Treatment methods for lupus nephritis with voclosporin

Abstract

This specification provides a method for treating lupus nephritis (LN) and its use involving the administration of voclosporine to subjects classified as having a specific biopsy class of LN. In some embodiments, this method and use relate to selecting subjects classified as having a specific biopsy class of LN for the administration of voclosporine. In some embodiments, this method and use relate to evaluating the responsiveness to voclosporine treatment and selecting subjects with a high responsiveness to voclosporine treatment. In some embodiments, this method and use include administering a therapeutically safe and effective amount of voclosporine to the selected subjects.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 505,394, filed on 31 May 2023, and U.S. Provisional Application No. 63 / 513,690, filed on 14 July 2023, the contents of which are incorporated herein by reference.

[0002] This disclosure relates to a method for treating lupus nephritis (LN) and its use involving the administration of voclosporine to subjects classified as having a specific biopsy class of LN. In some embodiments, the method and use relate to selecting subjects classified as having a specific biopsy class of LN for the administration of voclosporine. In some embodiments, the method and use relate to evaluating the responsiveness to voclosporine treatment and selecting subjects with a high responsiveness to voclosporine treatment. In some embodiments, the method and use include administering a therapeutically safe and effective amount of voclosporine to the selected subjects. [Background technology]

[0003] Lupus nephritis (LN) is a proteinuric kidney disease characterized by inflammation of the kidneys and can occur in up to 60% of patients with systemic lupus erythematosus (SLE). LN is a debilitating and costly disease, often leading to renal failure requiring dialysis or kidney transplantation, and can be fatal. Treatment is often difficult, and there is a need for improved treatment methods for LN. This specification provides methods and uses to meet such needs. [Overview of the project]

[0004] This specification provides methods and uses related to treatment using tacrolimus. In some of any of the provided embodiments, these methods and uses relate to the selection of a subject for treatment, including the treatment of lupus nephritis (LN) and the selection of a subject having a particular class or type of LN, for example, a particular biopsy class of LN. These methods and uses also include administering tacrolimus to the selected or identified subject.

[0005] This specification provides a method that includes (a) selecting a subject classified as having class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) LN based on renal biopsy classification, and (b) administering tacrolimus to the selected subject.

[0006] This specification also provides a method for lupus nephritis (LN) that includes administering tacrolimus to a subject previously classified as having class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) lupus nephritis (LN) based on renal biopsy classification.

[0007] This specification also provides a method for selecting a subject for treatment with tacrolimus that includes selecting a subject classified as having class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) lupus nephritis (LN) based on renal biopsy classification.

[0008] This specification also provides a method for assessing the likelihood of response to tacrolimus treatment that includes identifying a subject classified as having class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) lupus nephritis (LN) based on renal biopsy classification as having a high likelihood of response to tacrolimus treatment.

[0009] In some of any of the provided embodiments, this method also includes administering tacrolimus to the selected or identified subject.

[0010] In some of the embodiments provided, the renal biopsy classification includes the International Society of Nephrology / Renal Pathology Society (ISN / RPS) classification. In some of the embodiments provided, the renal biopsy classification includes the ISN / RPS 2003 classification. In some of the embodiments provided, the renal biopsy classification includes the ISN / RPS 2018 classification.

[0011] In some of the provided embodiments, a subject is selected for voclosporine administration if the subject is classified as having class III LN based on renal biopsy classification. In some of the provided embodiments, a subject is identified as having high responsiveness if the subject is classified as having class III LN based on renal biopsy classification.

[0012] In some of the provided embodiments, a subject is classified as having Class III LN if a renal biopsy from the subject shows focal proliferative glomerulonephritis. In some of the provided embodiments, a subject is classified as having Class III LN if a renal biopsy from the subject shows proliferative glomerulonephritis affecting less than approximately 50% of the glomeruli. In some of the provided embodiments, a subject is classified as having Class III LN if a renal biopsy from the subject shows active or inactive focal, segmental or whole-segmental intracapillary or extracapillary glomerulonephritis affecting less than approximately 50% of the total glomeruli, optionally with or without focal subendothelial immunodeposits and mesangial changes.

[0013] In some of the provided embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows endocapillary pleocytosis. In some of the provided embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows focal endocapillary pleocytosis. In some of the provided embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows endocapillary pleocytosis affecting less than approximately 50% of the glomeruli.

[0014] In any of the provided embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows segmental endovascular pleocytosis with substantial lumen reduction, endovascular pleocytosis with fibrinoid necrosis and cellular crescent formation, nuclear disintegration in glomerular segments, segmental sclerosis of the glomeruli, segmental subendothelial deposits as fuchsinophilic deposits on light microscopy, and / or segmental distribution of IgG immunodeposits and mesangial deposits in the glomerular capillary walls.

[0015] In any of the provided embodiments, a subject is classified as having a Class III LN if a renal biopsy from the subject shows lesions including extracapillary cell proliferation, crescents, the presence of fibrin and fibrous matrix, and / or more than 10% around Bowman's capsule showing extracapillary cell proliferation.

[0016] In some of the provided embodiments, if a subject is classified as having class IV LN based on renal biopsy classification, the subject is selected for voclosporine administration. In some of the provided embodiments, if a subject is classified as having class IV LN based on renal biopsy classification, the subject is identified as having high responsiveness.

[0017] In some of the provided embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows diffuse proliferative glomerulonephritis. In some of the provided embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows proliferative glomerulonephritis affecting more than approximately 50% of the glomeruli. In some of the provided embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows active or inactive diffuse, segmental or whole-segmental intracapillary or extracapillary glomerulonephritis affecting more than 50% of the total glomeruli, optionally with or without diffuse subendothelial immunodeposits and mesangial changes.

[0018] In some of the provided embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows endocapillary pleocytosis. In some of the provided embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows diffuse endocapillary pleocytosis. In some of the provided embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows endocapillary pleocytosis affecting more than approximately 50% of the glomeruli.

[0019] In any of the provided embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows diffuse segmental endocapillary proliferation, pansegmental endocapillary proliferation with leukocyte infiltration, endocapillary proliferation with extensive wire-loop appearance in the glomerular capillary wall showing subendothelial immunodeposits, subendothelial deposits as fuchsinophilic deposits, diffuse pansegmental wire-loop appearance without mesangial or endocapillary cell proliferation, and / or marked immunodeposit overload in the glomerular capillary wall.

[0020] In some of the provided embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows diffuse segmental lupus nephritis with segmental lesions extending less than half of the glomerular loops in more than 50% of the glomeruli involved, or diffuse pansegmental lupus nephritis with pansegmental lesions in more than 50% of the glomeruli involved.

[0021] In some of the provided embodiments, if a renal biopsy from a subject shows progressive sclerosing glomerulonephritis, the subject is classified as having class IV LN.

[0022] In any of the provided embodiments, a subject is classified as having a class IV LN if a renal biopsy from the subject shows lesions including extracapillary cell proliferation, crescents, the presence of fibrin and fibrous matrix, and / or more than 10% around Bowman's capsule showing extracapillary cell proliferation.

[0023] In any of the provided embodiments, the crescents include cellular crescents comprising more than 75% cells and fibrin and less than 25% fibrous matrix, fibrous crescents comprising more than 75% fibrous matrix and less than 25% cells and fibrin, and / or fibrous crescents comprising 25% to 75% cells and fibrin and the remaining fibrous matrix.

[0024] In some of the provided embodiments, a subject is selected for voclosporine administration if, based on renal biopsy classification, the subject is classified as having mixed class V+III / IV LN. In some of the provided embodiments, if a subject is classified as having mixed class V+III / IV LN based on renal biopsy classification, the subject is classified as having high responsiveness.

[0025] In some of the provided embodiments, if a renal biopsy from the subject shows non-wire-loop endocutaneous deposits within Class V and / or subepithelial deposits containing more than 50% of the glomeruli and more than 50% of the loops, the subject is classified as having Class A mixed Class V+III / IV LN.

[0026] In some of the provided embodiments, if a subject is classified as having pure class V LN based on renal biopsy classification, the subject is not selected for voclosporine administration. In some of the provided embodiments, if a subject is classified as having pure class V LN based on renal biopsy classification, the subject is not identified as having high responsiveness.

[0027] In some of the provided embodiments, a subject is classified as having pure class V LN if a renal biopsy from the subject shows membranous glomerulonephritis. In some of the provided embodiments, a subject is classified as having pure class V LN if a renal biopsy from the subject shows membranous LN with whole-segmental or segmental continuous granular subepithelial immunodeposits.

[0028] In some of the provided embodiments, a subject is classified as having pure class V LN if a renal biopsy from the subject shows significant glomerular capillary wall thickening in a whole-segmental distribution, subepithelial fuchsinophilic deposits, glomerular capillary wall spikes indicating membranous nephropathy, and / or continuous subepithelial IgG deposits in the glomerular capillary wall.

[0029] In some of the provided embodiments, subjects are further evaluated for the National Institutes of Health Activity Index (NIH-AI). In some of the provided embodiments, the NIH-AI is evaluated on a total score scale of 0 to 24 based on the sum of the scores of the following evaluations: endocapsular pleostasis scale of 0 to 3 with endocapsular pleostasis of less than 25% (1), 25% to 50% (2), or more than 50% (3) of the glomeruli; neutrophil / nuclear decay scale of 0 to 3 with neutrophil and / or nuclear decay of less than 25% (1), 25% to 50% (2), or more than 50% (3) of the glomeruli; fibrinoid necrosis scale of (0 to 3) × 2 with neutrophil and / or nuclear decay of less than 25% (1), 25% to 50% (2), Or, with more than 50% (3) fibrinoid necrosis, a scale of 0–3 for hyaline deposits, less than 25% (1), 25%–50% (2), or more than 50% (3) of wire-loop lesions and / or hyaline thrombi in the glomeruli, a scale of (0–3) × 2 for cellular / fibrous crescents in the glomeruli, less than 25% (1), 25%–50% (2), or more than 50% (3) of cellular and / or fibrous crescents in the glomeruli, and a scale of 0–3 for interstitial inflammation, with less than 25% (1), 25%–50% (2), or more than 50% (3) of interstitial leukocytes in the cortex.

[0030] In some of the provided embodiments, subjects are further evaluated based on the National Institutes of Health Chronicity Index (NIH-CI). In some of the provided embodiments, the NIH-CI is evaluated on a total score scale of 0 to 12 based on the sum of the scores of the following evaluations: a total glomerulosclerosis score of 0 to 3 with total and / or segmental sclerosis of less than 25% (1), 25% to 50% (2), or more than 50% (3) of the glomeruli; and a fibrous crescent scale of 0 to 3 with 25% of the glomeruli. Fibrous crescent formation of less than 25% (1), 25% to 50% (2), or more than 50% (3) of the renal tubules, with a scale of 0 to 3, with tubular atrophy of less than 25% (1), 25% to 50% (2), or more than 50% (3) of the cortical tubules, and interstitial fibrosis of less than 25% (1), 25% to 50% (2), or more than 50% (3) of the cortex.

[0031] In some of the provided embodiments, the renal biopsy is evaluated using light microscopy, immunofluorescence, and / or electron microscopy.

[0032] In some of the provided embodiments, voclosporine is administered in a daily dose of approximately 5 mg BID to approximately 50 mg BID. In some of the provided embodiments, voclosporine is administered in an initial daily dose of approximately 39.5 mg, approximately 31.6 mg, approximately 23.7 mg, approximately 15.8 mg, or approximately 7.9 mg BID. In some of the provided embodiments, voclosporine is administered in an initial daily dose of approximately 39.5 mg. In some of the provided embodiments, voclosporine is administered in an initial daily dose of approximately 23.7 mg. In some of the provided embodiments, voclosporine is administered in an initial daily dose of approximately 15.8 mg.

[0033] In some of the provided embodiments, voclosporine is administered over a predicted voclosporine treatment period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or at least 48 months.

[0034] In some of the provided embodiments, the method also includes evaluating the subject's estimated glomerular filtration rate (eGFR) at at least a first and a second time point on different days of the predicted treatment period, and if the subject's eGFR decreases between the first and second time points to a predetermined value by more than a target percentage, the daily dose is reduced by 7.9 mg BID increments or administration of voclosporine is discontinued, and if the subject's eGFR decreases between the first and second time points to less than a target percentage, the subject continues to receive the same predetermined daily dose of voclosporine.

[0035] In some of the provided embodiments, the predetermined values ​​are 50-90 ml / min / 1.73 m 2 This is within the range. In some of the provided embodiments, the given value is approximately 60 ml / min / 1.73 m 2 That is the case.

[0036] In some of the provided embodiments, the target percentage is in the range of 20% to 45%. In some of the provided embodiments, the target percentage is approximately 30%.

[0037] In some of the provided embodiments, the subject's eGFR decreased by more than 30% between the first and second time points to 60 mL / min / 1.73 m². 2 If the value falls below 60 ml / min / 1.73 m², discontinue administration of voclosporine to the subject, and if the subject's eGFR decreases by 20% to 30% between the first and second time points, the eGFR should be reduced to 60 ml / min / 1.73 m². 2 If the value falls below a certain level, the subject will be administered a reduced dose of voclosporine, and if the subject's eGFR decreases by less than 20% between the first and second time points, the subject will continue to be administered the same prescribed daily dose of voclosporine.

[0038] In some of the provided embodiments, the first time point is immediately before initiating administration of voclosporine. In some of the provided embodiments, the second time point is after the first time point, when administration of voclosporine is initiated. In some of the provided embodiments, the second time point is 8 weeks after initiating administration of voclosporine.

[0039] In some of the embodiments provided, the method also includes determining the target eGFR at a third time point, and if it is determined that the difference between the eGFR determined at the third time point and the eGFR determined at the first time point is less than a target percentage, administration of a predetermined daily dose of voclosporine is resumed.

[0040] In some of the provided embodiments, the method also includes measuring the urinary protein-creatinine ratio (UPCR) of the subject at a first and second time point, determining any decrease in the UPCR between the first and second time points, and discontinuing administration of voclosporine to the subject if the subject's UPCR does not show a decrease of at least 25% at the second time point.

[0041] In some of the provided embodiments, the method also includes measuring the concentration of C3 or C4 in the subject's blood at a first and a second time point, determining at the second time point whether the concentration of C3 or C4 has normalized, and, if normalization of C3 or C4 is found, resuming administration of voclosporine to the subject.

[0042] In some of the embodiments provided, the method also includes administering an effective amount of mycophenolate mofetil (MMF) to a subject.

[0043] In some of the embodiments provided, the method also includes administering an effective amount of corticosteroid to the subject.

[0044] In some of the provided embodiments, the voclosporine is a mixture of at least 90% E isomer and 10% or less Z isomer.

[0045] This specification also provides boxrosporin for use in accordance with any of the methods described herein.

[0046] This specification also provides the use of voclosporine in the manufacture of pharmaceuticals by any of the methods described herein.

[0047] This specification also provides the use of voclosporine by any of the methods described herein. [Brief explanation of the drawing]

[0048] [Figure 1]A–L show exemplary micrographs of renal biopsies for the LN class based on the ISN / RPS 2003 classification (see Weening et al., Kidney International (2004) 65, 521–530). Figure 1A shows an example of LN class II, i.e., a glomerulus with mild mesangial polycythemia (periodic acid Schiff staining (PAS)). Figure 1B shows an example of LN class III(A), i.e., a glomerulus with segmental endovascular polycythemia, mesangial polycythemia, capillary wall thickening, and early segmental capillary necrosis (methenamine silver). Figure 1C shows an example of LN class III(A), i.e., a glomerulus with partial capillary necrosis with preserved capillary loops, a vasculitis-like lesion (methenamine silver). Figure 1D shows an example of LN class IV-G(A), i.e., a glomerulus with whole-segmental involvement of vascular endothelium, mesangial polycythemia and matrix expansion, leukocyte influx, and occasional double contour lines (methenamine silver). Figure 1E shows LN Figure 1F shows a glomerulus exhibiting an example of class IV-S(A), namely, intraductal pleocellularity, double-contoured capillary walls, wire-loop lesions, and hyaline thrombosis (periodic acid schiff (PAS)). Figure 1F shows a light micrograph of a glomerulus exhibiting an example of LN class IV-G(A / C), namely, widespread severe intraductal and extraductal pleocellularity, wire-loop lesions, leukocyte influx, apoptotic bodies, capillary necrosis, and mesangial dilation with cytosis and matrix expansion, marked interstitial inflammatory infiltration [periodic acid schiff (PAS)]. Figure 1G shows a glomerulus exhibiting an example of LN class IV-G(A / C), namely, widespread intraductal proliferation, leukocyte influx, apoptotic bodies, double-contoured walls, crescent formation with tubular deformation, premature sclerosis, and Bowman's capsule destruction [periodic acid schiff (PAS)]. Figure 1H shows LN A Class IV-G(A) example shows glomeruli with extensive subendothelial immunodeposits (wire-loop lesions) accompanied by the formation of a new basement membrane along the inside of the capillaries, but without intraluminal leukocyte infiltration or cytoplasm (methenamine silver). Figure 1I shows a Class V LN example, glomeruli with advanced lupus membranous nephropathy (methenamine silver) characterized by large subepithelial accumulation of immunodeposits (IF, full house) and interlocking spike formation.Figure 1J shows examples of LN class IV and V(A / C), i.e., glomeruli (silver methenamine) with subepithelial spike formation, pansegmental endocapillary and mesangial pleoplasia, early crescent formation, and lupus membranous nephritis with early mesangial and capillary sclerosis. Figure 1K shows an example of LN class VI, i.e., renal cortex (silver methenamine) showing nearly diffuse pansegmental glomerulosclerosis with interstitial fibrosis, mononuclear inflammatory infiltration, and angiosclerosis. Figure 1L shows an example of thrombotic microangiopathy in a patient with systemic lupus erythematosus (SLE) and circulating lupus anticoagulant, glomeruli showing severe capillary and arteriole thrombosis, endothelial cell swelling and necrosis, neutrophil influx, and erythrocyte stasis, with no immunofluorescence evidence of immunodeposits (silver methenamine). [Figure 2] Figures A-F show exemplary micrographs of renal biopsies for specific features described for the LN class based on the ISN / RPS 2018 classification (see Bajema, et al., Kidney International (2018) 93, 789-796), namely, mesangial pleoplasia (Figure 2A), endocapillary pleoplasia (Figure 2B), cellular crescents (Figure 2C), fibrous crescents (Figure 2D), fibrous crescents (Figure 2E), and adhesions (Figure 2F). All micrographs show periodate Schiff (PAS) staining, and arrows indicate examples of the described features. [Figure 3]This schematic diagram shows the ultrastructural characteristics of a single glomerular capillary affected by lupus glomerulonephritis. In Class I, mesangial immunodeposits (black) are observed, but there is no mesangial cell proliferation (red) or leukocyte influx. In Class II, mesangial immunodeposits and mesangial cell proliferation are observed, but there is no leukocyte influx. In Class III / IV (upper right), leukocyte influx into the mesangium and capillaries is observed, and in Class III / IV (lower right), immunodeposits of the subendothelial capillary wall can be observed by light microscopy. While leukocyte influx into the mesangium is observed, leukocyte influx into the capillaries (dark green neutrophils and light green monocytes / macrophages) is not. Class III / IV+V shows leukocyte influx and numerous subepithelial immunodeposits in addition to subendothelial deposits, and Class V shows a large amount of subepithelial immunodeposits but no leukocyte influx (podocytes: outer green cells, endothelial cells: yellow cells, mesangial cells: red cells, neutrophils: green cells with segmented nuclei, monocytes / macrophages: light green cells). See Bajema; et al.; Kidney International (2018) 93;789-796. [Figure 4] This diagram shows a schematic of a study comparing the safety and efficacy of voclosporine at 24 and 48 weeks with placebo in subjects who received mycophenolate mofetil (MMF) and oral corticosteroids concurrently (upper panel) and followed the presented tapering protocol (lower panel). [Figure 5] A schematic diagram of the long-term safety and tolerability follow-up study is shown. As shown in the diagram, 216 of the 357 subjects who participated in the initial year of the study proceeded to the follow-up study. For the subject subgroups, baseline and repeat biopsy timings are also shown. [Figure 6] The mean estimated glomerular filtration rate (eGFR) at a follow-up period of 4 weeks over 36 months is shown for the 116 subjects in the voclosporin group and the 100 subjects in the control group. The number of subjects in each study group at the same time point is also shown. [Figure 7]The mean adjusted estimated glomerular filtration rate (eGFR, 95% confidence interval) and the mean change from pre-treatment baseline in adjusted eGFR at follow-up points of 4 weeks over 36 months for 116 subjects in the voclosporine group and 100 subjects in the control group are shown. The number of subjects in each study group at each point in time is also shown. Pre-treatment baseline was defined as the last value before subjects received their first dose of the study drug on day 1 of the initial 12-month trial (e.g., at the start of month 36). [Figure 8] This report shows the mean adjusted estimated glomerular filtration rate (eGFR) gradient and the change in eGFR (95% confidence interval) from month 12 for 116 subjects in the voclosporine group and 100 subjects in the control group over a 24-month period (i.e., months 12 to 36). The mean adjusted eGFR gradient and change in eGFR are calculated from the start of the continuation study (month 12 from the start of treatment) to the end of the continuation study (month 36 from the start of treatment). The number of subjects in each study group at the same point in time is also shown. [Figure 9] The mean UPCR (mg / mg) at a follow-up period of 4 weeks over 36 months for 116 subjects in the voclosporine group and 100 subjects in the control group is shown. The number of subjects in each study group at the same time point is also shown. [Figure 10] The data shows the percentage of subjects whose UPCR decreased by 50% every 6 months over a 36-month period, including an additional 4-week follow-up period. The number of subjects in each study group at the same time point is also shown. [Figure 11] The urinary protein-creatinine ratio (UPCR) levels of the voclosporine group and the control group after a 52-week post-hoc analysis period are shown. The number of subjects in each study group at the same time point is also shown. [Figure 12] The complete renal response rate (CRR) for each subgroup of the subjects at 12 months post-hoc analysis is shown. An OR greater than 1 indicates a therapeutic effect of voclosporine. [Figure 13] The complete renal response rate (CRR) for voclosporin and the control group is shown 12 months after the post-hoc analysis, and after classifying subjects by disease class based on biopsy results. [Figure 14]This shows the mean estimated glomerular filtration rate (eGFR) over 52 weeks in subjects in the voclosporin group and the control group. The number of subjects in each study group at the same time point is also shown. [Figure 15] The mean urinary protein-creatinine ratio (UPCR) over a 3-year study is shown for a subgroup of 26 subjects evaluated by repeated renal biopsies (16 in the voclosporine group and 10 in the control group) and for a total of 357 subjects evaluated in this study. [Figure 16] The mean urinary protein-creatinine ratio (UPCR) over a 3-year study is shown for a subgroup of 26 subjects evaluated by repeated renal biopsies (16 in the voclosporine group and 10 in the control group) and for a total of 357 subjects evaluated in this study. [Figure 17] This report shows the least squares mean of adjusted estimated glomerular filtration rate (eGFR) in a subgroup of 26 subjects evaluated by repeated renal biopsies (16 in the voclosporine group and 10 in the control group) and in the larger overall study group (n=216) from a 2-year follow-up study. Renal function was assessed using the adjusted eGFR (chronic kidney disease collaborative equation) with a pre-specified upper limit of 90 mL / min / 1.73m2. [Figure 18] Figures A and B are box plots showing disease activity (Figure 18A, assessed based on renal biopsies evaluating the National Institutes of Health Activity Index - NIH-AII, scale 0-24) and chronicity (Figure 18B, assessed based on renal biopsies evaluating the National Institutes of Health Chronicity Index - NIH-CI, scale 0-12) in a 3-year study of a subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group). These were assessed at baseline (BL) and at follow-up (approximately 18 months after voclosporin treatment). The symbol "x" represents the mean, and the horizontal thick line represents the median. The upper and lower boxes represent the third and first quartiles. Outliers are represented by individual dots. [Figure 19] This shows the mean (± standard deviation) of plasma concentrations of MPA after MMF monotherapy (day 1) and in the presence of voclosporine (day 7). [Figure 20] The mean (± standard deviation) of MPAG plasma concentrations after MMF monotherapy (day 1) and in the presence of voclosporine (day 7) are shown. [Modes for carrying out the invention]

[0049] This specification provides methods for treating lupus nephritis (LN), selection of subjects for treatment, and therapeutic uses of voclosporine, including the selection of a specific class or type of LN, such as subjects classified as having a specific biopsy class of LN. This specification also provides methods and uses for treatment, including identifying patients with a specific class or type of lupus nephritis (LN) based on renal biopsy classification as patients with a high likelihood of responding to treatment with voclosporine. In some embodiments, this method and use also includes administering voclosporine to the selected or identified subjects.

[0050] This disclosure relates to a method for treating lupus nephritis (LN) and its use, including administering voclosporine to subjects classified as having a specific class or type of LN, e.g., a specific biopsy class of LN. In some embodiments, this method and its use relate to selecting subjects classified as having a specific class or type of LN, e.g., a specific biopsy class of LN, for the administration of voclosporine. In some embodiments, this method and its use relate to evaluating the responsiveness to voclosporine treatment and selecting subjects with a high responsiveness to voclosporine treatment. In some embodiments, this method and its use include administering a therapeutically safe and effective amount of voclosporine to the selected subjects.

[0051] In some embodiments, the methods and uses provided are based on the observation that treatment with voclosporine for a specific class or type of LN, e.g., a specific biopsy class of LN, e.g., class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) LN, results in unexpectedly high renal response rates compared to control patients who did not receive voclosporine. As described herein, treatment of LN with voclosporine has been observed to be particularly effective in patients with class III, class IV, or mixed class V and class III or IV (mixed class V+III / IV) LN, showing unexpectedly high complete response rates (CRR) without a significant increase in susceptibility to or risk of adverse events compared to control patients who did not receive voclosporine. Voclosporine has been shown to have higher remission and response rates in long-term clinical trials compared to standard treatment while maintaining renal function without the clinical manifestations of toxicity shown with other CNIs such as cyclosporine or tacrolimus. In some aspects, the results provided herein support the effective and safe treatment of certain classes or types of LN with voclosporine, such as class III, class IV, or mixed class V and III or IV (mixed class V+III / IV), and specific renal biopsy classifications such as class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) are important criteria for identifying subjects with a high likelihood of responding to voclosporine and for selecting subjects who would substantially benefit from administering voclosporine to treat LN.

[0052] Voclosporin offers several advantages over other treatments for lumbago (LN) and was recently approved by the FDA as the first oral treatment for LN. The results described herein support the merits of using or switching to voclosporin in the treatment of LN, and the methods, treatment plans, protocols, and uses provided herein. Furthermore, these results support the merits of administering voclosporin to the treatment of LN by selecting specific subjects with Class III, Class IV, or mixed Class V and III or IV (mixed Class V+III / IV) LN based on renal biopsy classification. The merits and advantages include avoiding wasted medication and unnecessary exposure to potential side effects from unnecessary treatment. Such merits are particularly important for subjects at risk of side effects or toxicity, as LN treatment plans are typically long-term and may involve undesirable side effects.

[0053] Therefore, voclosporine can be administered to selected subjects who are likely to respond without an increase in adverse events. Furthermore, voclosporine has also been observed to exhibit remarkably high drug persistence. Approximately 24 months after voclosporine was approved as a treatment for lupus nephritis (LN), estimates based on patient databases indicate that approximately 26% of subjects are continuing voclosporine treatment, which is significantly higher than the predicted percentage. These observations support the use of voclosporine as a safe and effective treatment for LN, particularly for subjects who meet the criteria according to the provided embodiments. LN patients, especially those with class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) LN, can benefit in many ways from the use of voclosporine in treatment.

[0054] All publications, including patent documents, scientific articles, and databases, referenced in this application are incorporated by reference in whole for any purpose, to the same extent as if each individual publication were incorporated by reference individually. If any definitions contained herein conflict with or contradict any definitions contained herein by reference in any patent, application, publication, or other publication incorporated herein by reference, the definitions contained herein shall prevail.

[0055] The section headings used in this specification are for organizational purposes only and should not be construed as limiting the subject matter described.

[0056] I. Treatment methods and use of vocrossporine This specification provides methods and uses of treatment, including selecting patients with a specific class or type of lupus nephritis (LN) based on renal biopsy classification for treatment with voclosporine. This specification also provides methods and uses of treatment, including identifying patients with a specific class or type of lupus nephritis (LN) based on renal biopsy classification as having a high likelihood of responding to treatment with voclosporine. Methods and uses are also provided, for example, including administering voclosporine to selected subjects or subjects identified as having a high likelihood of responding, according to any of the methods or uses described herein. In some embodiments, the use of voclosporine or compositions containing voclosporine according to any of the methods described herein is also provided. Such uses include the use of voclosporine in such methods and treatments, and in the preparation of pharmaceuticals for performing such methods. In some embodiments, this method is performed by selecting subjects classified as having a specific class or type of LN based on renal biopsy classification, and administering voclosporine to the selected subjects. In some embodiments, the method is carried out by identifying subjects that are classified as having a particular class or type of LN based on renal biopsy classification and have a high likelihood of responding to voclosporine treatment, and by administering voclosporine to the identified subjects. In some embodiments, the provided method and use involve administering an effective amount of voclosporine to selected or identified subjects.

[0057] In some embodiments, the selection of subjects for voclosporine administration is based on any of the criteria or assays described herein (e.g., Section II). In some embodiments, subjects are selected for voclosporine based on renal biopsy. In some embodiments, voclosporine is based on any of the methods or treatment plans described herein (e.g., Section III).

[0058] A. Lupus nephritis (LN) Systemic lupus erythematosus (SLE) is an autoimmune disease that causes chronic inflammation and damage to various organs. When the kidneys are affected, the condition is known as lupus nephritis (LN). Assessing renal function in LN patients is important because timely detection and management of renal dysfunction significantly improves renal outcomes. Most SLE patients have histological evidence for LN, even in those who do not clinically present with renal disease. Monitoring for the onset of LN can be performed based on urinalysis, serum creatinine, and the ratio of urinary albumin to creatine. In some aspects, this method can be used to identify elevated serum creatinine levels from baseline and the presence of proteinuria, which is common in LN. Because LN carries a high risk of increased morbidity, treatment plays a crucial role in preventing progression to end-stage renal disease.

[0059] LN is a proteinuric kidney disease caused by systemic lupus erythematosus (SLE), which leads to inflammation of the kidneys. In some cases, up to 60% of SLE patients develop LN. LN is a debilitating and costly disease, often leading to renal failure requiring dialysis or a kidney transplant, and can be fatal. In fact, patients with renal failure have more than 60 times the risk of premature death compared to the general SLE patient. The clinical sign of LN is leakage of blood proteins into the urine, and the disease can be diagnosed by several factors, including the urinary protein / creatinine ratio (UPCR), with a UPCR exceeding 0.5 mg / mg indicating that the disease is active. In addition, certain blood markers, such as complement 3 (C3), complement 4 (C4), and anti-dsDNA antibodies, may also be diagnostic.

[0060] Standard treatments for lnephrosis (LN) have not been highly successful. Standard treatment involves the use of mycophenolate mofetil (MMF) or intravenous cyclophosphamide. With these treatments, partial remission was observed in only about 50% of cases, and complete remission was shown in less than 10% of subjects. Therefore, there is a clear need for treatments that improve these outcomes.

[0061] In some embodiments, subjects treated according to the methods and uses provided herein include subjects diagnosed with or suspected of having LN. In some embodiments, subjects treated according to the methods and uses provided herein include subjects diagnosed with or suspected of having a particular class of LN based on renal biopsy. In some embodiments, the provided methods and uses include selecting subjects diagnosed with a particular class of LN based on renal biopsy.

[0062] In some cases, the primary goal of treating LN is to normalize renal function and prevent progressive decline in renal function. Treatment options vary depending on the underlying lesion (Tamirou et al., J Clin Med. 2021 Feb 09;10(4)).

[0063] Lupus nephritis is primarily associated with the formation of immune complexes due to type III hypersensitivity reactions. In some embodiments, anti-double-stranded DNA (anti-dsDNA) antibodies bind to DNA, forming anti-dsDNA immune complexes. These complexes deposit in the mesangium, subepithelial, and / or subendothelial spaces near the glomerular basement membrane of the kidney, triggering an inflammatory response. In some cases, the complement pathway is activated, leading to an influx of neutrophils and other inflammatory cells. In some embodiments, autoimmune phenomena cause LN, but there are also genetic factors that predispose SLE patients to developing LN. For example, polymorphisms in alleles encoding immunoglobulin receptors on macrophages and APOL1 gene mutations found only in African American populations with SLE have been found to be associated with a predisposition to LN (Jorge et al., Ann Intern Med. 2019 Feb 19;170(4); Goyal et al., Ann Intern Med. 2019 Feb 19;170(4):266-267).

[0064] Vocrossporine therapy for B.LN Voclosporine is an analog of cyclosporine A and has been shown to be effective as an immunosuppressant in the treatment of autoimmune diseases and in organ transplantation.

[0065] Clinical studies of voclosporine in the treatment of lneofibular neuropathy (LN) have shown high response rates with no significant difference in adverse events compared to standard treatment controls. For example, in one study, subjects with LN were administered voclosporine 23.7 mg twice daily in combination with mycophenolate mofetil (MMF), and the corticosteroid dose was gradually reduced over 24 weeks. Inclusion criteria for the study included a urinary protein-creatinine ratio (UPCR) greater than 1.0 mg / mg or greater than 1.5 mg / mg, depending on the classification of the renal biopsy, and an eGFR (estimated glomerular filtration rate) of 45 mol / min / 1.73 m². 2 This included being above average and having serological evidence of LN. The study results showed complete or partial remission in the majority of subjects.

[0066] Furthermore, it was shown that subjects who experienced a 25% or greater reduction in UPCR levels within 8 weeks were more likely to maintain the effect throughout a 24-week or 48-week treatment period.

[0067] Another study showed that administering mycophenolate mofetil (MMF) and voclosporine at 23.7 mg or 39.5 mg twice daily to reduce corticosterone doses resulted in complete or partial remission at 24 and 48 weeks in a large number of patients.

[0068] Additional studies also presented data on the predictability of success regarding complete remission (CR) based on various criteria measured after 8 weeks of administration of voclosporine 23.7 mg BID along with MMF-1 and steroid tapering. These criteria included UPCR (a reduction of less than 25% was considered ineffective), as well as normalization of complement 3 and 4 (C3 and C4) and anti-dsDNA.

[0069] In some aspects, based on these therapeutic successes, voclosporine has recently received FDA approval for the treatment of active lupus nephritis (LN) in combination with background immunosuppressive therapy. Observations have shown that voclosporine is more potent and less toxic at a therapeutic level than other CNIs and other compounds in the treatment of LN.

[0070] CNIs are used as immunosuppressants for patients suffering from a variety of conditions, particularly those involving autoimmune elements. The immunosuppressive effects of CNIs are thought to help treat the direct causes of symptoms related to immune system activity. For example, CNIs are also used to treat LN. The immunosuppressive properties of CNIs are thought to arise from the inhibition of calcineurin, a phosphatase. Calcineurin is a key enzyme involved in the activation and proliferation of T cells. Cyclosporine and tacrolimus are thought to inhibit the phosphatase activity of calcineurin. This inhibition suppresses IL-2 production and thus suppresses T cell activation. Many immunosuppressants, including CNIs, need to be administered for at least one month, at least three months, at least six months, at least one year, or even longer, for example, five years or more.

[0071] Cyclosporine (sometimes called cyclosporine or cyclosporine) and cyclosporine derivatives such as cyclosporine A (CsA) are first-line CNIs used for transplant-related immunosuppression. Although cyclosporine A and voclosporine are structurally similar, the two compounds differ in metabolic stability and distribution, and certain metabolites of cyclosporine A have been reported to correlate with nephrotoxicity (Wu and Kuca, Current Drug Metabolism 2019;20(2):84-90(7)). In some embodiments, subjects are selected for voclosporine administration if they have a specific class of LN based on renal biopsy classification, such as class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) LN.

[0072] In some aspects, tacrolimus is also effectively used for transplant-related immunosuppression. Both cyclosporine and tacrolimus were first introduced in the 1980s for solid organ transplantation and are considered legacy CNIs or conventional first-generation CNIs. Currently, the majority of recipients employ CNI-based regimens as standard maintenance immunosuppression, and tacrolimus is preferred over cyclosporine (including derivatives such as cyclosporine A (CsA)) due to its superior long-term kidney transplant function, allogeneic transplant survival rates, and acute rejection rates (Ekberg et al., N Engl J.Med. 2007, 357(25):2562-75; Hariharan et al., N Engl J Med. 2021 Aug 19; 385(8):729-743).

[0073] Voclosporine offers significant advantages compared to other calcineurin inhibitors (CNIs). Conventional CNIs such as cyclosporine (including cyclosporine derivatives such as cyclosporine A (CsA)) and tacrolimus (TAC), or their derivatives, are potent immunosuppressants and have been tested to treat a variety of conditions that typically require long-term immunosuppression, such as in combination with organ or tissue transplantation. Conventional CNI compounds have, in some situations, been associated with adverse effects, side effects, or toxicity, including drug-induced nephrotoxicity.

[0074] II. Identification and Selection of Targets In some embodiments, the provided methods and uses include administering voclosporine to subjects selected according to the provided embodiments or to subjects identified as having a high likelihood of responding to treatment with voclosporine. In some embodiments, subjects are selected for voclosporine administration if they have a particular class or type of lupus nephritis (LN) based on renal biopsy classification.

[0075] In some embodiments, the provided methods and uses include evaluating or assessing the target LN based on renal biopsy classification, for example, based on any of those described herein.

[0076] In some embodiments, if a subject has class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) LN based on renal biopsy classification, the subject is selected for voclosporine administration. In some embodiments, if a subject has class III LN based on renal biopsy classification, the subject is selected for voclosporine administration. In some embodiments, if a subject has class IV based on renal biopsy classification, the subject is used for voclosporine administration. In some embodiments, if a subject has mixed class V and III or IV (mixed class V+III / IV) LN based on renal biopsy classification, the subject is used for voclosporine administration.

[0077] In some embodiments, a subject is identified as having a high likelihood of responding to voclosporine treatment if, based on renal biopsy classification, the subject has a Class III, Class IV, or mixed Class V and III or IV (mixed Class V+III / IV) LN classification. In some embodiments, a subject is identified as having a high likelihood of responding to voclosporine treatment if, based on renal biopsy classification, the subject has a Class III LN classification. In some embodiments, a subject is identified as having a high likelihood of responding to voclosporine treatment if, based on renal biopsy classification, the subject has a Class IV classification. In some embodiments, a subject is identified as having a high likelihood of responding to voclosporine treatment if, based on renal biopsy classification, the subject has a mixed Class V and III or IV (mixed Class V+III / IV) LN classification.

[0078] In some embodiments, the methods and uses provided involve administering an effective amount of voclosporine to a selected or identified subject. In some embodiments, the voclosporine is based on either the methods or treatment plans described herein (e.g., Section III).

[0079] A. Classification of kidney biopsies This specification provides a treatment method and use that includes selecting patients with a specific class or type of lupus nephritis (LN) for treatment with voclosporine based on renal biopsy classification. This specification also provides a treatment method and use that includes identifying patients with a specific class or type of LN based on renal biopsy classification as patients with a high likelihood of responding to treatment with voclosporine.

[0080] Methods and uses are also provided, for example, that involve administering voclosporine to selected subjects or subjects identified as having a high responsiveness, according to any of the methods or uses described herein. In some embodiments, uses of voclosporine or compositions comprising voclosporine by any of the methods described herein are also provided. Such uses include the use of voclosporine in such methods and treatments, and in the preparation of pharmaceuticals for performing such methods. In some embodiments, the method is carried out by selecting subjects having a specific class or type of LN, such as class III, class IV, or mixed class V and III or IV (mixed class V+III / IV)LN, based on renal biopsy classification, and administering voclosporine to the selected subjects. In some embodiments, the method is carried out by identifying subjects having a specific class or type of LN, such as class III, class IV, or mixed class V and III or IV (mixed class V+III / IV)LN, based on renal biopsy classification, as having a high responsiveness to voclosporine treatment, and administering voclosporine to the identified subjects. In some embodiments, the methods and uses provided involve administering an effective amount of voclosporine to selected or identified subjects.

[0081] In some embodiments, subjects are selected for voclosporine administration if they have previously been classified as Class III, Class IV, or mixed Class V+III / IV LN based on renal biopsy classification.

[0082] In some embodiments, if a subject is classified as Class III, Class IV, or mixed Class V+III / IV LN based on renal biopsy classification and is identified as having a high likelihood of responding to voclosporine treatment, the subject is selected for voclosporine administration.

[0083] In some embodiments, subjects are selected based on the classification of LN. In some embodiments, the LN class is based on one or more renal biopsies, and the classification is based on one or more renal biopsies.

[0084] In some embodiments, renal biopsies can be evaluated using light microscopy, immunofluorescence microscopy, or electron microscopy. The collected renal biopsies can be evaluated by hematoxylin-eosin staining (H&E), periodate Schiff staining (PAS), silver staining, trichrome staining, and collagen III immunohistochemistry. In some embodiments, renal biopsies can also be stained with immunofluorescence stains, including but not limited to C3, C4, C5, C1q, IgG, IgM, and IgA.

[0085] In some embodiments, the class or type of LN is assessed based on one or more renal biopsies. In some embodiments, one or more biopsies indicate class III LN. In some embodiments, one or more biopsies indicate class IV LN. In some embodiments, one or more biopsies indicate class V LN.

[0086] In some embodiments, one or more renal biopsies are classified based on the International Society of Nephrology / Renal Pathology Society (ISN / RPS) classification. In some embodiments, LN classes are classified as Class I, Class II, Class III, Class IV, Class V, Class VI, or mixed Class V and III or IV (mixed Class V+III / IV) LN based on the evaluation of one or more renal biopsies using the International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2003 classification. In some embodiments, LN classes are classified as Class I, Class II, Class III, Class IV, Class V, Class VI, or mixed Class V and III or IV (mixed Class V+III / IV) LN based on the evaluation of one or more renal biopsies using the International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2018 classification.

[0087] In some embodiments, the provided method and use include evaluating or assessing one or more pathological characteristics associated with the presence of LN in one or more renal biopsies. In some embodiments, the provided method and use include evaluating or assessing one or more pathological characteristics associated with the presence of LN class III in one or more renal biopsies. In some embodiments, the provided method and use include evaluating or assessing one or more pathological characteristics associated with the presence of LN class IV in one or more renal biopsies. In some embodiments, the provided method and use include evaluating or assessing one or more pathological characteristics associated with the presence of LN mixed class V+III / IV in one or more renal biopsies.

[0088] In some embodiments, this method and use involves evaluating or assessing the presence of one or more pathological properties that may be associated with the presence of a particular class or type of LN in one or more renal biopsies taken before the subject begins administration of voclosporine, and classifying the biopsies based on the presence of one or more indicators measured before administration of voclosporine, i.e., baseline. In some embodiments, this method and use involves classifying the subject's LN using the International Society of Nephrology and Renal Pathology Society (ISN / RPS) classification. In some embodiments, this method and use involves classifying the subject's LN using the ISN / RPS 2003 classification. In some embodiments, this method and use involves classifying the subject's LN using the ISN / RPS 2018 classification. In some embodiments, “baseline level” or “baseline measurement” refers to the level of one or more pathological properties measured or assessed in the subject before administration of voclosporine or its derivatives.

[0089] In some embodiments, one or more pathological characteristics that may be associated with the presence of LNs can be assessed based on methods and assays for evaluating and monitoring such pathological characteristics, as described herein. In some embodiments, this method and use involves evaluating or assessing one or more pathological characteristics that may be associated with the presence of a particular class or type of LN in one or more renal biopsies, and selecting subjects based on specific criteria or thresholds. In some embodiments, one or more pathological characteristics indicate subjects with a high likelihood of responding to treatment with voclosporine. In some embodiments, subjects are identified based on criteria or thresholds of one or more pathological characteristics associated with a high likelihood of responding to treatment with voclosporine, and voclosporine is administered to the identified subjects.

[0090] In some embodiments, the provided methods and uses include identifying subjects who are likely to respond well to treatment with voclosporine.

[0091] In some embodiments, LN can affect the glomeruli, interstitium, tubules, and capillary loops of the kidney. Besides anti-dsDNA immune complex deposits, immunoglobulin M (IgM), immunoglobulin G (IgG), immunoglobulin A (IgA), and complement (C1, C3, propagin) are commonly found as subepithelial, mesangial, and subendothelial deposits. In some embodiments, leukocytes may also be present. In some embodiments, the histological features of LN vary depending on various factors, including the antigen specificity and other characteristics of autoantibodies and the type of inflammatory response. In more severe LN, fibrosis occurs due to the production of substrate proteins and the proliferation of mesangial, endothelial, and epithelial cells.

[0092] In some aspects, renal biopsy can provide important information for the management of lN. In some aspects, the pattern of glomerular lesions observed on renal biopsy, the activity and chronicity of the disease, and the extent of lesions into the tubulointerstitium and vascular compartments are fundamental information for the diagnosis and treatment of LN.

[0093] Several classification systems have been developed for classifying LN. In some embodiments, one of the known renal biopsy classification systems for LN can be used to assess the biopsy class of a subject, in accordance with the methods and uses described herein. In some embodiments, exemplary known renal biopsy classification systems for LN include, but are not limited to, those described in Bajema, et al., Kidney International (2018) 93, 789-796, Weening et al., Kidney International (2004) 65, 521-530, Umeda et al., Arthritis Research & Therapy (2020) 22:260, Kiremitci et al., The Scientific World Journal (2014) Article ID 580620, and Hashmi et al., Cureus (2020) 12(9):e10520, each of which is incorporated herein by reference. In some cases, glomerular lesions are classified according to the International Society of Nephrology and Renal Pathology Society Classification (ISN / RPS) to correlate kidney disease with clinical symptoms and patient outcomes.

[0094] In some embodiments, the standardized classification system used to determine the class of LN based on renal biopsy includes those derived from the International Society of Nephrology and Renal Pathology Society (ISN / RPS) and World Health Organization (WHO) 2003 guidelines. In some embodiments, the standardized classification system used to determine the class of LN based on renal biopsy includes those derived from the ISN / RPS 2003 guidelines. In some embodiments, the standardized classification system used to determine the class of LN based on renal biopsy includes those derived from the ISN / RPS and WHO 2018 guidelines. In some embodiments, the standardized classification system used to determine the class of LN based on renal biopsy includes those derived from the ISN / RPS 2018 guidelines. In some embodiments, the biopsy classification is based on morphological changes in the glomeruli observed by microscopy, immunodeposits observed by immunofluorescence, and electron microscopy. Based on the exemplary renal biopsy classification system described, LN can be classified into six general classes: Class I, Class II, Class III, Class IV, Class V, and Class VI. In some embodiments, subjects can be classified as having mixed biopsy class LN, such as mixed class V and III or IV (mixed class V + III / IV) LN.

[0095] In some embodiments, exemplary classification systems for renal biopsies of LN include the ISN / RPS 2003 classification, summarized in Table 1. [Table 1-1] [Table 1-2]

[0096] Exemplary micrographs of renal biopsies of LN class based on the ISN / RPS 2003 classification are shown in Figures 1A–1L. Figure 1A shows an example of LN class II. Figure 1B shows an example of LN class III(A). Figure 1C shows an example of LN class III(A). Figure 1D shows an example of LN class IV-G(A). Figure 1E shows an example of LN class IV-S(A). Figure 1F shows an example of LN class IV-G(A / C). Figure 1G shows an example of LN class IV-G(A / C). Figure 1H shows an example of LN class IV-G(A). Figure 1I shows an example of LN class V. Figure 1J shows examples of LN class IV and V(A / C). Figure 1K shows an example of LN class VI. Figure 1L shows an example of thrombotic microangiopathy in a patient with systemic lupus erythematosus (SLE) and circulating lupus anticoagulant.

[0097] In some embodiments, with respect to renal biopsy of LN, "diffuse" can refer to a lesion in which most (more than 50%) of the glomeruli are affected. In some embodiments, with respect to renal biopsy of LN, "focal" can refer to a lesion in which less than 50% of the glomeruli are affected. In some embodiments, with respect to renal biopsy of LN, "segmental" can refer to a lesion in which more than half of the glomerular loops are affected. In some embodiments, with respect to renal biopsy of LN, "segmental" can refer to a lesion in which less than half of the glomerular loops are affected (i.e., at least half of the glomerular loops are preserved). In some embodiments, with respect to renal biopsy of LN, "mesangial pleoplasia" can refer to the presence of at least 3 mesangial cells per mesangial region in a 3-micron thick section. In some aspects, with respect to LN renal biopsy, "intracapillary proliferation" can refer to endocapillary pleocytosis, where the number of mesangial cells, endothelial cells, and infiltrating monocytes increases, causing narrowing of the glomerular capillary lumen. In some aspects, with respect to LN renal biopsy, "extracapillary proliferation or cellular crescents" can refer to extracapillary cell proliferation consisting of two or more layers of cells occupying more than one-quarter of the area surrounding the glomerular capsule. In some aspects, with respect to LN renal biopsy, "nuclear disintegration" can refer to the presence of nuclei that have undergone spontaneous cell death, condensed nuclei, or fragmented nuclei. In some aspects, with respect to LN renal biopsy, "necrosis" can refer to lesions characterized by nuclear fragmentation or destruction of the glomerular basement membrane, often accompanied by the presence of fibrin-rich material. In some aspects, with respect to LN renal biopsy, "hyaluronic thrombus" can refer to eosinophilic material in capillaries with uniform viscosity, shown to consist of immunodeposits by immunofluorescence testing. In some aspects, with respect to renal biopsy of LN, the "percentage of glomeruli involved" refers to the percentage of all glomeruli affected by lupus nephritis, including glomeruli hardened by lupus nephritis, but excluding ischemic glomeruli with insufficient perfusion due to vascular lesions other than lupus nephritis.

[0098] In some embodiments, exemplary classification systems for renal biopsies of LN include, for example, the ISN / RPS 2018 classification described in Bajema, et al., Kidney International (2018) 93, 789-796.

[0099] In some embodiments, with respect to Class II, mesangial proliferation can refer to four or more nuclei completely surrounded by the matrix in a mesangial region that does not include the portal vein region (see Figure 2A).

[0100] In some embodiments, for Class III and Class IV, endocapillary proliferation may also refer to endocapillary pleocellularity (see Figure 2B). In some embodiments, for Class III and Class IV, crescents may refer to lesions consisting of extracapillary pleocellularity composed of a mixture of various cells. In some embodiments, fibrin and fibrous matrix may be present. In some embodiments, more than 10% of the area surrounding Bowman's capsule may be affected. In some embodiments, for Class III and Class IV, cellular crescents may refer to those with more than 75% cells and fibrin and less than 25% fibrous matrix (see Figure 2C). In some embodiments, for Class III and Class IV, fibrous crescents may refer to those with more than 75% fibrous matrix and less than 25% cells and fibrin (see Figure 2D). In some embodiments, for Class III and Class IV, fibrous crescents may refer to those with 25% to 75% cells and fibrin and the remainder fibrous matrix (see Figure 2E). In some embodiments, adhesion can refer to a region of isolated continuity of extracellular matrix material between the loop and the capsule, even when there is no apparent hardening in the underlying segment (see Figure 2F).

[0101] In some embodiments, fibrinoid necrosis may refer to fibrin associated with the disruption of the glomerular basement membrane and / or the dissolution of the mesangial matrix. In some embodiments, fibrinoid necrosis does not require the presence of nuclear decay.

[0102] In some aspects, tubulointerstitial lesions indicate whether interstitial inflammation occurs, regardless of the presence or absence of interstitial fibrosis.

[0103] In some embodiments, class IV long necrosis (LN) is not subdivided into segmental and whole-segmental lesions.

[0104] In some aspects, activity and chronicity are assessed based on the National Institutes of Health Activity Index (NIH-AI) and the National Institutes of Health Chronicity Index (NIH-CI).

[0105] In some embodiments, exemplary schematic diagrams of the classification system for LN renal biopsies include those shown in Figure 3 (see Bajema, et al., Kidney International (2018) 93, 789-796). In some embodiments, Class I LNs show mesangial immunodeposits but no mesangial pleocellularity or leukocyte influx. In some embodiments, Class II LNs show mesangial immunodeposits and mesangial pleocellularity but no leukocyte influx. In some embodiments, Class III / IV LNs show leukocyte influx into the mesangium and capillaries. In some embodiments, Class III / IV LNs show immunodeposits on the subendothelial capillary walls and leukocyte influx in the mesangial layer, as confirmed by light microscopy, but no leukocyte influx into the capillaries. In some embodiments, class V+III / IV LNs show leukocyte influx and numerous subepithelial immunodeposits in addition to subendothelial deposits. In some embodiments, class V LNs show numerous subepithelial immunodeposits but no leukocyte influx.

[0106] In some embodiments, LN is Class I. In some embodiments, Class I LN includes a biopsy showing minimal mesangial LN with glomeruli appearing normal on light microscopy. In some embodiments, Class I LN includes a biopsy showing immune complex deposits in the mesangial lumen. In some embodiments, immune complex deposits in the mesangial lumen can be detected using immunofluorescence. In some embodiments, Class I LN includes a biopsy showing glomerular capillaries affected by lupus glomerulonephritis. In some embodiments, glomerular capillaries affected by lupus glomerulonephritis contain mesangial immunodeposits. In some embodiments, glomerular capillaries affected by lupus glomerulonephritis do not contain mesangial pleocytosis. In some embodiments, glomerular capillaries affected by lupus glomerulonephritis do not contain leukocyte influx (Bajema, et al., Kidney International (2018) 93, 789-796).

[0107] In some embodiments, the LN is Class II. In some embodiments, a Class II LN includes a biopsy showing a proliferative mesangial LN with mesangial pleoplasia, containing four or more nuclei surrounded by a matrix within the mesangial region, without a portal vein region observable by light microscopy. In some embodiments, a Class II LN includes a biopsy showing glomerular capillaries affected by lupus glomerulonephritis. In some embodiments, glomerular capillaries affected by lupus glomerulonephritis contain mesangial immunodeposits. In some embodiments, deposits of immune complexes in the mesangial lumen can be detected by immunofluorescence. In some embodiments, glomerular capillaries affected by lupus glomerulonephritis contain mesangial pleoplasia. In some embodiments, glomerular capillaries affected by lupus glomerulonephritis do not contain leukocyte influx (Bajema, et al., Kidney International (2018) 93, 789-796).

[0108] In some embodiments, LN is Class III. In some embodiments, Class III LN includes a biopsy showing focal proliferative glomerulonephritis affecting less than 50% of the total glomerulus. In some embodiments, Class III LN includes a biopsy showing affected glomeruli with endovascular pleoplasia, usually segmentally distributed subendothelial deposits, with or without capillary wall necrosis and crescent formation. In some embodiments, crescent formation is a lesion consisting of a mixture of various cells, comprising extracapillary pleoplasia, where fibrin and fibrous matrix may be present. In some embodiments, crescent formation should occupy more than 10% of the periphery of Bowman's capsule. In some embodiments, cellular crescent formation contains more than 75% cells and fibrin and less than 25% fibrous matrix. In some embodiments, fibrous crescent formation contains more than 75% fibrous matrix and less than 25% cells and fibrin. In some embodiments, fibrous crescent formation contains 25% to 75% cells and fibrin and the remainder fibrous matrix. In some embodiments, focal or diffuse mesangial changes, including mesangial proliferation or mesangial immunodeposits, may be associated with focal glomerular lesions. In some embodiments, class III lesions are segmental. When assessing the extent of the lesions, it may be necessary to consider glomeruli that have both active and sclerotic lesions. In some embodiments, focal or diffuse mesangial changes, including mesangial proliferation or mesangial immunodeposits, may be associated with focal glomerular lesions.

[0109] In some embodiments, if a subject is classified as having class III LN based on renal biopsy classification, the subject is selected for voclosporine administration. In some embodiments, if a subject is classified as having class III LN based on renal biopsy classification, the subject is identified as having high responsiveness.

[0110] In some embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows focal proliferative glomerulonephritis. In some embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows proliferative glomerulonephritis affecting less than approximately 50% of the glomeruli. In some embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows active or inactive focal, segmental or whole-segmental intracapillary or extracapillary glomerulonephritis affecting less than approximately 50% of the total glomeruli, and optionally with or without focal subendothelial immunodeposits and mesangial changes.

[0111] In some embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows endocapillary pleocytosis. In some embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows focal endocapillary pleocytosis. In some embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows endocapillary pleocytosis affecting less than approximately 50% of the glomeruli. In some embodiments, focal proliferative glomerulonephritis includes approximately 20%–50%, 30%–50%, 40%–50%, 20%–40%, 30%–40%, or less than 20%–30% of the total glomeruli. In some embodiments, focal proliferative glomerulonephritis includes approximately 50%, 40%, 30%, or less than 20% of the total glomeruli.

[0112] In some embodiments, renal biopsy includes assessment of the presence of affected glomeruli with endocapillary pleocytosis. In some embodiments, the affected glomeruli include capillary necrosis. In some embodiments, the affected glomeruli do not include capillary necrosis. In some embodiments, the affected glomeruli include subendothelial deposits. In some embodiments, the affected glomeruli include crescents. In some embodiments, renal biopsy includes assessment of the presence of affected glomeruli including crescents. In some embodiments, cellular crescents are present in approximately 10%–50%, 15%–50%, 20%–50%, 30%–50%, 10%–30%, 15%–30%, 20%–30%, 10%–20%, 15%–20%, or 10%–15% or more around Bowman's capsule. In some embodiments, cellular crescents make up about 10%, 15%, 20%, 30%, or more than 50% of the periphery of Bowman's capsule. In some embodiments, fibrous crescents make up about 25%–75%, 30%–65%, 40%–55%, or 50%–60% of the cells and fibrin. In some embodiments, cellular crescents make up about 75%, 80%, 85%, or more than 90% of the cells and fibrin. In some embodiments, cellular crescents make up about 25%, 20%, 15%, or less than 10% of the fibrous matrix. In some embodiments, cellular crescents make up about 75%, 80%, 85%, 90%, or more than 95% of the fibrous matrix. In some embodiments, fibrous crescents make up about 25%, 20%, 15%, or less than 10% of the cells and fibrin.

[0113] In some embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows one or more of the following: (a) segmental endovascular pleostia with substantial lumen reduction, (b) endovascular pleostia with fibrinoid necrosis and cellular crescent formation, (c) nuclear disintegration in glomerular segments, (d) segmental sclerosis of the glomeruli, (e) segmental subendothelial deposits as fuchsinophilic deposits on light microscopy, and / or (f) segmental distribution of IgG immunodeposits and mesangial deposits in the glomerular capillary walls.

[0114] In some embodiments, a subject is classified as having class III LN if a renal biopsy from the subject shows one or more of the following: (a) lesions including extracapillary cell proliferation, (b) crescents, (c) the presence of fibrin and fibrous matrix, and / or (d) 10% or more around Bowman's capsule showing extracapillary cell proliferation.

[0115] In some embodiments, LN is Class IV. In some embodiments, Class IV LN includes biopsies showing that more than 50% of the glomerulus is affected by diffuse LN. In some embodiments, Class III LN includes biopsies showing affected glomeruli with endovascular pleoplasia, usually segmentally distributed, with capillary wall necrosis and the presence or absence of crescent formations. In some embodiments, crescent formations are lesions consisting of a mixture of various cells, comprising extracapillary pleoplasia, where fibrin and fibrous matrix may be present. In some embodiments, crescent formations should occupy more than 10% of the periphery of Bowman's capsule. In some embodiments, cellular crescent formations contain more than 75% cells and fibrin and less than 25% fibrous matrix. In some embodiments, fibrous crescent formations contain more than 75% fibrous matrix and less than 25% cells and fibrin. In some embodiments, fibrous crescent formations contain 25% to 75% cells and fibrin and the remainder fibrous matrix. In some embodiments, fibrinoid necrosis is typically associated with endovascular pleostosis. In some embodiments, fibrinoid necrosis is defined as fibrin associated with the disruption of the glomerular basement membrane and / or the lysis of the mesangial matrix, and the presence of nuclear disintegration is not required in this lesion. Nuclear disintegration is defined as the presence of nuclei that have undergone spontaneous cell death, condensed nuclei, or fragmented nuclei, and this definition is used uniformly in other classification systems as well.

[0116] In some embodiments, if a subject is classified as having class IV LN based on renal biopsy classification, the subject is selected for voclosporine administration. In some embodiments, if a subject is classified as having class IV LN based on renal biopsy classification, the subject is identified as having high responsiveness.

[0117] In some embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows diffuse proliferative glomerulonephritis. In some embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows proliferative glomerulonephritis affecting more than approximately 50% of the glomeruli. In some embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows active or inactive diffuse, segmental or pansegmental intracapillary or extracapillary glomerulonephritis affecting more than 50% of the total glomeruli, and optionally with or without diffuse subendothelial immunodeposits and mesangial changes.

[0118] In some embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows endocapillary pleocytosis. In some embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows diffuse endocapillary pleocytosis. In some embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows endocapillary pleocytosis affecting more than about 50% of the glomeruli. In some embodiments, focal proliferative glomerulonephritis includes about 50%–80%, 60%–80%, 70%–80%, 50%–70%, 60%–70%, or more than 50–60% of the total glomeruli. In some embodiments, focal proliferative glomerulonephritis includes about 50%, 60%, 70%, or more than 80% of the total glomeruli.

[0119] In some embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows one or more of the following: (a) diffuse segmental endocapillary proliferation, (b) pansegmental endocapillary proliferation with leukocyte infiltration, (c) endocapillary proliferation with a widespread wire-loop appearance in the glomerular capillary wall showing subendothelial immunodeposits, (d) subendothelial deposits as fuchsinophilic deposits, (e) a diffuse pansegmental wire-loop appearance without mesangial or endocapillary cell proliferation, and / or (f) a marked immunodeposit overload in the glomerular capillary wall.

[0120] In some embodiments, a subject is classified as having class IV LN if a renal biopsy from the subject shows diffuse segmental lupus nephritis with segmental lesions extending to less than half of the glomerular loops in more than 50% of the involved glomeruli, or if it shows diffuse pansegmental lupus nephritis with pansegmental lesions in more than 50% of the involved glomeruli.

[0121] In some embodiments, if a renal biopsy from a subject shows progressive sclerosing glomerulonephritis, the subject is classified as having class IV LN.

[0122] In some embodiments, a subject is classified as having a class IV LN if a renal biopsy from the subject shows one or more of the following: (a) lesions including extracapillary cell proliferation, (b) crescents, (c) the presence of fibrin and fibrous matrix, and / or (d) 10% or more around Bowman's capsule showing extracapillary cell proliferation.

[0123] In some embodiments, the crescent includes one or more of the following: (a) cellular crescents comprising more than 75% cells and fibrin and less than 25% fibrous matrix; (b) fibrous crescents comprising more than 75% fibrous matrix and less than 25% cells and fibrin; and / or (c) fibrous crescents comprising 25% to 75% cells and fibrin and the remaining fibrous matrix.

[0124] In some embodiments, LN is Class III / IV. In some embodiments, Class III / IV LN includes a biopsy showing leukocyte influx into the mesangium and capillaries. In some embodiments, Class III / IV LN includes a biopsy showing immunodeposits in the subendothelial capillary wall visible by LM (optical microscopy). In some embodiments, Class III / IV LN includes leukocyte (neutrophils and monocytes / macrophages) influx into the mesangium but not into the capillaries (Bajema, et al., Kidney International (2018) 93, 789-796).

[0125] In some embodiments, LN is a mixed biopsy class. In some embodiments, LN is a mixed class V and class III or class IV (mixed class V + class III / IV). In some embodiments, mixed class V + class III / IV LN includes biopsies showing leukocyte influx. In some embodiments, mixed class V + III / IV LN includes biopsies showing numerous subepithelial immunodeposits. In some embodiments, mixed class V + III / IV includes biopsies showing subendothelial deposits (Bajema, et al., Kidney International (2018) 93, 789-796). In some embodiments, mixed class V + III / IV LN includes biopsies showing subendothelial deposits other than wire loops within class V.

[0126] In some embodiments, if a subject is classified as having mixed class V+III / IV LN based on renal biopsy classification, the subject is selected for voclosporine administration. In some embodiments, if a subject is classified as having mixed class V+III / IV LN based on renal biopsy classification, the subject is identified as having high responsiveness.

[0127] In some embodiments, a subject is classified as having a mixed class a class V+III / IV LN if a renal biopsy from the subject shows (a) non-wire-loop endocutaneous deposits within class V and / or (b) subepithelial deposits containing more than 50% of the glomeruli and more than 50% of the loops.

[0128] In some embodiments, the LN is class V. In some embodiments, class V LN includes biopsies showing membranous LN with whole-segmental or segmental continuous granular subepithelial immunodeposits, often accompanied by mesangial immunodeposits. In some embodiments, class V renal biopsies include mesangial pleocytosis. In some embodiments, class V LN includes biopsies showing scattered subendothelial immunodeposits identifiable by immunofluorescence or electron microscopy. In some embodiments, glomeruli affected by class V LN include biopsies showing subepithelial immunodeposits. In some embodiments, affected glomerular class V renal biopsies do not include leukocyte influx (Bajema, et al., Kidney International (2018) 93, 789-796).

[0129] In some embodiments, if a subject is classified as having pure class V LN based on renal biopsy classification, the subject is not selected for voclosporine administration. In some embodiments, if a subject is classified as having pure class V LN based on renal biopsy classification, the subject is not identified as having high responsiveness.

[0130] In some embodiments, a subject is classified as having pure class V LN if a renal biopsy from the subject shows membranous glomerulonephritis. In some embodiments, a subject is classified as having pure class V LN if a renal biopsy from the subject shows membranous LN with whole-segmental or segmental continuous granular subepithelial immunodeposits.

[0131] In some embodiments, a subject is classified as having pure class V LN if a renal biopsy from the subject shows one or more of the following: (a) marked thickening of the glomerular capillary wall in a whole-segmental distribution, (b) subepithelial fuchsinophilic deposits, (c) spikes in the glomerular capillary wall indicating membranous nephropathy, and / or (d) continuous subepithelial IgG deposits in the glomerular capillary wall.

[0132] In some embodiments, LN is Class VI. In some embodiments, Class VI LN includes biopsies showing more than 90% total glomerulosclerosis and with clinical or pathological evidence indicating that the sclerosis is attributable to LN. In some embodiments, Class VI renal biopsies do not show evidence of active, progressing glomerular disease (Weening et al., Kidney International (2004) 65, 521-530).

[0133] In some embodiments, the National Institutes of Health Activity Index (NIH-AI), the National Institutes of Health Chronicity Index (NIH-CI), or the Tubulointerstitial Activity Index (TIAI) is used to evaluate renal biopsies. In some embodiments, renal biopsies taken at baseline and / or after voclosporine administration can be evaluated to determine changes in the NIH-AI, NIH-CI, or TIAI, or the index.

[0134] In some embodiments, examples of NIH-AI and NIH-CI scoring systems are shown in Table 2 below (see, for example, Bajema et al. Kidney Int. 2018;93(4):789-796). [Table 2]

[0135] In some embodiments, the National Institutes of Health Activity Index (NIH-AI) is used to assess disease activity, including histological measurements of inflammation. In some embodiments, the NIH-AI score is determined based on component scores, including endocapillary pleocytosis, neutrophils and nuclear disintegration, hyaline deposits and wire loops, fibrinoid necrosis, cellular or fibrous crescent formation, and interstitial inflammation. In some embodiments, the NIH-AI is calculated based on the sum of the component scores. In some embodiments, the NIH-AI scores the percentage of glomeruli exhibiting each of the following features in a biopsy on a scale of 0 to 3 (score 0 = none, 1 = glomeruli <25%, 2 = glomeruli 25-50%, 3 = glomeruli >50%).

[0136] In some embodiments, the NIH-AI component score includes an endocapillary pleocytosis score on a scale of 0–3. In some embodiments, the NIH-AI component score includes a neutrophil and nuclear decay score on a scale of 0–3. In some embodiments, the NIH-AI component score includes a nitrate deposit and wire loop score on a scale of 0–3. In some embodiments, the NIH-AI component score includes a fibrinoid necrosis score on a scale of (0–3)x2. In some embodiments, the NIH-AI component score includes a cellular or fibrous crescent score on a scale of (0–3)x2. Fibrinoid necrosis and crescents are weighted twice as they have a negative impact on prognosis. In some embodiments, the NIH-AI component score includes an interstitial inflammation score on a scale of 0–3.

[0137] In some embodiments, the NIH-AI includes one or more component scores, with a total score out of 24. In some embodiments, the total NIH-AI score includes all component scores, with a total score out of 24. The score ranges from 0 to 24, with 0 being considered inactive. A high NIH-AI value (above 6) is considered to indicate a high level of kidney impairment.

[0138] In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 3 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 4 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 5 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 6 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 7 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 8 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 9 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 10 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 11 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-AI score of 12 or higher.

[0139] In some embodiments, the National Institutes of Health Chronicity Index (NIH-CI) is used to assess the degree of chronicity, such as irreversible kidney damage and scarring associated with end-stage renal disease. In some embodiments, the NIH-CI score is determined based on component scores, which may include whole-segmental and segmental glomerulosclerosis, fibrous crescents, tubular atrophy, or interstitial fibrosis. In some embodiments, the NIH-CI is calculated based on the sum of the component scores.

[0140] In some embodiments, the NIH-CI component score includes a 0-3 scale for whole-segmental and segmental glomerulosclerosis. In some embodiments, the NIH-CI component score includes a 0-3 scale for fibrous crescent score. In some embodiments, the NIH-CI component score includes a 0-3 scale for tubular atrophy score. In some embodiments, the NIH-CI component score includes a 0-3 scale for interstitial fibrosis score.

[0141] In some embodiments, the NIH-CI includes one or more component scores, and a total score out of 12 is used. In some embodiments, the total NIH-CI score includes all component scores, and a total score out of 12 is used. In some embodiments, the component scores (total renal chronicity score) are added together to classify the overall severity of chronic lesions into mild (total score 0-1), mild (total score 2-4), moderate (total score 5-7), and severe (total score 8 or higher). The NIH-CI index includes the total percentage of overall glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. The NIH-CI score ranges from 0 to 12, with 0 indicating no chronicity. High NIH-CI values ​​(greater than 3) correlate with progression to renal failure.

[0142] In some embodiments, subjects are selected for voclosporine administration if they have an NIH-CI score of 3, 4, 5, or 6 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-CI score of 3 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-CI score of 4 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-CI score of 5 or higher. In some embodiments, subjects are selected for voclosporine administration if they have an NIH-CI score of 6 or higher.

[0143] In some embodiments, this method and use include evaluating one or more of the subject's National Institutes of Health Activity Index (NIH-AI), National Institutes of Health Chronicity Index (NIH-CI), and Tubulointerstitial Activity Index (TIAI) by renal biopsy compared to baseline levels, and selecting the subject for voclosporine administration if the NIH-AI, NIH-CI, and / or TIAI are outside a predetermined range. In some embodiments, the predetermined range of the NIH-AI is one of approximately 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, 0-10, 0-11, 0-12, 0-13, 0-14, 0-15, 0-16, 0-17, 0-18, 0-19, or 0-20. In some embodiments, a predetermined range for NIH-AI is one of the following: less than 1, less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, less than 10, less than 11, less than 12, less than 13, less than 14, less than 15, less than 16, less than 17, less than 18, less than 19, or less than 20. In some embodiments, a predetermined range for NIH-AI is about 0 to 6. In some embodiments, a predetermined range for NIH-CI is one of the following: 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, or 0 to 10. In some embodiments, a predetermined range for NIH-CI is one of the following: less than 1, less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, or less than 10. In some embodiments, a predetermined range for NIH-CI is about 0 to 3. In some embodiments, a predetermined range of TIAI is one of approximately 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, 0-10, 0-11, 0-12, 0-13, 0-14, or 0-15. In some embodiments, a predetermined range of NIH-AI is one of less than 1, less than 2, less than 3, less than 4, less than 5, less than 6, less than 7, less than 8, less than 9, less than 10, less than 11, less than 12, less than 13, less than 14, or less than 15. In some embodiments, a predetermined range of TIAI is approximately 0-5.In some embodiments, a predetermined range for NIH-AI is approximately 0 to 6, or a predetermined range for NIH-CI is approximately 0 to 3, and / or a predetermined range for TIAI is approximately 0 to 5.

[0144] In some embodiments, one or more renal biopsies are taken at various points in time. In some embodiments, subjects are evaluated for one or more renal biopsies, including a baseline renal biopsy taken before voclosporine administration. In some embodiments, subjects are evaluated for one or more renal biopsies, including a renal biopsy taken after voclosporine administration.

[0145] III. Administration of voclosporine Methods and uses are provided, for example, including administering vocrossporine to a selected subject or a subject identified as having high responsiveness, according to any of the methods or uses described herein. In some embodiments, uses of vocrossporine or a composition containing vocrossporine by any of the methods described herein are also provided. In some embodiments, the methods and uses provided include administering an effective amount of vocrossporine to a selected or identified subject. In some embodiments, vocrossporine is administered to a selected or identified subject.

[0146] In some embodiments, voclosporine is administered in doses and timings in accordance with known, recommended, approved, or general treatment plans for voclosporine, such as those recommended or approved for the treatment of lupus nephritis (LN). In some embodiments, exemplary doses, timings, and treatment plans for voclosporine are described herein. In some embodiments, the doses, timings, and treatment plans for voclosporine may be adjusted based on modifications to recommended or approved treatment plans.

[0147] A. Composition In some embodiments, the methods and uses provided involve the use of compositions comprising vocrossporine. In some embodiments, the subjects treated according to the provided embodiments are subjects requiring immunosuppression, such as intermittent, long-term, or lifetime immunosuppression, using a CNI such as vocrossporine or a pharmaceutically acceptable salt thereof. In some embodiments, compositions comprising a therapeutically effective amount of the compound and / or vocrossporine or a pharmaceutically acceptable salt thereof are used in the provided compositions, methods, and uses. Uses include the use of vocrossporine or compositions comprising the same in methods such as therapeutic or preventive methods and treatment plans, and the use of vocrossporine, a pharmaceutically acceptable salt thereof, or compositions comprising the same in the preparation of pharmaceuticals for carrying out such therapeutic or preventive methods and treatments.

[0148] Voclosporine (VCS), described in U.S. Patent No. 9,765,119, which is incorporated herein by reference in its entirety, represents an excellent central immunosuppressant (CNI) due to its low toxicity and the ability to be administered in a range of doses to maximize patient tolerance and efficacy. In some embodiments, voclosporine is administered to patients requiring treatment with a CNI in combination with additional therapeutic agents, including background immunosuppression therapy. In some embodiments, voclosporine exhibits a linear pharmacokinetic profile, resulting in a consistent dose-concentration relationship. In some embodiments, voclosporine has the advantage of eliminating the need for therapeutic agent monitoring, which is typically associated with the use of CNIs.

[0149] Compared to cyclosporine A (CsA), voclosporine has a modified functional group at one amino acid residue in its molecule, resulting in enhanced binding to calcineurin and improved metabolic stability. Voclosporine has been studied in the fields of psoriasis and kidney transplantation, and recently received FDA approval for the treatment of active lupus nephritis (LN) in combination with background immunosuppressive therapy. Observations suggest that VCS is more potent and less toxic than other immunosuppressants in its class at the therapeutic level.

[0150] VCS has been shown to inhibit norovirus replication in a CypA-dependent manner and to be more effective than CsA. This modification alters the binding of voclosporin to calcineurin, and has been shown to increase binding affinity by up to 5 times compared to CsA, both in vitro and in vivo (Kuglstatter et al., Acta Cryst. 2011;D67:119-23). ​​This modification also altered the metabolic profile of voclosporin by shifting metabolism away from amino acid-1, the major metabolic site of CsA. This change in metabolic profile leads to faster excretion of metabolites and reduced metabolite exposure compared to CsA. The combination of increased potency and reduced metabolite exposure of voclosporin compared to CsA suggests the potential for improved PK / PD relationships, reduced doses, and improved safety profiles compared to CsA.

[0151] Voclosporine is a cyclosporine analog modified with a 1,3-diene substituent at a 1-amino acid residue. Voclosporine may exist as an isomer mixture of Z and E isomers, and in some embodiments, the mixture may contain at least about 90% (e.g., about 90% to about 95%) of E isomers and about 10% or less (e.g., about 10% to about 5%) of Z isomers. In some embodiments, a voclosporine composition comprises an isomer mixture of voclosporine and its pharmaceutically acceptable salts, the isomer mixture containing about 90% to about 95% of E isomers and about 10% to about 5% of Z isomers. In some embodiments, a voclosporine composition comprises an isomer mixture of voclosporine and its pharmaceutically acceptable salts, the isomer mixture containing about 90% to about 95% of E isomers and about 10% to about 5% of Z isomers. Boxrosporine has the structure shown below and is disclosed in U.S. Patent No. 7,332,472, which is incorporated herein by reference in its entirety. [ka]

[0152] A mixture of the E and Z isomers of voclosporine is described in U.S. Patent No. 6,998,385. A mixture in which the E isomer is dominant is described in U.S. Patent No. 7,332,472. Various formulations of voclosporine mixtures are also described in U.S. Patents No. 7,060,672, No. 7,429,562, and No. 7,829,533.

[0153] Boclosporine is cyclo{{(6E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6,8-nonadienoyl}-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl -L-Valyl}, (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-((1R,2R,E)-1-hydroxy-2-methylhepta-4,6-dien-1-yl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,1 0,13,16,19,22,25,28,31-Undecazacyclotritricontane-2,5,8,11,14,17,20,23,26,29,32-Undecaone, or (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methylhepta-4,6-dieny Also known as LUPKYNIS®-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone. Boxrosporine is a registered trademark of LUPKYNIS® and ISA. TXIt is also known as 247, ISA247, LX211, or Luveniq®. In some embodiments, references to voriconazole and administration of voriconazole may also include administration of a pharmaceutically acceptable salt of voriconazole and a pharmaceutically acceptable salt of voriconazole. In some embodiments, a "pharmaceutically acceptable salt" refers to any salt of a compound (e.g., voriconazole) that is known to be non-toxic and commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of voriconazole retains the biological effectiveness of voriconazole and is not undesirable biologically or otherwise.

[0154] The empirical formula of voriconazole is C 63 H 111 N 11 O 12 with a molecular weight of 1214.6 g / mol. At room temperature, voriconazole is soluble in acetone, acetonitrile, ethanol, methanol and is substantially insoluble in heptane (USP). Voriconazole is poorly soluble in water (less than 0.1 g / L at 20 °C) and decomposes and dissolves above 144 °C.

[0155] In some embodiments of the methods and uses provided herein, the method or treatment comprises administering voriconazole or a pharmaceutically acceptable salt thereof together with a therapeutically effective amount of MMF and / or a therapeutically effective amount of corticosteroid. In some embodiments, the method or treatment comprises administering voriconazole or a pharmaceutically acceptable salt thereof without administering a therapeutically effective amount of MMF and / or a therapeutically effective amount of corticosteroid.

[0156] In some embodiments, the method and use comprise administering a composition such as a pharmaceutical composition or a therapeutic composition comprising voriconazole. In some embodiments, the method and use comprise administering a composition comprising voriconazole.

[0157] In some embodiments, a composition containing voclosporine includes an isomer mixture of the voclosporine E isomer and the Z isomer. A mixture of the voclosporine E isomer and the Z isomer is described in U.S. Patent No. 6,998,385. A mixture predominantly composed of the E isomer is described in U.S. Patent No. 7,332,472, which describes typical indications that can be treated with an isomerized voclosporine mixture, including glomerulonephritis. Various formulations of voclosporine mixtures are also described in U.S. Patents No. 7,060,672, No. 7,429,562, and No. 7,829,533. In some embodiments, the isomer mixture contains at least about 99% by weight, about 98% by weight, about 97% by weight, about 96% by weight, about 95% by weight, about 94% by weight, about 93% by weight, about 92% by weight, about 91% by weight, about 90% by weight, about 80% by weight, about 70% by weight, about 60% by weight, about 50% by weight, about 40% by weight, about 30% by weight, about 20% by weight, or about 10% by weight of vocrossporine E isomers. In some embodiments, the isomer mixture contains at least 90% by weight of vocrossporine E isomers. In some embodiments, the isomer mixture contains at least 95% by weight of vocrossporine E isomers.

[0158] In some embodiments, the pharmaceutical composition (e.g., containing voclosporine) is a pharmaceutical formulation or comprises a pharmaceutical formulation. In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, buffers, carriers and / or vehicles. In some embodiments, the pharmaceutical composition contains a pharmaceutical carrier and excipients suitable for the intended type of administration.

[0159] In some embodiments, the generally pharmaceutically acceptable carrier or vehicle (e.g., one present in a pharmaceutically acceptable buffer) may be any known in the art. (Remington's Pharmaceutical Sciences, EW Martin, Mack Publishing Co., Easton, Pa., 19) thEdition (1995) describes compositions and formulations suitable for the pharmaceutically acceptable delivery of one or more therapeutic compounds. Pharmacopoeias are typically prepared in accordance with generally accepted pharmacopoeias for use in animals and humans, taking into consideration approval from regulatory authorities or other agencies.

[0160] A pharmaceutical composition may include a carrier administered with the compound, such as a diluent, adjuvant, excipient, or medium. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Such a composition generally contains a therapeutically effective amount of the compound in a purified form, along with an appropriate amount of carrier, providing a form for appropriate administration to the patient. Such pharmaceutical carriers may be sterile solutions, such as water, and oils, including those of petroleum, animal, plant, or synthetic origin. When the pharmaceutical composition is administered intravenously, water is the usual carrier. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid carriers, particularly for injectable formulations. The composition may also optionally contain small amounts of wetting or emulsifying agents or pH buffers. Typically, compositions containing the compound are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition, 1985, 126). Generally, the formulation method of the formulation differs depending on the route of administration. Exemplary formulations of voclosporine mixtures are also described in U.S. Patents No. 7,060,672, No. 7,429,562, and No. 7,829,533.

[0161] B. Dosage and timing of administration of voclosporine In some embodiments, voclosporine is administered in predetermined daily doses of 39.5 mg BID, 31.6 mg BID, 23.7 mg BID, 15.8 mg BID, and 7.9 mg BID. In some embodiments, the predetermined daily dose is one of approximately 7.9–23.7, 23.7–31.6, 31.6–39.5, or 39.5–79 mg of voclosporine. In some embodiments, the predetermined daily dose is approximately 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 60, 80, 100 mg of voclosporine, or any value in between.

[0162] In some embodiments, the first time point is one of approximately 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, or 48 hours before initiating voclosporine treatment. In some embodiments, the first time point is immediately before initiating voclosporine treatment. In some embodiments, the second time point is one of approximately 1, 2, 3, 4, 5, 10, 14, 15, 20, 25, 28, 30, 40, or 50 days or more after initiating voclosporine treatment, or any period in between. In some embodiments, the second time point is any one of the following: approximately 1, 2, 3, 4, 5, 8, 10, 12, 15, 16, 20, 24, 25, 28, 30, 32, 35, 36, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 150 weeks or more after the start of vocrossporine treatment, or any period in between.

[0163] In some embodiments, a given daily dose of voclosporine that is effective is one of 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, 35, 39.5, 40, 45, or 50 mg BIDs, or any amount in between. In some embodiments, a given daily dose of voclosporine is 39.5 mg BID, 31.6 mg BID, 23.7 mg BID, 15.8 mg BID, or 7.9 mg BID.

[0164] In some embodiments, the subject has severe renal impairment at baseline, and the prescribed daily effective dose of voclosporine is one of the following BIDs: 2, 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, or 35 mg. In some embodiments, the subject has severe renal impairment at baseline, and the prescribed daily effective dose of voclosporine is approximately 15.8 mg BID.

[0165] In some embodiments, the subject has moderate hepatic impairment, and the prescribed daily dose of effective voclosporine is one of 2, 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, or 35 mg BID, or any amount in between. In some embodiments, the subject has moderate hepatic impairment, and the prescribed daily dose of effective voclosporine is approximately 15.8 mg BID.

[0166] In some embodiments, voclosporine is administered over a long period of time. In some embodiments, voclosporine is administered once or more times. In some embodiments, administration of voclosporine includes an initial dose (or first dose) and one or more subsequent doses.

[0167] In some aspects of the methods and uses provided herein, voclosporine is administered four times daily, three times daily, twice daily (BID), or once daily. In some aspects, voclosporine is administered four times daily. In some aspects, voclosporine is administered three times daily. In some aspects, voclosporine is administered twice daily (BID). In some aspects, voclosporine is administered once daily.

[0168] In some embodiments, voclosporine is administered at a constant dose throughout the entire voclosporine treatment period. In some embodiments, the dose of voclosporine may be changed during the voclosporine treatment period, for example, based on an evaluation of the treatment.

[0169] In some embodiments, the daily dose of vocrossporine is approximately 1 mg to 250 mg, approximately 5 mg to 250 mg, approximately 10 mg to 250 mg, approximately 50 mg to 250 mg, approximately 100 mg to 250 mg, approximately 150 mg to 250 mg, approximately 200 mg to 250 mg, 1 mg to 200 mg, approximately 5 mg to 200 mg, approximately 10 mg to 200 mg, approximately 50 mg to 200 mg, approximately 100 mg to 250 mg. The dosages are 200mg, approximately 150mg to 200mg, approximately 1mg to 150mg, approximately 5mg to 150mg, approximately 10mg to 150mg, approximately 50mg to 150mg, approximately 100mg to 150mg, approximately 1mg to 100mg, approximately 5mg to 100mg, approximately 10mg to 100mg, approximately 50mg to 100mg, approximately 1mg to 50mg, approximately 5mg to 50mg, or approximately 10mg to 50mg. In some embodiments, the daily dose of voclosporine is approximately 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg. In some embodiments, the daily dose of voclosporine is at least about 1 mg, at least about 5 mg, at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, or at least about 200 mg.

[0170] In some embodiments, the dose of voclosporine is approximately 0.1 mg / kg / day to approximately 2 mg / kg / day, approximately 0.5 mg / kg / day to approximately 2 mg / kg / day, approximately 1 mg / kg / day to approximately 2 mg / kg / day, approximately 1.5 mg / kg / day to approximately 2 mg / kg / day, approximately 0.1 mg / kg / day to approximately 1.5 mg / kg / day, approximately 0.5 mg / kg / day to approximately 1.5 mg / kg / day, approximately 1 mg / kg / day to approximately 1.5 mg / kg / day, approximately 0.1 mg / kg / day to approximately 1.0 mg / kg / day, approximately 0.5 mg / kg / day to approximately 1.0 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 0.5 mg / kg / day. In some embodiments, the dose of voclosporine is approximately 0.1, approximately 0.2, approximately 0.3, approximately 0.4, approximately 0.5, approximately 0.6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, approximately 1.5, approximately 1.6, approximately 1.7, approximately 1.8, approximately 1.9, or approximately 2.0 mg / kg / day. In some embodiments, the daily dose of voclosporine is at least about 0.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, or at least about 2.0 mg / kg / day.

[0171] In some embodiments, the appropriate dose of voclosporine increases by approximately 7.9 mg in increments. In some embodiments, the dose of voclosporine is approximately 7.9 mg QD, approximately 15.8 mg QD, approximately 23.7 mg QD, approximately 31.6 mg QD, approximately 39.5 mg QD, approximately 47.4 mg QD, approximately 55.3 mg QD, approximately 63.2 mg QD, approximately 71.1 mg QD, approximately 79.0 mg QD, approximately 86.9 mg QD, approximately 94.8 mg QD, approximately 102.7 mg QD, or approximately 110.6 mg QD. In some embodiments, the dose of voclosporine is approximately 7.9 mg BID, approximately 15.8 mg BID, approximately 23.7 mg BID, approximately 31.6 mg BID, approximately 39.5 mg BID, approximately 47.4 mg BID, or approximately 55.3 mg BID. In some embodiments, the dose of voclosporine is approximately 7.9 mg BID. In some embodiments, the dose of voclosporine is approximately 15.8 mg BID.

[0172] In some embodiments, appropriate doses of voclosporine are increments of 7.9 mg, including 39.5 mg, 31.6 mg, 23.7 mg, 15.8 mg, or 7.9 mg. Lower doses yield better results compared to high doses of 39.5 mg twice daily. Low doses of 15.8 mg or 7.9 mg twice daily are also effective. In some embodiments, the dose of voclosporine is approximately 23.7 mg BID.

[0173] The indicated dose, for example 23.7 mg, is subject to slight variation (usually ±10%), or in the case of 23.7 mg, it may be specified between 21 mg and 26 mg BID. This is due to inconsistencies in the manufacturing of the drug, and the ideal dose is the specified dose, i.e., 23.7 mg BID. Equivalent variations apply to alternative doses and differential adjustments.

[0174] In some embodiments, the trough blood level is approximately 25 to approximately 60 ng / mL. In some embodiments, the trough blood level is approximately 25, approximately 30, approximately 35, approximately 40, approximately 45, approximately 50, approximately 55, or approximately 60 ng / mL.

[0175] In some embodiments, the therapeutically effective dose of voclosporine corresponds to a C-maximum at concentrations of approximately 0.05 μM to 10 μM, 0.1 μM to 5 μM, 0.2 μM to 2.5 μM, 0.3 μM to 1.0 μM, 0.4 μM to 0.9 μM, 0.5 μM to 0.8 μM, 0.1 μM to 0.5 μM, or 0.2 μM to 0.4 μM, and is an estimated, achievable, or attainable amount. In some embodiments, the therapeutically effective dose of voclosporine corresponds to a C-max at concentrations of approximately 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 μM or less, and is an estimated, achievable, or achievable amount. In some embodiments, the therapeutically effective dose of voclosporine corresponds to a C-max at a concentration of approximately 0.2 μM, and is an estimated, achievable, or achievable amount. In some embodiments, the therapeutically effective dose of voclosporine corresponds to a C-max at a concentration of approximately 0.3 μM and is an estimated, achievable, or attainable amount. In some embodiments, the therapeutically effective dose of voclosporine corresponds to a C-max at a concentration of approximately 0.4 μM and is an estimated, achievable, or attainable amount. In some embodiments, the therapeutically effective dose of voclosporine corresponds to a C-max at a concentration of approximately 0.5 μM and is an estimated, achievable, or attainable amount.

[0176] In some embodiments, voclosporine is administered according to a treatment plan over the voclosporine treatment period. In some embodiments, the voclosporine treatment plan further includes evaluating the subject's estimated glomerular filtration rate (eGFR) at at least a first and second time point on different days during the voclosporine treatment period, and if the subject's eGFR decreases between the first and second time points to a predetermined value exceeding a target percentage, reducing the daily dose by 7.9 mg BID increments or discontinuing voclosporine administration to the subject. In some embodiments, the voclosporine treatment plan further includes evaluating the subject's estimated glomerular filtration rate (eGFR) at at least a first and second time point on different days during the voclosporine treatment period, and if the subject's eGFR decreases between the first and second time points to a predetermined value exceeding a target percentage, reducing the daily dose by 7.9 mg BID increments or discontinuing voclosporine administration to the subject.

[0177] In some embodiments, the duration of voclosporine treatment is at least approximately 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 weeks, or one, two, or three years, or any duration in between. In some embodiments, the first time point is immediately before the start of voclosporine treatment. In some examples, the given values ​​are approximately 30 to approximately 110 ml / min / 1.73m 2 The range is as follows. In some embodiments, the predetermined value is approximately 50 to approximately 90 ml / min / 1.73 m 2 The range is as follows: In some embodiments, the specified values ​​are 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, and 100-110 ml / min / 1.73m 2 It is within one of the following ranges. In some embodiments, the given value is approximately 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m 2 It is one of the following. In some embodiments, the predetermined value is approximately 60 ml / min / 1.73 m 2In some embodiments, the target percentage is in the range of approximately 10% to approximately 60%. In some embodiments, the target percentage is in the range of approximately 20% to approximately 45%. In some embodiments, the target percentage is in one of the following ranges: approximately 10% to 20%, 20% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, and 55% to 60%. In some embodiments, the target percentage is approximately 20%. In some embodiments, the target percentage is approximately 30%.

[0178] In some embodiments, the voclosporine treatment plan involves evaluating the subject's estimated glomerular filtration rate (eGFR) at least at first and second time points on different days during the voclosporine treatment period, and determining when the subject's eGFR has decreased by 20% or more between the first and second time points to 60 ml / min / 1.73m². 2 If the dose falls below a certain level, the daily dose may be reduced by a 7.9 mg BID increment, or voclosporine administration to the subject may be discontinued. In some cases, the voclosporine treatment plan may further include assessing the subject's estimated glomerular filtration rate (eGFR) at least at first and second time points on different days during the voclosporine treatment period, and if the subject's eGFR decreases by more than 20% between the first and second time points to a predetermined level, the daily dose may be reduced by a 7.9 mg BID increment(s) or voclosporine administration to the subject may be discontinued.

[0179] In some embodiments, the treatment plan includes assessing the subject's estimated glomerular filtration rate (eGFR) at at least a first and second time point on different days during the voclosporine treatment period, the first time point being immediately before initiating voclosporine treatment. In some embodiments, the treatment plan further includes assessing the subject's eGFR every two weeks after initiating voclosporine treatment. In some embodiments, the treatment plan includes assessing the subject's eGFR every two weeks for the first month after initiating voclosporine treatment, and then every four weeks thereafter. In some embodiments, if the subject's eGFR decreases by more than a target percentage and falls below a predetermined value at any assessment after initiating voclosporine treatment, the treatment plan includes reducing the daily dose in 7.9 mg BID increments or discontinuing voclosporine administration to the subject.

[0180] In some embodiments, the treatment plan includes evaluating the subject's eGFR at at least a first and second time point on different days during the voclosporine treatment period, with the first time point being immediately before initiating voclosporine treatment. In some embodiments, if the subject's eGFR has decreased to a predetermined value by more than a target percentage compared to the eGFR at the first time point in the evaluation after initiating voclosporine treatment, the treatment plan includes reducing the daily dose by 7.9 mg BID. In some embodiments, if the subject's eGFR has decreased to a predetermined value by more than a target percentage compared to the eGFR at the first time point in the evaluation after initiating voclosporine treatment, and the daily dose has been reduced by 7.9 mg BID, the treatment plan includes evaluating the subject's eGFR two weeks after the dose reduction, and further includes reducing the daily dose by a second 7.9 mg BID if the subject's eGFR has decreased to a predetermined value by more than a target percentage compared to the eGFR at the first time point in the evaluation two weeks after the first dose reduction. In some embodiments, the treatment plan includes one or more dose reductions, and the treatment plan includes evaluating the subject's eGFR every two weeks after one or more dose reductions, and if the subject's eGFR has decreased to less than a target percentage compared to the eGFR at the first time point, the daily dose is increased by 7.9 mg BID at each eGFR evaluation. In some embodiments, the dose increase does not cause the dose to exceed the initial predetermined dose. In some examples, the predetermined value is approximately 30 to approximately 110 ml / min / 1.73 m 2 The range is as follows. In some embodiments, the predetermined value is approximately 50 to approximately 90 ml / min / 1.73 m 2 The range is as follows: In some embodiments, the specified values ​​are 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, and 100-110 ml / min / 1.73m 2 It is within one of the following ranges. In some embodiments, the given value is approximately 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m 2 It is one of the following. In some embodiments, the predetermined value is approximately 60 ml / min / 1.73 m 2In some embodiments, the target percentage is in the range of approximately 10% to approximately 60%. In some embodiments, the target percentage is in the range of approximately 10% to approximately 45%. In some embodiments, the target percentage is in one of the following ranges: approximately 10% to 20%, 20% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, and 55% to 60%. In some embodiments, the target percentage is approximately 20%.

[0181] In some aspects, the subject's eGFR decreased by approximately 20% to 30% compared to the eGFR at the first time point in the evaluation after the start of voclosporine treatment, reaching 60 ml / min / 1.73 m². 2 If the value falls below a certain level, the treatment plan includes reducing the daily dose by 7.9 mg BID. In some embodiments, the subject's eGFR decreases by approximately 20% to 30% compared to the eGFR at the first time point when evaluated after the initiation of voclosporine treatment, resulting in a 60 ml / min / 1.73 m² eGFR. 2 The patient's eGFR was reduced to less than 7.9 mg BID, and the treatment plan included evaluating the patient's eGFR two weeks after the dose reduction, and at the evaluation two weeks after the first dose reduction, the patient's eGFR was reduced by more than 20% compared to the eGFR at the first time point to 60 ml / min / 1.73 m 2 If the eGFR falls below a certain level, the daily dose is further reduced a second time by 7.9 mg BID. In some embodiments, the treatment plan includes one or more dose reductions, and the treatment plan includes evaluating the subject's eGFR every two weeks after one or more dose reductions, and if the subject's eGFR has decreased to less than 20% compared to the eGFR at the first time point, the daily dose is increased by 7.9 mg BID at each eGFR evaluation. In some embodiments, the dose increase does not result in a dose exceeding the initial prescribed dose.

[0182] In some embodiments, the treatment plan includes evaluating the subject's eGFR at at least a first and second time point on different days during the voclosporine treatment period, with the first time point being immediately before initiating voclosporine treatment. In some embodiments, if the subject's eGFR falls below a predetermined value by at least a first target percentage compared to the eGFR at the first time point in any evaluation after initiating voclosporine treatment, the treatment plan includes discontinuing voclosporine administration to the subject. In some embodiments, if the subject's eGFR falls below a predetermined value by at least a target percentage compared to the eGFR at the first time point in an evaluation after initiating voclosporine treatment, and voclosporine administration to the subject is discontinued, the treatment plan includes evaluating the subject's eGFR two weeks after discontinuation, and further includes resuming administration at the initial predetermined dose if, two weeks after discontinuation, the subject's eGFR falls below a second target percentage compared to the eGFR at the first time point in the evaluation. In some embodiments, the predetermined value is approximately 50 to approximately 90 ml / min / 1.73 m 2 The range is as follows: In some embodiments, the specified values ​​are 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, and 100-110 ml / min / 1.73m 2 It is within one of the following ranges. In some embodiments, the given value is approximately 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m 2 It is one of the following. In some embodiments, the predetermined value is approximately 60 ml / min / 1.73 m 2In some embodiments, the first target percentage is in the range of approximately 10% to approximately 60%. In some embodiments, the first target percentage is in the range of approximately 20% to approximately 45%. In some embodiments, the first target percentage is in one of the following ranges: approximately 10% to 20%, 20% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55%, and 55% to 60%. In some embodiments, the first target percentage is approximately 30%. In some embodiments, the second target percentage is in the range of approximately 10% to approximately 60%. In some embodiments, the second target percentage is in the range of approximately 10% to approximately 45%. In some embodiments, the second target percentage is one of the following ranges: approximately 10%–20%, 20%–30%, 30%–35%, 35%–40%, 40%–45%, 45%–50%, 50%–55%, and 55%–60%. In some embodiments, the second target percentage is approximately 20%.

[0183] In some embodiments, the subject's eGFR decreased by 30% or more compared to the eGFR at the first time point, at any assessment after the start of voclosporine treatment, to 60 ml / min / 1.73 m². 2 If the eGFR falls below this level, the treatment plan includes discontinuing voclosporine administration to the subject. In some embodiments, the evaluation after the start of voclosporine treatment indicates that the subject's eGFR has decreased by 30% or more compared to the eGFR at the first time point and is 60 ml / min / 1.73m². 2 If the eGFR falls below a certain level and administration of voclosporine to the subject is discontinued, the treatment plan further includes evaluating the subject's eGFR two weeks after discontinuation, and if, two weeks after discontinuation of voclosporine, the subject's eGFR has decreased by less than 20% compared to the eGFR at the first time point in the evaluation, administration will be resumed at the initial prescribed dose.

[0184] An exemplary treatment plan for voclosporine includes measuring eGFR immediately before the first dose of voclosporine and at a second time point at least one day later, and (i) The subject's eGFR decreased by more than 30% between the first time point and the second time point, reaching 60 mL / min / 1.73 m 2If the value falls below a certain level, discontinue administration of voclosporine to the subject or reduce the dose. (ii) The subject's eGFR decreased by 20% to 30% between the first and second time points and reached 60 ml / min / 1.73 m². 2 If the value falls below a certain level, administer a reduced dose of voclosporine to the subject, and (iii) If the subject's eGFR decreases by less than 20% between the first and second time points, the subject will continue to be administered the same prescribed daily dose of voclosporine.

[0185] In some aspects, the voclosporine treatment plan involves determining, before implementing the treatment plan in the subject, that (a) the subject's urinary protein-creatinine ratio (UPCR) is greater than 1 mg / mg as measured in the first morning urination or 24-hour urine, and (b) the subject's eGFR is 45 ml / min / 1.73 mm as measured by the Cooperative Equation for Chronic Kidney Disease (CKD-EP1). 2 This even includes determining that the subject is suitable for a treatment plan by determining that it exceeds a certain threshold, and the subject is deemed suitable for a treatment plan if conditions (a) and (b) are met. In some embodiments, the treatment plan includes determining that the subject's urinary protein-creatinine ratio (UPCR), measured in the subject's first morning urination or 24-hour urine, is greater than 1.5 mg / mg.

[0186] In some embodiments, voclosporine is administered to the subject once or more times. In some embodiments, the subject has previously received one or more doses of mycophenolate mofetil (MMF) and a low-dose steroid (e.g., methylprednisolone, prednisone, or a derivative thereof). In some embodiments, the first of the one or more doses of voclosporine is administered after the first of the one or more doses of mycophenolate mofetil (MMF) and a low-dose steroid (e.g., methylprednisolone, prednisone, or a derivative thereof) for immunosuppression. In some embodiments, the administration of mycophenolate mofetil (MMF) and a low-dose steroid (e.g., methylprednisolone, prednisone, or a derivative thereof) for immunosuppression is performed concurrently with the administration of voclosporine.

[0187] In some embodiments, the predicted duration of voclosporine treatment is approximately 10–100 weeks, 10–90 weeks, 10–80 weeks, 10–70 weeks, 10–60 weeks, 10–50 weeks, 10–40 weeks, 10–30 weeks, or 10–20 weeks. In some embodiments, the predicted duration of voclosporine treatment is at least approximately 24 weeks, 36 weeks, 48 ​​weeks, 52 weeks, 60 weeks, 72 weeks, 84 weeks, or 96 weeks or more. In some embodiments, the predicted duration of voclosporine treatment is at least approximately 24 weeks. In some embodiments, the predicted duration of voclosporine treatment is at least approximately 48 weeks. In some embodiments, the predicted duration of voclosporine treatment is at least approximately 52 weeks. In some embodiments, the predicted duration of voclosporine treatment is at least approximately 18 months. In some embodiments, the predicted duration of voclosporine treatment is at least approximately 24 months. In some embodiments, the predicted duration of voclosporin treatment is at least approximately 36 months. In some embodiments, the predicted duration of voclosporin treatment is at least approximately 48 months.

[0188] C. Route of administration In some embodiments of the methods and uses disclosed herein, voclosporine may be administered in any suitable form and via any suitable route that provides a sufficient level of voclosporine, such as enteral administration (e.g., oral, sublingual, or rectal administration) or parenteral administration (e.g., intravenous injection, intramuscular injection, subcutaneous injection, intravenous infusion, or inhalation / blow-in).

[0189] In some embodiments, voclosporine is administered enterally. Exemplary routes of enteral administration include, but are not limited to, oral administration, sublingual administration, and rectal administration (e.g., via the rectum). In some embodiments, the enteral administration includes oral administration. In some embodiments, the enteral administration includes sublingual administration. In some embodiments, the enteral administration includes rectal administration.

[0190] In some embodiments, voclosporine is administered parenterally. Exemplary routes of parenteral administration include, but are not limited to, intravenous injection, intramuscular injection, subcutaneous injection, intravenous infusion, and inhalation / blow-in.

[0191] In some embodiments, voclosporine is administered by inhalation or inhalation. Exemplary types of preparations for inhalation and / or inhalation include, but are not limited to, sprays, aerosols, mists, capsules, powders, or cartridges for use with inhalers or inhalers, and solutions / suspensions for spraying. In some embodiments, voclosporine is administered in the form of an aerosol, spray, mist, or powder. In some embodiments, voclosporine is administered in the form of an aerosol. Examples of various types of devices for administration by inhalation or inhalation include, but are not limited to, nebulizers, medium-dose inhalers (MDIs), and dry powder inhalers.

[0192] D. Additional medications In some embodiments, this method or treatment also includes administering an effective amount of an additional therapeutic agent. In some embodiments, the method also includes administering an effective amount of an additional therapeutic agent. In some embodiments, the additional therapeutic agent includes a background immunosuppressive therapy such as mycophenolate mofetil (MMF), or one or more corticosteroids.

[0193] In some embodiments, subjects are administered voclosporine concurrently with mycophenolate mofetil (MMF) and a low-dose steroid (e.g., methylprednisolone, prednisone, or a derivative thereof) for immunosuppression. In some embodiments, voclosporine is administered to subjects selected according to the criteria described herein. In some embodiments, the administration of mycophenolate mofetil (MMF) and a low-dose steroid (e.g., methylprednisolone, prednisone, or a derivative thereof) for immunosuppression is carried out using a tapering protocol, and subjects are administered voclosporine.

[0194] In some embodiments, this method or use further comprises administering an effective amount of mycophenolate mofetil (MMF) to the subject. In some embodiments, this method or use further comprises administering an effective amount of corticosteroid to the subject.

[0195] In some embodiments, in addition to voclosporine, administration of MMF and a reduction in the dose of corticosteroids are also performed. In some embodiments, the exemplary dose of MMF includes 2 g per day, and the exemplary dose of oral corticosteroids includes a dose that is gradually reduced from 20-25 mg per day to 2.5 mg per day over 16 weeks.

[0196] For example, with regard to corticosteroids, subjects weighing 45 kg or more receive 0.5 g of methylprednisolone intravenously on days 1 and 2 of the study, and oral corticosteroid therapy is started from day 3. Subjects weighing less than 45 kg receive only half the dose.

[0197] For oral prednisone, exemplary starting doses for oral administration, including 20 mg / day for subjects weighing less than 45 kg and 25 mg / day for subjects weighing more than 45 kg, are shown in Tables 3 and 4 below, along with an example corticosteroid administration schedule. [Table 3] [Table 4]

[0198] Voclosporine is a sensitive CYP3A4 substrate. Concomitant administration with potent or moderate CYP3A4 inhibitors increases voclosporine exposure. In some embodiments, subjects treated with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) or moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole, diltiazem) showed higher voclosporine C2 levels compared to corresponding subjects not treated with such inhibitors. 最大 and / or AUC increases. In some embodiments, subjects administered with a potent or moderate CYP3A4 inhibitor showed increased C of voclosporine compared to corresponding subjects not administered with such CYP3A4 inhibitor. 最大 The AUC of voclosporine increases by approximately 1.1 times, 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2.0 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, 3.0 times, 4.0 times, 5.0 times, or 10.0 times or more. In some embodiments, subjects administered with a potent or moderate CYP3A4 inhibitor show an increase of approximately 2.0 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, 3.0 times, 3.0 times, 3.2 times, 3.4 times, 3.6 times, 3.8 times, 4.0 times, 5.0 times, or 10.0 times or more compared to corresponding subjects not administered with such a CYP3A4 inhibitor.

[0199] IV. Definition As used herein, in the appended claims, the singular forms "a," "an," and "the" also include the plural forms unless the context clearly indicates otherwise.

[0200] Where used herein, unless otherwise specified, the terms “about” and “approximately” when used in relation to dosage or quantity refer to dosages or quantities within 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified dosage or quantity.

[0201] As used herein, “pharmaceutically acceptable” means that a substance is not biologically or otherwise undesirable, for example, that, when incorporated into a pharmaceutical composition administered to a patient, does not cause a significant undesirable biological effect or have harmful interactions with other components of the composition containing the substance. Pharmacologically acceptable carriers or excipients preferably meet the necessary standards for toxicity and manufacturing testing and / or are listed in the Inactive Ingredient Guide prepared by the US Food and Drug Administration.

[0202] The term “pharmaceutically acceptable salt” refers to any salt of any of the compounds herein that is known to be nontoxic and is commonly used in pharmaceutical literature. In some embodiments, pharmaceutically acceptable salts of compounds retain the biological efficacy of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Bergeetal, Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0203] When the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, when the compound is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds (see, for example, Bergeetal, Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19). Those skilled in the art will understand the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0204] As used herein, “therapeutic dose” means the amount that produces a desired pharmacological and / or physiological effect on a condition. Such effect may be prophylactic in that it completely or partially prevents a condition or its symptoms, and / or therapeutic in that it partially or completely cures the condition and / or side effects caused by the condition.

[0205] The terms “to treat,” “to treat,” and “treatment” refer to an approach to obtain an outcome, including beneficial or desired clinical outcomes. Beneficial or desired outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms of a disease or disorder; reducing the severity of a disease or disorder; stabilizing a disease or disorder (e.g., preventing or delaying the worsening of a disease or disorder); delaying the onset or recurrence of a disease or disorder; delaying or slowing the progression of a disease or disorder; improving the state of a disease or disorder; providing remission (partial or complete) of a disease or disorder; reducing the dose of one or more other medications required to treat a disease or disorder; enhancing the effect of another medication used to treat a disease or disorder; delaying the progression of a disease or disorder; improving quality of life; and / or extending the patient’s survival. Similarly, “treatment” includes mitigating the pathological consequences of a disease or disorder. The methods of this disclosure aim to achieve any one or more of these forms of treatment.

[0206] The term "subject" refers to animals including, but not limited to, primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. In this specification, the terms "subject" and "patient" are used interchangeably to refer to mammalian subjects, such as humans.

[0207] V. Exemplary Embodiments The provided embodiments are as follows: 1. A method for treating lupus nephritis (LN), wherein the method is: (a) Select subjects who are classified as having Class III, Class IV, or mixed Class V and III or IV (mixed Class V+III / IV) LN based on renal biopsy classification, (b) The method comprising administering voclosporine to the selected subject. 2. A method for treating lupus nephritis (LN), the method comprising administering voclosporine to a subject previously classified as having class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) lupus nephritis (LN) based on renal biopsy classification. 3. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects classified as having class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) lupus nephritis (LN) based on renal biopsy classification. 4. A method for evaluating the likelihood of responding to voclosporine treatment, the method comprising identifying subjects classified as having class III, class IV, or mixed class V and III or IV (mixed class V+III / IV) lupus nephritis (LN) based on renal biopsy classification as having a high likelihood of responding to voclosporine treatment. 5. The method according to Embodiment 3 or 4, further comprising administering voclosporine to the selected subject or the identified subject. 6. The renal biopsy classification is the method according to any one of Embodiments 1 to 5, including the International Society of Nephrology / Renal Pathology Society (ISN / RPS) classification. 7. The renal biopsy classification is the method according to any one of Embodiments 1 to 6, including the International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2003 classification. 8. The renal biopsy classification is the method according to any one of Embodiments 1 to 6, including the International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2018 classification. 9. The method according to any one of Embodiments 1 to 8, wherein if the subject is classified as having Class III LN based on renal biopsy classification, the subject is selected for administration of voclosporine. 10. The method according to any one of embodiments 1 to 9, wherein if the subject is classified as having class III LN based on renal biopsy classification, the subject is identified as having a high likelihood of response. 11. The method according to any one of Embodiments 1 to 10, wherein if a renal biopsy from the subject shows focal proliferative glomerulonephritis, the subject is classified as having class III LN. 12. The method according to any one of Embodiments 1 to 11, wherein if a renal biopsy from the subject shows proliferative glomerulonephritis affecting less than approximately 50% of the glomeruli, the subject is classified as having class III LN. 13. If a renal biopsy from the subject shows active or inactive focal, segmental or whole-segmental intracapillary or extracapillary glomerulonephritis affecting less than approximately 50% of the total glomeruli, the subject is classified as having class III LN, and optionally, with or without focal subendothelial immunodeposition and mesangial changes, the method according to any one of Embodiments 1 to 12. 14. The method according to any one of Embodiments 1 to 13, wherein if a renal biopsy from the subject shows endocapillary pleocytosis, the subject is classified as having class III LN. 15. The method according to any one of Embodiments 1 to 14, wherein if a renal biopsy from the subject shows focal intraluminal pleocytosis, the subject is classified as having class III LN. 16. The method according to any one of Embodiments 1 to 15, wherein if a renal biopsy from the subject shows endocapillary pleocytosis affecting less than approximately 50% of the glomeruli, the subject is classified as having class III LN. 17. Renal biopsy from the above subjects (a) Segmental endovascular pleoplasia accompanied by substantial lumen reduction, (b) Intratubular cytosis with fibrinoid necrosis and cellular crescent formation, (c) Nuclear decay in glomerular segmentation, (d) Segmental sclerosis of the glomeruli, (e) Segmental subendothelial deposits as fuchsinophilic deposits by optical microscopy, and / or (f) The method according to any one of Embodiments 1 to 16, wherein the subject is classified as having class III LN, if it shows segmental distribution of IgG immunodeposits and mesangial deposits in the glomerular capillary wall. 18. Renal biopsy from the above subjects (a) Lesions including extracapillary cell proliferation, (b) crescent; (c) presence of fibrin and fibrous matrix, and / or (d) The method according to any one of Embodiments 1 to 17, wherein the subject is classified as having a class III LN if it shows more than 10% of the area around Bowman's capsule exhibiting extracapillary cell proliferation. 19. The method according to any one of Embodiments 1 to 10, wherein if the subject is classified as having class IV LN based on renal biopsy classification, the subject is selected for administration of voclosporine. 20. The method according to any one of embodiments 1 to 10 and 19, wherein if the subject is classified as having class IV LN based on renal biopsy classification, the subject is identified as having a high likelihood of response. 21. The method according to any one of embodiments 1 to 10, 19, and 20, wherein if a renal biopsy from the subject shows diffuse proliferative glomerulonephritis, the subject is classified as having class IV LN. 22. The method according to any one of embodiments 1 to 10 and 19 to 21, wherein if a renal biopsy from the subject shows proliferative glomerulonephritis affecting more than approximately 50% of the glomeruli, the subject is classified as having class IV LN. 23. If a renal biopsy from the subject shows active or inactive diffuse, segmental or pansegmental intracapillary or extracapillary glomerulonephritis affecting 50% or more of the entire glomerulus, the subject is classified as having class IV LN, and optionally has diffuse subendothelial immunodeposits with or without mesangial changes, the method according to any one of embodiments 1 to 10 and 19 to 22. 24. The method according to any one of embodiments 1 to 10 and 19 to 23, wherein if a renal biopsy from the subject shows endocapillary pleocytosis, the subject is classified as having class IV LN. 25. The method according to any one of embodiments 1 to 10 and 19 to 24, wherein if a renal biopsy from the subject shows diffuse endocapillary pleocytosis, the subject is classified as having class IV LN. 26. The method according to any one of embodiments 1 to 10 and 19 to 25, wherein if a renal biopsy from the subject shows endocapillary pleocytosis affecting more than approximately 50% of the glomeruli, the subject is classified as having class IV LN. 27. Renal biopsies from the above subjects are (a) Diffuse segmental intratubular proliferation, (b) Pantomimeal intraductal proliferation with leukocyte infiltration, (c) Intravascular proliferation with extensive wire-loop appearance in glomerular capillary walls showing subendothelial immunodeposits. (d) Subendothelial deposits as fuchsinophilic deposition, (e) The appearance of diffuse, segmental wire loops without mesangium or intracapillary cell proliferation, and / or (f) The method according to any one of embodiments 1 to 10 and 19 to 26, wherein the subject is classified as having a class IV LN if it shows a significant overload of immunodeposits in the glomerular capillary wall. 28. The method according to any one of embodiments 1 to 10 and 19 to 27, wherein a renal biopsy from the subject shows diffuse segmental lupus nephritis, with more than 50% of the involved glomeruli having segmental lesions extending to less than half of the glomerular loop, or shows diffuse pansegmental lupus nephritis, with more than 50% of the involved glomeruli having pansegmental lesions, the subject is classified as having class IV LN. 29. The method according to any one of embodiments 1 to 10 and 19 to 28, wherein if a renal biopsy from the subject shows progressive sclerosing glomerulonephritis, the subject is classified as having class IV LN. 30. Renal biopsies from the above subjects (a) Lesions including extracapillary cell proliferation, (b) crescent; (c) presence of fibrin and fibrous matrix, and / or (d) If the subject shows more than 10% of the area around Bowman's capsule exhibiting extracapillary cell proliferation, the subject is classified as having class III LN, according to any one of embodiments 1 to 10 and 19 to 29. 31. The crescent shape is (a) Cellular crescents containing more than 75% cells and fibrin and less than 25% fibrous matrix, (b) Fibrous crescents comprising more than 75% fibrous matrix and less than 25% cells and fibrin, and / or (c) The method according to any one of embodiments 17, 18, and 30, comprising a crescent of a fibrillary cell containing 25% to 75% cells and fibrin and the remaining fibrous matrix. 32. The method according to any one of Embodiments 1 to 31, wherein if the subject is classified as having mixed class V+III / IV LN based on renal biopsy classification, the subject is selected for administration of voclosporine. 33. The method according to any one of embodiments 1 to 32, wherein if the subject is classified as having mixed class V+III / IV LN based on renal biopsy classification, the subject is classified as having high responsiveness. 34. Renal biopsy from the above subjects (a) Non-wire-loop subcutaneous deposits within Class V, and / or (b) The method according to any one of embodiments 1 to 33, wherein the subject is classified as having a mixed class a class V+III / IV LN if it exhibits subepithelial deposits comprising more than 50% of the glomeruli and more than 50% of the capillaries. 35. The method according to any one of embodiments 1 to 34, wherein if the subject is classified as having pure class V LN based on renal biopsy classification, the subject is not selected for administration of voclosporine. 36. The method according to any one of embodiments 1 to 35, wherein if the subject is classified as having pure class V LN based on renal biopsy classification, the subject is not identified as having high responsiveness. 37. The method according to embodiment 35 or 36, wherein if a renal biopsy from the subject shows membranous glomerulonephritis, the subject is classified as having pure class V LN. 38. The method according to any one of embodiments 35 to 37, wherein if a renal biopsy from the subject shows membranous LNs with whole-segmental or segmental continuous granular subepithelial immunodeposits, the subject is classified as having pure class V LNs. 39. Renal biopsies from the above subjects, (a) Significant thickening of the glomerular capillary wall in a whole-segmental distribution, (b) Subepithelial fuchsinophilic deposits, (c) Spikes in the glomerular capillary walls indicating membranous nephropathy, and / or (d) The method according to any one of embodiments 35 to 38, wherein the subject is classified as having pure class V LN, if it shows continuous subepithelial IgG deposits in the glomerular capillary wall. 40. The method according to any one of Embodiments 1 to 39, wherein the subject is further evaluated based on the National Institutes of Health Activity Index (NIH-AI). 41. The NIH-AI is evaluated on a total score scale of 0 to 24 based on the sum of the scores of the following evaluations: (a) The scale of endocapsular pleostosis is 0-3, and endocapsular pleostosis is present in less than 25% (1), 25-50% (2), or more than 50% (3) of the glomeruli. (b) Neutrophil / nuclear decay scale is 0-3, with less than 25% (1), 25-50% (2), or more than 50% (3) of the glomeruli, (c) Fibrinoid necrosis scale is (0-3) × 2, with fibrinoid necrosis of less than 25% (1), 25%-50% (2), or more than 50% (3) of the glomeruli. (d) The hyaline deposit scale is 0-3, and there are wire-loop lesions and / or hyaline thrombi in less than 25% (1), 25-50% (2), or more than 50% (3) of the glomeruli. (e) The scale of cellular / fibrous crescents is (0-3) × 2, with cellular and / or fibrous crescents accounting for less than 25% (1), 25%-50% (2), or more than 50% (3) of the glomerulus, and (f) The method according to Embodiment 40, wherein the interstitial inflammation scale is 0 to 3 and there are less than 25% (1), 25% to 50% (2), or more than 50% (3) interstitial leukocytes in the cortex. 42. The method according to any one of Embodiments 1 to 41, wherein the subject is further evaluated based on the National Institutes of Health Chronicity Index (NIH-CI). 43. The NIH-CI is evaluated on a total score scale of 0 to 12, based on the sum of the scores of the following evaluations: (a) A total glomerulosclerosis score of 0–3 on the scale, with total and / or segmental sclerosis affecting less than 25% (1), 25%–50% (2), or more than 50% (3) of the glomeruli, (b) Fibrous crescent scale is 0-3, with fibrillary crescents accounting for less than 25% (1), 25-50% (2), or more than 50% (3) of the glomerulus. (c) A scale of tubular atrophy of 0-3, with tubular atrophy of less than 25% (1), 25-50% (2), or more than 50% (3) of the cortical tubules, and (d) The method according to Embodiment 42, wherein the interstitial fibrosis scale is 0 to 3 and there is interstitial fibrosis of less than 25% (1), 25% to 50% (2), or more than 50% (3) in the cortex. 44. The method according to any one of Embodiments 1 to 43, wherein the renal biopsy is evaluated using light microscopy, immunofluorescence, and / or electron microscopy. 45. The method according to any one of Embodiments 1 to 44, wherein the voclosporine is administered in a daily dose of approximately 5 mg BID to approximately 50 mg BID. 46. ​​The method according to any one of Embodiments 1 to 45, wherein the voclosporine is administered in an initial daily dose of approximately 39.5 mg, approximately 31.6 mg, approximately 23.7 mg, approximately 15.8 mg, or approximately 7.9 mg BID. 47. The method according to any one of Embodiments 1 to 46, wherein the voclosporine is administered at an initial daily dose of approximately 39.5 mg. 48. The method according to any one of Embodiments 1 to 46, wherein the voclosporine is administered at an initial daily dose of approximately 23.7 mg. 49. The method according to any one of Embodiments 1 to 46, wherein the voclosporine is administered in an initial daily dose of approximately 15.8 mg. 50. The method according to any one of Embodiments 1 to 49, wherein the voclosporine is administered over a predicted voclosporine treatment period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or at least 48 months. 51. The method further comprises evaluating the estimated glomerular filtration rate (eGFR) of the subject at at least a first and a second time point on different days of the predicted treatment period, and (i) If the eGFR of the subject decreases between the first and second time points to a target percentage and below a predetermined value, reduce the daily dose by 7.9 mg BID increments (multiple increments are possible), or discontinue administration of voclosporine. (ii) The method according to any one of Embodiments 1 to 50, wherein if the subject's eGFR decreases to less than the target % between the first time point and the second time point, the subject continues to be administered the same predetermined daily dose of voclosporine. 52. The specified value is 50-90 ml / min / 1.73 m 2 The method according to Embodiment 51, which is within the range of [the specified range]. 53. The aforementioned predetermined value is approximately 60 ml / min / 1.73 m 2 The method according to embodiment 51 or 52. 54. The method according to any one of embodiments 51 to 53, wherein the target percentage is in the range of 20% to 45%. 55. The method according to any one of embodiments 51 to 54, wherein the target percentage is approximately 30%. 56. (i) The eGFR of the subject decreases by more than 30% between the first time point and the second time point to 60 mL / min / 1.73 m². 2 If the value falls below a certain level, discontinue administration of voclosporine to the subject. (ii) The eGFR of the subject decreases by 20% to 30% between the first and second time points to 60 ml / min / 1.73m². 2If the value falls below a certain level, administer a reduced dose of voclosporine to the subject, and (iii) If the subject's eGFR decreases by less than 20% between the first time point and the second time point, the subject continues to be administered the same predetermined daily dose of voclosporine, according to any one of embodiments 51 to 55. 57. The method according to any one of embodiments 51 to 56, wherein the first time point is immediately before initiating the administration of voclosporine. 58. The method according to any one of embodiments 51 to 57, wherein the second time point is after the first time point, in which the administration of voclosporine is initiated. 59. The method according to any one of embodiments 51 to 58, wherein the second time point is eight weeks after the commencement of the administration of voclosporine. 60. The method according to any one of embodiments 51 to 59, further comprising determining the eGFR of the subject at a third time point, and if the difference between the eGFR determined at the third time point and the eGFR determined at the first time point is less than a target percent, resuming administration of the predetermined daily dose of voclosporine. 61. The method comprises measuring the urinary protein-creatinine ratio (UPCR) of the subject at the first and second time points, and determining any decrease in the UPCR between the first and second time points, and The method according to any one of embodiments 51 to 60, wherein if the UPCR of the subject does not show a decrease of at least 25% at the second time point, administration of voclosporine to the subject is discontinued. 62. The method according to any one of Embodiments 51 to 61, further comprising measuring the concentration of C3 or C4 in the subject's blood at a first time point and a second time point, determining whether the concentration of C3 or C4 has normalized at the second time point, and, if normalization of C3 or C4 is found, resuming administration of voclosporine to the subject. 63. The method according to any one of Embodiments 1 to 62, further comprising administering an effective amount of mycophenolate mofetil (MMF) to the subject. 64. The method according to any one of embodiments 1 to 63, further comprising administering an effective amount of corticosteroid to the subject. 65. The method according to any one of embodiments 1 to 64, wherein the cyclosporine is a mixture of at least 90% E isomer and 10% or less Z isomer. 66. Cyclosporine for use in the method according to any one of embodiments 1 to 65. 67. Use of cyclosporine in the manufacture of a pharmaceutical by the method according to any one of embodiments 1 to 65. 68. Use of cyclosporine in the method according to any one of embodiments 1 to 65.

Example

[0208] VI. Example The following examples are described for illustrative purposes only and are not intended to limit the scope of the present invention.

[0209] Example 1. 48-week study on the treatment of lupus nephritis The subjects participating in the study were divided into three groups. 88 subjects were included in the control group, and the control group was administered 2 g of MMF and oral corticosteroid (prednisone with a gradually decreasing dose as shown in the graph in Figure 4) daily. It started at 20 - 25 mg per day initially and was gradually reduced to 2.5 mg per day after the 12th week. In addition to this background treatment, 89 subjects in the low-dose group were administered 3 capsules containing 7.9 mg (i.e., 23.7 mg) of cyclosporine twice a day. The cyclosporine used in this study was composed of 90% or more E isomer. The third group consisted of 88 subjects who received the same background treatment but were further administered 5 capsules of 7.9 mg (i.e., 39.5 mg twice a day). The study was conducted over 48 weeks, and safety was evaluated at 24 weeks.

[0210] Subjects were screened prior to study entry by (a) having a urinary protein creatinine ratio (UPCR) measured in the first morning voiding exceeding 1.5 mg / mg and (b) having an estimated glomerular filtration rate (eGFR) measured by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) exceeding 45 mL / min / 1.73 m 2 Subjects were evaluated at 24 weeks and 48 weeks, and further evaluated at 50 weeks.

[0211] Low-dose administration resulted in better outcomes than high-dose administration of tacrolimus. Put simply, 32.6% of low-dose patients showed a complete response (CR) at 24 weeks compared to 19.3% in the control group. Also, 70% of low-dose patients showed a partial response (PR) compared to 49% in the control group.

[0212] CR in this example is a composite endpoint that includes efficacy, safety, and low-dose steroids. UPCR ≤ 0.5 mg / mg (confirmed), eGFR > 60 mL / min / 1.73 m 2 or within 20% of baseline, steroids ≤ 10 mg / day, no rescue medication administration.

[0213] PR is a composite endpoint that includes safety and efficacy (50% reduction in UPCR from baseline and no use of rescue medication).

[0214] To determine the effectiveness of the pharmacodynamic protocol of reducing or discontinuing the dose depending on the presence or absence of an indicator of decline in eGFR experienced as a side effect, these three patient groups were evaluated 24 weeks and 48 weeks after treatment, taking into account whether the treatment was changed according to the treatment. In all three groups, patients were evaluated according to the criteria defined in the above exemplary protocol, i.e., the eGFR of each patient was measured immediately prior to the first administration of tacrolimus and at least one day later at a second time point, and (i) if the eGFR of the above subject decreased by more than 30% between the first and second time points to a value less than 60 mL / min / 1.73 m 2 the administration of tacrolimus to the subject was discontinued, (ii) The eGFR of the subject described above decreases by 20% to 30% between the first and second time points, reaching 60 ml / min / 1.73m². 2 If the value falls below a certain level, administer a reduced dose of voclosporine to the above subjects, and (iii) If the eGFR of the subject decreases by less than 20% between the first and second time points, the subject shall continue to be administered the same prescribed daily dose of voclosporine.

[0215] The results are shown in Tables E1 and E2 below. Table E1 shows the percentage of complete remission (CR) or partial remission (PR) at 24 weeks, and Table E2 shows these values ​​at 48 weeks for patients who did not reduce their dose and for patients who did. [Table 5] [Table 6] [Table 7] [Table 8]

[0216] In this study, complete response (CR) was defined as UPCR ≤ 0.5 mg / mg; eGFR > 60 mL / min / 1.73 m². 2 It was defined as a composite of, or within 20% of baseline, ≤10 mg / day of steroids, and no rescue medication. PR was defined as a 50% decrease in UPCR from baseline and no emergency medication was used.

[0217] As shown in Table E1, after 24 weeks, 12.5% ​​of patients in the placebo group, 43.8% of patients in the low-dose voclosporine group, and 53.4% ​​of patients in the high-dose voclosporine group reduced their dose during treatment. The proportion of patients achieving complete response was not affected by pharmacodynamic dose in any dose group, and the proportion of patients achieving partial response was also nearly the same, although the proportion of patients showing partial reduction improved in the high-dose group. Table E2 shows similar results at 48 weeks, despite a high proportion of patients reducing their dose.

[0218] Example 2. Long-term safety and tolerability study Participants who completed 12 months of voclosporin treatment with mycophenolate mofetil (MMF) and steroids for lupus nephritis (LN) were enrolled in a long-term follow-up study in which the same treatment was continued for an additional 2 years. A total of 37 months of follow-up was conducted, including the first 12 months of the follow-up study and the remaining 25 months (including a 4-week safety visit after discontinuation of the study drug).

[0219] A double-blind, 1-year randomized controlled study (n=357) comparing voclosporine (23.7 mg twice daily [BID]) with placebo in the treatment of lupus nephritis. Participants had active LN, UPCR ≥ 1.5 mg / mg (≥ 2 mg / mg for class V), and eGFR > 45 mL / min / 1.73 mm. 2Patients with lupus nephritis were included. All patients received mycophenolate mofetil (MMF) (target 1g BID) and low-dose steroids (rapidly reduced to 2.5 mg / day at week 16). The tapering of glucocorticoids included intravenous methylprednisolone on days 1 and 2. Oral glucocorticoids were initiated with 20-25 mg / day of prednisone on day 3 and gradually reduced to the target dose of 2.5 mg / day from week 16 onward. This study showed that the addition of voclosporine to MMF and low-dose steroids increased the complete renal response rate by 18% over one year compared to MMF and low-dose steroids alone (22.5% in the control group, n=178; 40.8% in the voclosporine treatment group, n-179; odds ratio [OR] 2.65; p<0.0001; 95% CI 1.64; 4.27).

[0220] In the follow-up study, voclosporine was evaluated against placebo in combination with mycophenolate mofetil (MMF) and low-dose steroids in patients with lupus nephritis, as generally described in Example 1. The follow-up study included 216 of the 357 subjects included in the initial one-year study, continuing in the same treatment groups. 116 patients in the voclosporine group received voclosporine 23.7 mg twice daily in combination with low-dose steroids, while 100 patients in the control group received placebo in combination with MMF 1 g twice daily in combination with low-dose steroids (see Figure 5 for general details). This treatment was continued for a further 24 months. At the end of the study, 90 subjects in the voclosporine group and 78 subjects in the control group had received a total of 36 months of treatment. The demographics of the subjects are shown in Table E3. The values ​​in this table are pre-treatment baseline values ​​(baseline is defined as the last value before the subject received the initial study drug on day 1 of the study, i.e., at the start of the three-year study).

[0221] In this study, changes in the dose of the investigational drug were permitted at the discretion of the investigator. The protocol provided guidance for interrupting or reducing the study drug if the estimated glomerular filtration rate (eGFR) decreased by more than 30% in a patient, or in the case of blood pressure, if it exceeded the acceptable range. At the end of the first 12 months, the majority of the subjects (78.4% for tacrolimus and 90.0% for the control) were receiving 23.7 mg of tacrolimus twice a day (BID) or an equivalent placebo. At the end of the continuing study (after 3 years), 49.1% of the tacrolimus group and 64.0% of the control group were receiving 23.7 mg BID of tacrolimus or an equivalent placebo. Changes in the dose of the study drug decreased over time, and the majority of patients who had reduced the dose by the end of the study (more patients in the tacrolimus group) had received a dose change due to changes in eGFR, etc.

Table 9-1

Table 9-2

[0222] Table E4 shows the observed values of the mean corrected estimated glomerular filtration rate (eGFR) and the mean urinary protein creatinine ratio (UPCR) at the pre-treatment baseline, the baseline at 1 year (12 months) of treatment, and the baseline at 3 years (36 months) of treatment.

Table 10

[0223] In the 116 subjects treated with voclosporine, mean estimated glomerular filtration rate (eGFR) remained within the normal range in both treatment groups over 36 months, as shown in Figures 6 and 7. The change in eGFR from baseline before treatment, shown in Figure 7, indicates that mean eGFR remained stable in both treatment groups over 36 months. Furthermore, compared to the control group, baseline eGFR increased by +2.7 mL / min at 36 months in the voclosporine treatment group. Overall, the data from 3 years of voclosporine exposure demonstrated stable renal function throughout the study period, as measured by mean eGFR and gradient.

[0224] Long-term renal function was assessed by examining the eGFR gradient over a 24-month follow-up study. Figure 8 shows that the adjusted eGFR gradient over a two-year period (e.g., a two-year follow-up study after completion of the initial one-year study) was -0.2 ml / min / 1.73 mm in the voclosporine group. 2 (95% CI -3.0, 2.7), control group: -5.4 ml / min / 1.73 m 2 This indicates that the values ​​were (95% CI -8.4, -2.3). Finally, over the three-year period, 14 patients (12.1%) in the voclosporine group and 10 patients (10%) in the control group experienced a ≥30% decrease in adjusted eGFR from baseline before treatment.

[0225] As shown in Figure 9, the mean UPCR decreased at all time points over the 3-year period in the voclosporine treatment group. At the start of the continuation study (e.g., month 12 of the 3-year study), the mean UPCR of the control group in the voclosporine treatment group (0.86 mg / mg) was lower than the mean UPCR of the control group (1.47 mg / mg), reflecting the improvement in disease control with voclosporine in the first year of treatment. Furthermore, as shown in Figure 9, a mixed-effects model repeated measures (MMRM) analysis confirmed that a statistically significant reduction in UPCR from baseline was achieved in the voclosporine group compared to the control group at all time points except month 36. In particular, at follow-up safety examinations, the mean UPCR was 0.78 mg / mg in the voclosporine group and 1.47 mg / mg in the control group.

[0226] Figure 10 shows the percentage of controls who achieved a ≥50% reduction in UPCR from baseline at different time points in the two treatment groups. Overall, the percentage of patients whose UPCR was reduced by ≥50% from baseline and whose UPCR was ≤0.5 mg / mg increased up to 12 and 18 months and was maintained throughout the entire treatment period.

[0227] Furthermore, significant improvements were observed in complete renal function (CRR) and partial renal function (PRR). Complete renal function (CRR) was defined as a UPCR of ≤0.5 mg / mg and an eGFR of 60 ml / min / 1.73 m². 2 The above, or a decrease in eGFR from baseline before treatment of 20 ml / min / 1.73 m², is the cause. 2 It was defined as not being confirmed to be ultra-negative, not having received emergency medication for LN, not having received prednisone for three consecutive days or a total of seven days or more in the eight weeks prior to endpoint evaluation, and not having received more than 10 mg of prednisone. PRR was defined as a reduction of 50% or more in UPCR from pre-treatment baseline (e.g., 3 years prior to treatment).

[0228] As shown in Table E5, at 36 months, more controls in the voclosporine group achieved CRR than in the control group (50.9% vs. 39.0%, odds ratio 1.74, 95% CI 1.00, 3.03), mainly due to a higher proportion of controls in the voclosporine group showing a reduction in proteinuria to 0.5 mg / mg or less by UPCR (54.3% vs. 43.0%, odds ratio 1.66, 95% CI: 0.96, 2.88). More controls in the voclosporine group achieved PRR (74.1% vs. 69.0%, odds ratio 1.39, 95% CI: 0.75, 2.58). In a forward-final observational analysis of patients with no data at 36 months, 12 out of 17 patients (70.6%) in the voclosporine group and 5 out of 13 patients (38.5%) in the control group achieved a reduction of 50% or more from baseline in UPCR based on final UPCR measurements. [Table 11-1] [Table 11-2]

[0229] Furthermore, at the start of the continuation trial (12 months), more patients treated with voclosporine showed favorable renal function outcomes than the control group, demonstrating a clear clinical benefit of voclosporine. Overall, 3 years of treatment demonstrated that significantly more controls in the voclosporine group achieved favorable renal outcomes compared to the control group (66.4% vs. 54.0%, odds ratio 0.56, 95% CI 0.32, 0.99). Favorable renal outcomes were defined as achieving an adequate response with a UPCR ≤ 0.7 mg / mg and the absence of subsequent renal relapse, as determined by a blinded Clinical Endpoints Committee (CEC). Renal flare was analyzed in controls that showed a adequate response and determined by blinded CEC, defined as an increase in post-response UPCR from <0.2 mg / mg to >1 mg / mg, or an increase in post-response UPCR from 0.2–1.0 mg / mg to >2 mg / mg. A sustained decrease in UPCR of 0.7 mg / mg or less was considered an adequate response based on CEC assessment. Non-renal flare was defined based on AEs, abnormal laboratory values, and / or other presented information and determined by blinded CEC. Among controls that showed an adequate response (101 in the voclosporine group and 73 in the control group), a similar proportion of controls in each group experienced nephritis. A similar proportion of controls in each group also experienced non-renal flare.

[0230] Finally, mean blood pressure, serum creatinine (sCr), glucose, hemoglobin A1c, and lipid levels remained stable over time in both groups. Mean levels of potassium and magnesium were also maintained within the normal range over time in both groups.

[0231] Voclosporin was well-tolerated, and no unexpected safety signs were observed. Table E6 summarizes the adverse events. The incidence of serious adverse events was similar in both study groups, 19% in the voclosporin treatment group and 24% in the active control group. Furthermore, there were no deaths in the voclosporin treatment group, but there were four deaths in the active control group. The active control group had a higher withdrawal rate (15.0% withdrawal) compared to the voclosporin treatment group (12.9% withdrawal). [Table 12]

[0232] 86.1% of the control group completed the follow-up study, and a summary of adverse events (AEs) during the follow-up study is shown in Table E7. The proportion of control groups experiencing AEs during the follow-up study was similar between the two groups (86.2% in the voclosporine group and 80.0% in the control group). The incidence of serious AEs (SAEs) was also similar. Most control groups that experienced AEs experienced mild or moderate AEs. Discontinuation of the study drug due to AEs occurred in 9.5% of the voclosporine group and 17.0% of the control group. The unique pharmacokinetic and pharmacodynamic properties of voclosporine, such as its low metabolite load and eGFR-based dose, are thought to contribute to the favorable safety profile observed with voclosporine.

[0233] In the follow-up study, adverse events reported by the principal investigators included decreased glomerular filtration rate (GFR) in 12 patients (10.3%) in the voclosporine group and 5 patients (5.0%) in the control group. Conversely, hypertension was reported by the principal investigators in 10 patients (8.6%) in the voclosporine group and 7 patients (7.0%) in the control group. Three patients (2.6%) in the voclosporine group and 10 patients (10.0%) in the control group initiated antihypertensive treatment after the initial dose in the follow-up study. [Table 13]

[0234] The overall adverse event (AE) profiles were similar in the voclosporine group and the control group, with AEs decreasing annually and very few controls discontinuing treatment due to AEs. AEs related to hemodynamic effects of CNI drug classes, such as hypertension and decreased GFR, occurred more frequently in the voclosporine group, but AEs decreased over time and were managed by dose adjustments. Furthermore, the incidence of type 2 diabetes, hyperkalemia, and hyperlipidemia was very low in both groups during the study period. In addition, the frequency of drug discontinuation was lower in the voclosporine group compared to the control group.

[0235] Finally, as shown in Table E8, throughout the three years of treatment, infection was the most common type of AE by SOC (voclosporin 69.8%, control 72.0%), and the incidence of serious infections was low in both groups (voclosporin 12.9%, control 17.0%). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurred in 7 patients in the voclosporin group and 12 patients in the control group, and these events were serious in 2 patients in the voclosporin group and 5 patients in the control group. [Table 14-1] [Table 14-2]

[0236] In summary, the results of a 3-year long-term follow-up study evaluating the long-term safety and tolerability of voclosporin in the treatment of adults with active lupus nephritis (LN), a serious complication of systemic lupus erythematosus (SLE), in combination with background immunosuppressive therapy, support long-term voclosporin treatment for LN patients. The significant and meaningful reduction in proteinuria achieved in the initial study was maintained for the following 2 years, the mean estimated glomerular filtration rate (eGFR) remained stable throughout the 3-year treatment period, the incidence of serious adverse events was similar, and no unexpected safety events occurred. Furthermore, the continued reduction in UPCR, increase in CRR, and maintenance of renal function all suggest a positive benefit profile of voclosporin in lupus nephritis patients. In conclusion, the results demonstrate the long-term safety and tolerability of voclosporin treatment for LN, showing minimal impact on eGFR, sustained effective treatment, and significant reduction in proteinuria even after up to 3 years of treatment.

[0237] Example 3. Evaluation of voclosporine treatment for lupus nephritis in patients with hyperproteinuria. From the studies described in Examples 1 and 2 above, data from subjects treated with placebo and voclosporine with moderate to high levels of baseline proteinuria were collected for further analysis.

[0238] From the two studies described in Examples 1 and 2 above, subjects showing moderate to high levels of proteinuria (baseline urinary protein-creatinine ratio (UPCR) of 2 mg / mg or higher) were selected for further analysis.

[0239] A. Baseline characteristics Of the 534 patients in the pooled dataset, 432 patients (215 in the control group and 217 in the voclosporine group) had a baseline UPCR of 2 mg / mg or higher. As shown in Table E9, the baseline characteristics of patients with a baseline UPCR of 2 mg / mg or higher were similar in the control group and the voclosporine group, with mean UPCR values ​​of 4.6 mg / mg in the control group and 5.1 mg / mg in the voclosporine group. [Table 15]

[0240] B. Proteinuria Twelve months after the start of treatment, proteinuria levels showed a significant decrease in UPCR values ​​from baseline in the voclosporine group compared to the control group. As shown in Figure 11, at one year, the change from baseline in least squares (LS) mean (standard error [SE]) UPCR was -3.8 (0.1) mg / mg in the voclosporine group compared to -3.1 (0.2) mg / mg in the control group (difference from control, -0.7, p=0.0003).

[0241] C. Complete renal response Complete renal response (CRR) was evaluated in various subgroups of the subjects. Complete renal response was defined as UPCR ≤ 0.5 mg / mg and estimated glomerular filtration rate (eGFR) ≥ 60 mL / min / 1.73 m². 2 Or no decrease exceeding 20%, UPCR 0.5 mg / mg, eGFR 60 ml / min / 1.73 m² 2 Alternatively, it was defined as no decrease of more than 20% from baseline, low-dose glucocorticoids, and no emergency medication. Odds ratios (ORs) were calculated for each subgroup, with OR > 1 indicating a therapeutic effect of voclosporine.

[0242] As shown in Figure 12, higher renal response rates were observed in the voclosporine group across all subgroups, regardless of baseline demographic or clinical characteristics. CRR rates were numerically higher in the subgroup of patients treated with voclosporine, in both sexes and across all assessed ages, races, ethnicities, biopsy classes, and eGFR levels (indicated by OR>1). Overall, the proportion of subjects achieving CRR at 12 months was significantly higher in the voclosporine group compared to the control group (41.0% vs. 21.9%, or 2.48, p<0.0001).

[0243] Consistent with the results of the overall integrated study population, patients with UPCR ≥ 2 mg / mg treated with voclosporine achieved a significantly higher renal response than patients treated with MMF and low-dose glucocorticoids alone.

[0244] D. Complete renal response by biopsy class Further analysis of biopsy class data showed that the highest CRR rates were achieved in the voclosporin groups for Class III and Class IV disease, or mixed Class V and Class III or Class IV disease (Figure 13). Significant differences in CRR rates were observed in the voclosporin treatment groups in the Class III, Class IV, or Class V and mixed Class III or Class IV subgroups, indicating a more pronounced effect of voclosporin treatment in these groups. The difference in CRR achieved between the voclosporin groups and the control group for Class V disease was not as substantial.

[0245] E. Estimated glomerular filtration rate (eGFR) As shown in Figure 14, the changes in estimated glomerular filtration rate (eGFR) in the voclosporine group and the control group throughout the study period showed that, as expected, eGFR decreased slightly in the voclosporine group due to the hemodynamic effects of the calcineurin inhibitor (CNI), but in both groups, the least squares (LS) mean-corrected eGFR remained stable throughout the one-year treatment period.

[0246] F. Adverse Events The incidence of serious adverse events was similar in the voclosporine group and the control group, and no unexpected safety events occurred. Table E10 summarizes the adverse events. As shown, the safety outcomes were comparable between the voclosporine treatment group and the control group, and there was no evidence of worsening renal function. [Table 16]

[0247] These results support the use of voclosporine as an effective treatment for LN in patients with moderate to severe proteinuria. The results demonstrated long-term safety, efficacy, and tolerability, showing minimal impact on eGFR and significant reduction in proteinuria even after up to 52 weeks of treatment. Furthermore, the results support voclosporine as a safe and effective treatment for LN, showing significantly higher response rates compared to the control group, particularly in class III, class IV, or mixed class V patients and controls with class III or class IV disease.

[0248] Example 4: Evaluation of renal biopsy for the assessment of voclosporin in the treatment of lupus nephritis Proteinuria is widely recognized as a biomarker of treatment response and overall prognosis in lupus nephritis. Repeated renal biopsies may provide additional information about the kidney condition in patients receiving treatment for lupus nephritis. The long-term histological effects of voclosporine on the kidneys were further characterized by repeated biopsies from a representative subset of patients who received long-term voclosporine treatment.

[0249] Urine protein-creatinine ratio (UPCR) ≥ 1.5 mg / mg (≥ 2 mg / mg for Class V), and eGFR > 45 mL / min / m² 2 Based on the above, patients with active lupus nephritis were included in the clinical trial, largely as described in Examples 1 and 2 above. Patients were randomly assigned to receive either voclosporine or a control group for one year, followed by a maximum of two years of the same treatment. All patients underwent a renal biopsy before screening, and if enrolled for an additional two years, some patients underwent repeated renal biopsies in the first year of the additional two years of treatment (see Figure 5). Biopsies were blinded, processed, stained, evaluated, and scored by renal histopathologists in specialized renal pathology laboratories, in accordance with the 2018 ISN / RPS guidelines (Bajema et al. Kidney Int. 2018;93(4):789-796).

[0250] Specifically, biopsy samples were collected from a subgroup of 16 patients in the voclosporine group and 10 patients in the control group. Efficacy results included mean UPCR over time, as well as complete renal response (defined as CRR, UPCR ≤ 0.5 mg / mg, eGFR stabilization, low-dose steroids, no emergency medication) and partial renal response (defined as PRR, UPCR decreased by ≥ 50% from baseline) at 36 months. Mean eGFR over time was also evaluated.

[0251] The subgroups evaluated by biopsy had similar patient demographics and renal characteristics to the underlying study population (Table E11). [Table 17]

[0252] Table E12 shows that baseline histological activity scores were similar between the two groups, and that scores decreased with treatment in both groups. Histological chronicity scores were also similar between the two groups at baseline and remained stable over time in most patients in both groups. No differences were observed in baseline or repeat biopsy activity or chronicity scores between patients treated with voclosporine and those treated with the control group.

[0253] Within the entire study population, the voclosporine group (who received voclosporine in addition to MMF and low-dose steroids, as described in Examples 1 and 2 above) showed a more early and significant reduction in proteinuria while maintaining stable renal function, as evidenced by the stable eGFR gradient over time.

[0254] In patients treated with voclosporine, repeated biopsies revealed a decrease in mean UPCR values, indicating an improvement in UPCR (Table E12). Mean eGFR values ​​remained stable over time in both treatment groups (Table E12). Patients treated with voclosporine showed an increase in both CRR and PRR rates at 36 months. The results of the evaluated patient subgroups were consistent with those observed in the larger overall study population, as shown in Figure 15 (UPCR) and Figure 16 (eGFR). Specifically, the mean eGFR values ​​over time in the biopsy substudy of 26 subjects remained stable for 3 years, consistent with the values ​​observed in the larger overall study population in the 2-year follow-up study (n=216) (see Figure 17). [Table 18]

[0255] As shown in Table E12 and Figure 18A, baseline activity scores, a measure of active inflammation in the lnix nephrocyte, were similar between the voclosporine group and the control group, and the scores in both groups decreased with treatment. As shown in Table E12 and Figure 18B, chronicity scores, a measure of irreversible renal impairment including scarring, were also similar between both arms at baseline and remained stable over time in most patients with both arms. No differences were observed in activity scores or chronicity scores at baseline or at repeat biopsies between patients treated with voclosporine and those treated with the control. In both treatment groups, activity scores decreased with improvement in the urinary protein-creatinine ratio (UPCR).

[0256] In particular, for the 26 subjects in the biopsy subgroup, all chronicity index variables remained stable from baseline to follow-up in both groups, as shown in Table E13. Exposure to voclosporine was not associated with chronic disability, and the mean chronicity index remained stable in both groups from baseline to follow-up. Therefore, subjects treated with voclosporine (n=16) showed improvement in histological activity with standardized chronicity scores similar to the control subjects (n=10). [Table 19]

[0257] The results showed that patients treated with voclosporine exhibited similar improvements in histological activity and stable chronicity scores to the control group (MMF and low-dose steroids) over an average treatment period of 18 months until repeated biopsies. Disease activity scores, a histological indicator of renal inflammation, decreased significantly in both the voclosporine and control groups compared to baseline. Furthermore, repeated biopsy samples did not show the typical renal impairment patterns seen in conventional CNIs such as tacrolimus or cyclosporine. Both the voclosporine and control groups showed stability in the chronicity index, a histological measure of irreversible renal impairment and scarring associated with end-stage renal disease, demonstrating that, unlike conventional CNIs, exposure to voclosporine did not increase chronic impairment. In particular, the efficacy and safety results obtained from the biopsy subgroup were consistent with those obtained from the larger study population.

[0258] These results support the safe and effective long-term use of voclosporine in patients requiring immunosuppression with CNIs, as assessed by renal biopsy showed no worsening of nephrotoxicity or development of the conventional CNI-associated renal impairment pattern. The absence of typical conventional CNI-associated chronic changes, such as scarring, is an important observation indicating a lower incidence of chronic nephrotoxicity with voclosporine compared to conventional CNIs. Chronic nephrotoxicity associated with conventional CNIs such as tacrolimus or cyclosporine limits the long-term usefulness of conventional CNIs in LN, while supporting the usefulness of voclosporine for longer-term immunosuppression. These results also support the long-term efficacy and safety of voclosporine, as repeated biopsies approximately 18 months after the initiation of voclosporine treatment showed that patients maintained their clinical response and no significant histological evidence of nephrotoxicity was observed, in contrast to conventional CNIs, which have considerably greater side effects and toxicity, significantly limiting their use as immunosuppressants in long-term treatment.

[0259] Example 5. Evaluation of voclosporine as a urinary biomarker. In patients with active lupus nephritis, elevated levels of several biomarkers associated with kidney damage, inflammation, and fibrosis have been reported. Exemplary biomarkers include kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemotactic protein (MCP-1), and transforming growth factor beta (TGF-β1). Treatment with conventional calcineurin inhibitors (CNIs) has also been associated with kidney damage and elevated levels of pro-fibrosis biomarkers, including KIM-1, NGAL, MCP-1, TGF-β1, CD163, CD206, and IL-16.

[0260] From the one-year double-blind, randomized controlled study of voclosporine administration described in Example 2 above, a subgroup of 120 randomly selected patients was included in 43 urine analytes. Patients were evaluated based on treatment response (Table E14; responders were defined as those whose urinary protein-creatinine ratio [UPCR] decreased by ≥50% from baseline at year 1 of treatment). Patients with an estimated glomerular filtration rate (eGFR) decreased by ≥30% were analyzed individually. [Table 20]

[0261] In all responders, non-responders, and those with reduced eGFR, there were no significant differences in the change from baseline in normal urinary concentrations of KIM-1, NGAL, MCP-1, and TGF-β1 between the voclosporine treatment group and the control treatment group. The results indicate that LN patients treated with oral voclosporine in addition to MMF and low-dose steroids did not experience the increase in urinary nephropathy and pro-fibrosis markers, which are indicators of renal fibrosis and kidney impairment, as reported with conventional CNI treatment. These results support the use of voclosporine in controls requiring long-term immunosuppression with CNI.

[0262] Example 6. Evaluation of electrolyte profiles in lupus nephritis patients treated with voclosporine. In association with the use of conventional CNIs such as tacrolimus in solid organ transplantation, electrolyte imbalances regulated within the kidney have been reported. Based on clinical studies, the effect of voclosporine in combination with immunosuppressive therapy on urinary electrolytes in patients with lupus nephritis was investigated by evaluating changes in urinary and / or serum electrolyte concentrations over time.

[0263] From the double-blind, randomized controlled study of voclosporine administration over one year, as described in Example 2 above, 24-hour urine samples were selected from 60 patients in each treatment group, and urinary electrolytes were analyzed. The samples included patients who responded to treatment in the first year and whose urinary protein-creatinine ratio (UPCR) decreased by at least 50% from baseline (treatment responders), patients who did not respond (non-responders), and patients whose estimated glomerular filtration rate (eGFR) decreased by at least 30% from baseline during the study period. The mean changes in magnesium, potassium, and sodium from baseline to one year are shown as 24-hour urinary excretion concentrations.

[0264] The mean change from baseline in urinary electrolyte excretion concentrations was small for magnesium (<13.4 mg / dL) and potassium (<6.4 mmol / L), and there were no significant differences between treatment groups in any subgroup. Sodium excretion concentrations decreased from baseline at 1 year (<30.5 mmol / L) in all subgroups except for the control group responder (an increase of 14.0 mmol / L) (Table E15). [Table 21]

[0265] In patients treated with voclosporine, the mean serum electrolyte levels were within the normal range (Rovin et al., Lancet. 2021 May 29;397(10289):2070-2080). At the time of the study administration of voclosporine, changes from baseline in urinary electrolyte excretion concentrations of magnesium, potassium, and sodium were not clinically significant in any treatment group, regardless of the response to treatment.

[0266] The results of this study, along with normal serum electrolyte concentrations, support the finding that voclosporine does not significantly affect the mean electrolyte concentration. This further supports the safety and efficacy of voclosporine in the treatment of patients requiring CNI therapy, particularly those who have previously received conventional CNI, which may inhibit calcium and magnesium reabsorption in the renal tubules.

[0267] Example 7. Evaluation of lipid profiles in lupus nephritis patients treated with voclosporine. Dyslipidemia is a potential side effect of certain CNIs, such as cyclosporine. LN is an independent risk factor for increased risk of cardiovascular disease (CVD) and can be exacerbated by dyslipidemia associated with inflammatory and immunosuppressant drugs.

[0268] This study investigated the effects of voclosporine in combination with immunosuppressive therapy on lipid levels in LN patients.

[0269] Patients diagnosed with active lupus nephritis (class III, IV, or V±III / IV) by biopsy and with proteinuria of ≥1.5 mg / mg (≥2 mg / mg for class V) were enrolled in phase 2 and 3 clinical trials evaluating the efficacy and safety of voclosporine compared to placebo (control). All patients received mycophenolate mofetil (MMF) (targeted 1 g BID) and rapidly tapering low-dose steroids concurrently. Pooled data from similarly designed clinical trials showed that adding voclosporine to MMF and low-dose steroids resulted in significantly higher complete renal response rates (CRR) at 1 year of treatment (43.7% and 23.3%; OR 2.76; P<0.0001).

[0270] The pooled dataset was further analyzed to investigate the effect of voclosporine on lipid concentrations in subjects with LN. The pooled data included 268 patients in the voclosporine (23.7 mg BID) group and 266 patients in the placebo control group. Fasting total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglycerides were measured in a central CLIA-accredited laboratory at baseline and at 1 year follow-up.

[0271] Table E16 shows the changes in lipid profiles from baseline to 1 year in subjects treated with voclosporine or placebo (control). Mean total cholesterol, LDL, and triglycerides were above the normal range at baseline, but decreased in both the voclosporine and placebo groups during the study period. At 1 year, the decrease from baseline was significantly greater in the voclosporine group than in the control group for total cholesterol (P=0.0062) and LDL (P=0.023). The overall decrease in triglycerides from baseline was also greater in voclosporine-treated patients at 1 year (P=0.0768).

[0272] At one year, the percentage of patients with normal total cholesterol increased by approximately 42% in the voclosporine group (from 17.3% at baseline to 59.2%) and by 29% in the control group (from 19.4% at baseline to 48.3%). The percentage of patients with normal LDL increased by approximately 42% in the voclosporine group (from 29.7% at baseline to 71.4%) compared to approximately 21% in the control group (from 34.5% at baseline to 55.2%). The percentage of subjects with normal triglycerides increased from 32.3% to 56.1% in the voclosporine group and from 36.1% to 53.6% in the control group. Mean HDL levels were within the normal range at baseline in both groups and remained stable throughout the study period. [Table 22-1] [Table 22-2]

[0273] From baseline to one year of follow-up, total cholesterol, LDL cholesterol, and triglyceride levels improved in both treatment groups. The voclosporine group showed a significant reduction in lipids, along with a higher CRR rate, and an overall higher percentage of subjects falling within the normal lipid range. Considering the cardiovascular disease risk in LN patients, the improvements in CRR and favorable effects on lipid levels observed in the clinical trial further support the use of CNI voclosporine in the treatment of LN and other conditions.

[0274] In clinical trials using voclosporine, favorable renal clinical responses and conventional lipoprotein changes were observed. Therefore, the lipid profiles of some of the study participants were further evaluated to assess whether the beneficial therapeutic response was partially mediated by changes in circulating lipids, such as inflammatory lipids.

[0275] Lipid class levels were further evaluated and compared in participants randomly selected from the control group (placebo group) (N=30) and the voclosporine group (N=28). All subjects received mycophenolate mofetil (MMF) and low-dose steroids. 918 serum lipids from 14 classes were compared by lipid composition analysis from baseline to week 52. The difference in lipids from baseline at week 52 was calculated, and Z-scores were standardized and used in a mixed linear model.

[0276] Changes in lipid class levels were assessed as a function of the voclosporine effect and by the achievement of full renal response (CRR) or partial renal response (PRR) (Table E17). Voclosporine and the renal clinical response (CRR or PRR) independently contributed to decreases in ceramide (CER) and triacylglycerol (TAG), and increases in dihydroceramide (DCER) and phosphatidylinositol (PI). Therefore, CER, DCER, PI, and TAG are altered by voclosporine.

[0277] The results indicate that voclosporine and renal clinical responses have an additive effect on corresponding lipid changes. Voclosporine, CRR, and PRR were independently associated with changes in phosphatidylcholine PC(C16), PI, and TAG. Changes in PC, PI, and TAG correlated with renal outcomes independently of voclosporine.

[0278] A pooled analysis showed significant correlations between saturated diacylglycerol (DAG) and monoacylglycerol (MAG, C>16), TAG, sphingomyelin (SM), CER, unsaturated PEP, and palmitoyl PC (C16) after controlling for CRR or PRR.

[0279] Overall, these findings support the idea that voclosporine reduces lipogenesis by decreasing the uptake of fatty acid precursors and inflammatory lipids, and that the favorable therapeutic response is partially mediated by the promotion of corresponding lipid class changes. [Table 23]

[0280] Example 8. Evaluation of drug interactions between vocroporin and mycophenolate motefil (MMF). A clinical study was conducted to evaluate the effect of voclosporine on mycophenolate mofetil (MMF). Conventional CNIs such as cyclosporine have been reported to show drug interactions with MMF, a drug often administered together with CNIs. Cyclosporine can lower the effective blood concentrations of the active parts of MMF, mycophenolate (MPA), and other metabolites. The effect of voclosporine on the blood concentrations of mycophenolate (MPA, the active part of MMF) and MPA glucuronide conjugate (MPAG, a pharmacologically inactive metabolite of MMF) after MMF administration was evaluated in patients with systemic lupus erythematosus (SLE).

[0281] MMF was administered orally at a dose of 1 g twice daily for at least 28 days prior to the start of the study, and this dose of 1 g was continued throughout the study period. Voclosporine was administered orally at a dose of 23.7 mg twice daily for 7 consecutive days. Voclosporine was first administered in the evening of day 1 and ended with the morning administration on day 7. High-density pharmacokinetic blood samples were collected before the morning administration and 0.25–12 hours after the morning administration.

[0282] In 24 patients, the maximum serum concentration (C) 最大 ) and area under the concentration curve (AUC) from 0 to 12 hours 0~12 MPA exposure, as assessed by ), was similar with and without voclosporine. 最大 The AUC was 16.5 μg / mL (day 1) when voclosporine was absent, and 15.8 μg / mL (day 7) when voclosporine was present. 0~12 The blood glucose level was 39.1 μg / h / mL (day 1) when voclosporine was absent, and 40.8 μg / h / mL (day 7) when voclosporine was present. 最大 Geometric mean ratio 0.94, AUC 0~12 Based on a geometric mean ratio of 1.09, MPA exposure was similar in the presence and absence of voclosporine.

[0283] The mean concentration-time profile of MPA in plasma was similar in the presence and absence of voclosporine (Figure 19). Trough concentration on day 7 (C トラフ The value was similar to the pre-administration concentration in the morning, indicating that a steady state was achieved in the presence of voclosporine.

[0284] In the same 24 patients, the mean concentration-time profile of MPAG in plasma was observed to be slightly increased in the presence of voclosporine (Figure 20). Trough concentrations on day 1 and day 7 (C トラフ The values ​​were similar to the morning concentration before administration. MPAG exposure after MMF administration in the presence of voclosporine was higher than after MMF administration alone. 最大The AUC was 65.0 μg / mL (day 1) when voclosporine was absent, and 71.4 μg / mL (day 7) when voclosporine was present. 0~12 The blood glucose level was 444 μg / h / mL (day 1) when voclosporine was absent, and 532 μg / h / mL (day 7) when voclosporine was present. Based on the geometric mean ratio, MPAG C was present in the presence of voclosporine. 最大 and AUC 0~12 These figures were 12.0% and 27.0% higher, respectively.

[0285] These results support the well-tolerated combination therapy of voclosporine and MMF, and that voclosporine and MMF can be administered together without dose adjustment. There were no clinically significant interactions between voclosporine and MMF. These results support the combination of voclosporine with other common immunosuppressants such as MMF, as voclosporine does not exhibit drug interactions with other immunosuppressants, in contrast to some conventional CNIs that may reduce the blood concentrations and exposure of other immunosuppressants.

[0286] The present invention is not intended to be limited to specific disclosed embodiments provided, for example, to illustrate various aspects of the invention. Various modifications to the compositions and methods described herein will become apparent from the description and teachings herein. Such modifications may be made without departing from the true scope and spirit of the disclosure and are intended to be included within the scope of the disclosure.

Claims

1. A method for treating lupus nephritis (LN), wherein the method is: (a) Select subjects who are classified as having Class III, Class IV, or mixed Class V and III or IV (mixed Class V + III / IV) LN based on renal biopsy classification, (b) The method comprising administering voclosporine to the selected subject.

2. A method for treating lupus nephritis (LN), the method comprising administering voclosporine to a subject previously classified as having class III, class IV, or mixed class V and III or IV (mixed class V + III / IV) lupus nephritis (LN) based on renal biopsy classification.

3. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects classified as having class III, class IV, or mixed class V and III or IV (mixed class V + III / IV) lupus nephritis (LN) based on renal biopsy classification.

4. A method for evaluating the likelihood of responding to voclosporine treatment, the method comprising identifying subjects classified as having class III, class IV, or mixed class V and III or IV (mixed class V + III / IV) lupus nephritis (LN) based on renal biopsy classification as having a high likelihood of responding to voclosporine treatment.

5. The method according to claim 3 or 4, further comprising administering voclosporine to the selected subject or the identified subject.

6. The method according to any one of claims 1 to 5, wherein the renal biopsy classification includes the International Society of Nephrology / Renal Pathology Society (ISN / RPS) classification.

7. The method according to any one of claims 1 to 6, wherein the renal biopsy classification includes the International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2003 classification.

8. The method according to any one of claims 1 to 6, wherein the renal biopsy classification includes the International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2018 classification.

9. The method according to any one of claims 1 to 8, wherein if the subject is classified as having class III LN based on renal biopsy classification, the subject is selected for administration of voclosporine.

10. The method according to any one of claims 1 to 9, wherein if the subject is classified as having class III LN based on renal biopsy classification, the subject is identified as having high responsiveness.

11. The method according to any one of claims 1 to 10, wherein if a renal biopsy from the subject shows focal proliferative glomerulonephritis, the subject is classified as having class III LN.

12. The method according to any one of claims 1 to 11, wherein if a renal biopsy from the subject shows proliferative glomerulonephritis affecting less than approximately 50% of the glomeruli, the subject is classified as having class III LN.

13. The method according to any one of claims 1 to 12, wherein if a renal biopsy from the subject shows active or inactive focal, segmental or whole-segmental intracapillary or extracapillary glomerulonephritis affecting less than approximately 50% of the total glomeruli, the subject is classified as having class III LN, and optionally has focal subendothelial immunodeposits and is accompanied by or without mesangial changes.

14. The method according to any one of claims 1 to 13, wherein if a renal biopsy from the subject shows endocapillary pleocytosis, the subject is classified as having class III LN.

15. The method according to any one of claims 1 to 14, wherein if a renal biopsy from the subject shows focal intraluminal pleocellularity, the subject is classified as having class III LN.

16. The method according to any one of claims 1 to 15, wherein if a renal biopsy from the subject shows endocapillary pleoplasia affecting less than 50% of the glomeruli, the subject is classified as having class III LN.

17. A kidney biopsy from the aforementioned subject (a) Segmental intratubular pleoplasia accompanied by substantial lumen reduction, (b) Intratubular cytosis with fibrinoid necrosis and cellular crescent formation, (c) Nuclear decay in glomerular segmentation, (d) Segmental sclerosis of the glomeruli, (e) Segmental subendothelial deposits as fuchsinophilic deposits by optical microscopy, and / or (f) The method according to any one of claims 1 to 16, wherein the subject is classified as having class III LN when it shows segmental distribution of IgG immunodeposits and mesangial deposits in the glomerular capillary wall.

18. A kidney biopsy from the aforementioned subject (a) Lesions including extracapillary cell proliferation, (b) crescent, (c) The presence of fibrin and fibrous matrix, and / or (d) The method according to any one of claims 1 to 17, wherein if the area around Bowman's capsule shows extracapillary cell proliferation in more than 10%, the subject is classified as having a class III LN.

19. The method according to any one of claims 1 to 10, wherein if the subject is classified as having class IV LN based on renal biopsy classification, the subject is selected for administration of voclosporine.

20. The method according to any one of claims 1 to 10 and 19, wherein if the subject is classified as having class IV LN based on renal biopsy classification, the subject is identified as having a high responsiveness.

21. The method according to any one of claims 1 to 10, 19, and 20, wherein if a renal biopsy from the subject shows diffuse proliferative glomerulonephritis, the subject is classified as having class IV LN.

22. The method according to any one of claims 1 to 10 and 19 to 21, wherein if a renal biopsy from the subject shows proliferative glomerulonephritis affecting more than approximately 50% of the glomeruli, the subject is classified as having class IV LN.

23. The method according to any one of claims 1 to 10 and 19 to 22, wherein if a renal biopsy from the subject shows active or inactive diffuse, segmental or pansegmental intracapillary or extracapillary glomerulonephritis affecting 50% or more of the total glomeruli, the subject is classified as having class IV LN, and optionally has diffuse subendothelial immunodeposits and is accompanied by or without mesangial changes.

24. The method according to any one of claims 1 to 10 and 19 to 23, wherein if a renal biopsy from the subject shows endocapillary pleocytosis, the subject is classified as having class IV LN.

25. The method according to any one of claims 1 to 10 and 19 to 24, wherein if a renal biopsy from the subject shows diffuse endocapillary pleocytosis, the subject is classified as having class IV LN.

26. The method according to any one of claims 1 to 10 and 19 to 25, wherein if a renal biopsy from the subject shows endocapillary pleoplasia affecting more than 50% of the glomeruli, the subject is classified as having class IV LN.

27. A kidney biopsy from the aforementioned subject was performed (a) Diffuse segmental intratubular proliferation, (b) Pantomimetic intraductal proliferation with leukocyte infiltration, (c) Intravascular proliferation with extensive wire-loop appearance in glomerular capillary walls showing subendothelial immunodeposits. (d) Subendothelial deposits as fuchsinophilic deposits, (e) The appearance of diffuse, fully segmented wire loops without mesangium or intracapillary cell proliferation, and / or (f) The method according to any one of claims 1 to 10 and 19 to 26, wherein the subject is classified as having a class IV LN if it shows a significant overload of immunodeposits in the glomerular capillary wall.

28. The method according to any one of claims 1 to 10 and 19 to 27, wherein a renal biopsy from the subject shows diffuse segmental lupus nephritis, with more than 50% of the involved glomeruli having segmental lesions extending to less than half of the glomerular loop, or shows diffuse pansegmental lupus nephritis, with more than 50% of the involved glomeruli having pansegmental lesions, the subject is classified as having class IV LN.

29. The method according to any one of claims 1 to 10 and 19 to 28, wherein if a renal biopsy from the subject shows progressive sclerosing glomerulonephritis, the subject is classified as having class IV LN.

30. A kidney biopsy from the aforementioned subject was performed (a) Lesions including extracapillary cell proliferation, (b) crescent, (c) The presence of fibrin and fibrous matrix, and / or (d) If the area around Bowman's capsule shows extracapillary cell proliferation in more than 10%, the subject is classified as having a class III LN, according to any one of claims 1 to 10 and 19 to 29.

31. The aforementioned crescent shape is (a) Cellular crescents containing more than 75% cells and fibrin and less than 25% fibrous matrix, (b) Fibrous crescents comprising more than 75% fibrous matrix and less than 25% cells and fibrin, and / or (c) The method according to any one of claims 17, 18, and 30, comprising a crescent of a fibrillary cell containing 25% to 75% cells and fibrin and the remaining fibrous matrix.

32. The method according to any one of claims 1 to 31, wherein if the subject is classified as having mixed class V+III / IV LN based on renal biopsy classification, the subject is selected for administration of voclosporine.

33. The method according to any one of claims 1 to 32, wherein if the subject is classified as having mixed class V+III / IV LN based on renal biopsy classification, the subject is classified as having high responsiveness.

34. A kidney biopsy from the aforementioned subject (a) Non-wire loop subcutaneous deposits within Class V, and / or (b) The method according to any one of claims 1 to 33, wherein if the subject exhibits subepithelial deposits comprising more than 50% of the loops of more than 50% of the glomeruli, the subject is classified as having a mixed class a class V+III / IV LN.

35. The method according to any one of claims 1 to 34, wherein if the subject is classified as having pure class V LN based on renal biopsy classification, the subject is not selected for administration of voclosporine.

36. The method according to any one of claims 1 to 35, wherein if the subject is classified as having pure class V LN based on renal biopsy classification, the subject is not identified as having high responsiveness.

37. The method according to claim 35 or 36, wherein if a renal biopsy from the subject shows membranous glomerulonephritis, the subject is classified as having pure class V LN.

38. The method according to any one of claims 35 to 37, wherein if a renal biopsy from the subject shows membranous LNs with whole-segmental or segmental continuous granular subepithelial immunodeposits, the subject is classified as having pure class V LNs.

39. A kidney biopsy from the aforementioned subject was performed (a) Significant thickening of the glomerular capillary wall in a whole-segmental distribution, (b) Subepithelial fuchsinophilic deposits, (c) Spikes in the glomerular capillary walls indicating membranous nephropathy, and / or (d) The method according to any one of claims 35 to 38, wherein, in the case of continuous subepithelial IgG deposits in the glomerular capillary wall, the subject is classified as having pure class V LN.

40. The method according to any one of claims 1 to 39, wherein the subject is further evaluated with respect to the National Institutes of Health Activity Index (NIH-AI).

41. The NIH-AI is evaluated on a total score scale of 0 to 24, based on the sum of the scores of the following evaluations: (a) The scale of endocapsular pleoplasia is 0 to 3, and is accompanied by endocapsular pleoplasia of less than 25% (1), 25% to 50% (2), or more than 50% (3) of the glomeruli. (b) Neutrophil / nuclear decay scale is 0 to 3, with less than 25% (1), 25% to 50% (2), or more than 50% (3) of glomeruli neutrophils and / or nuclear decay, (c) Fibrinoid necrosis scale is (0-3) x 2, with fibrinoid necrosis of less than 25% (1), 25%-50% (2), or more than 50% (3) of the glomeruli. (d) A scale of 0–3 of hyaline deposits, accompanied by wire-loop lesions and / or hyaline thrombi in less than 25% (1), 25%–50% (2), or more than 50% (3) of the glomeruli, (e) The scale of cellular / fibrous crescents is (0–3) × 2, with cellular and / or fibrous crescents accounting for less than 25% (1), 25%–50% (2), or more than 50% (3) of the glomerulus, and (f) The method according to claim 40, wherein the interstitial inflammation scale is 0 to 3 and is accompanied by less than 25% (1), 25% to 50% (2), or more than 50% (3) interstitial leukocytes in the cortex.

42. The method according to any one of claims 1 to 41, wherein the subject is further evaluated based on the National Institutes of Health Chronicity Index (NIH-CI).

43. The NIH-CI is evaluated on a total score scale of 0 to 12, based on the sum of the scores of the following evaluations: (a) The total glomerulosclerosis score is 0–3, and there is total and / or segmental sclerosis affecting less than 25% (1), 25%–50% (2), or more than 50% (3) of the glomeruli. (b) The fibrous crescent scale is 0 to 3, and is associated with less than 25% (1), 25% to 50% (2), or more than 50% (3) of the glomerulus. (c) A scale of tubular atrophy of 0 to 3, with tubular atrophy of less than 25% (1), 25% to 50% (2), or more than 50% (3) of the cortical tubules, and (d) The method according to claim 42, wherein the interstitial fibrosis scale is 0 to 3, and there is interstitial fibrosis of less than 25% (1), 25% to 50% (2), or more than 50% (3) in the cortex.

44. The method according to any one of claims 1 to 43, wherein the renal biopsy is evaluated using light microscopy, immunofluorescence, and / or electron microscopy.

45. The method according to any one of claims 1 to 44, wherein the voclosporine is administered in a daily dose of approximately 5 mg BID to approximately 50 mg BID.

46. The method according to any one of claims 1 to 45, wherein the voclosporine is administered in an initial daily dose of approximately 39.5 mg, approximately 31.6 mg, approximately 23.7 mg, approximately 15.8 mg, or approximately 7.9 mg BID.

47. The method according to any one of claims 1 to 46, wherein the voclosporine is administered in an initial daily dose of approximately 39.5 mg.

48. The method according to any one of claims 1 to 46, wherein the voclosporine is administered in an initial daily dose of approximately 23.7 mg.

49. The method according to any one of claims 1 to 46, wherein the voclosporine is administered in an initial daily dose of approximately 15.8 mg.

50. The method according to any one of claims 1 to 49, wherein the voclosporine is administered over a predicted voclosporine treatment period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or at least 48 months.

51. The method further includes evaluating the estimated glomerular filtration rate (eGFR) of the subject at at least a first and a second time point on different days of the predicted treatment period, and (i) If the eGFR of the subject decreases between the first and second time points to a target percentage and then to a predetermined value, reduce the daily dose by 7.9 mg BID increments (multiple increments are possible), or discontinue administration of voclosporine. (ii) If the eGFR of the subject decreases to less than the target percentage between the first time point and the second time point, the subject is continued to be administered the same predetermined daily dose of voclosporine, according to any one of claims 1 to 50.

52. The aforementioned predetermined values ​​are 50 to 90 ml / min / 1.73 m ２ The method according to claim 51, which is within the range of claim 51.

53. The aforementioned predetermined value is approximately 60 ml / min / 1.73 m ２ The method according to claim 51 or 52.

54. The method according to any one of claims 51 to 53, wherein the target percentage is in the range of 20% to 45%.

55. The method according to any one of claims 51 to 54, wherein the target percentage is approximately 30%.

56. (i) The eGFR of the subject decreases by more than 30% between the first time point and the second time point to 60 mL / min / 1.73 m ２ If the value falls below a certain level, discontinue administration of voclosporine to the subject. (ii) The eGFR of the subject decreases by 20% to 30% between the first time point and the second time point to 60 ml / min / 1.73 m ２ If the value falls below a certain level, administer a reduced dose of voclosporine to the subject, and (iii) If the eGFR of the subject decreases by less than 20% between the first time point and the second time point, the subject continues to be administered the same predetermined daily dose of voclosporine, the method according to any one of claims 51 to 55.

57. The method according to any one of claims 51 to 56, wherein the first time point is immediately before the administration of voclosporine is started.

58. The method according to any one of claims 51 to 57, wherein the second time point is after the first time point, in which the administration of voclosporine is initiated.

59. The method according to any one of claims 51 to 58, wherein the second time point is eight weeks after the commencement of the administration of voclosporine.

60. The method according to any one of claims 51 to 59, further comprising determining the eGFR of the subject at a third time point, and if the difference between the eGFR determined at the third time point and the eGFR determined at the first time point is less than a target percentage, the administration of the predetermined daily dose of voclosporine is resumed.

61. The method includes measuring the urinary protein-creatinine ratio (UPCR) of the subject at the first and second time points, and determining any decrease in the UPCR between the first and second time points, and The method according to any one of claims 51 to 60, wherein if the UPCR of the subject does not show a decrease of at least 25% at the second time point, administration of voclosporine to the subject is discontinued.

62. The method according to any one of claims 51 to 61, further comprising measuring the concentration of C3 or C4 in the subject's blood at a first time point and a second time point, determining whether the concentration of C3 or C4 has normalized at the second time point, and, if normalization of C3 or C4 is found, resuming administration of voclosporine to the subject.

63. The method according to any one of claims 1 to 62, further comprising administering an effective amount of mycophenolate mofetil (MMF) to the subject.

64. The method according to any one of claims 1 to 63, further comprising administering an effective amount of corticosteroid to the subject.

65. The method according to any one of claims 1 to 64, wherein the boclosporine is a mixture of at least 90% E isomer and 10% or less Z isomer.

66. A boxrosporin for use in the method according to any one of claims 1 to 65.

67. Use of voclosporine in the manufacture of a pharmaceutical product according to any one of claims 1 to 65.

68. Use of vocrossporine in the method according to any one of claims 1 to 65.

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