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Immunotherapies in Late-Stage Development for Patients With Severe SLE and/or Lupus Nephritis
Systemic lupus erythematosus (SLE)—commonly known as lupus—is an inflammatory autoimmune disorder that occurs in women of childbearing age. It is more common among African-Americans and Asians than among whites.1 SLE is the predominant form of lupus; other types affect only the skin or are triggered by certain medications.2 Because SLE is relatively uncommon and not a reportable disease, recent estimates of prevalence and incidence in the United States are unavailable.3 A study published in 2008 estimated a U.S. prevalence of 161,000 people with definite SLE and 322,000 with definite or probable SLE.4
SLE is classified as either mild or severe. Mild disease is characterized by fever, arthritis, pleurisy, pericarditis, headache, and/or rash, whereas patients with severe disease may present with hemolytic anemia, thrombocytopenic purpura, pleural and pericardial involvement, renal damage, acute vasculitis of the extremities or gastrointestinal tract, and/or central nervous system involvement. Mild SLE is treated with nonsteroidal anti-inflammatory drugs and antimalarials. Severe disease is treated with corticosteroids (predominantly prednisone); the antimalarial drug hydroxychloroquine; and immunosuppressants.1,3
Lupus nephritis (LN)—one of the most challenging manifestations of severe SLE—occurs when SLE causes inflammation in the kidney’s nephrons (the structures that filter blood). Left untreated, LN can lead to scarring, permanent kidney damage, and possibly end-stage renal disease.5
Patients with SLE are usually treated by rheumatologists; however, manifestations of severe SLE involving the kidneys or the heart may be managed by specialists in those fields.2
Analysts have identified several unmet needs in the SLE marketplace, including:6
- Drugs with superior efficacy and safety profiles, particularly for LN
- Better drug formulations for improved compliance
- Reduction of SLE-associated morbidity and mortality.
With these needs in mind, pharmaceutical companies are working to develop novel immunomodulatory treatments for patients with SLE and/or LN (
Abatacept (Orencia, Bristol-Myers Squibb), a selective T-cell costimulation modulator, is currently approved for the treatment of patients with adult rheumatoid arthritis (RA) or juvenile idiopathic arthritis.7 It is also being evaluated as a potential treatment for patients with LN.6 The product is a soluble fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte– associated antigen 4 linked to the modified Fc portion of human immunoglobulin G1. Abatacept inhibits T-cell activation by binding to proteins CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T cells, which have been implicated in the pathogenesis of RA.7
Bristol-Myers Squibb initially investigated abatacept as a potential treatment for patients with SLE, but disappointing phase 2b data led the company to shift its attention to patients with LN.6,8 A subsequent phase 2 trial, however, found no difference in response rates between abatacept and placebo in patients with class III or class IV LN.9
Nevertheless, a phase 3 randomized, double-blind, placebo-controlled study is evaluating the efficacy and safety of abatacept versus placebo, both administered on a background of mycophenolate mofetil and prednisone, in patients with active class III or class IV LN. A total of 400 adults (18 years of age and older) are expected to participate in the study, which began in January 2013, with an estimated completion date of May 2021. The study’s primary endpoint is the proportion of patients achieving a complete response of renal disease—defined as a composite endpoint based on renal function, proteinuria, urine sediment, and corticosteroid dose—after 52 weeks of treatment.10 Top-line results from this study are expected in May 2019, potentially resulting in expanded labeling for abatacept the following year. The new label would include patients with class III or class IV LN in the nephrotic range.6
Anifrolumab (AstraZeneca/Med-Immune) is an antagonist human monoclonal antibody that targets interferon-alpha receptor 1 (IFNAR1). Anifrolumab inhibits the binding of IFN ligands to IFNAR1, thereby blocking the formation of the ternary IFN/IFNAR1/IFNAR2 signaling complex.11 It is believed that dysregulation of IFN activity and/or signaling is implicated in SLE.6
Anifrolumab is being evaluated as a potential SLE treatment in two phase 3 studies; both are expected to be completed in May 2018.12,13 In the first study, an estimated 360 adults (18 to 70 years of age) with moderately to severely active, autoantibody-positive SLE are being treated with anifrolumab or placebo every four weeks from week 0 to week 48 for a total of 13 doses. The primary outcome measure is the difference in the proportion of patients who achieve an SLE Responder Index score of 4 (SRI-4) or greater at week 52.12 The second study is following the same design in the same age group, but involves two unspecified doses of anifrolumab in an estimated 450 patients.13
A phase 2b trial (TULIP-LN1) is also evaluating anifrolumab as a potential treatment for patients with LN.14 Anifrolumab (two unspecified doses) or placebo is being administered every four weeks from week 0 to week 100 in addition to standard of care (mycophenolate mofetil and corticosteroids), which will continue until week 112. An estimated 150 adults (18 to 70 years of age) with active, proliferative LN are participating in the study. The expected completion date is September 2019.
Analysts had expected anifrolumab to be submitted to the FDA in 2019 and to be launched in 2021. If anifrolumab achieves a U.S. launch in SLE, it may have a hard time wresting market share from belimumab (Benlysta, GlaxoSmithKline) because of its unfavorable intravenous mode of administration. On the other hand, it would have a good chance of competing successfully against belimumab and abatacept in the LN market. If approved for SLE, anifrolumab is expected to have its label expanded to include LN in 2022 at the earliest.6
Blisibimod (Anthera/Amgen) is a selective peptibody antagonist of the B-cell activating factor (BAFF) cytokine, also known as B-lymphocyte stimulator. BAFF is a member of the tumor necrosis factor family and is critical to the development, maintenance, and survival of B cells and plasma cells. It interacts with three receptor subtypes expressed primarily on B cells and plasma cells: BAFF receptor, B-cell maturation antigen, and transmembrane activator and cyclophilin ligand interactor. Blisibimod was developed as an alternative to antibodies and is produced in Escherichia coli.15
The pivotal phase 3 CHABLIS-SC1 trial was designed to evaluate the efficacy and safety of subcutaneous (SC) blisibimod administered in addition to standard therapy in patients with active SLE despite ongoing stable corticosteroid therapy.16 In November 2016, Anthera Pharmaceuticals announced that the study had failed to meet its primary endpoint: the proportion of patients achieving an SRI-6 response at week 52. This endpoint was reached in 47% of patients in the blisibimod arm compared with 42% of patients in the placebo arm, but the difference was not statistically significant. An SRI-6 response requires a reduction of at least six points in Safety of Estrogens in Lupus Erythematosus National Assessment/Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) scores. The magnitude of blisibimod treatment effects for other SRI scores (SRI-4 and SRI-8) also did not reach statistical significance.17
Another pivotal phase 3 trial of SC blisibimod in patients with SLE (with or without LN) is currently under way. The primary objective of the CHABLIS 7.5 trial is to evaluate the clinical efficacy of blisibimod, as measured by the SRI, in a population of patients who, despite corticosteroid use, continue to have clinically active SLE. The primary endpoint is the SRI-6 response at week 52. The study began recruiting participants in June 2016, and its estimated completion date is December 2018.18,19 The U.S. patent for blisibimod is scheduled to expire in November 2023.6
If approved by the FDA, blisibimod is expected to be launched in 2020 as a third-line treatment for patients with SLE and/or in SLE patients who are refractory to standard-of-care therapy.6
Lupuzor (ImmuPharma)—also known as P140 peptide—is a 21-mer linear peptide (sequence 131–151) derived from the spliceosomal small nuclear ribonucleoprotein U1-70K, a major antibody target for lupus autoantibodies.20 In lupus-prone mice, Lupuzor was found to act as an immunomodulator and not as an immunosuppressant.21
Clinical efficacy data were provided by a phase 2b trial in which 49 intent-to-treat (ITT) patients with SLE were randomly assigned to receive Lupuzor (200 mcg SC) every four weeks (group 1; n = 49), Lupuzor every two weeks (group 2; n = 51), or placebo (n = 49) in addition to standard of care.22 In this population, 53% in group 1 (P = 0.048 versus placebo), 45% in group 2 (P = 0.18 versus placebo), and 36% in the placebo group achieved an SRI response at week 12. Slightly more impressive results were obtained from a target ITT group of 136 patients with clinical SLEDAI scores of 6 or greater at baseline. Among these patients, 62% in group 1 (P = 0.016), 48% in group 2 (P = 0.18), and 39% in the placebo group achieved an SRI response at week 12.
In 2013, the FDA granted ImmuPharma a special protocol assessment (SPA) for a planned phase 3 study of Lupuzor. Under the SPA, the study was allowed to include a smaller-than-usual patient population, which reduced the cost of conducting the trial, but it also meant that Lupuzor has to demonstrate a high degree of disease-modifying activity in order to reach statistical significance. The FDA also granted the study a fast-track designation.6
The 52-week, randomized, double-blind, parallel-group, placebo-controlled trial is evaluating a 200-mcg dose of Lupuzor plus standard of care in an estimated 200 patients with SLE. The primary outcome measure is an assessment of the SRI at week 52. The study began in March 2015 and is scheduled to conclude in March 2018.23
If Lupuzor is approved by the FDA, analysts expect it to be launched in 2019 as a third-line, add-on treatment for patients with moderate-to-severe SLE.6
Voclosporin (Orelvo, Aurinia Pharmaceuticals) is a calcineurin inhibitor and a structural analogue of cyclosporine A with immunosuppressive activity. It is being developed as a potential add-on treatment for patients with advanced LN (stages III–V).6,24
A phase 2b study compared the efficacy of two dosages of voclosporin (23.7 mg twice daily and 39.6 mg twice daily) added to current standard of care (mycophenolate mofetil) with that of placebo added to standard of care in achieving complete remission (CR) in 265 patients with active LN. Both treatment arms also received low doses of corticosteroids as background therapy.25,26
The difference in CR rates between lower-dose voclosporin (23.7 mg twice daily) and placebo barely reached statistical significance (32.6% versus 19.3%, respectively; P = 0.045). Higher-dose voclosporin (39.6 mg twice daily) and placebo were not significantly different.25 Both voclosporin dosages, however, were significantly superior to placebo on all secondary endpoints. For example, the time to CR was 19.7 weeks for the lower dose (P < 0.001) and 23.4 weeks for the higher dose (P = 0.001) compared with placebo (time to CR not achieved). Similarly, the rate of partial remission was 70% for lower-dose voclosporin (P = 0.007) and 66% for higher-dose voclosporin (P = 0.024) compared with 49% for placebo.26
In November 2016, Aurinia announced plans for a 52-week, phase 3, double-blind, placebo-controlled study of voclosporin (23.7 mg twice daily) plus mycophenolate mofetil versus placebo plus mycophenolate mofetil in approximately 320 patients with active LN. Both treatment arms will also receive low-dose corticosteroids. Again, the primary endpoint is CR, defined as the achievement of a renal response.27 The anticipated start date was April 2017, with a completion date of March 2020.28 If voclosporin wins FDA approval, analysts expect a 2021 launch.6
Immunotherapies in Late-Stage Development for SLE and/or Lupus Nephritis
||Mechanism of Action||Targeted Indication||Route of Administration||Expected Pricing Strategy||Estimated Average Cost per Year in U.S.||Anticipated U.S. Launch Date|
||Immunomodulator (T-cell costimulation modulator)||Adults with class III or IV LN in nephrotic range (third line)||IV||Likely to retain price as marketed for RA||$65,930||2020 (expanded label)|
||Immunomodulator (human mAb targeting IFNAR1)||Adults with SLE or moderate-to-severe LN (second line)||IV||Likely to be priced at 25% premium to belimumab (Benlysta, GlaxoSmithKline)||$54,390||2021 (SLE) 2022 (LN; expanded label)|
||Immunomodulator (peptibody antagonist of BAFF cytokine)||Adults with moderate-to-severe SLE and/or SLE patients refractory to SoC (third line)||SC||Likely to be priced at approximately 10% discount to belimumab||$36,860||2020|
||Immunomodulator (P140 peptide from nuclear ribonucleo-protein U1-70K)||Adults with moderate-to-severe SLE (third line)||SC||Likely to be priced at approximately 10% discount to belimumab||$36,860||2019|
||Immunosuppressive (calcineurin inhibitor)||Add-on to steroids and other immunosuppressive treatments in patients with advanced LN (class III–V)||Oral||Likely to be priced at 10% discount to belimumab||$50,000 to $100,000||2021|
BAFF = B-cell activating factor; IFNAR1 = interferon-alpha receptor 1; IV = intravenous; LN = lupus nephritis; mAb = monoclonal antibody; RA = rheumatoid arthritis; SC = subcutaneous; SLE = systemic lupus erythematosus; SoC = standard of care.
- Hajj-ali RA. Systemic lupus erythematosus (SLE) (disseminated lupus erythematosus). Merk Manual: Professional Version June 2013; Available at: www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/autoimmune-rheumatic-disorders/systemic-lupus-erythematosus-sle. Accessed February 15, 2017
- Lupus Research Alliance. Lupus fact sheet 2016; Available at: www.lupusresearchinstitute.org/lupus-facts/lupus-fact-sheet. Accessed February 15, 2017
- Centers for Disease Control and Prevention. Lupus detailed fact sheet January 30, 2017; Available at: www.cdc.gov/lupus/facts/detailed.html. Accessed February 15, 2017
- Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheum 2008;58:15–25.
- Lupus Foundation of America. Lupus nephritis July 12, 2013; Available at: www.lupus.org/answers/entry/lupus-and-kidneys. Accessed February 21, 2017
- Gehrke SS. PharmaPoint: Systemic Lupus Erythematosus and Lupus Nephritis—Global Drug Forecast and Market Analysis to 2025 New York, New York: GlobalData. December 2016;
- Orencia (abatacept) prescribing information Princeton, New Jersey: Bristol-Myers Squibb Company. June 2016; Available at: https://packageinserts.bms.com/pi/pi_orencia.pdf. Accessed February 21, 2017
- Borba HH, Funka A, Wiens A, et al. Update on biologic therapies for systemic lupus erythematosus. Curr Rheumatol Rep 2016;18:44
- ACCESS Trial Group. Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study. Arthritis Rheumatol 2014;66:3096–3104.
- ClinicalTrials.gov. Efficacy and safety study of abatacept to treat lupus nephritis. NCT01714817 February 16, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT01714817. Accessed February 21, 2017
- Peng L, Oganesyan V, Wu H, et al. Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-α receptor 1 antibody. MAbs 2015;7:428–439.
- ClinicalTrials.gov. Efficacy and safety study of anifrolumab compared to placebo in adult subjects with active systemic lupus erythematosus. NCT02446899 November 22, 2016; Available at: https://clinicaltrials.gov/ct2/show/NCT02446899. Accessed February 22, 2017
- ClinicalTrials.gov. Efficacy and safety of two doses of anifrolumab compared to placebo in adult subjects with active systemic lupus erythematosus. NCT02446912 November 22, 2016; Available at: https://clinicaltrials.gov/ct2/show/NCT02446912. Accessed February 22, 2017
- ClinicalTrials.gov. Safety and efficacy of two doses of anifrolumab compared to placebo in adult subjects with active proliferative lupus nephritis (TULIP-LN1). NCT02547922 February 7, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02547922. Accessed February 22, 2017
- Anthera Pharmaceuticals. Blisibimod 2016; Available at: www.anthera.com/product-pipeline/blisibimod. Accessed February 23, 2017
- ClinicalTrials.gov. CHABLIS-SC1: a study of the efficacy and safety of subcutaneous blisibimod in subjects with systemic lupus erythematosus. NCT01395745 February 2, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT01395745. Accessed February 24, 2017
- Anthera Pharmaceuticals. Anthera announces that the blisibimod CHABLIS-SC1 phase 3 study did not achieve the primary end point in patients with active systemic lupus erythematosus November 10, 2016; Available at: http://investor.anthera.com/releasedetail.cfm?releaseid=998740. Accessed February 24, 2017
- ClinicalTrials.gov. CHABLIS 7.5: a study of the efficacy and safety of subcutaneous blisibimod in subjects with systemic lupus erythematosus with or without nephritis. NCT02514967 February 2, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02514967. Accessed February 24, 2017
- Anthera Pharmaceuticals. Anthera provides clinical program updates for blisibimod and Sollpura June 28, 2016; Available at: http://investor.anthera.com/releasedetail.cfm?releaseid=977464. Accessed March 3, 2017
- ImmuPharma. The development of Lupuzor 2015; Available at: www.lupuzor.com/Lupuzor_Research_and_Development.html. Accessed March 15, 2017
- Schall N, Page N, Macri C, et al. Peptide-based approaches to treat lupus and other autoimmune diseases. J Autoimmun 2012;39:143–153.
- Zimmer R, Scherbarth HR, Rillo RL, et al. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann Rheum Dis 2013;72;(11):1830–1835.
- ClinicalTrials.gov. A 52-week, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of a 200-mcg dose of IPP-201101 plus standard of care in patients with systemic lupus erythematosus (Lupuzor). NCT02504645 January 24, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02504645. Accessed March 15, 2017
- Aurinia Pharmaceuticals. Voclosporin: mechanism of action 2017; Available at: www.auriniapharma.com/for-patients-physicians/clinical-trials#aurion. Accessed March 16, 2017
- Aurinia Pharmaceuticals. Aurinia Pharmaceuticals announces voclosporin meets primary endpoint in phase IIb AURORA-LV study in lupus nephritis August 15, 2016; Available at: http://ir.auriniapharma.com/press-releases/detail/49/aurinia-pharmaceuticals-announces-voclosporin-meets-primary. Accessed March 16, 2017
- Aurinia Pharmaceuticals. Aurinia announces that voclosporin achieves primary and all pre-specified secondary endpoints in its phase 2b AURA-LV study for lupus nephritis (LN) September 29, 2016; Available at: http://ir.auriniapharma.com/press-releases/detail/53/aurinia-announces-that-voclosporin-achieves-primary-and-all. Accessed March 16, 2017
- Aurinia Pharmaceuticals. Aurinia announces plans for single phase III clinical trial for voclosporin in the treatment of lupus nephritis following successful completion of end of phase II meeting with FDA November 2, 2016; Available at: http://ir.auriniapharma.com/press-releases/detail/57/aurinia-announces-plans-for-single-phase-iii-clinical-trial. Accessed March 16, 2017
- ClinicalTrials.gov. A randomized controlled double-blind study comparing the efficacy and safety of Orelvo (voclosporin) (23.7 mg twice daily) with placebo in achieving renal response in subjects with active lupus nephritis. NCT03021499 January 23, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT03021499. Accessed March 16, 2017