arena. It is the most expensive pipeline biologic, with an expected treatment cost of approximately $71,600 in the U.S. (see Table 3).4 Tocilizumab (Actemra, Genentech/ Roche) is a recombinant humanized antihuman IL-6 receptor monoclonal antibody of the IgG1 kappa subclass. IL-6 is a proinflammatory cytokine produced by a variety of cell types, including T and
Table 2 Leading Treatments for Vasculitis in the U.S. (2015) 4 Drug Name Brands
Therapeutic Class
Indication(s)
Immunosuppressive antimetabolite
Vasculitis
Alkylating agent
Vasculitis
IgG human antibody
KD, LVV
Folic acid analog; anti neoplastic/antimetabolite
Vasculitis
Mycophenolate mofetil CellCept, Myfortic, generics
IMPDH inhibitor
Vasculitis
Prednisone, prednisolone, methylprednisolone Numerous generics
Glucocorticoids
Vasculitis
CD-20 protein inhibitor
MPA, WG
Azathioprine Imuran, Imurel, generics Cyclophosphamide Endoxan, Cytoxan, generics Immunoglobulin (IV) Numerous brands, including Privigen, Kiovig, Gammagard Methotrexate Numerous generics
Rituximab* Rituxan (Biogen Idec/Genentech)
*Only rituximab is approved by the Food and Drug Administration for the treatment of patients with vasculitis. IgG = immunoglobulin G; IMPDH = inosine monophosphate dehydrogenase; IV = intravenous; KD = Kawasaki’s disease; LVV = large-vessel vasculitis; MPA = microscopic polyangiitis; WG = Wegener’s granulomatosis.
B cells, lymphocytes, monocytes, and fibroblasts. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors and has been shown to inhibit IL-6–mediated signaling through those receptors. Tocilizumab is the only drug in late-stage development for largevessel vasculitis (i.e., giant cell arteritis and Takayasu’s arteritis).4
The vasculitis market in the U.S. is expected to grow at an annual rate of 3.8% during the decade between 2014 and 2024, reaching sales of $316 million. Key drivers of market growth will include the launch of mepolizumab for eGPA in 2018; the launch of tocilizumab for large-vessel vasculitis in 2019; and the launch of abatacept for microscopic polyangiitis and GPA in 2020 (see
Table 3 Late-Stage Vasculitis Pipeline as of December 2015 4 Product Name Company
Therapeutic Class
Targeted Indication(s)
Developmental Stage(s)
Selective co-stimulating modulator (inhibits T cell activation)
BD, GPA, MPA†
Phase 2 (BD) Phase 3 (GPA)
$41,642
2020 (GPA)
PDE4 inhibitor
BD
Phase 3
$6,220
2018
Belimumab (Benlysta) GlaxoSmithKline
BLyS-specific inhibitor
GPA, MPA
Phase 3
$50,190
2018 (GPA, MPA)
Infliximab (Remicade) Janssen Biotech
TNF inhibitor
KD
Phase 3
$17,180
2016
Mepolizumab (Nucala) GlaxoSmithKline
IL-5 antagonist
eGPA
Phase 3
$71,617
2018
Tocilizumab (Actemra) Genentech/Roche
Anti–IL-6 monoclonal antibody
GCA, TA
Phase 3
$19,728
2019 (LVV)
Abatacept (Orencia) Bristol-Myers Squibb/Ono Pharmaceuticals Apremilast (Otezla) Celgene
Expected U.S. Expected U.S. Treatment Cost Launch Date
†Abatacept is expected to be used off-label for MPA. BD = Behçet’s disease; BLyS = B lymphocyte stimulator; eGPA = eosinophilic granulomatosis with polyangiitis; GCA = giant cell arteritis; GPA = granulomatosis with polyangiitis; IL-1 = interleukin 1 family; IL-5 = interleukin 5 family; IL-6 = interleukin 6 family; IL-6R = interleukin 6 receptor; KD = Kawasaki’s disease; LVV = largevessel vasculitis; MPA = microscopic polyangiitis; PDE4 = phosphodiesterase 4; TA = Takayasu’s arteritis; TNF = tumor necrosis factor.
Vol. 41 No. 4 • April 2016 • P&T 259 ®
PIPELINE PLUS Table 3). At the same time, the launch of biosimilars (adalimumab in 2016, rituximab and infliximab in 2018, abatacept and tocilizumab in 2019, and belimumab in 2023) will cut into the sales of major brands.4
REFERENCES 1.
National Heart, Lung, and Blood Institute. Types of vasculitis. September 23, 2014. Available at: www.nhlbi.nih.gov/health/ health-topics/topics/vas/types. Accessed February 8, 2016. 2. Mayo Clinic. Vasculitis: definition. October 8, 2014. Available at: www.mayoclinic.org/diseases-conditions/vasculitis/basics/definition/con-20026049. Accessed February 8, 2016. 3. Gross WL, Trabandt A. Vasculitis: aims of therapy diagnosis and evaluation of vasculitis. Rheumatology 2000;39:245–252. 4. Annis A. OpportunityAnalyzer: Vasculitis––Opportunity Analysis and Forecast to 2024. New York, New York: GlobalData; January 2016. 5. Mayo Clinic. Vasculitis: treatment and drugs. October 8, 2014. Available at: www. mayoclinic.org/diseases-conditions/vasculitis/basics/treatment/con-20026049. Accessed February 9, 2016. 6. Food and Drug Administration. FDA approves Rituxan to treat two rare disorders. April 19, 2011. Available at: www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm251946.htm. Accessed February 10, 2016. 7. Rituxan (rituximab for injection) prescribing information. South San Francisco, California: Genentech, Inc.; August 2014. Available at: www.gene.com/download/pdf/rituxan_prescribing.pdf. Accessed February 10, 2016. 8. McCoy KD, Le Gros G. The role of CTLA-4 in the regulation of T cell immune re sponses. Immunol Cell Biol 1999;77:1–10. 9. Orencia (abatacept for injection) prescribing information. Princeton, New Jersey: Bristol-Myers Squibb Company; June 2015. Available at: http://packageinserts. bms.com/pi/pi_orencia.pdf. Accessed February 10, 2016. 10. Otezla (apremilast tablets) prescribing information. Summit, New Jersey: Celgene Corporation; December 2015. Available at: www.otezla.com/otezla-prescribing-information.pdf. Accessed February 10, 2016. 11. Celgene Corporation. Apremilast Palace program demonstrates robust and consistent statistically significant clinical benefit across three pivotal phase III studies (PALACE-1, 2 & 3) in psoriatic arthritis. September 6, 2012. Available at: http://ir.celgene. com/releasedetail.cfm?ReleaseID=795548. Accessed February 10, 2016. 12. Benlysta (belimumab for injection) prescribing information. Research Triangle Park, North Carolina: GlaxoSmithKline; November 2015. Available at: www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENLYSTA-PIMG.PDF. Accessed February 10, 2016. n
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