Methods for treating lupus nephritis with voclosporin

Abstract

Provided herein are methods of treatment of lupus nephritis (LN) and uses involving administration of voclosporin to a subject that has been classified as having a particular biopsy class of LN. In some aspects, the methods and uses relate to selecting a subject that has been classified as having a particular biopsy class of LN. for administration of voclosporin. In some aspects, the methods relate to assessing the likelihood of response to voclosporin treatment and selecting subjects that have a high likelihood of response for treatment of voclosporin. In some aspects, the methods and uses involve administering a therapeutically safe and effective amount of voclosporin to the selected subject.

Description

METHODS FOR TREATING LUPUS NEPHRITIS WITH VOCLOSPORINCross-Reference to Related Applications

[0001] This application claims priority from U.S. provisional application Nos. 63 / 505,394, filed May 31, 2023, and 63 / 513,690, filed July 14, 2023, the contents of each of which are incorporated by reference herein in their entirety.Field

[0002] The present disclosure relates to methods of treatment of lupus nephritis (LN) and uses involving administration of voclosporin to a subject that has been classified as having a particular biopsy class of LN. In some aspects, the methods and uses relate to selecting a subject that has been classified as having a particular biopsy class of LN. for administration of voclosporin. In some aspects, the methods relate to assessing the likelihood of response to voclosporin treatment and selecting subjects that have a high likelihood of response for treatment of voclosporin. In some aspects, the methods and uses involve administering a therapeutically safe and effective amount of voclosporin to the selected subject.Background

[0003] Lupus nephritis (LN) is one of a number of proteinuric kidney diseases involving 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 which requires dialysis, or renal transplant and can often result in death. Treatment can often be difficult, and an improved method for treatment of LN is needed. Provided herein are methods and uses that meet such needs.Summary

[0004] Provided herein are methods and uses related to treatment using voclosporin. In some of any of the provided embodiments, the methods and uses relate to treatment of lupus nephritis (LN) and selecting subjects for treatment that involves selecting subjects that have been classified as having a particular class or type of LN, such as a particular biopsy class of LN. The methods and uses also involve administering voclosporin to the selected or identified subjects.

[0005] Provided herein are methods of treating lupus nephritis (LN) that involve selecting a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification; and administeringvoclosporin to the selected subject.

[0006] Also provided herein are methods of lupus nephritis (LN) that involve administering voclosporin to a subject that has previously been classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification.

[0007] Also provided herein are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification.

[0008] Also provided herein are methods of assessing the likelihood of response to voclosporin treatment that involve identifying a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification, as having a high likelihood of response to voclosporin treatment.

[0009] In some of any of the provided embodiments, the methods also involve administering voclosporin to the selected subject or the identified subject.

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

[0011] In some of any of the provided embodiments, the subject is selected for administration of voclosporin if the subject is classified as having a Class III LN based on a renal biopsy classification. In some of any of the provided embodiments, the subject is identified as having a high likelihood of response if the subject is classified as having a Class III LN based on a renal biopsy classification.

[0012] In some of any of the provided embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits focal proliferative glomerulonephritis. In some of any of the provided embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits proliferative glomerulonephritis affecting fewer than about 50% of the glomeruli. In some of any of the provided embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving fewer than about 50%of all glomeruli, optionally with focal subendothelial immune deposits, with or without mesangial alterations.

[0013] In some of any of the provided embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits endocapillary hypercellularity. In some of any of the provided embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits focal endocapillary hypercellularity. In some of any of the provided embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits endocapillary hypercellularity affecting fewer than about 50% of the glomeruli.

[0014] In some of any of the provided embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits: segmental endocapillary hypercellularity with substantial luminal reduction; endocapillary hypercellularity with fibrinoid necrosis and cellular crescent formation; karyorrhexis in a segment of a glomerulus; segmental sclerosis of a glomerulus; segmental subendothelial deposits by light microscopy as fuchsinophilic deposits; and / or IgG immune deposits in glomerular capillary wall in segmental distribution and mesangial deposits.

[0015] In some of any of the provided embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits: a lesion comprising extracapillary hypercellularity; a crescent; the presence of Fibrin and fibrous matrix; and / or 10% or more of the circumference of Bowman’s capsule showing extracapillary hypercellularity.

[0016] In some of any of the provided embodiments, the subject is selected for administration of voclosporin if the subject is classified as having a Class IV LN based on a renal biopsy classification. In some of any of the provided embodiments, the subject is identified as having a high likelihood of response if the subject is classified as having a Class IV LN based on a renal biopsy classification.

[0017] In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits diffuse proliferative glomerulonephritis. In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits proliferative glomerulonephritis affecting greater than about 50% of the glomeruli. In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving >50% of allglomeruli, optionally with diffuse subendothelial immune deposits, with or without mesangial alterations.

[0018] In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits endocapillary hypercellularity. In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits diffuse endocapillary hypercellularity. In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits endocapillary hypercellularity affecting greater than about 50% of the glomeruli.

[0019] In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits: diffuse segmental endocapillary proliferation; global endocapillary proliferation with leukocyte infiltration; endocapillary proliferation with widespread wire loop appearance in the glomerular capillary wall indicator of subendothelial immune deposits; subendothelial deposits as fuchsinophilic deposits; diffuse global wire loop appearance without mesangial or endocapillary cellular proliferation; and / or significant immune deposit overload in glomerular capillary wall.

[0020] In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits a diffuse segmental lupus nephritis with greater than 50% of the involved glomeruli have segmental lesions that involve less than half of the glomerular tuft; or a diffuse global lupus nephritis with greater than 50% of the involved glomeruli have global lesions.

[0021] In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits advanced sclerosing glomerulonephritis.

[0022] In some of any of the provided embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits: a lesion comprising extracapillary hypercellularity; a crescent; the presence of Fibrin and fibrous matrix; and / or 10% or more of the circumference of Bowman’s capsule showing extracapillary hypercellularity.

[0023] In some of any of the provided embodiments, the crescent comprises: a cellular crescent comprising more than 75% cells and fibrin and less than 25% fibrous matrix; a fibrous crescent comprising more than 75% fibrous matrix and less than 25% cells and fibrin; and / or a fibrocellular crescent comprising 25%-75% cells and fibrin and the remainder fibrous matrix.

[0024] In some of any of the provided embodiments, the subject is selected foradministration of voclosporin if the subject is classified as having a Mixed Class V + III / IV LN based on a renal biopsy classification. In some of any of the provided embodiments, the subject is identified as having a high likelihood of response if the subject is classified as having a Mixed Class V + III / IV LN based on a renal biopsy classification.

[0025] In some of any of the provided embodiments, the subject is classified as having a Class a Mixed Class V + III / IV LN if a renal biopsy from the subject exhibits: non- wire-loop subendothelial deposits within Class V, and / or subepithelial deposits involving >50% of the tuft of >50% of the glomeruli.

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

[0027] In some of any of the provided embodiments, the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits membranous glomerulonephritis. In some of any of the provided embodiments, the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits membranous LN with global or segmental continuous granular subepithelial immune deposits.

[0028] In some of any of the provided embodiments, the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits: significant glomerular capillary wall thickening in global distribution; subepithelial fuchsinophilic deposits; spikes in glomerular capillary wall indicator of membranous nephropathy; and / or continuous subepithelial IgG deposits in the glomerular capillary wall.

[0029] In some of any of the provided embodiments, the subject is further assessed for a National Institutes of Health Activity Index (NIH-AI). In some of any of the provided embodiments, the NIH-AI is assessed on a total score scale between 0 and 24, based on the sum of the scores of the following assessments: Endocapillary hypercellularity on a scale of 0-3, with endocapillary hypercellularity in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;Neutrophils / karyorrhexis on a scale of 0-3, with neutrophils and / or karyorrhexis in <25% (1), 25%-50% (2), or >50% (3) of glomeruli; Fibrinoid necrosis on a scale of (0-3) x 2, with fibrinoid necrosis in <25% (1), 25%-50% (2), or >50% (3) of glomeruli; Hyaline deposits on a scale of 0-3, with wire loop lesions and / or hyaline thrombi in <25% (1), 25%-50% (2), or >50%(3) of glomeruli; Cellular / fibrocellular crescents on a scale of (0-3) x 2, with cellular and / or fibrocellular crescents in <25% (1), 25%-50% (2), or >50% (3) of glomeruli; and Interstitial Inflammation on a scale of 0-3, with interstitial leukocytes in <25% (1), 25%-50% (2), or >50% (3) in the cortex.

[0030] In some of any of the provided embodiments, the subject is further assessed for a National Institutes of Health Chronicity Index (NIH-CI). In some of any of the provided embodiments, the NIH-CI is assessed on a total score scale between 0 and 12, based on the sum of the scores of the following assessments: Total glomerulosclerosis score on a scale of 0-3, with global and / or segmental sclerosis in <25% (1), 25%-50% (2), or >50% (3) of glomeruli; Fibrous crescents on a scale of 0-3, with fibrous crescents in <25% (1), 25%-50% (2), or >50% (3) of glomeruli; Tubular atrophy on a scale of 0-3, with tubular atrophy in <25% (1), 25%-50% (2), or >50% (3) of the cortical tubules; and Interstitial fibrosis on a scale of 0-3, with interstitial fibrosis in <25% (1), 25%-50% (2), or >50% (3) in the cortex.

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

[0032] In some of any of the provided embodiments, the voclosporin is administered at a daily dose of between about 5 mg BID to about 50 mg BID. In some of any of the provided embodiments, the voclosporin is administered at an initial daily dose of about 39.5 mg, about 31.6 mg, about 23.7 mg, about 15.8 mg, or about 7.9 mg BID. In some of any of the provided embodiments, the voclosporin is administered at an initial daily dose of about 39.5 mg. In some of any of the provided embodiments, the voclosporin is administered at an initial daily dose of about 23.7 mg. In some of any of the provided embodiments, the voclosporin is administered at an initial daily dose of about 15.8 mg.

[0033] In some of any of the provided embodiments, the voclosporin is administered over a projected voclosporin 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 or longer.

[0034] In some of any of the provided embodiments, the methods also involve assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of the projected treatment period; and if the eGFR of the subject decreases by more than a target % to below a predetermined value, between the first and second time points, reducing the daily dose by increment(s) of 7.9 mg BID or stopping theadministering of voclosporin; if the eGFR of the subject decreases by less than the target %, between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0035] In some of any of the provided embodiments, the predetermined value is in the range of 50-90 ml / min / 1.73m2. In some of any of the provided embodiments, the predetermined value is approximately 60 ml / min / 1.73m2.

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

[0037] In some of any of the provided embodiments, if the eGFR of the subject decreases by > 30% to a value of below 60 mL / min / 1.73m2between the first and second time points, stopping the administering of voclosporin to the subject; if the eGFR of the subject decreases by between 20% to 30% to a value of below 60 ml / min / 1.73m2between the first and second time points, administering a reduced dosage of voclosporin to the subject; and if the eGFR of the subject decreases by < 20% between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0038] In some of any of the provided embodiments, the first time point is immediately preceding initiating the administration of voclosporin. In some of any of the provided embodiments, the second time point is after the first time point and initiating the administration of voclosporin. In some of any of the provided embodiments, the second time point is 8 weeks after initiating the administration of voclosporin.

[0039] In some of any of the provided embodiments, the methods also involve determining the eGFR of the subject at a third time point and if the eGFR is determined at the third time point to differ from the eGFR determined at the first time point by less than the target %, resuming administering the predetermined daily dosage of voclosporin.

[0040] In some of any of the provided embodiments, the methods also involve measuring urinary protein creatinine ratio (UPCR) of the subject at the first time point and the second time point and determining any reduction of the UPCR between the first and second time points, and if the UPCR of the subject fails to show a reduction of at least 25% at the second time point, discontinuing administering voclosporin to the subject.

[0041] In some of any of the provided embodiments, the methods also involve measuring the concentration of C3 or C4 in the blood of the subject at the first time point and the second time point, and determining whether the concentration of C3 or C4 is normalized at the second timepoint, and if normalization of C3 or C4 is found, reinstating the administering voclosporin to the subject.

[0042] In some of any of the provided embodiments, the methods also involve administering to the subject an effective amount of my cophenolate mofetil (MMF).

[0043] In some of any of the provided embodiments, the methods also involve administering to the subject an effective amount of a corticosteroid.

[0044] In some of any of the provided embodiments, the voclosporin is a mixture of at least 90% E isomer and not more than 10% Z isomer.

[0045] Also provided herein is voclosporin for use in accordance with any of the methods described herein.

[0046] Also provided herein are uses of voclosporin in the manufacture of a medicament in accordance with any of the methods described herein.

[0047] Also provided herein are uses of voclosporin in accordance with any of the methods described herein.Brief Description of the Drawings

[0048] FIG. 1A-FIG. IL depict exemplary micrographs of renal biopsies for classes of LN based on the ISN / RPS 2003 classification (see Weening et al., Kidney International (2004) 65, 521-530).

[0049] FIG. 1A depicts an example of LN Class II: Light micrograph of a glomerulus with mild mesangial hypercellularity [periodic-acid Schiff (PAS)].

[0050] FIG. IB depicts an example of LN Class III (A): Light micrograph showing a glomerulus with segmental endocapillary hypercellularity, mesangial hypercellularity, capillary wall thickening and early segmental capillary necrosis (methenamine silver).

[0051] FIG. 1C depicts an example of LN Class III (A): Light micrograph showing a glomerulus with segmental capillary necrosis with sparing of the remainder of the capillary tuft, a vasculitis-like lesion (methenamine silver).

[0052] FIG. ID depicts an example of LN Class IV-G (A): Light micrograph showing a glomerulus with global involvement of endocapillary and mesangial hypercellularity and matrix expansion, influx of leukocytes, and occasional double contours (methenamine silver).

[0053] FIG. IE depicts an example of LN Class IV-S (A): Segment of a glomerulus showingendocapillary hypercellularity, capillary wall double contours, wireloop lesions and hyaline thrombi [periodic-acid Schiff (PAS)].

[0054] FIG. IF depicts an example of LN Class IV-G (A / C): Light micrograph of a glomerulus showing global severe endo- and extracapillary proliferation, wireloop lesions, leukocyte influx, apoptotic bodies, capillary necrosis, and mesangial expansion with hypercellularity and matrix expansion; marked interstitial inflammatory infdtration [periodic- acid Schiff (PAS)].

[0055] FIG. 1G depicts an example of LN Class IV-G (A / C): Glomerulus with global endocapillary proliferation, leukocyte influx, and apoptotic bodies, double contours, crescent formation with tubular transformation, early sclerosis, and disruption of Bowman’s capsule [periodic-acid Schiff (PAS)].

[0056] FIG. 1H depicts an example of LN Class IV-G (A): Glomerulus with widespread subendothelial immune deposits (wireloop lesions) associated with new basement membrane formation along the inner side of the capillaries, but without endocapillary leukocyte infdtration or hypercellularity (methenamine silver).

[0057] FIG. II depicts an example of LN Class V: Glomerulus with advanced stage lupus membranous nephropathy characterized by massive subepithelial accumulation of immune deposits (IF, full house) and interdigitating spike formation (methenamine silver).

[0058] FIG. 1J depicts an example of LN Class IV and V (A / C): Glomerulus with lupus membranous nephritis with subepithelial spike formation combined with global endocapillary and mesangial hypercellularity, early crescent formation, and early mesangial and capillary sclerosis (methenamine silver).

[0059] FIG. IK depicts an example of LN Class VI: Renal cortex showing almost diffuse, global glomerular sclerosis accompanied by interstitial fibrosis, mononuclear inflammatory infiltrates, and vascular sclerosis (methenamine silver).

[0060] FIG. IL depicts an example of thrombotic microangiopathy in a patient with systemic lupus erythematosus (SLE) and circulating lupus anticoagulant: A glomerulus showing severe capillary and arteriolar thrombosis, endothelial cell swelling and necrosis, neutrophil influx, and stasis of erythrocytes, without evidence of immune deposits by immunofluorescence (methenamine silver).

[0061] FIG. 2A-FIG. 2F depict exemplary micrographs of renal biopsies for particularfeatures described for the classes of LN based on the ISN / RPS 2018 classification (see Bajema, et al., Kidney International (2018) 93, 789-796): Mesangial hypercellularity (FIG. 2A), endocapillary hypercellularity (FIG. 2B), cellular crescent (FIG. 2C), fibrous crescent (FIG. 2D), fibrocellular crescent (FIG. 2E), and adhesion (FIG. 2F). All micrographs show Periodic acid-Schiff (PAS) staining, and arrows point to examples of the described features.

[0062] FIG. 3 depicts exemplary schematics of ultrastructural features of a single glomerular capillary affected by lupus glomerulonephritis: Class I with mesangial immune deposits (black) but no mesangial cell (red) hypercellularity or influx of leukocytes; Class II with mesangial immune deposits and mesangial cell hypercellularity but no influx of leukocytes; Class III / IV (upper right) with mesangial and capillary influx of leukocytes; Class III / IV (lower right) with subendothelial capillary wall immune deposits that can be seen by light microscopy and mesangial but no capillary influx of leukocytes (dark green neutrophils and light green monocytes / macrophages); Class III / IV + V with an influx of leukocytes and numerous subepithelial immune deposits in addition to subendothelial deposits; and Class V with numerous subepithelial immune deposits but no influx of leukocytes (podocyte: outer green cell; endothelial cell: yellow cell; mesangial cell: red cell; neutrophil: green cell with segmented nucleus; monocyte / macrophage: light green cell); see Bajema; et al.; Kidney International (2018) 93; 789-796.

[0063] FIG. 4 shows a schematic representation of a trial comparing the safety and efficacy of voclosporin to placebo at 24 and 48 weeks in subjects concurrently administered my cophenolate mofetil (MMF) and oral corticosteroids (top panel), which were subject to the presented tapering protocol (bottom panel).

[0064] FIG. 5 shows a schematic representation of the long-term safety and tolerability continuation study. As depicted, 216 subjects out of the 357 subjects who were included in the initial 1-year study continued on to the continuation study. Time points for baseline and repeat biopsies are also shown for the subgroup of subjects.

[0065] FIG. 6 shows the mean estimated glomerular filtration rates (eGFR) for the 116 subjects in the voclosporin group and the 100 subjects in the control group over a period of 36 months with an additional 4-week follow-up time point. The number of subjects in each study arm over the same time points is also depicted.

[0066] FIG. 7 shows the mean corrected estimated glomerular filtration rates (eGFR; 95% Confidence Interval) as well as the mean change from pretreatment baseline in corrected eGFRfor the 116 subjects in the voclosporin group and the 100 subjects in the control group over a period of 36 months with an additional 4-week follow-up time point. The number of subjects in each study arm over the time points is also depicted. Pretreatment baseline was defined as the last value before subject received first dose of study drug on Day 1 of the initial 12 months study (e.g., at the beginning of the 36 months).

[0067] FIG. 8 shows the mean corrected estimated glomerular filtration rates (eGFR) slope and eGFR change (95% Confidence Interval) from Month 12 for the 116 subjects in the voclosporin group and the 100 subjects in the control group over a period of 24 months (i.e., Month 12 to Month 36). Mean corrected eGFR slope and eGFR change are calculated from entry into the continuation study (month 12 of treatment) to the end of the continuation study (month 36 of treatment). The number of subjects in each study arm at the same time points is also depicted.

[0068] FIG. 9 shows the mean UPCR (mg / mg) for the 116 subjects in the voclosporin and the 100 subjects in the control group over a period of 36 months, with an additional 4-week follow-up time point. The number of subjects in each study arm at the same time points is also depicted.

[0069] FIG. 10 shows the proportion of subjects with 50% reduction in UPCR at every 6 months for a duration of 36 months, and includes the additional 4-week follow up time point. The number of subjects in each study arm at the same time points is also depicted.

[0070] FIG. 11 shows urine protein creatinine ratio (UPCR) levels for Voclosporin and control subjects after over a 52-week post hoc analysis period. The number of subjects in each study group over the same time points is also depicted.

[0071] FIG. 12 shows complete renal response rates (CRR) by subject subgroup at 12 months of post hoc analysis. OR>1 demonstrates treatment benefit of voclosporin.

[0072] FIG. 13 shows complete renal response rates (CRR) for voclosporin and control subjects at 12 months of post hoc analysis and after classifying subjects by disease class based on results of subject's biopsies.

[0073] FIG. 14 shows the mean estimated glomerular filtration rates (eGFR) for the subjects in the Voclosporin group and the control group over a period of 52 weeks. The number of subjects in each study group over the same time points is also depicted.

[0074] FIG. 15 shows the mean urine protein creatinine ratio (UPCR) over a 3-year study forthe subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group) that were assessed by repeat renal biopsies, and the 357 total study subjects evaluated in the study.

[0075] FIG. 16 shows the mean estimated glomerular fdtration rates (eGFR) over a 3-year study for the subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group) that were assessed by repeat renal biopsies, and the 357 total study subjects evaluated in the study.

[0076] FIG. 17 shows the least squares mean corrected estimated glomerular fdtration rate (eGFR) over a 3-year study for the subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group) who were assessed by repeat renal biopsies, and the subjects of the larger total study group for the 2-year continuation study (n = 216). Renal function was assessed with corrected eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) using a prespecified ceiling of 90 mL / min / 1.73 m2

[0077] FIG. 18A-FIG. 18B are box plots depicting disease activity (FIG. 18A; as assessed based on renal biopsies assessing the National Institutes of Health Activity Index - NIH-AI; scale 0-24) and chronicity (FIG. 18B; as assessed based on renal biopsies assessing the National Institutes of Health Chronicity Index - NIH-CI; scale 0-12) over a 3-year study for the subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group), assessed at baseline (BL) and a follow-up (approximately 18 months after treatment with voclosporin). The symbol “x” represents mean and the horizontal bold line represents median. The top and bottom boxes represent the 75thand 25thpercentiles. Outliers are represented as individual dots.

[0078] FIG. 19 shows the mean (± standard deviation) plasma concentration of MPA after administration of MMF alone (Day 1) and in the presence of voclosporin (Day 7).

[0079] FIG. 20 shows the mean (± standard deviation) plasma concentration of MP AG after administration of MMF alone (Day 1) and in the presence of voclosporin (Day 7).Detailed Description

[0080] Provided herein are methods of treatment of lupus nephritis (LN) and selecting subjects for treatment, and uses such as therapeutic uses of voclosporin, that involves selecting subjects that have been classified as having a particular class or type of LN, such as a particular biopsy class of LN. Also provided herein are methods of treatment and uses involving identifying lupus nephritis (LN) subjects that has a particular class or type of LN based on a renal biopsy classification, as subjects that have a high likelihood of response to treatment withvoclosporin. In some aspects, the methods and uses also involve administering voclosporin to the selected or identified subjects.

[0081] The present disclosure relates to methods of treatment of lupus nephritis (LN) and uses involving administration of voclosporin to a subject that has been classified as having a particular class or type of LN, such as a particular biopsy class of LN. In some aspects, the methods and uses relate to selecting a subject that has been classified as having a particular class or type of LN, such as a particular biopsy class of LN for administration of voclosporin. In some aspects, the methods relate to assessing the likelihood of response to voclosporin treatment and selecting subjects that have a high likelihood of response for treatment of voclosporin. In some aspects, the methods and uses involve administering a therapeutically safe and effective amount of voclosporin to the selected subject.

[0082] In some aspects, the provided methods and uses are based on an observation that treatment with voclosporin in a particular class or type of LN, such as a particular biopsy class of LN, such as a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN, results in unexpectedly high renal response rates compared to control patients that did not receive voclosporin. As described herein, voclosporin treatment for LN was observed to be particularly effective for patients with a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN, with unexpectedly and substantially higher complete response rates (CRR) compared to control patients that did not receive voclosporin, without a substantial increase in susceptibility to or risk of adverse events. Voclosporin has been shown to have higher rates of remission and response over long term clinical trials, compared to standard of care treatment while preserving renal function without the clinical manifestation of toxicities shown with other CNIs, such as cyclosporin or tacrolimus. In some aspects, the results provided herein support effective and safe treatment of a particular class or type of LN, such as a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN with voclosporin, and that particular renal biopsy classification, such as a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN, is an important criterion for identifying subjects that have a high likelihood of response to voclosporin, and to select subjects that would substantially benefit from administration of voclosporin to treat LN.

[0083] Voclosporin provides multiple advantages over other treatment for LN, and was recently FDA-approved as the first oral treatment for LN. The results described herein support the advantages of using or switching to voclosporin, and the methods, treatment regimen, protocols and uses provided herein, for treatment of LN. Further, the results support the benefitof selecting particular subjects, such as those with a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification, for voclosporin administration to treat the LN. Advantages and benefits include avoiding futile medication and unnecessary exposure to potential side effects from unnecessary treatment. Such advantages are particularly critical subjects who are at risk of adverse effects or toxi cities, because treatment regimens for LN typically are long-term, and may be associated with undesirable side effects.

[0084] Accordingly, voclosporin can be administered to the selected subjects that have a high likelihood of response without an increase in adverse events. In addition, voclosporin also was observed to have a surprisingly high drug persistency. At about 24 months after the approval of voclosporin for the treatment of lupus nephritis (LN), approximately 26% of the subjects have remained on voclosporin treatment, as estimated based on patient databases, which was substantially higher than the projected rate. These observations support that voclosporin can be used as a safe and effective LN treatment, particularly for subjects that meet the criteria in accordance with the provided embodiments. Subject with LN, particularly those with a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN would benefit in many respects from using voclosporin for treatment.

[0085] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0086] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.I. METHODS OF TREATMENT AND USES OF VOCLOSPORIN

[0087] Provided herein are methods of treatment and uses involving selecting lupus nephritis (LN) subjects that have a particular class or type of LN based on a renal biopsy classification, for treatment with voclosporin. Also provided herein are methods of treatment and uses involving identifying lupus nephritis (LN) subjects that has a particular class or type of LN based on a renal biopsy classification, as subjects that have a high likelihood of response to treatment with voclosporin. Also provided are methods and uses that involve administering voclosporin to theselected subject or the subject identified to have a high likelihood of response, for example in accordance with any of the methods or uses described herein. In some aspects, also provided are uses of voclosporin or compositions comprising voclosporin in accordance with any of the methods described herein. Uses include uses of voclosporin in such methods and treatments, and in the preparation of a medicament in order to carry out such methods. In some embodiments, the methods are carried out by selecting a subject that is classified as having a particular class or type of LN based on a renal biopsy classification, and administering voclosporin to the selected subject. In some embodiments, the methods are carried out by identifying a subject that is classified as having a particular class or type of LN based on a renal biopsy classification as having a high likelihood of response to voclosporin treatment, and administering voclosporin to the identified subject. In some aspects, the provided methods and uses involve administration of an effective amount of voclosporin to the selected or identified subject.

[0088] In some aspects, the selection of subjects for administration of voclosporin is based on any of the criteria or assays described herein, for example in Section II. In some aspects, the subject is selected for voclosporin based on a renal biopsy. In some aspects, voclosporin is based on any of the methods or treatment regimen described herein, for example in Section III.A. Lupus Nephritis (LN)

[0089] Systemic lupus erythematosus (SLE) is an autoimmune disease that results in chronic inflammation and damage to diverse organs. When the kidneys are affected, the condition is known as lupus nephritis (LN). Evaluating kidney function in patients suffering from LN is important as timely detection and management of renal impairment can greatly improve renal outcomes. Histological evidence of LN is present in most patients with SLE, even in those who do not clinically manifest renal disease. Monitoring for the development of LN can be performed based on urinalysis, serum creatinine, and urine albumin-to-creatine ratio. In some aspects, a rise in serum creatinine value from the baseline and the presence of proteinuria that is commonly observed with LN can be identified based on these methods. Treatment plays an important role in preventing progression to end-stage renal disease since LN carries a high risk for increased morbidity.

[0090] LN a proteinuric kidney diseases wherein an inflammation of the kidneys is caused by systemic lupus erythematosus (SLE). In some cases, up to 60% of SLE patients develop LN. LN is a debilitating and costly disease often leading to renal failure which requires dialysis, or renal transplant and often results in death. Indeed, patients with renal failure have an over 60-fold increased risk of premature death compared to SLE patients in general. A clinical sign of LN is leakage of blood proteins into the urine and the disease can be diagnosed by a number of factors, including urinary protein / creatinine ratio (UPCR) wherein a UPCR of greater than 0.5 mg / mg is indicative of the condition being in an active state. Further, certain markers in the blood can also be diagnostic - for example, complement 3 (C3), complement 4 (C4) and anti- dsDNA antibodies.

[0091] The standard of care for LN has not met with a great deal of success. The standard of care is use of mycophenolate mofetil (MMF) or intravenous cyclophosphamide. With these treatments partial remission was found only in approximately 50% of cases and complete remission was shown in less than 10% of the subjects. Thus, there is clearly a need for a treatment that improves these outcomes.

[0092] In some embodiments, the subject to be treated in accordance with the methods and uses provided herein include subjects that has or has been diagnosed with LN. In some embodiments, the subject to be treated in accordance with the methods and uses provided herein include subjects that has or has been diagnosed with a particular class of LN based on a renal biopsy. In some aspects, the provided methods and uses involve selecting subjects that have been diagnosed with a particular class of LN based on a renal biopsy.

[0093] In some aspects, the main goal of treatment in LN is the normalization of the kidney function and the prevention of progressive decline of kidney function. Treatment options vary depending on the underlying pathologic lesion. (Tamirou et al., J Clin Med. 2021 Feb 09; 10(4)).

[0094] Lupus nephritis is primarily associated with the formation of immune complexes due to a Type III hypersensitivity reaction. In some aspects, anti-double-stranded DNA (anti- dsDNA) antibodies bind to DNA, forming anti-dsDNA immune complexes that are deposited on the mesangium, subepithelial and / or subendothelial space near the glomerular basement membrane of the kidney leading to an inflammatory response. In some cases, the complement pathway is activated with a resultant influx of neutrophils and other inflammatory cells. In some aspects, while an autoimmune phenomenon causes LN, there are also genetic components that may predispose an SLE patient to develop LN. For instance, polymorphisms in the allele coding for the immunoglobulin receptors on macrophages and APOL1 gene variations found exclusively in African American populations with SLE were found to be associated with 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).B. Voclosporin Treatment for LN

[0095] Voclosporin is an analog of cyclosporin A that has been found useful for treating autoimmune diseases and as an immunosuppressant in organ transplantation.

[0096] Clinical studies for voclosporin for the treatment of LN have shown a high response rate with no substantial differences in adverse events compared to standard-of-care controls. For example, in one study, subjects with LN were dosed with 23.7 mg of voclosporin twice daily in combination with my cophenolate mofetil (MMF) and reducing cortical steroid dose over 24 weeks or longer. Entry criteria for the study included determination of a urine protein creatinine ratio (UPCR) of >1.0 mg / mg or >1.5 mg / mg depending on the classification of a renal biopsy and an eGFR (estimated glomerular filtration rate) of >45 mol / min / 1.73m2as well as serologic evidence of LN. The results of the study showed complete remission or partial remission in a large percentage of subjects.

[0097] In addition, it was shown that subjects who achieved a >25% reduction in UPCR at 8 weeks were likely to maintain benefit throughout the 24-week or 48-week treatment.

[0098] In another study, my cophenolate mofetil (MMF) and reducing corticosterone dosage with either 23.7 mg or 39.5 mg of voclosporin twice daily showed successful complete or partial remission in a large number of patients at 24 weeks and 48 weeks.

[0099] An additional study also showed data regarding the predictability of success with respect to complete remission (CR) based on various criteria measured after 8 weeks of treatment with 23.7 mg BID of voclosporin along with MMF-1 and steroid taper. These criteria included UPCR (less than 25% reduction considered to show ineffectiveness) as well as normalization of complements 3 and 4 (C3 and C4) and of anti-dsDNA.

[0100] In some aspects, based on such results of successful treatment, voclosporin was recently FDA-approved for treatment of active lupus nephritis (LN) in combination with background immunosuppressive therapy. Observations show that voclosporin is more potent and less toxic at therapeutic levels than other CNIs or other compounds for treatment of LN.

[0101] CNIs are used as immunosuppressants for subjects suffering from a variety of conditions, particularly those conditions that include an autoimmunity component to the pathology. The immunosuppressant activity of CNIs is thought to help treat the direct causes of symptoms of conditions associated immune system activity. For example, CNIs are also used to treat LN. The immunosuppressive properties of CNIs are thought to result from inhibition of calcineurin, a phosphatase. Calcineurin is a key enzyme involved in T cell activation andproliferation. Cyclosporin and tacrolimus are thought to inhibit the phosphatase activity of calcineurin. This inhibition in turn suppresses IL-2 production, and thus T cell activation. For many of the immunosuppressants, including CNIs, need to be administered for an extended period of time, such as at least 1 month, at least 3 months, at least 6 months, at least 1 year, or longer, for example, for more than 5 years.

[0102] Cyclosporin (in some cases called cyclosporine or ciclosporin) and derivatives of cyclosporin, such as cyclosporine A (CsA) have been a front line CNI used for immunosuppression related to transplant. Although cyclosporine A and voclosporin are structurally similar, the two compounds display different metabolic stability and distribution, and certain metabolites of cyclosporine A have been correlated with nephrotoxicity (Wu and Kuca, Current Drug Metabolism 2019;20(2): 84-90(7)). In some aspects, the subject is selected for administration of voclosporin if the subject has a particular class of LN based on a renal biopsy, such as a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification.

[0103] In some aspects, tacrolimus has also been used successfully for immunosuppression related to transplant. Both cyclosporine and tacrolimus were first introduced for solid organ transplantation in the 1980s and are considered legacy CNIs or traditional, first-generation CNI. Currently, the majority of KTRs have a CNI-based regimen as standard maintenance immunosuppression with a preference for tacrolimus over cyclosporine (including derivatives such as cyclosporine A (CsA)) because of tacrolimus’ superiority on long-term renal graft function, allograft survival, 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).

[0104] Voclosporin also shows substantial advantages compared to other calcineurin inhibitors (CNIs). Legacy CNIs, such as cyclosporin (including derivatives of cyclosporin, such as cyclosporine A (CsA)) and tacrolimus (TAC), or derivatives thereof, are potent immunosuppressants, and have been tested for the treatment of a variety of conditions that typically require long-term immunosuppression, including use in conjunction with organ or tissue transplant. The legacy CNI compounds in some contexts have been associated with adverse effects, side effects or toxicities, such as drug-induced nephrotoxicity.II. IDENTIFICATION AND SELECTION OF SUBJECTS

[0105] In some aspects, the provided methods and uses involve administration of voclosporin to selected subjects in accordance with the provided embodiments, or subjectsidentified as having a high likelihood of response to treatment with voclosporin. In some aspects, the subject is selected for administration of voclosporin if the subject has a particular class or type of lupus nephritis (LN) based on a renal biopsy classification.

[0106] In some aspects, the provided methods and uses involve evaluating or assessing the subject’s LN based on a renal biopsy classification, such as based on any described herein.

[0107] In some aspects, the subject is selected for administration of voclosporin if the subject has a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification. In some aspects, the subject is selected for administration of voclosporin if the subject has a Class III LN based on a renal biopsy classification. In some aspects, the subject is selected for administration of voclosporin if the subject has a Class IV based on a renal biopsy classification. In some aspects, the subject is selected for administration of voclosporin if the subject has a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification.

[0108] In some aspects, the subject is identified as having a high likelihood of response to voclosporin treatment if the subject has a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification. In some aspects, the subject is identified as having a high likelihood of response to voclosporin treatment if the subject has a Class III LN based on a renal biopsy classification. In some aspects, the subject is identified as having a high likelihood of response to voclosporin treatment if the subject has a Class IV based on a renal biopsy classification. In some aspects, the subject is identified as having a high likelihood of response to voclosporin treatment if the subject has a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification.

[0109] In some aspects, the provided methods and uses involve administration of an effective amount of voclosporin to the selected or identified subject. In some aspects, voclosporin is based on any of the methods or treatment regimen described herein, for example in Section III.A. Renal Biopsy Classifications

[0110] Provided herein are methods of treatment and uses involving selecting lupus nephritis (LN) subjects that have a particular class or type of LN based on a renal biopsy classification, for treatment with voclosporin. Also provided herein are methods of treatment and uses involving identifying LN subjects that has a particular class or type of LN based on a renal biopsy classification, as subjects that have a high likelihood of response to treatment with voclosporin.

[0111] Also provided are methods and uses that involve administering voclosporin to the selected subject or the subject identified to have a high likelihood of response, for example in accordance with any of the methods or uses described herein. In some aspects, also provided are uses of voclosporin or compositions comprising voclosporin in accordance with any of the methods described herein. Uses include uses of voclosporin in such methods and treatments, and in the preparation of a medicament in order to carry out such methods. In some embodiments, the methods are carried out by selecting a subject that has a particular class or type of LN based on a renal biopsy classification, such as a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification, and administering voclosporin to the selected subject. In some embodiments, the methods are carried out by identifying a subject that has a particular class or type of LN based on a renal biopsy classification, such as a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification as having a high likelihood of response to voclosporin treatment, and administering voclosporin to the identified subject. In some aspects, the provided methods and uses involve administration of an effective amount of voclosporin to the selected or identified subject.

[0112] In some aspects, the subject is selected for administration of voclosporin if the subject has previously been classified as having a Class III, a Class IV, or a Mixed Class V + III / IV LN based on a renal biopsy classification.

[0113] In some aspects, the subject is selected for administration of voclosporin if the subject is classified as having a Class III, a Class IV, or a Mixed Class V + III / IV LN based on a renal biopsy classification, is identified as having a high likelihood of response to voclosporin treatment.

[0114] In some aspects, the subjects are selected based on the classification of LN. In some aspects, the class of LN is based on one or more renal biopsies, and classifications based on the one or more renal biopsies.

[0115] In some aspects, renal biopsies can be assessed using light microscopy, immunofluorescent microscopy or electron microscopy. Collected renal biopsies can be assessed by hematoxylin and eosin staining (H&E), periodic acid-Schiff (PAS), silver and trichrome stains and collagen III immunohistochemistry. In some aspects, renal biopsies can also be stained for immunofluorescence with, including but not limited to, C3, C4, C5, Clq, IgG, IgM, and IgA.

[0116] In some aspects, the class or type of LN is assessed based on one or more renal biopsies. In some aspects, the one or more biopsies exhibit a Class III LN. In some aspects, the one or more biopsies exhibit a Class IV LN. In some aspects, the one or more biopsies exhibit a Class V LN.

[0117] In some aspects, the one or more renal biopsies are classified based on an International Society of Nephrology / Renal Pathology Society (ISN / RPS) classification. In some aspects, the class of LN is classified as Class I, Class II, Class III, Class IV, Class V, Class VI, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on the evaluation of one or more renal biopsies using an International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2003 classification. In some aspects, the class of LN is classified as Class I, Class II, Class III, Class IV, Class V, Class VI, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on the evaluation of one or more renal biopsies using an International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2018 classification.

[0118] In some aspects, the provided methods and uses involve evaluating or assessing in one or more renal biopsies one or more pathological characteristics that is associated with the presence of LN. In some aspects, the provided methods and uses involve evaluating or assessing in one or more renal biopsies one or more pathological characteristics that is associated with the presence of LN Class III. In some aspects, the provided methods and uses involve evaluating or assessing in one or more renal biopsies one or more pathological characteristics that is associated with the presence of LN Class IV. In some aspects, the provided methods and uses involve evaluating or assessing in one or more renal biopsies one or more pathological characteristics that is associated with the presence of LN Mixed Class V + III / IV.

[0119] In some aspects, the methods and uses involve evaluating or assessing the presence of one or more pathological characteristics that can be associated with the presence a particular class or type of LN in one or more renal biopsies sampled before the subject has started receiving voclosporin, and classifying the biopsy based on the presence of the one or more indicators as measured at a baseline, i.e., before receiving voclosporin. In some aspects, the methods and uses involve classifying the subject’s LN using the International Society of Nephrology and Renal Pathology Society (ISN / RPS) classification. In some aspects, the methods and uses involve classifying the subject’s LN using the ISN / RPS 2003 classification. In some aspects, the methods and uses involve classifying the subject’s LN using the ISN / RPS 2018 classification. In some aspects, a “baseline level” or “baseline measurement,” refers to the levels of the one or more pathological characteristics that are measured or assessed in the subject before receivingvoclosporin, or derivatives thereof.

[0120] In some aspects, the one or more pathological characteristics that can be associated with the presence of LN can be evaluated based on methods and assays to assess and monitor such pathological characteristics, such as any described herein. In some aspects, the methods and uses involve evaluating or assessing in one or more renal biopsies one or more pathological characteristics that can be associated with the presence of a particular class or type of LN, and selecting subjects based on particular criteria or thresholds. In some aspects, the one or more pathological characteristic is indicative of a subject having a high likelihood of response to treatment with voclosporin. In some aspects, the subject is identified based on the criteria or thresholds for the one or more pathological characteristics associated with having a high likelihood of response to treatment with voclosporin, and voclosporin is administered to the identified subject.

[0121] In some aspects, the provided methods and uses involve identifying subjects having a high likelihood of response to treatment with voclosporin.

[0122] In some aspects, LN can affect the glomeruli, interstitium, tubules, and capillary loops of the kidneys. Other than anti-dsDNA immune complex deposits, immunoglobulin M (IgM), immunoglobulin G (IgG), immunoglobulin A (IgA), and complement (Cl, C3, and properdin) are commonly found as subepithelial, mesangial, and subendothelial deposits. In some aspects, leukocytes can also be present. In some aspects, histologic characteristics of LN depend on various factors, including the antigen specificity and other properties of the autoantibodies, and the type of inflammatory response. In more severe forms of LN, the production of matrix proteins and the proliferation of mesangial, endothelial, and epithelial cells leads to fibrosis.

[0123] In some aspects, renal biopsy can provide important information for the management of LN. In some aspects, the patterns of glomerular lesion present in a renal biopsy, the degree of activity and the chronicity of the disease and extent of lesions to the tubulointerstitial and vascular compartments are fundamental information for diagnostic and treatment of LN.

[0124] Several classification systems for classifying LN have been developed. In some aspects, any of the known renal biopsy classification systems for LN can be used to assess the biopsy class of the subject, for use in accordance with the methods and uses as described herein. In some aspects, exemplary known renal biopsy classification systems for LN include but are not limited to those described in, for example, 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): e!0520, each of which are incorporated herein by reference. In some cases, to correlate the kidney disease with clinical manifestations and patient outcome, the glomerular lesions are classified according to the International Society of Nephrology and Renal Pathology Society Classification (ISN / RPS).

[0125] In some aspects, a standardized classification system used to determine the class of LN based on renal biopsies includes those derived from the International Society of Nephrology and Renal Pathology Society (ISN / RPS) and the World Health Organization (WHO) 2003 guidelines. In some aspects, a standardized classification system used to determine the class of LN based on renal biopsies includes those derived from the ISN / RPS 2003 guidelines. In some aspects, a standardized classification system used to determine the class of LN based on renal biopsies includes those derived from the ISN / RPS and the WHO 2018 guidelines. In some aspects, a standardized classification system used to determine the class of LN based on renal biopsies includes those derived from the ISN / RPS 2018 guidelines. In some aspects, the biopsy classification is based on glomerular morphologic changes seen on microscopy, immune deposits seen on immunofluorescence, and electronic microscopy. Based on the described exemplary renal biopsy classification systems, LN can be classified in six general classes: Class I, Class II, Class III, Class IV, Class V, and Class VI. In some aspects, the subject can be classified as having a mixed biopsy class LN, such as a Mixed Class V and III or IV (Mixed Class V + III / IV) LN.

[0126] In some aspects, exemplary classification system for renal biopsies for LN include the ISN / RPS 2003 classification summarized in Table 1._Indicate and grade (mild, moderate, severe) tubular atrophy, interstitial inflammation and fibrosis, severity of arteriosclerosis or other vascular lesions.“indicate the proportion of glomeruli with active and with sclerotic lesions.bindicate the proportion of glomeruli with fibrinoid necrosis and / or cellular crescents.

[0127] Exemplary micrographs of renal biopsies for classes of LN based on the ISN / RPS 2003 classification are shown in FIGS. 1A-1L. FIG. 1A depicts an example of LN Class II. FIG. IB depicts an example of LN Class III (A). FIG. 1C depicts an example of LN Class III (A). FIG. ID depicts an example of LN Class IV-G (A). FIG. IE depicts an example of LN Class IV-S (A). FIG. IF depicts an example of LN Class IV-G (A / C). FIG. 1G depicts an example of LN Class IV-G (A / C). FIG. 1H depicts an example of LN Class IV-G (A). FIG. II depicts an example of LN Class V. FIG. 1J depicts an example of LN Class IV and V (A / C).FIG. IK depicts an example of LN Class VI. FIG. IL depicts an example of thrombotic microangiopathy in a patient with systemic lupus erythematosus (SLE) and circulating lupus anticoagulant.

[0128] In some aspects, with respect to renal biopsies for LN, “diffuse” can refer to a lesion involving most (>50%) glomeruli. In some aspects, with respect to renal biopsies for LN, “focal” can refer to a lesion involving <50% of glomeruli. In some aspects, with respect to renal biopsies for LN, “global” can refer to a lesion involving more than half of the glomerular tuft. In some aspects, with respect to renal biopsies for LN, “segmental” can refer to a lesion involving less than half of the glomerular tuft (i.e., at least half of the glomerular tuft is spared). In some aspects, with respect to renal biopsies for LN, “mesangial hypercellularity” can refer to at least three mesangial cells per mesangial region in a 3 micron thick section. In some aspects, with respect to renal biopsies for LN, “endocapillary proliferation” can refer to endocapillary hypercellularity due to increased number of mesangial cells, endothelial cells, and infdtrating monocytes, and causing narrowing of the glomerular capillary lumina. In some aspects, with respect to renal biopsies for LN, “extracapillary proliferation or cellular crescent” can refer to extracapillary cell proliferation of more than two cell layers occupying one fourth or more of the glomerular capsular circumference. In some aspects, with respect to renal biopsies for LN, “karyorrhexis” can refer to the presence of apoptotic, pyknotic, and fragmented nuclei. In some aspects, with respect to renal biopsies for LN, “necrosis” can refer to a lesion characterized by fragmentation of nuclei or disruption of the glomerular basement membrane, often associated with the presence of fibrin-rich material. In some aspects, with respect to renal biopsies for LN, “hyaline thrombi” can refer to intracapillary eosinophilic material of a homogeneous consistency by which immunofluorescence has been shown to consist of immune deposits. In some aspects, with respect to renal biopsies for LN, “proportion of involved glomeruli” can refer to the percentage of total glomeruli affected by lupus nephritis, including the glomeruli that are sclerosed due to lupus nephritis, but excluding ischemic glomeruli with inadequate perfusion due to vascular pathology separate from lupus nephritis.

[0129] In some aspects, exemplary classification system for renal biopsies for LN include the ISN / RPS 2018 classification, for example as described in Bajema, et al., Kidney International (2018) 93, 789-796.

[0130] In some aspects, with respect to Class II, mesangial hypercellularity can refer to four or more nuclei fully surrounded by matrix in the mesangial area not including the hilar region (see FIG. 2A).

[0131] In some aspects, with respect to Class III and Class IV, endocapillary proliferation also refers to endocapillary hypercellularity (see FIG. 2B). In some aspects, with respect to Class III and Class IV, crescent can refer to a lesion consisting of extracapillary hypercellularity, composed of a variable mixture of cells. In some aspects, fibrin and fibrous matrix may be present. In some aspects, 10% or more of the circumference of Bowman’s capsule can be involved. In some aspects, with respect to Class III and Class IV, cellular crescent can refer to more than 75% cells and fibrin and less than 25% fibrous matrix (see FIG. 2C). In some aspects, with respect to Class III and Class IV, fibrous crescent can refer to more than 75% fibrous matrix and less than 25% cells and fibrin (see FIG. 2D). In some aspects, with respect to Class III and Class IV, fibrocellular crescent can refer to 25%-75% cells and fibrin and the remainder fibrous matrix (see FIG. 2E). In some aspects, adhesion can refer to an area of isolated continuity of extracellular matrix material between the tuft and capsule even when the underlying segment does not have overt sclerosis (see FIG. 2F).

[0132] In some aspects, fibrinoid necrosis can refer to fibrin associated with glomerular basement membrane disruption and / or lysis of the mesangial matrix. In some aspects, fibrinoid necrosis does not require the presence of karyorrhexis.

[0133] In some aspects, tubulointerstitial lesions can indicate whether interstitial inflammation occurs in presence or absence of interstitial fibrosis.

[0134] In some aspects, Class IV LN is not subdivided between segmental and global lesions.

[0135] In some aspects, activity and chronicity is assessed based on the National Institutes of Health Activity Index (NIH-AI) and the National Institutes of Health Chronicity Index (NIH-CI).

[0136] In some aspects, exemplary schematic diagrams for the classification system for renal biopsies for LN include those depicted in FIG. 3 (see Bajema, et al., Kidney International (2018) 93, 789-796). In some aspects, Class I LN exhibits mesangial immune deposits but no mesangial cell hypercellularity or influx of leukocytes. In some aspects, Class II LN exhibits mesangial immune deposits and mesangial cell hypercellularity but no influx of leukocytes. In some aspects, Class III / IV LN exhibits mesangial and capillary influx of leukocytes. In some aspects, Class III / IV LN exhibits subendothelial capillary wall immune deposits that can be seen by light microscopy and mesangial but no capillary influx of leukocytes. In some aspects, Class V + III / IV LN exhibits an influx of leukocytes and numerous subepithelial immune deposits in addition to subendothelial deposits. In some aspects, Class V LN exhibits numeroussubepithelial immune deposits but no influx of leukocytes.

[0137] In some aspects, the LN is Class I. In some aspects, Class I LN includes a biopsy exhibiting minimal mesangial LN, in which glomeruli appear normal on light microscopy. In some aspects, Class I LN includes a biopsy exhibiting immune complex deposits in the mesangial space. In some aspects, the immune complex deposits in the mesangial space can be detected using immunofluorescence. In some aspects, Class I LN includes a biopsy exhibiting glomerular capillaries affected by lupus glomerulonephritis. In some aspects, the glomerular capillaries affected by lupus glomerulonephritis include mesangial immune deposits. In some aspects, the glomerular capillaries affected by lupus glomerulonephritis do not include mesangial cell hypercellularity. In some aspects, the glomerular capillaries affected by lupus glomerulonephritis do not include an influx of leukocytes (Bajema, et al., Kidney International (2018) 93, 789-796).

[0138] In some aspects, the LN is Class II. In some aspects, Class II LN includes a biopsy exhibiting proliferative mesangial LN with mesangial hypercellularity including four or more nuclei surrounded by matrix in the mesangial area without including the hilar region that can be observed on light microscopy. In some aspects, Class II LN includes a biopsy exhibiting glomerular capillaries affected by lupus glomerulonephritis. In some aspects, the glomerular capillaries affected by lupus glomerulonephritis include mesangial immune deposits. In some aspects, the immune complex deposits in the mesangial space can be shown by immunofluorescence. In some aspects, the glomerular capillaries affected by lupus glomerulonephritis include mesangial cell hypercellularity. In some aspects, the glomerular capillaries affected by lupus glomerulonephritis do not include an influx of leukocytes (Bajema, et al., Kidney International (2018) 93, 789-796).

[0139] In some aspects, the LN is Class III. In some aspects, Class III LN includes a biopsy exhibiting focal proliferative glomerulonephritis involving less than 50% of all glomeruli. In some aspects, Class III LN includes a biopsy exhibiting affected glomeruli including endocapillary hypercellularity, with or without capillary wall necrosis and crescents, with subendothelial deposits, usually in a segmental distribution. In some aspects, crescents are lesions consisting of extracapillary hypercellularity, composed of a variable mixture of cells, in which fibrin and fibrous matrix may be present. In some aspects, crescent should involve 10% or more of the circumference of Bowman’s capsule. In some aspects, cellular crescent includes more than 75% cells and fibrin and less than 25% fibrous matrix. In some aspects, fibrous crescent includes more than 75% fibrous matrix and less than 25% cells and fibrin. In someaspects, fibrocellular crescent includes 25%-75% cells and fibrin and the remainder fibrous matrix. In some aspects, focal or diffuse mesangial alterations, including mesangial proliferation or mesangial immune deposits, may accompany the focal glomerular lesions. In some aspects, Class III lesions are segmental. In some aspects, glomeruli with both active and sclerotic lesions are taken into account when assessing the extent of the lesions. In some aspects, focal or diffuse mesangial alterations, including mesangial proliferation or mesangial immune deposits, may accompany the focal glomerular lesions.

[0140] In some embodiments, the subject is selected for administration of voclosporin if the subject is classified as having a Class III LN based on a renal biopsy classification. In some embodiments, the subject is identified as having a high likelihood of response if the subject is classified as having a Class III LN based on a renal biopsy classification.

[0141] In some embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits focal proliferative glomerulonephritis. In some embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits proliferative glomerulonephritis affecting fewer than about 50% of the glomeruli. In some embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving fewer than about 50% of all glomeruli, optionally with focal subendothelial immune deposits, with or without mesangial alterations.

[0142] In some embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits endocapillary hypercellularity. In some embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits focal endocapillary hypercellularity. In some embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits endocapillary hypercellularity affecting fewer than about 50% of the glomeruli. In some aspects, focal proliferative glomerulonephritis involves less than or between about 20%-50%, 30%-50%, 40%- 50%, 20%-40%, 30%-40%, or 20%-30% of all glomeruli. In some aspects, focal proliferative glomerulonephritis involves less than about 50%, 40%, 30%, or 20% of all glomeruli.

[0143] In some aspects, renal biopsies include assessment of the presence of affected glomeruli with endocapillary hypercellularity. In some aspects, the affected glomeruli include capillary necrosis. In some aspects, the affected glomeruli do not include capillary necrosis. In some aspects, the affected glomeruli include subendothelial deposits. In some aspects, the affected glomeruli include crescents. In some aspects, renal biopsies include assessment of thepresence of affected glomeruli including crescents. In some aspects, cellular crescent is present at about 10%-50%, 15%-50%, 20%-50%, 30%-50%, 10%-30%, 15%-30%, 20%-30%, 10%- 20%, 15%-20%, or 10%-15% or more of the circumference of Bowman’s capsule. In some aspects, cellular crescent is present at about 10%, 15%, 20%, 30%, 50% or more of the circumference of Bowman’s capsule. In some aspects, fibrocellular crescent is present at about 25%-75%, 30%-65%, 40%-55%, 50%-60% cells and fibrin. In some aspects, cellular crescent is present at about 75%, 80%, 85%, or 90% or more of the cells and fibrin. In some aspects, cellular crescent is present at less than about 25%, 20%, 15%, or 10% fibrous matrix. In some aspects, fibrous crescent is present at more than about 75%, 80%, 85%, 90%, or 95% fibrous matrix. In some aspects fibrous crescent is present at less than about 25%, 20%, 15%, or 10% cells and fibrin.

[0144] In some embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits one or more of: (a) segmental endocapillary hypercellularity with substantial luminal reduction; (b) endocapillary hypercellularity with fibrinoid necrosis and cellular crescent formation; (c) karyorrhexis in a segment of a glomerulus; (d) segmental sclerosis of a glomerulus; (e) segmental subendothelial deposits by light microscopy as fuchsinophilic deposits; and / or (f) IgG immune deposits in glomerular capillary wall in segmental distribution and mesangial deposits.

[0145] In some embodiments, the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits one or more of: (a) a lesion comprising extracapillary hypercellularity; (b) a crescent; (c) the presence of Fibrin and fibrous matrix; and / or (d) 10% or more of the circumference of Bowman’s capsule showing extracapillary hypercellularity.

[0146] In some aspects, the LN is Class IV. In some aspects, Class IV LN includes a biopsy exhibiting diffuse LN involving 50% or more of glomeruli in the biopsy. In some aspects, Class III LN includes a biopsy exhibiting affected glomeruli including endocapillary hypercellularity, with or without capillary wall necrosis and crescents, with subendothelial deposits, usually in a segmental distribution. In some aspects, crescents are lesions consisting of extracapillary hypercellularity, composed of a variable mixture of cells, in which fibrin and fibrous matrix may be present. In some aspects, crescent should involve 10% or more of the circumference of Bowman’s capsule. In some aspects, cellular crescent includes more than 75% cells and fibrin and less than 25% fibrous matrix. In some aspects, fibrous crescent includes more than 75% fibrous matrix and less than 25% cells and fibrin. In some aspects, fibrocellular crescent includes 25%-75% cells and fibrin and the remainder fibrous matrix. In some aspects, fibrinoid necrosisis usually associated with endocapillary hypercellularity. In some aspects, fibrinoid necrosis is defined as fibrin associated with glomerular basement membrane disruption and / or lysis of the mesangial matrix and this lesion does not require the presence of karyorrhexis. Karyorrhexis is defined as the presence of apoptotic, pyknotic and fragmented nuclei — a definition used uniformly in other classification systems.

[0147] In some embodiments, the subject is selected for administration of voclosporin if the subject is classified as having a Class IV LN based on a renal biopsy classification. In some embodiments, the subject is identified as having a high likelihood of response if the subject is classified as having a Class IV LN based on a renal biopsy classification.

[0148] In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits diffuse proliferative glomerulonephritis. In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits proliferative glomerulonephritis affecting greater than about 50% of the glomeruli. In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving >50% of all glomeruli, optionally with diffuse subendothelial immune deposits, with or without mesangial alterations.

[0149] In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits endocapillary hypercellularity. In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits diffuse endocapillary hypercellularity. In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits endocapillary hypercellularity affecting greater than about 50% of the glomeruli. In some aspects, focal proliferative glomerulonephritis involves greater than about 50%-80%, 60%-80%, 70%-80%, 50%-70%, 60%-70%, or 50-60% of all glomeruli. In some aspects, focal proliferative glomerulonephritis involves greater than about 50%, 60%, 70%, or 80% of all glomeruli.

[0150] In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits one or more of: (a) diffuse segmental endocapillary proliferation; (b) global endocapillary proliferation with leukocyte infiltration; (c) endocapillary proliferation with widespread wire loop appearance in the glomerular capillary wall indicator of subendothelial immune deposits; (d) subendothelial deposits as fuchsinophilic deposits; (e) diffuse global wire loop appearance without mesangial or endocapillary cellular proliferation; and / or (f) significant immune deposit overload in glomerular capillary wall.

[0151] In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits a diffuse segmental lupus nephritis with greater than 50% of the involved glomeruli have segmental lesions that involve less than half of the glomerular tuft; or a diffuse global lupus nephritis with greater than 50% of the involved glomeruli have global lesions.

[0152] In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits advanced sclerosing glomerulonephritis.

[0153] In some embodiments, the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits one or more of: (a) a lesion comprising extracapillary hypercellularity; (b) a crescent; (c) the presence of Fibrin and fibrous matrix; and / or (d) 10% or more of the circumference of Bowman’s capsule showing extracapillary hypercellularity.

[0154] In some embodiments, the crescent comprises one or more of: (a) a cellular crescent comprising more than 75% cells and fibrin and less than 25% fibrous matrix; (b) a fibrous crescent comprising more than 75% fibrous matrix and less than 25% cells and fibrin; and / or (c) a fibrocellular crescent comprising 25%-75% cells and fibrin and the remainder fibrous matrix.

[0155] In some aspects, the LN is Class III / IV. In some aspects, Class III / IV LN includes a biopsy exhibiting mesangial and capillary influx of leukocytes. In some aspects, Class III / IV LN includes a biopsy exhibiting subendothelial capillary wall immune deposits that can be seen by LM (light microscopy). In some aspects Class III / IV LN includes a biopsy exhibiting mesangial but no capillary influx of leukocytes (neutrophils and monocytes / macrophages) (Bajema, et al., Kidney International (2018) 93, 789-796).

[0156] In some aspects, the LN is a mixed biopsy class. In some aspects, the LN is a Mixed Class V and III or IV (Mixed Class V + III / IV) LN. In some aspects, Mixed Class V + III / IV LN includes a biopsy exhibiting an influx of leukocytes. In some aspects, Mixed Class V + III / IV LN includes a biopsy exhibiting numerous subepithelial immune deposits. In some aspects, Mixed Class V + III / IV includes a biopsy exhibiting subendothelial deposits (Bajema, et al., Kidney International (2018) 93, 789-796). In some aspects, Mixed Class V + III / IV LN includes a biopsy exhibiting non-wire-loop subendothelial deposits within Class V.

[0157] In some embodiments, the subject is selected for administration of voclosporin if the subject is classified as having a Mixed Class V + III / IV LN based on a renal biopsy classification. In some embodiments, the subject is identified as having a high likelihood of response if the subject is classified as having a Mixed Class V + III / IV LN based on a renalbiopsy classification.

[0158] In some embodiments, the subject is classified as having a Class a Mixed Class V + III / IV LN if a renal biopsy from the subject exhibits one or more of: (a) non-wire-loop subendothelial deposits within Class V, and / or (b) subepithelial deposits involving >50% of the tuft of >50% of the glomeruli.

[0159] In some aspects, the LN is Class V. In some aspects, Class V LN includes a biopsy exhibiting membranous LN with global or segmental continuous granular subepithelial immune deposits, often with concomitant mesangial immune deposits. In some aspects, kidney biopsy Class V includes mesangial hypercellularity. In some aspects, Class V LN includes a biopsy exhibiting scattered subendothelial immune deposits that can be identified by immunofluorescence or electron microscopy. In some aspects, affected glomeruli in Class V LN includes a biopsy exhibiting subepithelial immune deposits. In some aspects, affected glomeruli Class V kidney biopsy does not include an influx of leukocytes (Bajema, et al., Kidney International (2018) 93, 789-796).

[0160] In some embodiments, the subject is not selected for administration of voclosporin if the subject is classified as having a pure Class V LN based on a renal biopsy classification. In some embodiments, the subject is not identified as having a high likelihood of response if the subject is classified as having a pure Class V LN based on a renal biopsy classification.

[0161] In some embodiments, the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits membranous glomerulonephritis. In some embodiments, the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits membranous LN with global or segmental continuous granular subepithelial immune deposits.

[0162] In some embodiments, the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits one or more of: (a) significant glomerular capillary wall thickening in global distribution; (b) subepithelial fuchsinophilic deposits; (c) spikes in glomerular capillary wall indicator of membranous nephropathy; and / or (d) continuous subepithelial IgG deposits in the glomerular capillary wall.

[0163] In some aspects, the LN is Class VI. In some aspects, Class VI LN includes a biopsy exhibiting biopsies with >90% global glomerulosclerosis and in which there is clinical or pathologic evidence that the sclerosis is attributable to LN. In some aspects, Class VI kidney biopsy does not include evidence of ongoing active glomerular disease (Weening et al., Kidney International (2004) 65, 521-530).

[0164] In some embodiments, National Institutes of Health Activity Index (NIH-AI), the National Institutes of Health Chronicity Index (NIH-CI), or the Tubulointerstitial Activity Index (TIAI) are used to assess the renal biopsies. In some embodiments, renal biopsies collected at baseline and / or after administration of voclosporin can be assessed to determine NIH-AI, NIH- CI, or TIAI or any changes in the indices.

[0165] In some aspects, an exemplary scoring system for NIH-AI and NIH-CI is set forth in Table 2 below (see, e.g., Bajema et al. Kidney Int. 2018;93(4):789-796).Table 2: National Institutes of Health Activity Index (NIH-AI) and National Institutes of Health Chronicity Index (NIH-CI)

[0166] In some embodiments, the National Institutes of Health Activity Index (NIH-AI) is used to assess disease activity, including histologic measures of inflammation. In some embodiments, the NIH-AI score is determined based on component scores that can include endocapillary hypercellularity, neutrophils and karyorrhexis, hyaline deposits and wire loops, fibrinoid necrosis, cellular or fibrocellular crescents, and interstitial inflammation. In some aspects, the NIH-AI is calculated based on a total score of the component scores. In someaspects, the NIH-AI comprises scoring the percentage of glomeruli that display each feature described below in the biopsy on a scale of 0 to 3 (a score of 0 = not present, 1 = < 25% glomeruli, 2 = 25-50% glomeruli, and 3 indicating >50% glomeruli).

[0167] In some embodiments, a component score of the NIH-AI includes endocapillary hypercellularity score, on a scale of 0-3. In some embodiments, a component score of the NIH- AI includes neutrophils and karyorrhexis score, on a scale of 0-3. In some embodiments, a component score of the NIH-AI includes hyaline deposits and wire loops score, on a scale of 0-3. In some embodiments, a component score of the NIH-AI includes fibrinoid necrosis score, on a scale of (0-3) x 2. In some embodiments, a component score of the NIH-AI includes cellular or fibrocellular crescents score, on a scale of (0-3) x 2. Fibrinoid necrosis and crescents are weighted twice as they have a worse impact on prognosis. In some embodiments, a component score of the NIH-AI includes interstitial inflammation score, on a scale of 0-3.

[0168] In some embodiments, the NIH-AI includes one or more of the component scores and a total score out of 24 is used. In some embodiments, the total NIH-AI score includes all of the component scores and a total score out of 24 is used. The score range is 0-24, with 0 considered inactive. A high NIH-AI value (> 6) is considered a high level of renal damage.

[0169] In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 3 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 4 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 5 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 6 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 7 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 8 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 9 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 10 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 11 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 12 or higher.

[0170] In some embodiments, the National Institutes of Health Chronicity Index (NIH-CI) isused to assess chronicity, including irreversible kidney damage and scarring associated with endstage kidney disease. In some aspects, the NIH-CI score is determined based on component scores that can include global and segmental glomerulosclerosis, fibrous crescents, tubular atrophy, or interstitial fibrosis. In some aspects, the NIH-CI is calculated based on a total score of the component scores.

[0171] In some aspects, a component score of the NIH-CI includes global and segmental glomerulosclerosis score, on a scale of 0-3. In some embodiments, a component score of the NIH-CI includes fibrous crescents score, on a scale of 0-3. In some embodiments, a component score of the NIH-CI includes tubular atrophy score, on a scale of 0-3. In some embodiments, a component score of the NIH-CI includes interstitial fibrosis score, on a scale of 0-3.

[0172] In some embodiments, the NIH-CI includes one or more of the component scores and a total score out of 12 is used. In some embodiments, the total NIH-CI score includes all of the component scores and a total score out of 12 is used. In some aspects, the component scores are added (total renal chronicity score) to grade the overall severity of the chronic lesions into minimal (0-1 total score), mild (2-4 total score), moderate (5-7 total score) and severe (>8 total score), indicators of NIH-CI include the total percentage of global glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. The NIH-CI score range is 0 - 12, with 0 representing no chronicity. A high NIH-CI value (> 3) is correlated with progression to renal failure.

[0173] In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 3, 4, 5, 6 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 3 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 4 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 5 or higher. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 6 or higher.

[0174] In some embodiments, the methods and uses involve assessing one or more of the National Institutes of Health Activity Index (NIH-AI), the National Institutes of Health Chronicity Index (NIH-CI), and the Tubulointerstitial Activity Index (TIAI) of the subject by renal biopsies compared to a baseline level, and if the NIH-AI, NIH-CI, and / or TIAI are outside of predetermined ranges, selecting the subject for voclosporin administration. In some embodiments, the predetermined range of NIH-AI is about any one of 0 to 1, 0 to 2, 0 to 3, 0 to4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, 0 to 10, 0 to 11, 0 to 12, 0 to 13, 0 to 14, 0 to 15, 0 to 16, 0to 17, 0 to 18, 0 to 19 or 0 to 20. In some embodiments, the predetermined range ofNIH-AI is any one of <1, < 2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13, <14, <15, <16, <17, <18, <19, or < 20. In some embodiments, the predetermined range of NIH-AI is about 0 to 6. In some embodiments, the predetermined range of NIH-CI is about any one of 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, the predetermined range of NIH-CI is any one of <1, < 2, <3, <4, <5, <6, <7, <8, <9, or <10. In some embodiments, the predetermined range of NIH-CI is about 0-3. In some embodiments, the predetermined range of TIAI is about any one of 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, 0 to 10, 0 to 11, 0 to 12, 0 to 13, 0 to 14, or 0 to 15. In some embodiments, the predetermined range of NIH-AI is any one of <1, < 2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13, <14, or <15. In some embodiments, the predetermined range of TIAI is about 0 to 5. In some embodiments, the predetermined range of NIH-AI is about 0 to 6, or the predetermined range of NIH-CI is about 0 to 3, and / or the predetermined range of TIAI is about 0 to 5. In some embodiments, the predetermined range of NIH-AI is 0 to 6, and the predetermined range of NIH- CI is 0 to 3, or the predetermined range of TIAI is 0 to 5.

[0175] In some aspects, the one or more renal biopsies are collected at various time points. In some aspects, the subject is assessed for one or more renal biopsies, including a baseline renal biopsy collected before administration of voclosporin. In some aspects, the subject is assessed for one or more renal biopsies, including a renal biopsy collected following the administration of voclosporin.III. ADMINISTRATION OF VOCLOSPORIN

[0176] Provided are methods and uses that involve administering voclosporin to the selected subject or the subject identified to have a high likelihood of response, for example in accordance with any of the methods or uses described herein. In some aspects, also provided are uses of voclosporin or compositions comprising voclosporin in accordance with any of the methods described herein. In some aspects, the provided methods and uses involve administration of an effective amount of voclosporin to the selected or identified subject. In some aspects, voclosporin is administered to the selected or identified subjects.

[0177] In some embodiments, voclosporin is administered at a dose and timing that follows a known, recommended, approved or typical treatment regimen for voclosporin, for example as recommended or approved for the treatment of lupus nephritis (LN). In some aspects, exemplary dosages, timing and treatment regimen for voclosporin are described herein. In some aspects,dosages, timing and treatment regimen for voclosporin can be adjusted based on changes in recommendations or approved treatment regimen.A. Compositions

[0178] In some aspects, compositions comprising voclosporin are employed in the provided methods and uses. In some embodiments, a subject to be treated in accordance with the provided embodiments is a subject is in need of immunosuppression, such as intermittent, long-term or even life-long immunosuppression, for example, using CNIs such as voclosporin or a pharmaceutically acceptable salt thereof. In some aspects, voclosporin, a therapeutically effective amount thereof, and / or a composition comprising voclosporin or a pharmaceutically acceptable salt thereof, is employed in the provided compositions, methods and uses. Uses include uses of voclosporin or composition comprising the same, in such methods, such as therapeutic or prophylactic methods, and treatments, such as a treatment regimen, and uses of voclosporin, a pharmaceutically acceptable salt thereof, or composition comprising the same, in the preparation of a medicament, in order to carry out such therapeutic or prophylactic methods and treatments.

[0179] Voclosporin (VCS), described in US Patent No. 9,765,119, hereby incorporated by reference in its entirety, represents a superior CNI, due to its reduced toxicity and ability to be variably dosed to maximize subject tolerance and efficacy. In some aspects, voclosporin is administered to a subject in need of therapy with a CNI, in combination with additional therapeutic agents, including background immunosuppressive therapy. In some aspects, voclosporin exhibits a linear pharmacokinetic profile resulting in a consistent dose-concentration relationship. In some aspects, voclosporin provides an advantage of eliminating the need for therapeutic drug monitoring typically associated with use of CNI.

[0180] Voclosporin has a modification of a functional group on the amino acid-1 residue of the molecule compared to cyclosporine A (CsA), which enhances its binding to calcineurin, and confers better metabolic stability. Voclosporin has been studied in psoriasis, renal organ transplantation, and was recently FDA-approved for treatment of active lupus nephritis (LN) in combination with background immunosuppressive therapy. Observations show that VCS is more potent and less toxic at therapeutic levels than other immunosuppressants in its class.

[0181] VCS has shown to inhibit norovirus replication in a CypA-dependent manner and more effectively than CsA. This alteration has changed the binding of voclosporin to calcineurin and has been shown both in vitro and in vivo to increase the binding affinity up to five-foldcompared to CsA (Kuglstatter et al., Acta Cryst. 2011; D67: 119-23). This modification has also changed the metabolic profile of voclosporin by shifting metabolism away from amino acid-1, which is the major site of metabolism for CsA. The altered metabolic profile has led to a faster elimination of metabolites resulting in lower metabolite exposure compared to CsA. The combination of increased potency and decreased metabolite exposure for voclosporin compared to CsA, has led to better PK / PD relationship, administration of lower doses, and a potentially improved safety profile compared to CsA.

[0182] Voclosporin is a cyclosporine analogue modified at the 1 -amino acid residue with a 1,3-diene substituent. Voclosporin may exist as an isomeric mixture of Z- and E- isomers, and in some embodiments may be a mixture comprising at least about 90% (e.g., about 90% to about 95%) of the E-isomer and no more than about 10% (e.g., about 10% to about 5%) of the Z- isomer. In some aspects, the voclosporin composition comprises an isomeric mixture of voclosporin a pharmaceutically acceptable salt thereof, wherein the isomeric mixture comprises about 90% to about 95% of the E-isomer and about 10% to about 5% of the Z-isomer. In some aspects, the voclosporin composition comprises an isomeric mixture of voclosporin a pharmaceutically acceptable salt thereof, wherein the isomeric mixture comprises about 90% to about 95% of the E-isomer and about 10% to about 5% of the Z-isomer. Voclosporin 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.

[0183] Mixtures of the E and Z isomers of voclosporin are described in U.S. Patent6,998,385. Mixtures with a preponderance of the E-isomer are described in U.S. Patent7,332,472. Various formulations of voclosporin mixtures are also described in U.S. Patent Nos. 7,060,672; 7,429,562 and 7,829,533.

[0184] Voclosporin may be referred to as cyclo{{(6E)-(2S,3R,4R)-3-hydroxy-4-methyl-2- (methylamino)-6, 8-nonadi enoyl} -L-2-aminobuty ryl-N-methyl-gly cyl-N-methyl-L-1 eucyl-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-((lR,2R,E)-l-hydroxy-2- methylhepta-4,6-dien-l-yl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl-l,4,7,10,12,15,19,25,28- nonamethyl-l,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan- 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-[(lR,2R,4E)-l-hydroxy-2-methylhepta-4,6-dienyl]-l,4,7,10,12,15,19,25,28- nonamethyl-6,9, 18,24-tetrakis(2-methylpropyl)-3,21 -di(propan-2-yl)- l,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,l l,14,17,20,23,26,29,32- undecone. Voclosporin is also known as LUPKYNIS®, ISATX247, ISA247, LX211, or Luveniq®. In some aspects, reference to voclosporin and administration of voclosporin also can include a pharmaceutically acceptable salt of voclosporin, and administration of a pharmaceutically acceptable salt of voclosporin. In some aspects, a “pharmaceutically acceptable salt” refers to a salt of any of the compounds (e.g., voclosporin) which are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of voclosporin retains the biological effectiveness of voclosporin and are not biologically or otherwise undesirable.

[0185] Voclosporin has an empirical formula of C63H111N11O12 and a molecular weight of 1214.6 g / mole. At ambient temperature, voclosporin is freely soluble in acetone, acetonitrile, ethanol, and methanol, and practically insoluble in heptanes (USP). Voclosporin is practically insoluble (less than 0.1 g / L at 20°C) in water and melts above 144°C with decomposition.

[0186] In some embodiments of the methods and uses provided herein, the method or the treatment comprises administering voclosporin or a pharmaceutically acceptable salt thereof with a therapeutically effective amount of MMF and / or a therapeutically effective amount of a corticosteroid. In some embodiments, the method treatment comprises administering voclosporin or a pharmaceutically acceptable salt thereof without a therapeutically effective amount of MMF and / or a therapeutically effective amount of a corticosteroid.

[0187] In some embodiments, the methods and uses involve administering a composition, such as a pharmaceutical composition or a therapeutic composition, comprising voclosporin. In some embodiments, the methods and uses involve administering a composition comprising voclosporin.

[0188] In some embodiments, the composition comprising voclosporin comprises anisomeric mixture of voclosporin E-isomer and Z-isomer. Mixtures of the E and Z isomers of voclosporin are described in U.S. Patent 6,998,385. Mixtures with a preponderance of the E- isomer are described in U.S. Patent 7,332,472 describing exemplary indications that can be treated with the isomeric voclosporin mixture including glomerulonephritis. Various formulations of voclosporin mixtures are also described in U.S. Patent Nos. 7,060,672; 7,429,562 and 7,829,533. In some embodiments, the isomeric mixture comprises at least about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% of voclosporin E-isomer by weight. In some embodiments, the isomeric mixture comprises at least 90% of voclosporin E-isomer by weight. In some embodiments, the isomeric mixture comprises at least 95% of voclosporin E-isomer by weight.

[0189] In some embodiments, the pharmaceutical compositions (e.g., comprising voclosporin) is 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 pharmaceutical carriers and excipients appropriate for the type of administration contemplated.

[0190] In some aspects, generally, the pharmaceutically acceptable carriers or vehicles, such as those present in the pharmaceutically acceptable buffer, can be any known in the art. Remington’s Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, Pa., 19thEdition (1995), describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compounds. Pharmaceutically acceptable compositions generally are prepared in view of approvals for a regulatory agency or other agency prepared in accordance with generally recognized pharmacopeia for use in animals and in humans.

[0191] Pharmaceutical compositions can include carriers such as a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Examples of suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, generally in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin. Water is a typical carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions also can be employed as liquid carriers,particularly for injectable solutions. A composition, if desired, also can contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Typically, the compositions containing the compounds are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition, 1985, 126). Generally, the mode of formulation is a function of the route of administration. Exemplary formulations of voclosporin mixtures are also described in U.S.Patent Nos. 7,060,672; 7,429,562 and 7,829,533.B. Dose and Timing of Voclosporin Administration

[0192] In some aspects, voclosporin is administered in a predetermined daily dosage of 39.5 mg BID, 31.6 mg BID, 23.7 mg BID, 15.8 mg BID, of 7.9 mg BID. In some aspects, the predetermined daily dosage is any one of about 7.9 to 23.7, 23.7 to 31.6, 31.6 to 39.5, or 39.5 to 79 mg voclosporin. In some aspects, the predetermined daily dosage is about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 60, 80, 100 mg voclosporin, or any values there between.

[0193] In some aspects, the first time point is any one of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, or 48 hours preceding initiating the voclosporin treatment. In some aspects, the first time point is immediately preceding initiating the voclosporin treatment. In some aspects, the second time point is any one of about 1, 2, 3, 4, 5, 10, 14, 15, 20, 25, 28, 30, 40, 50 or more days subsequent to initiating the voclosporin treatment, or any time periods there between. In some aspects, the second time point is any one of about 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 or more weeks subsequent to initiating the voclosporin treatment, or any time periods there between.

[0194] In some aspects, the predetermined daily dosage of effective amounts of voclosporin is about any one of 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, 35, 39.5, 40, 45, 50 mg BID, or any amounts there between. In some aspects, the predetermined daily dosage of voclosporin is 39.5 mg BID, 31.6 mg BID, 23.7 mg BID, 15.8 mg BID, or 7.9 mg BID.

[0195] In some aspects, the subject has severe renal impairment at baseline, the predetermined daily dosage of effective amounts of voclosporin is about any one of 2, 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, 35 mg BID, or any amounts there between. In some aspects, the subject has severe renal impairment at baseline, the predetermined daily dosage of effective amounts of voclosporin is about 15.8 mg BID.

[0196] In some aspects, the subject has moderate hepatic impairment, the predetermined daily dosage of effective amounts of voclosporin is about any one of 2, 5, 7.9, 10, 12, 15, 15.8,20, 23.7, 25, 28, 30, 31.6, 35 mg BID, or any amounts there between. In some aspects, the subject has moderate hepatic impairment, the predetermined daily dosage of effective amounts of voclosporin is about 15.8 mg BID.

[0197] In some aspects, voclosporin is administered long-term. In some aspects, voclosporin is administered in one or more doses. In some aspects, voclosporin administration comprises an initial dose (or a first dose) and one or more subsequent doses.

[0198] In some aspects of the methods and uses provided herein, voclosporin is administered four times a day, three time a day, twice a day (BID), or once a day. In some aspects, voclosporin is administered four times a day. In some aspects, voclosporin is administered three times a day. In some aspects, voclosporin is administered twice a day (BID). In some aspects, voclosporin is administered once a day.

[0199] In some aspects, voclosporin is administered at a constant dose throughout the voclosporin treatment period. In some aspects, the dosage of voclosporin can vary during the voclosporin treatment period, for example, based on the assessment of therapy.

[0200] In some aspects, daily dosage of voclosporin is about 1 mg to about 250 mg, about 5 mg to about 250 mg, about 10 mg to about 250 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 150 mg to about 250 mg, about 200 mg to about 250 mg, 1 mg to about 200 mg, about 5 mg to about 200 mg, about 10 mg to about 200 mg, about 50 mg to about 200 mg, about 100 mg to about 200 mg, about 150 mg to about 200 mg, about 1 mg to about 150 mg, about 5 mg to about 150 mg, about 10 mg to about 150 mg, about 50 mg to about 150 mg, about 100 mg to about 150 mg, about 1 mg to about 100 mg, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 100 mg, about 1 mg to about 50 mg, about 5 mg to about 50 mg, or about 10 mg to about 50 mg. In some aspects, daily dosage of voclosporin is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg. In some aspects, daily dosage of voclosporin 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.

[0201] In some aspects, dosage of voclosporin is about 0. 1 mg / kg / day to about 2 mg / kg / day, about 0.5 mg / kg / day to about 2 mg / kg / day, about 1 mg / kg / day to about 2 mg / kg / day, about 1.5 mg / kg / day to about 2 mg / kg / day, about 0.1 mg / kg / day to about 1.5 mg / kg / day, about 0.5 mg / kg / day to about 1.5 mg / kg / day, about 1 mg / kg / day to about 1.5 mg / kg / day, about 0.1 mg / kg / day to about 1.0 mg / kg / day, about 0.5 mg / kg / day to about 1.0 mg / kg / day, or about 0.1 mg / kg / day to about 0.5 mg / kg / day. In some aspects, dosage of voclosporin is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 mg / kg / day. In some aspects, dosage of voclosporin 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.

[0202] In some aspects, suitable dosages of voclosporin are in increment of about 7.9 mg. In some aspects, the dosage of voclosporin is about 7.9 mg QD, about 15.8 mg QD, about 23.7 mg QD, about 31.6 mg QD, about 39.5 mg QD, about 47.4 mg QD, about 55.3 mg QD, about 63.2 mg QD, about 71.1 mg QD, about 79.0 mg QD, about 86.9 mg QD, about 94.8 mg QD, about 102.7 mg QD, or about 110.6 mg QD. In some aspects, the dosage of voclosporin is about 7.9 mg BID, about 15.8 mg BID, about 23.7 mg BID, about 31.6 mg BID, about 39.5 mg BID, about 47.4 mg BID, or about 55.3 mg BID. In some aspects, the dosage of voclosporin is about 7.9 mg BID. In some aspects, the dosage of voclosporin is about 15.8 mg BID.

[0203] In some aspects, suitable dosages of voclosporin are in increments of 7.9 mg including 39.5 mg, 31.6 mg, 23.7 mg, 15.8 mg or 7.9 mg. Low dosages show superior results compared to a higher dose of 39.5 mg each of such administrations carried out twice daily. Doses as low as 15.8 mg or 7.9 mg twice daily are effective. In some aspects, the dosage of voclosporin is about 23.7 mg BID.

[0204] The dosage indicated, for example 23.7 mg is subject to slight variations, typically ±10% or, alternatively, for 23.7 mg specified between 21 mg and 26 mg BID. This is due to inconsistencies in pharmaceutical manufacture and the ideal dosage is the specified dose — i.e., for example, 23.7 mg BID. Comparable variations applied to the alternative dosages, and to the differential adjustment.

[0205] In some aspects, the blood trough level is about 25 to about 60 ng / mL. In some aspects, the blood trough level is about 25, about 30, about 35, about 40, about 45, about 50,about 55, or about 60 ng / mL.

[0206] In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of between about 0.05 pM and about 10 pM, about 0.1 pM and about 5 pM, about 0.2 pM and about 2.5 pM, about 0.3 pM and about 1.0 pM, about 0.4 pM and about 0.9 pM, about 0.5 pM and about 0.8 pM, about 0.1 pM and about 0.5 pM, or about 0.2 pM and about 0.4 pM. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 6.0, about 7.0, about 8.0, about 9.0, or about 10.0 pM or less. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.2 pM. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.3 pM. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.4 pM. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.5 pM.

[0207] In some aspects, voclosporin is administered based on a treatment regimen over a voclosporin treatment period. In some aspects, the voclosporin treatment regimen further includes assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, and if the eGFR of the subject decreases by more than a target % to below a predetermined value, between said first and second time points, reducing the daily dosage by increment(s) of 7.9 mg BID or stopping the administering of voclosporin to the subject. In some examples, the voclosporin treatment regimen further includes assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, and if the eGFR of the subject decreases by less than said target %, between said first and second time points, the method includes continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0208] In some aspects, the voclosporin treatment period is at least any one of about 50, 55,60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 weeks, or 1, 2, or 3 years, or any length of treatment periods there between. In some aspects, the first time point is immediately preceding initiating the voclosporin treatment. In some examples, the predetermined value is in the range of about 30 to about 110 ml / min / 1.73m2. In some aspects, the predetermined value is in the range of about 50 to about 90 ml / min / 1.73 m2In some aspects, the predetermined value is in the range of about any one of 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 and 100-110 ml / min / 1.73 m2In some aspects, the predetermined value is any one of about 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m2In some aspects, the predetermined value is about 60 ml / min / 1.73 m2In some aspects, the target % is in the range of about 10% to about 60%. In some aspects, the target % is in the range of about 20% to about 45%. In some aspects, the target % is in the range of about any one of 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 aspects, the target % is approximately 20%. In some aspects, the target % is approximately 30%.

[0209] In some aspects, the voclosporin treatment regimen further includes assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, and if the eGFR of the subject decreases by more than a 20% to below 60 ml / min / 1.73 m2, between said first and second time points, reducing the daily dosage by increment(s) of 7.9 mg BID or stopping the administering of voclosporin to the subject. In some examples, the voclosporin treatment regimen further includes assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, and if the eGFR of the subject decreases by less than 20%, between said first and second time points, the method includes continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0210] In some aspects, the treatment regimen comprises assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, the first time point is immediately preceding initiating the voclosporin treatment. In some embodiment, the treatment regimen further comprises assessing eGFR of the subject every two weeks subsequent to initiating the voclosporin treatment. In some aspects, the treatment regimen comprises assessing eGFR of the subject every two weeks in the first month, and every four weeks thereafter, subsequent to initiating the voclosporin treatment. In some aspects, eGFR of the subject decreases by more than a target % to below a predetermined value at any assessment subsequent to initiating thevoclosporin treatment, the treatment regimen comprises reducing the daily dosage by increment(s) of 7.9 mg BID or stopping the administering of voclosporin to the subject.

[0211] In some aspects, the treatment regimen comprises assessing the eGFR of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, the first time point is immediately preceding initiating the voclosporin treatment. In some aspects, eGFR of the subject decreases by more than a target % compared to eGFR at the first time point to below a predetermined value at an assessment subsequent to initiating the voclosporin treatment, the treatment regimen comprises reducing the daily dosage by 7.9 mg BID. In some aspects, eGFR of the subject decreases by more than the target % compared to eGFR at the first time point to below the predetermined value at an assessment subsequent to initiating the voclosporin treatment, and the daily dosage is reduced by 7.9 mg BID, the treatment regimen comprises assessing eGFR of the subject two weeks subsequent to dosage reduction, and further comprises a second reduction of daily dosage by 7.9 mg BID if eGFR of the subject decreases by more than the target % compared to eGFR at the first time point to the predetermined value in the assessment two weeks subsequent to the first dosage reduction. In some aspects, the treatment regimen comprises one or more dosage reductions, the treatment regimen comprises assessing eGFR of the subject every two weeks subsequent to the one or more dosage reductions, and comprises increasing the daily dosage by 7.9 mg BID for each eGFR assessment where eGFR of the subject decreases by less than the target % compared to eGFR at the first time point. In some aspects, the dosage increase does not cause the dosage to exceed the initial predetermined dosage. In some examples, the predetermined value is in the range of about 30 to about 110 ml / min / 1.73 m2In some aspects, the predetermined value is in the range of about 50 to about 90 ml / min / 1.73 m2In some aspects, the predetermined value is in the range of about any one of 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 and 100-110 ml / min / 1.73 m2In some aspects, the predetermined value is any one of about 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m2In some aspects, the predetermined value is about 60 ml / min / 1.73 m2In some aspects, the target % is in the range of about 10% to about 60%. In some aspects, the target % is in the range of about 10% to about 45%. In some aspects, the target % is in the range of about any one of 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 aspects, the target % is approximately 20%.

[0212] In some aspects, eGFR of the subject decreases by between about 20% to about 30% compared to eGFR at the first time point to below 60 ml / min / 1.73 m2at an assessmentsubsequent to initiating the voclosporin treatment, the treatment regimen comprises reducing the daily dosage by 7.9 mg BID. In some aspects, eGFR of the subject decreases by between about 20% to about 30% compared to eGFR at the first time point, to below 60 ml / min / 1.73 m2at an assessment subsequent to initiating the voclosporin treatment, and the daily dosage is reduced by 7.9 mg BID, the treatment regimen comprises assessing eGFR of the subject two weeks subsequent to dosage reduction, and further comprises a second reduction of daily dosage by 7.9 mg BID if eGFR of the subject decreases by more than 20% compared to eGFR at the first time point to below 60 ml / min / 1.73 m2in the assessment two weeks subsequent to the first dosage reduction. In some aspects, the treatment regimen comprises one or more dosage reductions, the treatment regimen comprises assessing eGFR of the subject every two weeks subsequent to the one or more dosage reductions, and comprises increasing the daily dosage by 7.9 mg BID for each eGFR assessment where eGFR of the subject decreases by less than 20% compared to eGFR at the first time point. In some aspects, the dosage increase does not cause the dosage to exceed the initial predetermined dosage.

[0213] In some aspects, the treatment regimen comprises assessing the eGFR of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, the first time point is immediately preceding initiating the voclosporin treatment. In some aspects, eGFR of the subject decreases by equal to or more than a first target % compared to eGFR at the first time point to below a predetermined value at any assessment subsequent to initiating the voclosporin treatment, the treatment regimen comprises stopping the administering of voclosporin to the subject. In some aspects, eGFR of the subject decreases by equal or more than the target % compared to eGFR at the first time point to below the predetermined value at an assessment subsequent to initiating the voclosporin treatment, and the administration of voclosporin to the subject is stopped, the treatment regimen comprises assessing eGFR of the subject two weeks subsequent to stopping administration, and further comprises re-initiating the administration at the initial predetermined dosage if eGFR of the subject decreases by less than a second target % compared to eGFR at the first time point in the assessment two weeks subsequent to the stopping of administration of voclosporin. In some aspects, the predetermined value is in the range of about 50 to about 90 ml / min / 1.73m2. In some aspects, the predetermined value is in the range of about any one of 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 and 100-110 ml / min / 1.73m2. In some aspects, the predetermined value is any one of about 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m2In some aspects, the predetermined value is about 60 ml / min / 1.73 m2In some aspects, the first target % is in the range of about 10% to about 60%. In some aspects, the first target % is in the range of about 20% to about45%. In some aspects, the first target % is in the range of about any one of 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 aspects, the first target % is approximately 30%. In some aspects, the second target % is in the range of about 10% to about 60%. In some aspects, the second target % is in the range of about 10% to about 45%. In some aspects, the second target % is in the range of about any one of 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 aspects, the second target % is approximately 20%.

[0214] In some aspects, eGFR of the subject decreases by equal to or more than 30% compared to eGFR at the first time point to below 60 ml / min / 1.73 m2at any assessment subsequent to initiating the voclosporin treatment, the treatment regimen comprises stopping the administering of voclosporin to the subject. In some aspects, eGFR of the subject decreases by equal or more than 30% compared to eGFR at the first time point to below 60 ml / min / 1.73 m2at an assessment subsequent to initiating the voclosporin treatment, and the administration of voclosporin to the subject is stopped, the treatment regimen comprises assessing eGFR of the subject two weeks subsequent to stopping administration, and further comprises re-initiating the administration at the initial predetermined dosage if eGFR of the subject decreases by less than 20% compared to eGFR at the first time point in the assessment two weeks subsequent to the stopping of administration of voclosporin.

[0215] Exemplary treatment regimen for voclosporin include, measuring eGFR immediately prior to administering the first dose of voclosporin and at a second time point at least a day later and:(i) if the eGFR of the subject decreased by >30% to a value of below 60 mL / min / 1.73m2between said first and second time points, stopping the administering of Voclosporin or reducing dosage thereof to the subject;(ii) if the eGFR of the subject decreased by between 20% to 30% to a value of below 60 ml / min / 1.73m2between said first and second time points, administering a reduced dosage of voclosporin to the subject; and(iii) if the eGFR of the subject decreased by <20% between said first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0216] In some aspects, the voclosporin treatment regimen further includes identifying a subject as appropriate for the treatment regimen prior to conducting the treatment regimen on the subject by (a) determining that the urine protein creatinine ratio (UPCR) of the subject is > 1mg / mg as measured by first morning void or 24 hour urine, and (b) determining that the subject has an eGFR as measured by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EP1) of > 45 ml / min / 1.73 m2; if the conditions of (a) and (b) are met, the subject is identified as appropriate for the treatment regimen. In some aspects, the treatment regimen comprises determining that the urine protein creatinine ratio (UPCR) of the subject is > 1.5 mg / mg as measured by first morning void or 24 hour urine.

[0217] In some aspects, one or more doses of voclosporin is administered to a subject. In some aspects, one more doses of my cophenolate mofetil (MMF) and low-dose steroids (e.g., methylprednisolone, prednisone, or a derivative thereof) , was previously administered to the subject. In some aspects, a first dose of the one or more doses of the voclosporin is administered later than a first dose of the one or more doses of my cophenolate mofetil (MMF) and low-dose steroids (e.g., methylprednisolone, prednisone, or a derivative thereof) for immunosuppression. In some aspects, the administration of the my cophenolate mofetil (MMF) and low-dose steroids (e.g., methylprednisolone, prednisone, or a derivative thereof) for immunosuppression is administered concurrently with voclosporin.

[0218] In some aspects, the projected voclosporin treatment period is between about 10 to 100 weeks, 10 to 90 weeks, 10 to 80 weeks, 10 to 70 weeks, 10 to 60 weeks, 10 to 50 weeks, 10 to 40 weeks, 10 to 30 weeks, or 10 to 20 weeks. In some aspects, the projected voclosporin treatment period is at least about 24 weeks, 36 weeks, 48 weeks, 52 weeks, 60 weeks, 72 weeks, 84 weeks or 96 weeks or longer. In some aspects, the projected voclosporin treatment period is at least about 24 weeks. In some aspects, the projected voclosporin treatment period is at least about 48 weeks. In some aspects, the projected voclosporin treatment period is at least about 52 weeks. In some aspects, the projected voclosporin treatment period is at least about 18 months. In some aspects, the projected voclosporin treatment period is at least about 24 months. In some aspects, the projected voclosporin treatment period is at least about 36 months. In some aspects, the projected voclosporin treatment period is at least about 48 months.C. Routes of Administration

[0219] In some embodiments of methods and uses disclosed herein, voclosporin may be administered in any suitable form and by any suitable route that will provide sufficient level of voclosporin such as by enteral administration (e.g., oral administration, sublingual administration, or rectal administration) or parenteral administration (e.g., intravenous injection, intramuscular injection, subcutaneous injection, intravenous infusion, or inhalation / insufflation).

[0220] In some embodiments, voclosporin is administered by enteral administration. Exemplary routes of enteral administration include, without limitation, oral administration, sublingual administration, and rectal administration (e.g., through the rectum). In some embodiments, the enteral administration comprises oral administration. In some embodiments, the enteral administration comprises sublingual administration. In some embodiments, the enteral administration comprises rectal administration.

[0221] In some embodiments, voclosporin is administered by parenteral administration. Exemplary routes of parenteral administration include, without limitation, intravenous injection, intramuscular injection, subcutaneous injection, intravenous infusion, and inhalation / insufflation.

[0222] In some embodiments, voclosporin is administered by inhalation or insufflation. Exemplary types of preparations for inhalation and / or insufflation include, without limitation, sprays, aerosols, mists, capsules, powders, or cartridges for use in an inhaler or insufflator and solutions / suspensions for nebulization. In some embodiments, voclosporin is administered in the form of an aerosol, a spray, a mist, or a powder. In some embodiments, voclosporin is administered in the form of an aerosol. Examples of various types of devices for administering by inhalation or insufflation include, without limitation, a nebulizer, a metered dose inhaler (MDI), and a dry powder inhaler.D. Additional Therapeutic Agent

[0223] In some embodiments, the method or the treatment also involves administering a therapeutically effective amount of an additional therapeutic agent. In some embodiments, the method also comprises administering a therapeutically effective amount of an additional therapeutic agent. In some aspects, additional therapeutic agents include background immunosuppressive therapy, such as my cophenolate mofetil (MMF) or one or more corticosteroids.

[0224] In some embodiments, the subject is administered voclosporin concurrently with my cophenolate mofetil (MMF) and low-dose steroids (e.g., methylprednisolone, prednisone, or a derivative thereof) for immunosuppression. In some aspects, voclosporin is administered to a subject selected in accordance with the criteria described herein. In some aspects, the administration of my cophenolate mofetil (MMF) and low-dose steroids (e.g., methylprednisolone, prednisone, or a derivative thereof) for immunosuppression is administered in a tapering dosage protocol, and the subject is administered voclosporin.

[0225] In some embodiments, the method or use further includes administering to saidsubject an effective amount of my cophenolate mofetil (MMF). In some embodiments, the method or use further includes administering to said subject an effective amount of a corticosteroid.

[0226] In some embodiments, a dosage of MMF and a reducing dosage of corticosteroid is also administered in addition to voclosporin. In some aspects, exemplary doses of MMF includes 2 g daily; and exemplary doses of oral corticosteroids include daily dosages diminishing from 20-25 mg daily to 2.5 mg daily over a period of 16 weeks.

[0227] For example, with respect to corticosteroids, subjects who weigh 45kg or more may receive 0.5 g of methylprednisolone on days 1 and 2 of the study intravenously and then beginning on day 3, oral corticosteroid therapy. Subjects weighing <45 kg receive only half these dosages.

[0228] For oral prednisone, exemplary starting dosage for oral administration includes 20 mg / day for subjects < 45kg and 25 mg / day for subjects who weigh _45kg. Exemplary dosing schedule for corticosteroids are set forth in Tables 3 and 4 below:Table 3: Standard of Care Dosing Schedule for IV methylprednisolone and daily oral prednisone:Table 4: Lowered Dosing Schedule for IV methylprednisolone and daily oral prednisone:

[0229] Voclosporin is a sensitive CYP3A4 substrate. Co-administration with strong or moderate CYP3A4 inhibitors increases voclosporin exposure. In some embodiments, thevoclosporin Cmaxand / or AUC are increased in subjects receiving strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) or moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole, diltiazem) compared to corresponding subjects without receiving such CYP3A4 inhibitors. In some embodiments, the voclosporin Cmaxis increased by about any one of 1.1 -fold, 1.2-fold, 1.4-fold, 1.6-fold, 1.8-fold, 2.0-fold, 2.2-fold, 2.4-fold, 2.6-fold, 2.8-fold, 3.0-fold, 4.0- fold, 5.0-fold, 10.0-fold or more in subjects receiving strong or moderate CYP3A4 inhibitors compared to corresponding subjects without receiving such CYP3A4 inhibitors. In some embodiments, the voclosporin AUC is increased by about any one of 2.0-fold, 2.2-fold, 2.4-fold, 2.6-fold, 2.8-fold, 3.0-fold, 3.0-fold, 3.2-fold, 3.4-fold, 3.6-fold, 3.8-fold, 4.0-fold, 5.0-fold, 10.0-fold or more in subjects receiving strong or moderate CYP3A4 inhibitors compared to corresponding subjects without receiving such CYP3A4 inhibitors.IV. DEFINITIONS

[0230] As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural forms, unless the context clearly dictates otherwise.

[0231] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses or amounts, contemplate a dose or amount within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose or amount.

[0232] As used herein, “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0233] The term “pharmaceutically acceptable salt” refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceuticallyacceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, 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- hydroxy ethylsulfonic acid, p-toluenesulfonic acid, stearic acid and salicylic acid.Pharmaceutically acceptable base addition salts can be formed with 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, potassium, sodium, calcium, and magnesium salts.

[0234] If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly 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, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1- 19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.

[0235] As used herein, “therapeutically effective amount” indicates an amount that results in a desired pharmacological and / or physiological effect for the condition. The effect may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for the condition and / or adverse effect attributable to the condition.

[0236] The terms “treat,” “treating,” and “treatment” refer to an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing thedisease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of this disclosure contemplate any one or more of these aspects of treatment.

[0237] The term “subject” refers to an animal, including, but not limited to, a primate (e.g. , human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.V. EXEMPLARY EMBODIMENTS

[0238] Among the provided embodiments are:1. A method of treating lupus nephritis (LN), the method comprising:(a) selecting a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification; and(b) administering voclosporin to the selected subject.2. A method of treating lupus nephritis (LN), the method comprising administering voclosporin to a subject that has previously been classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification.3. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification.4. A method of assessing the likelihood of response to voclosporin treatment, the method comprising identifying a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification, as having a high likelihood of response to voclosporin treatment.5. The method of embodiment 3 or 4, wherein the method further comprises administering voclosporin to the selected subject or the identified subject.6. The method of any of embodiments 1-5, wherein the renal biopsy classification comprises an International Society of Nephrology / Renal Pathology Society (ISN / RPS) classification.7. The method of any of embodiments 1-6, wherein the renal biopsy classification comprises an International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2003 classification.8. The method of any of embodiments 1-6, wherein the renal biopsy classification comprises an International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2018 classification.9. The method of any of embodiments 1-8, wherein the subject is selected for administration of voclosporin if the subject is classified as having a Class III LN based on a renal biopsy classification.10. The method of any of embodiments 1-9, wherein the subject is identified as having a high likelihood of response if the subject is classified as having a Class III LN based on a renal biopsy classification.11. The method of any of embodiments 1-10, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits focal proliferative glomerulonephritis.12. The method of any of embodiments 1-11, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits proliferative glomerulonephritis affecting fewer than about 50% of the glomeruli.13. The method of any of embodiments 1-12, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving fewer than about 50% of all glomeruli, optionally with focal subendothelial immune deposits, with or without mesangial alterations.14. The method of any of embodiments 1-13, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits endocapillary hypercellularity.15. The method of any of embodiments 1-14, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits focal endocapillary hypercellularity.16. The method of any of embodiments 1-15, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits endocapillary hypercellularity affecting fewer than about 50% of the glomeruli.17. The method of any of embodiments 1-16, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits:(a) segmental endocapillary hypercellularity with substantial luminal reduction;(b) endocapillary hypercellularity with fibrinoid necrosis and cellular crescent formation;(c) karyorrhexis in a segment of a glomerulus;(d) segmental sclerosis of a glomerulus;(e) segmental subendothelial deposits by light microscopy as fuchsinophilic deposits; and / or(f) IgG immune deposits in glomerular capillary wall in segmental distribution and mesangial deposits.18. The method of any of embodiments 1-17, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits:(a) a lesion comprising extracapillary hypercellularity;(b) a crescent;(c) the presence of Fibrin and fibrous matrix; and / or(d) 10% or more of the circumference of Bowman’s capsule showing extracapillary hypercellularity.19. The method of any of embodiments 1-10, wherein the subject is selected for administration of voclosporin if the subject is classified as having a Class IV LN based on a renal biopsy classification.20. The method of any of embodiments 1-10 and 19, wherein the subject is identified as having a high likelihood of response if the subject is classified as having a Class IV LN based on a renal biopsy classification.21. The method of any of embodiments 1-10, 19, and 20, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits diffuse proliferative glomerulonephritis.22. The method of any of embodiments 1-10 and 19-21, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits proliferative glomerulonephritis affecting greater than about 50% of the glomeruli.23. The method of any of embodiments 1-10 and 19-22, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving >50% of all glomeruli, optionally with diffuse subendothelial immune deposits, with or without mesangial alterations.24. The method of any of embodiments 1-10 and 19-23, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits endocapillary hypercellularity.25. The method of any of embodiments 1-10 and 19-24, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits diffuse endocapillary hypercellularity.26. The method of any of embodiments 1-10 and 19-25, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits endocapillary hypercellularity affecting greater than about 50% of the glomeruli.27. The method of any of embodiments 1-10 and 19-26, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits:(a) diffuse segmental endocapillary proliferation;(b) global endocapillary proliferation with leukocyte infiltration;(c) endocapillary proliferation with widespread wire loop appearance in the glomerular capillary wall indicator of subendothelial immune deposits;(d) subendothelial deposits as fuchsinophilic deposits;(e) diffuse global wire loop appearance without mesangial or endocapillary cellular proliferation; and / or(f) significant immune deposit overload in glomerular capillary wall.28. The method of any of embodiments 1-10 and 19-27, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits a diffuse segmental lupus nephritis with greater than 50% of the involved glomeruli have segmental lesions that involve less than half of the glomerular tuft; or a diffuse global lupus nephritis with greater than 50% of the involved glomeruli have global lesions.29. The method of any of embodiments 1-10 and 19-28, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits advanced sclerosing glomerulonephritis.30. The method of any of embodiments 1-10 and 19-29, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits:(a) a lesion comprising extracapillary hypercellularity;(b) a crescent;(c) the presence of Fibrin and fibrous matrix; and / or(d) 10% or more of the circumference of Bowman’s capsule showing extracapillary hypercellularity.31. The method of any of embodiments 17, 18, and 30, wherein the crescent comprises:(a) a cellular crescent comprising more than 75% cells and fibrin and less than 25% fibrous matrix;(b) a fibrous crescent comprising more than 75% fibrous matrix and less than 25% cells and fibrin; and / or(c) a fibrocellular crescent comprising 25%-75% cells and fibrin and the remainder fibrous matrix.32. The method of any of embodiments 1-31, wherein the subject is selected for administration of voclosporin if the subject is classified as having a Mixed Class V + III / IV LN based on a renal biopsy classification.33. The method of any of embodiments 1-32, wherein the subject is identified as having a high likelihood of response if the subject is classified as having a Mixed Class V + III / IV LN based on a renal biopsy classification.34. The method of any of embodiments 1-33, wherein the subject is classified as having a Class a Mixed Class V + III / IV LN if a renal biopsy from the subject exhibits:(a) non-wire-loop subendothelial deposits within Class V, and / or(b) subepithelial deposits involving >50% of the tuft of >50% of the glomeruli.35. The method of any of embodiments 1-34, wherein the subject is not selected for administration of voclosporin if the subject is classified as having a pure Class V LN based on a renal biopsy classification.36. The method of any of embodiments 1-35, wherein the subject is not identified as having a high likelihood of response if the subject is classified as having a pure Class V LN based on a renal biopsy classification.37. The method of embodiment 35 or 36, wherein the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits membranous glomerulonephritis.38. The method of any of embodiments 35-37, wherein the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits membranous LN with global or segmental continuous granular subepithelial immune deposits.39. The method of any of embodiments 35-38, wherein the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits:(a) significant glomerular capillary wall thickening in global distribution;(b) subepithelial fuchsinophilic deposits;(c) spikes in glomerular capillary wall indicator of membranous nephropathy; and / or(d) continuous subepithelial IgG deposits in the glomerular capillary wall.40. The method of any of embodiments 1-39, wherein the subject is further assessed for a National Institutes of Health Activity Index (NIH-AI).41. The method of embodiment 40, wherein the NIH-AI is assessed on a total score scale between 0 and 24, based on the sum of the scores of the following assessments:(a) Endocapillary hypercellularity on a scale of 0-3, with endocapillary hypercellularity in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(b) Neutrophils / karyorrhexis on a scale of 0-3, with neutrophils and / or karyorrhexis in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(c) Fibrinoid necrosis on a scale of (0-3) x 2, with fibrinoid necrosis in <25% (1), 25%- 50% (2), or >50% (3) of glomeruli;(d) Hyaline deposits on a scale of 0-3, with wire loop lesions and / or hyaline thrombi in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(e) Cellular / fibrocellular crescents on a scale of (0-3) x 2, with cellular and / or fibrocellular crescents in <25% (1), 25%-50% (2), or >50% (3) of glomeruli; and(f) Interstitial Inflammation on a scale of 0-3, with interstitial leukocytes in <25% (1), 25%-50% (2), or >50% (3) in the cortex.42. The method of any of embodiments 1-41, wherein the subject is further assessed for a National Institutes of Health Chronicity Index (NIH-CI).43. The method of embodiment 42, wherein the NIH-CI is assessed on a total score scale between 0 and 12, based on the sum of the scores of the following assessments:(a) Total glomerulosclerosis score on a scale of 0-3, with global and / or segmental sclerosis in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(b) Fibrous crescents on a scale of 0-3, with fibrous crescents in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(c) Tubular atrophy on a scale of 0-3, with tubular atrophy in <25% (1), 25%-50% (2), or >50% (3) of the cortical tubules; and(d) Interstitial fibrosis on a scale of 0-3, with interstitial fibrosis in <25% (1), 25%-50% (2), or >50% (3) in the cortex.44. The method of any of embodiments 1-43, wherein the renal biopsy is assessed using light microscopy, immunofluorescence, and / or electron microscopy.45. The method of any of embodiments 1-44, wherein the voclosporin is administered at a daily dose of between about 5 mg BID to about 50 mg BID.46. The method of any of embodiments 1-45, wherein the voclosporin is administered at an initial daily dose of about 39.5 mg, about 31.6 mg, about 23.7 mg, about 15.8 mg, or about 7.9 mg BID.47. The method of any of embodiments 1-46, wherein the voclosporin is administered at an initial daily dose of about 39.5 mg.48. The method of any of embodiments 1-46, wherein the voclosporin is administered at an initial daily dose of about 23.7 mg.49. The method of any of embodiments 1-46, wherein the voclosporin is administered at an initial daily dose of about 15.8 mg.50. The method of any of embodiments 1-49, wherein the voclosporin is administered over a projected voclosporin 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 or longer.51. The method of any of embodiments 1-50, wherein the method further comprises assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of the projected treatment period; and(i) if the eGFR of the subject decreases by more than a target % to below a predetermined value, between the first and second time points, reducing the daily dose by increment(s) of 7.9 mg BID or stopping the administering of voclosporin;(ii) if the eGFR of the subject decreases by less than the target %, between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.52. The method of embodiment 51, wherein the predetermined value is in the range of 50-90 ml / min / 1.73m2.53. The method of embodiment 51 or 52, wherein the predetermined value is approximately 60 ml / min / 1.73m2.54. The method of any of embodiments 51-53, wherein the target % is in the range of 20%-45%.55. The method of any of embodiments 51-54, wherein the target % is approximately 30%.56. The method of any of embodiments 51-55, wherein:(i) if the eGFR of the subject decreases by > 30% to a value of below 60 mL / min / 1.73m2between the first and second time points, stopping the administering of voclosporin to the subject;(ii) if the eGFR of the subject decreases by between 20% to 30% to a value of below 60 ml / min / 1.73m2between the first and second time points, administering a reduced dosage of voclosporin to the subject; and(iii) if the eGFR of the subject decreases by < 20% between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.57. The method of any of embodiments 51-56, wherein the first time point is immediately preceding initiating the administration of voclosporin.58. The method of any of embodiments 51-57, wherein the second time point is after the first time point and initiating the administration of voclosporin.59. The method of any of embodiments 51-58, wherein the second time point is 8 weeks after initiating the administration of voclosporin.60. The method of any of embodiments 51-59, wherein the method further comprises determining the eGFR of the subject at a third time point and if the eGFR is determined at the third time point to differ from the eGFR determined at the first time point by less than the target %, resuming administering the predetermined daily dosage of voclosporin.61. The method of any of embodiments 51-60, wherein the method further comprises measuring urinary protein creatinine ratio (UPCR) of the subject at the first time point and the second time point and determining any reduction of the UPCR between the first and second time points, and if the UPCR of the subject fails to show a reduction of at least 25% at the second time point, discontinuing administering voclosporin to the subject.62. The method of any of embodiments 51-61, wherein the method further comprises measuring the concentration of C3 or C4 in the blood of the subject at the first time point and the second time point, and determining whether the concentration of C3 or C4 is normalized at the second time point, and if normalization of C3 or C4 is found, reinstating the administering voclosporin to the subject.63. The method of any of embodiments 1-62, wherein the method further comprises administering to the subject an effective amount of my cophenolate mofetil (MMF).64. The method of any of embodiments 1-63, wherein the method further comprises administering to the subject an effective amount of a corticosteroid.65. The method of any of embodiments 1-64, wherein the voclosporin is a mixture of at least 90% E isomer and not more than 10% Z isomer.66. Voclosporin for use in the method of any of embodiments 1-65.67. Use of voclosporin in the manufacture of a medicament according to the method of any of embodiments 1-65.68. Use of voclosporin in the method of any of embodiments 1-65.VI. EXAMPLES

[0239] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.Example 1: 48 WEEK STUDY OF LUPUS NEPHRITIS TREATMENT

[0240] The subjects enrolled in the study were divided into three groups, 88 subjects were in a control group who were administered 2 g MMF daily as well as oral corticosteroids — i.e., prednisone in a tapering dosage shown graphically in FIG. 4 — beginning at 20-25 mg daily reduced gradually after the 12thweek to 2.5 mg daily. 89 subjects in the low dosage group received this background treatment, but in addition were administered three capsules containing 7.9 mg (i.e., 23.7 mg) of voclosporin each twice daily. The voclosporin used in this study comprised greater than 90% E isomer. A third group which was comprised of 88 subjects received a similar background treatment but in addition were dosed with five 7.9 mg capsules i.e., 39.5 mg twice daily. The study was conducted over a period of 48 weeks and safety was evaluated at 24 weeks.

[0241] Subjects were screened prior to admission to the study by (a) determining that the urine protein creatinine ratio (UPCR) as > 1.5 mg / mg as measured by first morning void, and (b) that the eGFR as measured by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EP1) of > 45 ml / min / 1.73 m2Subjects were assessed after 24 weeks and 48 weeks as well as a subsequent evaluation at 50 weeks.

[0242] The low dosage administration achieved better results than administration of voclosporin at higher dosages. Briefly, 32.6% of low dosage patients showed CR at 24 weeks compared to 19.3% of controls and 70% showed PR compared to 49% of controls.

[0243] CR in this example is a composite end-point which includes efficacy, safety and low- dose steroids: UPCR < 0.5 mg / mg (confirmed); eGFR > 60ml / min / 1.73 m2or within 20% of baseline; steroids < 10 mg / day; no administration of rescue medication.

[0244] PR is a composite end-point that includes safety and efficacy: UPCR reduction of50% from baseline and no use of rescue medication.

[0245] To determine the efficacy of the pharmacodynamics protocol wherein dosage is reduced or stopped according to the presence or absence of indicators of the decrease in eGFR experienced as a side effect, these three groups of patients were assessed after 24 weeks and 48 weeks of treatment in consideration of whether treatment was altered according to the treatment. In all three groups, the patients were evaluated according to the criteria set forth in the exemplary protocol above — i.e., wherein the eGFR of each patient was measured immediately prior to administering the first dose of voclosporin and at a second time point at least a day later and(i) if the eGFR of said subject decreases by > 30% to a value of below 60 mL / min / 1.73 m2, between said first and second time points, stopping the administering of voclosporin to said subject;(ii) if the eGFR of said subject decreases by between 20% to 30% to a value of below 60 ml / min / 1.73 m2, between said first and second time points, administering a reduced dosage of voclosporin to said subject; and(iii) if the eGFR of said subject decreases by < 20%, between said first and second time points, continuing administering the same predetermined daily dosage of voclosporin to said subject.

[0246] The results are shown in Tables El and E2 below. Table El shows percentages with complete remission (CR) or partial remission (PR) after 24 weeks and Table E2 shows these values after 48 weeks for patients who had no dose reduction and those who did have dose reduction.Table El: Patients with a No Dose Reductions (24 weeks)Patients with Dose Reductions (pharmacodynamically dosed)Table E2: Patients with No Dose Reductions (48 Weeks)Patients with Dose Reductions (pharmacodynamically dosed)

[0247] In this study, CR was defined as a composite of UPCR < 0.5 mg / mg; eGFR > 60 mL / min / 1.73 m2or within 20% of baseline, steroids at < 10 mg / day and no administration of rescue medication. PR is defined as UPCR reduction of 50% from baseline and no use of rescue medication.

[0248] As shown in Table El, after 24 weeks, 12.5% of patients on placebo, 43.8% of patients on low dose and 53.4% of patients on high dose voclosporin underwent dose reduction during the treatment. The percentage of patients with complete response was not affected in either dosage groups by the pharmacodynamic dosage and the percentage with partial response was also roughly the same, although with the high dose group, the percentage with partial reduction improved. Table E2 shows similar results at 48 weeks, although a higher percentage of patients were subjected to dose reduction.Example 2: LONG-TERM SAFETY AND TOLERABILITY CONTINUATION STUDY

[0249] Subjects who previously completed twelve months of voclosporin treatment in combination with my cophenolate mofetil (MMF) and steroids for lupus nephritis (LN), were enrolled in a long-term continuation study for an additional two years with the same treatment. There was a total of 37 months follow-up, inclusive of the initial 12 months and latter 25 months of the continuation study (including a safety visit at four weeks after the study drug discontinuation).

[0250] In a double-blind, one-year randomized controlled study of voclosporin (23.7 mgtwice daily [BID]) compared to placebo for the treatment of lupus nephritis (n=357). Patients with active LN, UPCR > 1.5 mg / mg (> 2 mg / mg for Class V) and eGFR > 45 mL / min / 1.73 m2were included. All patients received my cophenolate mofetil (MMF) (target 1g BID) and low- dose steroids (rapidly tapered to 2.5 mg / day at Week 16). Glucocorticoid taper included intravenous methylprednisolone on Days 1 and 2. Oral glucocorticoid was initiated on Day 3 with 20-25 mg / day prednisone and tapered to a target dose of 2.5 mg / day at Week 16 and thereafter. The study showed that compared to MMF and low-dose steroids alone, the addition of voclosporin increased complete renal response rates by 18% at one year of treatment (22.5% in control group, n=178; 40.8% in voclosporin treated group, n-179; odds ratio [OR] 2.65, p<0.0001; 95% CI 1.64, 4.27) in patients with lupus nephritis.

[0251] The continuation study evaluated voclosporin compared to placebo, in combination with my cophenolate mofetil (MMF) and low-dose steroids, in subjects with lupus nephritis, generally as described in Example 1. The continuation study involved 216 subjects out of the 357 subjects who were included in the initial 1 year study, and continued in the same treatment groups: 116 patients in the voclosporin group, receiving the same treatment of voclosporin at 23.7 mg twice daily, in combination with MMF at 1 g twice daily with low-dose steroids, and 100 patients in the control group receiving placebo in combination with MMF at 1 g twice daily with low-dose steroids, generally as shown in FIG. 5, for an additional 24 months. 90 subjects in the voclosporin group and 78 subjects in the control group received 36 months of total treatment at the completion of the study. Subject demographics are shown in Table E3. Values in this table are pretreatment baseline values (baseline is defined as the last value before the subject received a first dose of study drug on Day 1 of the study , i.e., at the beginning of the three year study).

[0252] Study drug dose modifications were allowed in this study per investigator discretion. The protocol provided guidance to interrupt or reduce study drug for any patient with >30% decrease in estimated glomerular filtration rate (eGFR) or in the case of blood pressure, outside of acceptable limits. At the end of the first twelve months, the majority of subjects (78.4% voclosporin; 90.0% control) were receiving 23.7 mg twice daily (BID) voclosporin or equivalent placebo. At the end of the continuation study (i.e., at the end of the three years), 49.1% of the voclosporin and 64.0% of the control group were receiving 23.7 mg BID of voclosporin or equivalent placebo. Study drug dose changes decreased over time; the majority of patients on a lowered dose at end of study, including more patients in the voclosporin arm, underwent dose changes due to, for example, changes in eGFR.Table E3: Demographics

[0253] Table E4 shows observed values in the mean corrected estimated glomerular filtration rate (eGFR) and mean urine protein creatinine ratio (UPCR) at pre-treatment baseline, at one year of treatment (Month 12) baseline, and at three years of treatment (Month 36).Table E4: Corrected eGFR and UPCR Values at Pre-Treatment and at One Year or Three Years of Treatment

[0254] In the 116 subjects in the voclosporin-treated group, mean estimated glomerular filtration rate (eGFR) was within normal range and in both treatment groups over 36 months as shown in FIGS. 6 and 7. The eGFR change from pretreatment baseline shown in FIG. 7 demonstrates that mean eGFR remained stable in both treatment groups over the 36 months. Additionally, compared to the active control group, the voclosporin-treated group showed an increase from baseline eGFR of +2.7 mL / min, at 36 months. Overall, data across three years of voclosporin exposure showed stable kidney function, as measured with mean eGFR and slope throughout the study.

[0255] Long-term renal function was evaluated by examining the eGFR slope over the 24- month period of the continuation study. FIG. 8 exhibits that the corrected eGFR slope over the two-year period (e.g., two years of continuation study following the completion of the initial one-year study) was -0.2 ml / min / 1.73 m2(95% CI -3.0, 2.7) in the voclosporin group and -5.4 ml / min / 1.73 m2(95% CI -8.4, -2.3) in the control group. Finally, over the three year period, a >30% decrease from pretreatment baseline in corrected eGFR was reported in 14 subjects (12.1%) in the voclosporin group and 10 subject (10%) in the control group.

[0256] The mean UPCR was lower in the voclosporin-treated groups at all time points during the three years as shown in FIG. 9. At the start of the continuation study (e.g., Month 12 of the three year study), mean UPCR was lower for the subjects in the voclosporin group (0.86 mg / mg) than those in the control group (1.47 mg / mg), reflecting improved disease control by voclosporin in the first year of treatment. Moreover, Mixed Effect Model Repeated Measures (MMRM) analysis confirmed that statistically significant greater reductions from baseline in UPCR were achieved in the voclosporin group compared with the control group at all time points exceptMonth 36 as exhibited in FIG. 9. In particular, at the follow-up safety visit, mean UPCR was 0.78 mg / mg in the voclosporin group and 1.47 mg / mg in the control group.

[0257] FIG. 10 examines the proportion (%) of subject achieving >50% reduction from baseline in UPCR for the two treatment groups across different time points. Overall, the proportions of patients achieving >50% reduction from baseline in UPCR and UPCR <0.5 mg / mg increased up to Months 12 and 18 and were maintained over the total treatment period.

[0258] In addition, there was a significant improvement in complete renal rate (CRR) and partial renal response (PRR). Complete renal rate (CRR) was defined as UPCR of <0.5 mg / mg, eGFR >60 ml / min / 1.73 m2or no confirmed decrease from pretreatment baseline in eGFR of >20 ml / min / 1.73 m2, received no rescue medication received for LN, and received no more than 10 mg prednisone for >3 consecutive days or for >7 days in total during the eight weeks prior to endpoint assessment. PRR was defined as a >50% reduction in UPCR from pretreatment baseline (e.g., prior to the three years of treatment).

[0259] At month 36, more subjects in the voclosporin group than in the control group achieved a CRR (50.9% vs. 39.0%; odds ratio 1.74; 95% CI 1.00, 3.03) as shown in Table E5, which was largely driven by more subjects achieving a proteinuria reduction in UPCR to <0.5 mg / mg (54.3% vs. 43.0%; odds ratio 1.66; 95% CI: 0.96, 2.88). More subjects in the voclosporin group also achieved a PRR (74.1% vs. 69.0%; odds ratio 1.39; 95% CI: 0.75, 2.58). In a last observation carried forward analysis of patients without data at month 36, 12 of 17 patients (70.6%) in the voclosporin group and 5 of 13 patients (38.5%) in the control group achieved >50% reduction from baseline in UPCR based on their final UPCR measurement.Table E5: Efficacy Analyses

[0260] Additionally, more voclosporin patients had a good renal outcome than those in the control group at the beginning of the continuation study (i.e., at Month 12), demonstrating a clear clinical benefit of voclosporin. Overall, the three year treatment demonstrated that significantly more subjects in the voclosporin group than in the control group achieved a good renal outcome (66.4% vs 54.0%; odds ratio 0.56; 95% CI 0.32, 0.99). Good renal outcome was defined based on achievement of an adequate response with UPCR <0.7 mg / mg and no subsequent renal flare, as adjudicated by the blinded Clinical Endpoints Committee (CEC). Renal flares were analyzed in subjects who achieved an adequate response and defined as an increase to UPCR >1 mg / mg from a post-response UPCR of <0.2 mg / mg or an increase to UPCR >2 mg / mg from a postresponse UPCR of 0.2 to 1.0 mg / mg, adjudicated by the blinded CEC. Adequate response was considered a sustained UPCR reduction <0.7 mg / mg, adjudicated by the CEC. Non-renal flares were defined based on AEs, laboratory abnormalities and / or any other information presented, adjudicated by the blinded CEC. Of the subjects who achieved an adequate response (101 subjects in the voclosporin group and 73 subject sin the control group), similar proportions of subjects in each group experienced renal flares. Similar proportions of subjects in each group also experienced non-renal flares.

[0261] Finally, mean levels of blood pressure, serum creatinine (sCr), glucose, hemoglobin Ale, and lipids were stable over time in both groups. Mean levels of potassium and magnesium also remained within normal ranges over time in both groups.

[0262] Voclosporin was well tolerated with no unexpected safety signals observed. Table E6 shows a summary of adverse events. There were comparable serious adverse event rates in both study arms, 19% for the voclosporin-treated group and 24% for the active control group. Additionally, there were no deaths in the voclosporin-treated group whereas there were four deaths in the active control group. The active control group had a higher percentage of withdrawals (15.0% withdrawal) compared to the voclosporin-treated group (12.9% withdrawal).Table E6: Summary of Adverse Events for Overall Three Year Treatment Period

[0263] 86.1% of the subjects completed the continuation study; the summary of adverse events (AEs) during the continuation study is presented in Table E7. During the continuation study, the proportion of subjects experiencing AEs was comparable between the two groups (86.2% in the voclosporin group; 80.0% in the control group). The incidence of serious AEs (SAEs) was also comparable. Of the subjects who experienced AEs, most experienced AEs that were mild or moderate in severity. Study drug discontinuation due to AEs occurred in 9.5% of the voclosporin and 17.0% of the control group. Unique pharmacokinetic-pharmacodynamic properties, including the low metabolite load and eGFR-based dosing of voclosporin are likely responsible for the benign safety profile observed with voclosporin.

[0264] In the continuation study, investigator reported adverse events GFR decrease occurred in 12 subjects (10.3%) in the voclosporin group and in 5 subjects (5.0%) in the control group while investigator reported adverse event hypertension occurred in 10 subjects (8.6%) in the voclosporin group and 7 subjects (7.0%) in the control group. Antihypertensive treatment started after the first dose of treatment in the continuation study was initiated by 3 subjects (2.6%) in the voclosporin arm, and 10 subjects (10.0%) in the control arm.Table E7: Summary of Adverse Events During the Continuation Study

[0265] Overall adverse event (AE) profiles between voclosporin and control groups were comparable, with AEs declining annually and few subjects discontinuing due to AEs. Although AEs associated with the hemodynamic effects of the CNI drug class, such as hypertension and GFR decrease, occurred more often in the voclosporin group, the AEs decreased over time, and were managed through dose modifications. Additionally, there were very few events of Type 2 diabetes mellitus, hyperkalemia, or hyperlipidemia in either group over the course of the study. Furthermore, drug discontinuations were less frequent in the voclosporin group compared to the control group.

[0266] Finally, as shown by Table E8, across the three years of treatment, infections were the most common type of AE by SOC (69.8% voclosporin; 72.0% control) with low rates of serious infections in both groups (12.9% voclosporin, 17.0% control). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection occurred in seven patients in the voclosporin group and 12 patients in the control group; these events were serious in two patients in the voclosporin group and five patients in the control group.Table E8: Summary of Adverse Events by Year of Study (Data reported are n (%))*The SOC of Investigations is driven by eGFR decrease (Overall, voclosporin, n=28 [24.1%], 47 events; control, n=9 [9.0%], 13 events).

[0267] In sum, the results of the long-term continuation study of three years, evaluating the long-term safety and tolerability of voclosporin for the treatment of adults with active lupus nephritis (LN), a serious complication in subjects with systemic lupus erythematosus (SLE), in combination with background immunosuppressive therapy, support a long-term treatment with voclosporin for subjects with LN. The significant and meaningful reductions in proteinuria achieved in the initial study were maintained for an additional two years, and the mean estimated glomerular filtration rate (eGFR) remained stable over three years of treatment, with similar serious adverse event rates and no unexpected safety events. Moreover, continued reduced UPCR, increased CRR and preserved kidney function all suggest a positive benefit-risk profile for voclosporin in lupus nephritis subjects. In conclusion, the results show long-term safety and tolerability of voclosporin treatment for LN, minimal impact on eGFR even after up to three years of treatment, while maintaining effective treatment and substantial reduction in proteinuria.Example 3: ASSESSMENT OF VOCLOSPORIN TREATMENT FOR LUPUS NEPHRITIS IN SUBJECTS WITH HIGH LEVELS OF PROTEINURIA

[0268] Data from placebo and voclosporin treated subjects with moderate to high levels of baseline proteinuria from the studies as described in Examples 1 and 2 above were pooled for further analysis.

[0269] Subjects with moderate to high levels of proteinuria (a baseline urine protein creatinine ratio (UPCR) > 2 mg / mg) from the two studies as described in Examples 1 and 2 above, were pooled for further analysis.A. Baseline Characteristics

[0270] Among the 534 patients in the pooled dataset, 432 patients (215 in the control group, 217 in the voclosporin group) had a baseline UPCR of > 2 mg / mg. As shown in Table E9, baseline characteristics of subjects with baseline UPCR of >2 mg / mg were similar in the control and voclosporin groups with a mean UPCR value of 4.6 mg / mg for the control group and 5.1 mg / mg for the voclosporin group.Table E9: DemographicsB. Proteinuria

[0271] Proteinuria levels at 12 months from the start of the treatment showed a significant reduction in UPCR values from baseline for the voclosporin group compared to the control group. As shown in FIG. 11, at one year, the change from baseline in the least squares (LS) mean (standard error [SE]) UPCR was -3.8 (0.1) mg / mg in the voclosporin group compared to - 3.1 (0.2) mg / mg in the control group (difference vs. control, -0.7; p=0.0003).C. Complete Renal Response

[0272] Complete renal response rates (CRR) rates were assessed in various different subgroups of subjects. Complete renal response was defined as UPCR of < 0.5 mg / mg, estimated glomerular filtration rate (eGFR) > 60 mL / min / 1.73 m2or no decrease >20% UPCR of0.5 mg / mg, eGFR 60 ml / min / 1.73 m2or no decrease > 20% from baseline, low-dose glucocorticoids, and no rescue medications. Odds ratios (OR) were calculated for each subject subgroup, with an OR>1 indicating treatment benefit of voclosporin.

[0273] As shown in FIG. 12, higher renal response rates were observed in the voclosporin group across subgroups regardless of baseline demographics or clinical characteristics. CRR rates were numerically higher in subgroups of voclosporin-treated patients, including both sexes and across all ages, races, ethnicities, biopsy classes, and eGFR levels assessed (as indicated with OR > 1). Overall, significantly more subjects from the voclosporin group achieved CRR at 12 months compared to the control group (41.0% vs 21.9%; or 2.48, p < 0.0001).

[0274] Consistent with results from the overall pooled study population, patients with UPCR of > 2 mg / mg treated with voclosporin achieved significantly higher renal response rates than patients treated with MMF and low-dose glucocorticoids alone.D. Complete Renal Response by Biopsy Class

[0275] Further analysis of the biopsy class data showed that the highest rates of CRR were achieved in the voclosporin groups with Class III and Class IV disease, or a mixed Class V and III or IV (FIG. 13). In the Class III, Class IV or mixed Class V and III or IV subgroups, a substantial difference between the CRR rates of the voclosporin treated group were observed, indicating that the effect of voclosporin treatment was marked in these groups. The difference between the CRR achieved in the voclosporin and control groups with Class V disease was less substantial.E. Estimated glomerular filtration rate (eGFR)

[0276] The estimated glomerular fdtration rate (eGFR) changes throughout the study period in the voclosporin and control groups showed that after an expected, small decrease in eGFR in the voclosporin arm due to the hemodynamic effect of calcineurin inhibitors (CNIs), the least squares (LS) Mean corrected eGFR was stable over one year of treatment in both groups, as shown in FIG. 14.F. Adverse Events

[0277] The rate of serious adverse events was similar between the voclosporin group and the control group, and there were no unexpected safety events. Table E10 shows a summary of adverse events. As shown, safety outcomes were comparable in the voclosporin treated and control groups with no evidence of worsening kidney function.Table E10: Summary of Adverse Events

[0278] The results support the use of voclosporin as an effective therapy for LN in subjects with moderate to high proteinuria. The results show long-term safety, efficacy, and tolerability, minimal impact on eGFR even after up to 52 weeks of treatment, while maintaining substantial reduction in proteinuria. Further, the results support that voclosporin is a safe and effective therapy for LN, particularly showing substantially higher response rate compared to control, for subjects that have Class III, Class IV, or a mixed Class V and III or IV disease.Example 4: ASSESSMENT OF KIDNEY BIOPSIES EVALUATING VOCLOSPORIN FOR THE TREATMENT OF LUPUS NEPHRITIS

[0279] Proteinuria is a widely accepted biomarker of treatment response and overall prognosis in lupus nephritis. Repeat renal biopsies may provide additional information on renal status in patients undergoing treatment for lupus nephritis. The long-term impact of voclosporin on the kidney at the histologic level was further characterized based on repeat biopsies from a representative subset of patients that were administered voclosporin long-term.

[0280] Patients with active lupus nephritis based on urine protein creatinine ratio (UPCR) > 1.5 mg / mg (> 2 mg / mg for Class V), and eGFR > 45 mL / min / m2were included in a clinical study, generally as described in Examples 1 and 2 above. Patients were randomized to voclosporin or control for 1 year and continued the same therapy for up to an additional 2 years. All patients had a kidney biopsy prior to screening and if enrolled for an additional 2 years, a subset of the patients received repeat renal biopsies in the first year of the additional 2-year treatment (see FIG. 5). Biopsies were blinded, processed, stained, and evaluated and scored by renal histopathologists at a specialized renal pathology laboratory according to the 2018 ISN / RPS guidelines (Bajema et al. Kidney Int. 2018;93(4):789-796).

[0281] Specifically, biopsy samples were collected from a subgroup of 16 patients in thevoclosporin arm and 10 patients in the control arm. Efficacy outcomes included mean UPCR over time as well as complete renal response (CRR; defined as UPCR <0.5 mg / mg, stable eGFR, low-dose steroids, and no rescue medication) and partial renal response (PRR; defined as reduction in UPCR of >50% from baseline) at Month 36. Mean eGFR over time was also assessed.

[0282] The subjects in the subgroup assessed by biopsy had similar patient demographics and renal characteristics to the underlying study population (Table Ell).Table Ell: Patient Demographics* Includes self-identified mixed race.

[0283] Table E12 demonstrates baseline histologic activity scores were similar between arms, with scores in both arms decreasing with treatment. Histologic chronicity scores were also similar between arms at baseline and remained stable over time in most patients in both arms. No difference was observed between voclosporin-treated patients and control-treated patients in either activity or chronicity scores at baseline or upon repeat biopsy.

[0284] In the total study subject population, the voclosporin group (who received voclosporin in addition to MMF and low-dose steroids, as described in Examples 1 and 2 above), led to significantly earlier and greater reductions in proteinuria while maintaining stable renal function, as evidenced by a stable eGFR slope over time.

[0285] UPCR Improvement was observed in voclosporin patients with repeat biopsies, as demonstrated by the decreases in mean UPCR values (Table E12). Mean eGFR values remained stable in both treatment arms over time (Table E12). Higher rates of both CRR and PRR were observed in voclosporin-treated patients at month 36. The results in the subgroup of patients assessed were consistent with the results observed in the larger total study subject population, as shown in FIG. 15 (UPCR) and FIG. 16 (eGFR). Specifically, mean eGFR values over time in the biopsy sub-study of 26 subjects were stable over three years and consistent with those observed in the larger total study subject population in the 2-year continuation study (n = 216) (see FIG. 17).Table E12: Clinical Outcomes and Activity and Chronicity Index Scores Over TimeRenal function assessed with corrected eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) using a prespecified ceiling of 90 mL / min / 1.73 m2. Histopathologic grading based on the National Institutes of Health indices for lupus nephritis activity (scale 0-24) and chronicity (scale 0-12).CRR, complete renal response; eGFR, estimated glomerular filtration rate; PRR, partial renal response; SD, standard deviation; UPCR, urine protein creatinine ratio. CRR is defined as UPCR <0.5 mg / mg, stable eGFR, low-dose steroids, and no rescue medication. eGFR. PRR is defined as reduction in UPCR of >50% from baseline.

[0286] As shown in Table E12 and FIG. 18A, baseline activity scores, a measure of active inflammation in LN, were similar between the voclosporin and the control arms, with scores in both arms decreasing with treatment. As shown in Table E12 and FIG. 18B, chronicity scores, a measure of irreversible kidney injury including scarring, were also similar between arms at baseline; and remained stable over time in most patients in both arms. No difference was observed between voclosporin-treated patients and control-treated patients in either activity or chronicity scores at baseline or upon repeat biopsy. Activity scores decreased in conjunction with improvements in urine protein creatinine ratio (UPCR) in both treatment arms.

[0287] In particular, for the 26 subjects in the biopsy subgroup, all chronicity index variables remained stable from baseline to follow-up in both arms, as shown in Table E13. Exposure to voclosporin was not associated with chronic injury, with the average chronicity index remaining stable in both arms from baseline to follow-up. Accordingly, the subjects who received voclosporin (n=16) demonstrated histologic activity improvement with standard chronicityscores similar to the control subjects (n=10).Table E13: Mean Chronicity Index Variables Over TimeHistopathologic grading based on the National Institutes of Health index for lupus nephritis chronicity, with each variable scored on a scale from 0-3.

[0288] The results show that voclosporin-treated patients demonstrate histologic activity improvement and stable chronicity scores similar to those in the active control arm (MMF and low dose steroids), over the 18-month average treatment period until the repeat biopsy. Disease activity scores, a histological measure of kidney inflammation, decreased substantially in voclosporin and control arms compared to baseline. Further, the repeat biopsy samples were devoid of renal injury patterns typically seen with legacy CNIs such as tacrolimus or cyclosporin. Voclosporin and control patient groups both showed stability in chronicity index, a histological measure of irreversible kidney damage and scarring, associated with end-stage kidney disease, indicating that exposure to voclosporin did not increase chronic injury, unlike legacy CNIs. Notably, efficacy and safety results from the subjects in the biopsy subgroup were consistent with outcomes from the larger total study subject population.

[0289] The results support the safe and efficacious long-term use of voclosporin in subjects in need of immunosuppression using a CNI, without worsening of nephrotoxicity or development of legacy CNI-associated renal injury patterns, as assessed by renal biopsies. The absence of typical legacy CNI-related chronicity changes, such as scarring, are critical observations that show a low rate of chronic kidney toxicity of voclosporin, when compared to the legacy CNIs. The chronic kidney toxicity associated with legacy CNIs, such as tacrolimus or cyclosporin, has limited the long-term utility of the legacy CNIs in LN and supports the utility of voclosporin in longer term immunosuppression. The results also support the long-term efficacy and safety of voclosporin, as after about 18 months of therapy with voclosporin, repeat biopsy showed that patients maintained clinical response and showed no important histologic evidence of nephrotoxicity, in contrast with legacy CNIs which have substantial adverse effects and toxicities, substantially limiting their use as immunosuppressants in longer term treatment.Example 5: ASSESSMENT OF VOCLOSPORIN ON URINE BIOMARKERS

[0290] For active lupus nephritis patients, several biomarkers associated with kidney, injury inflammation, and fibrosis have been reported to be elevated. Exemplary biomarkers include kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattract protein (MCP-1) and transforming growth factor beta (TGF-f> I ).Treatment with legacy calcineurin inhibitors (CNIs) has also been associated with kidney injury and elevated levels of profibrotic biomarkers, including KIM-1, NGAL, MCP-1, TGF- 1, CD 163, CD206, and IL- 16.

[0291] From the one-year double-blind, randomized controlled study of voclosporin administration described in Example 2 above, a subgroup of 120 patients randomly selected were included in a study of 43 urinary analytes. Patients were evaluated based on treatment response (Table E14; a responder was defined as having a > 50% reduction from baseline in urine protein creatinine ratio [UPCR] at one year of treatment). Patients who experienced a> 30 % decrease in estimated glomerular filtration rate (eGFR) were separately analyzed.Table E14: Analysis of normalized urinary concentrations of KIM-1, TGF- 1, MCP-1 and NGAL* Subgroup analysis of 60 patients is presented. Mean ± SD change from baseline to one year of treatment in the trial was analyzed with 24-hour urinary excretion concentrations. Responders were defined as having >50% reduction from baseline in urine protein creatinine ratio at one year. Patients who had >30% reduction from baseline in estimated glomerular filtration rate (eGFR) during the study were included in eGFR decrease cohort.

[0292] Across responders, non-responders, and eGFR decrease subjects, there were no significant differences in change from baseline for normalized urinary concentration of KIM- 1, NGAL, MCP-1, and TGF- 1 between voclosporin and control treatment arms. The results demonstrate that subjects with LN treated with oral voclosporin in addition to MMF and low- dose steroids, did not experience and increase in urinary kidney injury and pro-fibrotic markers, which are indicative of renal fibrosis and kidney damage and have been reported for treatment with legacy CNIs. The results support use of voclosporin in subjects that require long-termimmunosuppression using CNIs.Example 6: ASSESSMENT OF ELECTROLYTE PROFILES IN LUPUS NEPHRITISPATIENTS TREATED WITH VOCLOSPORIN

[0293] Electrolyte imbalances, modulating within the kidney, have been reported in connection with use of legacy CNIs such as tacrolimus in solid organ transplantation. The effect of voclosporin in combination with immunosuppressive therapy on the urinary electrolytes in subjects with lupus nephritis were investigated based on a clinical study, by evaluating changes in urinary and / or serum electrolyte concentrations over time.

[0294] From the one-year double-blind, randomized controlled study of voclosporin administration described in Example 2 above, twenty-four-hour urine samples from 60 patients in each treatment arm were selected for urinary analysis of electrolytes. Samples were included from patients who responded to treatment at one year with at least 50% reduction in urine protein creatinine ratio (UPCR) from baseline (treatment responders), patients who had not (nonresponders), and patients who had at least 30% reduction from baseline in estimated glomerular filtration rate (eGFR) during the study. The mean change from baseline to one year in magnesium, potassium and sodium were presented as 24-hour urinary excretion concentrations.

[0295] Mean changes from baseline in urinary electrolyte excretion concentrations were small for magnesium (<13.4 mg / dL) and potassium (<6.4 mmol / L), with no significant differences between treatment arms for any of the subgroups. Sodium excretion concentrations decreased from baseline in all subgroups (<30.5 mmol / L) except for responders in the control arm (increase of 14.0 mmol / L) at one year (Table E15).Table E15*: Analysis of electrolyte urinary excretion concentrations* Subgroup analysis of 60 patients is presented. Mean ± SEM change from baseline to one year of treatment in the trial was analyzed with 24-hour urinary excretion concentrations. Responders were defined as having >50% reduction from baseline in urine protein creatinine ratio at one year. Patients who had >30% reduction from baseline in estimated glomerular fdtration rate (eGFR) during the study were included in eGFR decrease cohort.

[0296] Mean serum electrolyte concentrations of patients treated with voclosporin were within normal ranges (Rovin et al., Lancet. 2021 May 29;397(10289):2070-2080). At the studied dose of voclosporin, changes from baseline in urinary electrolyte excretion concentrations of magnesium, potassium, and sodium were not clinically meaningful in either treatment arm regardless of response to treatment.

[0297] The results of the study, together with the reported normal electrolyte concentrations in serum, confirms that voclosporin does not have substantial impact on the mean concentrations of electrolytes. The results further support the safety and efficacy of voclosporin for the treatment of subjects that are in need of CNI therapy, particularly for subjects who have previously received a legacy CNI that may inhibit kidney tubular calcium and magnesium reabsorption.Example 7: ASSESSMENT OF LIPID PROFILES IN LUPUS NEPHRITIS PATIENTS TREATED WITH VOCLOSPORIN

[0298] Dyslipidemia is a potential side effect of certain CNIs, such as cyclosporin. LN is an independent risk factor for an increased risk of cardiovascular disease (CVD), which can be exacerbated by dyslipidemia associated with inflammation and the immunosuppressant.

[0299] The effect of voclosporin in combination with immunosuppressive therapy on lipid levels of subjects with LN was investigated.

[0300] Subjects with biopsy-proven active lupus nephritis (class III, IV, or V ± III / IV) and proteinuria > 1.5 mg / mg (> 2 mg / mg for class V) were enrolled in Phase 2 and Phase 3 clinical studies to assess the efficacy and safety of voclosporin in comparison to a placebo (control). All patients were concurrently administered my cophenolate mofetil (MMF) (target 1 g BID) and rapidly -tapered, low-dose steroids. Pooled data from the similarly designed clinical studies demonstrated that the addition of voclosporin to MMF and low-dose steroids resulted in significantly higher complete renal response rates (CRR) at one year of treatment (43.7% vs. 23.3%; OR 2.76; PO.OOOl).

[0301] The pooled dataset was further analyzed to evaluate the impact of voclosporin on lipid levels in subjects with LN. Pooled data included 268 patients in the voclosporin (23.7 mg BID) arm and 266 patients in the placebo-treated control arm. Fasting total cholesterol, low- density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), andtriglycerides were measured at baseline and at a one year follow-up in a central, CLIA-certified laboratory.

[0302] Table E16 shows changes in the lipid profdes of subjects treated with voclosporin or placebo (control) from baseline to one year. Mean values for total cholesterol, LDL, and triglycerides were above the respective normal ranges at baseline and decreased during the study in both voclosporin and placebo arms. At one year, the decreases from baseline were significantly greater in the voclosporin arm than the control arm for total cholesterol ( A).0062) and LDL (P=0.023). The overall reduction from baseline in triglycerides was also greater in voclosporin-treated patients at one year ( =0.0768).

[0303] At one year, the percentage of patients with total cholesterol in the normal range increased by about 42% (from 17.3% at baseline to 59.2%) in the voclosporin arm versus about a29% increase (from 19.4% at baseline to 48.3%) in the control arm. The percentage with normal LDL increased by about 42% (from 29.7% at baseline to 71.4%) in the voclosporin arm compared to an increase of about 21% (from 34.5% at baseline to 55.2%) in the control arm.The percentage of subjects with normal triglycerides increased from 32.3% to 56.1% in the voclosporin arm and from 36.1% to 53.6% in the control arm. Mean HDL levels were within the normal range at baseline in both arms and remained stable throughout the study.Table E16: Lipid Profde at Baseline and One Year

[0304] From baseline to the one year follow-up, total cholesterol, LDL cholesterol, and triglyceride levels improved in both treatment arms. Along with higher CRR rates, the voclosporin arm exhibited greater reductions in lipids and an overall greater percentage of subject entry to normal lipid ranges. Given the risk of cardiovascular disease in LN patients, the improvements in CRR and favorable impact on lipid levels observed in the clinical studies further support the use of the CNI voclosporin for the treatment of LN and other diseases.

[0305] As favorable renal clinical response and changes in traditional lipoproteins were observed in a clinical study with voclosporin, the lipid profde of some of the subjects from the studies was further evaluated, to assess whether the beneficial therapeutic response is mediated in part by alteration in circulating lipids, such as inflammatory lipids.

[0306] Lipid class levels were further assessed in randomly selected participants from control (placebo) (N = 30) and voclosporin (N = 28) arms were compared. All subjects received my cophenolate mofetil (MMF) and low-dose steroids. 918 serum lipids in 14 classes from baseline and week 52 were compared in a lipi domic analysis. The difference of lipids at week 52 from baseline was calculated, z-score standardized, and used in mixed linear models.

[0307] The alterations of lipid class levels were assessed as a function of voclosporin effect and by achievement of either complete renal response (CRR) or partial renal response (PRR) (Table E17). Voclosporin and renal clinical response (CRR or PRR) contributed to decline in ceramides (CERs) and triacylglycerol (TAGs) and increase in dihydroceramide (DCERs) and phosphatidylinositol (Pls) independent of each other. CERs, DcERs, Pls, and TAGs are thusaltered by voclosporin.

[0308] Results indicate the additive effects of voclosporin and renal clinical response on alteration of corresponding lipids. Voclosporin, CRR and PRR were independently associated with alteration of phosphatidylcholine PC(C16), Pls, and TAGs. Alterations of PC, PI and TAGs correlate with renal outcome independent of voclosporin.

[0309] An integrative analysis showed significant correlations between saturated diacylglycerol (DAGs) and monoacylglycerol (MAGs; C>16),TAGs, sphingomyelin (SMs), CERs, unsaturated PEPs, and palmitoyl PCs(C16) after controlling for CRR or PRR.

[0310] Collectively, these findings support that voclosporin reduces lipogenesis by decreasing incorporation of fatty acid precursors and inflammatory lipids, and a favorable therapeutic response is mediated in part by promotion of change in corresponding lipid class.Table E17: Alteration of Lipid Class Levels* Each column shows the change in mean of lipid class from baseline to week 52 by the main effects of voclosporin, clinical response, and their interactions. Complete renal response assessed at Week 52 was defined as urine protein creatinine ratio (UPCR) < 0.5 mg / mg, stable renal function (eGFR > 60 mL / min / 1.73 m2or no decrease >20% from baseline), presence of sustained, low-dose steroids (in the 8 weeks prior to assessment) and no use of rescue medication. Partial renal response defined as > 50% reduction from baseline in UPCR. P values are <0.027.Example 8: ASSESSMENT OF DRUG-DRUG INTERACTIONS BETWEENVOCLOPORIN AND MYCOPHENOLATE MOTEFIL (MMF)

[0311] A clinical study was conducted to evaluate the effect of voclosporin onmy cophenolate mofetil (MMF). Legacy CNIs, such as cyclosporin has been reported to exhibit drug-drug interaction with MMF, a drug that is commonly administered together with CNIs. Cyclosporin can reduce the effective blood concentration of the active moiety of MMF, mycophenolic acid (MPA), and other metabolites. The effect of voclosporin following dosing with MMF on blood levels of mycophenolic acid (MPA, the active moiety of MMF) and MPA glucuronide (MP AG, the pharmacologically inactive metabolite of MMF) in subjects with systemic lupus erythematosus (SLE) was evaluated.

[0312] MMF was orally administered at a dose of 1g twice a day for at least 28 days prior to the study and continued at 1 g throughout the study. Voclosporin was orally administered at a dose of 23.7 mg twice a day for 7 consecutive days. Voclosporin was first administered as an evening dose on day 1 and ended with a morning dose on day 7. Dense pharmacokinetic blood samples were collected pre-dose in the morning and from 0.25 to 12 hours after the morning doses.

[0313] In 24 patients, MPA exposure, evaluated by maximum serum concentration (Cmaxand area under the concentration curve from time 0 to 12 hours (AUC0-12), was similar in the presence or absence of voclosporin. Cmaxwas 16.5 pg / mL (Day 1) in the absence of voclosporin versus 15.8 pg / mL (Day 7) in the presence of voclosporin. AUC0 12 was 39.1 pg / h / mL (Day 1) in the absence of voclosporin versus 40.8 pg / h / mL (Day 7) in the presence of voclosporin.Based on the geometric mean ratios of 0.94 for Cmaxand 1.09 for AUC0-12, MPA exposure was similar in the presence and absence of voclosporin.

[0314] The mean concentration-time profiles of MPA in plasma were similar in the presence and absence of voclosporin (FIG. 19). The trough concentration (Ctrough) values on Day 7 were similar to the morning pre-dose concentrations, indicating achievement of steady-state conditions in the presence of voclosporin.

[0315] In the same 24 patients, it was observed the mean concentration-time profiles of MP AG in plasma showed a small increase in the presence of voclosporin (FIG. 20). The trough concentration (Ctrough) values on Day 1 and Day 7 were similar to the morning pre-dose concentrations. MP AG exposure was higher following administration of MMF in the presence of voclosporin compared with administration of MMF alone. Cmaxwas 65.0 pg / mL (Day 1) in the absence of voclosporin versus 71.4 pg / mL (Day 7) in the presence of voclosporin. AUC0 12 was 444 pg / h / mL (Day 1) in the absence of voclosporin versus 532 pg / h / mL (Day 7) in the presence of voclosporin. Based on the geometric mean ratios, MP AG Cmaxand AUC0 12 were 12.0% and 27.0% higher, respectively, in the presence of voclosporin.

[0316] Together, the results support that the combination therapy of voclosporin and MMF is well tolerated and that voclosporin and MMF can be administered concomitantly without the need for dose adjustment. There is no clinically meaningful interaction between voclosporin and MMF. The results support the use of voclosporin in combination with other common immunosuppressants such as MMF, as voclosporin does not exhibit negative drug-drug interactions with the other immunosuppressant, in contrast to some legacy CNIs that can reduce the blood levels and exposure of other immunosuppressant drugs.

[0317] The present invention is not intended to be limited in scope to the particular disclosed embodiments, which are provided, for example, to illustrate various aspects of the invention. Various modifications to the compositions and methods described will become apparent from the description and teachings herein. Such variations may be practiced without departing from the true scope and spirit of the disclosure and are intended to fall within the scope of the present disclosure.

Claims

Claims1. A method of treating lupus nephritis (LN), the method comprising:(a) selecting a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) LN based on a renal biopsy classification; and(b) administering voclosporin to the selected subject.

2. A method of treating lupus nephritis (LN), the method comprising administering voclosporin to a subject that has previously been classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification.

3. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification.

4. A method of assessing the likelihood of response to voclosporin treatment, the method comprising identifying a subject that is classified as having a Class III, a Class IV, or a Mixed Class V and III or IV (Mixed Class V + III / IV) lupus nephritis (LN) based on a renal biopsy classification, as having a high likelihood of response to voclosporin treatment.

5. The method of claim 3 or 4, wherein the method further comprises administering voclosporin to the selected subject or the identified subject.

6. The method of any of claims 1-5, wherein the renal biopsy classification comprises an International Society of Nephrology / Renal Pathology Society (ISN / RPS) classification.

7. The method of any of claims 1-6, wherein the renal biopsy classification comprises an International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2003 classification.

8. The method of any of claims 1-6, wherein the renal biopsy classification comprises an International Society of Nephrology / Renal Pathology Society (ISN / RPS) 2018 classification.

9. The method of any of claims 1-8, wherein the subject is selected for administration of voclosporin if the subject is classified as having a Class III LN based on a renal biopsy classification.

10. The method of any of claims 1-9, wherein the subject is identified as having a high likelihood of response if the subject is classified as having a Class III LN based on a renal biopsy classification.

11. The method of any of claims 1-10, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits focal proliferative glomerulonephritis.

12. The method of any of claims 1-11, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits proliferative glomerulonephritis affecting fewer than about 50% of the glomeruli.

13. The method of any of claims 1-12, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving fewer than about 50% of all glomeruli, optionally with focal subendothelial immune deposits, with or without mesangial alterations.

14. The method of any of claims 1-13, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits endocapillary hypercellularity.

15. The method of any of claims 1-14, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits focal endocapillary hypercellularity.

16. The method of any of claims 1-15, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits endocapillary hypercellularity affecting fewer than about 50% of the glomeruli.

17. The method of any of claims 1-16, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits:(a) segmental endocapillary hypercellularity with substantial luminal reduction;(b) endocapillary hypercellularity with fibrinoid necrosis and cellular crescent formation;(c) karyorrhexis in a segment of a glomerulus;(d) segmental sclerosis of a glomerulus;(e) segmental subendothelial deposits by light microscopy as fuchsinophilic deposits; and / or(f) IgG immune deposits in glomerular capillary wall in segmental distribution and mesangial deposits.

18. The method of any of claims 1-17, wherein the subject is classified as having a Class III LN if a renal biopsy from the subject exhibits:(a) a lesion comprising extracapillary hypercellularity;(b) a crescent;(c) the presence of Fibrin and fibrous matrix; and / or(d) 10% or more of the circumference of Bowman’s capsule showing extracapillary hypercellularity.

19. The method of any of claims 1-10, wherein the subject is selected for administration of voclosporin if the subject is classified as having a Class IV LN based on a renal biopsy classification.

20. The method of any of claims 1-10 and 19, wherein the subject is identified as having a high likelihood of response if the subject is classified as having a Class IV LN based on a renal biopsy classification.

21. The method of any of claims 1-10, 19, and 20, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits diffuse proliferative glomerulonephritis.

22. The method of any of claims 1-10 and 19-21, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits proliferative glomerulonephritis affecting greater than about 50% of the glomeruli.

23. The method of any of claims 1-10 and 19-22, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving >50% of all glomeruli, optionally with diffuse subendothelial immune deposits, with or without mesangial alterations.

24. The method of any of claims 1-10 and 19-23, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits endocapillary hypercellularity.

25. The method of any of claims 1-10 and 19-24, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits diffuse endocapillary hypercellularity.

26. The method of any of claims 1-10 and 19-25, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits endocapillary hypercellularity affecting greater than about 50% of the glomeruli.

27. The method of any of claims 1-10 and 19-26, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits:(a) diffuse segmental endocapillary proliferation;(b) global endocapillary proliferation with leukocyte infiltration;(c) endocapillary proliferation with widespread wire loop appearance in the glomerular capillary wall indicator of subendothelial immune deposits;(d) subendothelial deposits as fuchsinophilic deposits;(e) diffuse global wire loop appearance without mesangial or endocapillary cellular proliferation; and / or(f) significant immune deposit overload in glomerular capillary wall.

28. The method of any of claims 1-10 and 19-27, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits a diffuse segmental lupus nephritis with greater than 50% of the involved glomeruli have segmental lesions that involveless than half of the glomerular tuft; or a diffuse global lupus nephritis with greater than 50% of the involved glomeruli have global lesions.

29. The method of any of claims 1-10 and 19-28, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits advanced sclerosing glomerulonephritis.

30. The method of any of claims 1-10 and 19-29, wherein the subject is classified as having a Class IV LN if a renal biopsy from the subject exhibits:(a) a lesion comprising extracapillary hypercellularity;(b) a crescent;(c) the presence of Fibrin and fibrous matrix; and / or(d) 10% or more of the circumference of Bowman’s capsule showing extracapillary hypercellularity.

31. The method of any of claims 17, 18, and 30, wherein the crescent comprises:(a) a cellular crescent comprising more than 75% cells and fibrin and less than 25% fibrous matrix;(b) a fibrous crescent comprising more than 75% fibrous matrix and less than 25% cells and fibrin; and / or(c) a fibrocellular crescent comprising 25%-75% cells and fibrin and the remainder fibrous matrix.

32. The method of any of claims 1-31, wherein the subject is selected for administration of voclosporin if the subject is classified as having a Mixed Class V + III / IV LN based on a renal biopsy classification.

33. The method of any of claims 1-32, wherein the subject is identified as having a high likelihood of response if the subject is classified as having a Mixed Class V + III / IV LN based on a renal biopsy classification.

34. The method of any of claims 1-33, wherein the subject is classified as having a Class a Mixed Class V + III / IV LN if a renal biopsy from the subject exhibits:(a) non-wire-loop subendothelial deposits within Class V, and / or(b) subepithelial deposits involving >50% of the tuft of >50% of the glomeruli.

35. The method of any of claims 1-34, wherein the subject is not selected for administration of voclosporin if the subject is classified as having a pure Class V LN based on a renal biopsy classification.

36. The method of any of claims 1-35, wherein the subject is not identified as having a high likelihood of response if the subject is classified as having a pure Class V LN based on a renal biopsy classification.

37. The method of claim 35 or 36, wherein the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits membranous glomerulonephritis.

38. The method of any of claims 35-37, wherein the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits membranous LN with global or segmental continuous granular subepithelial immune deposits.

39. The method of any of claims 35-38, wherein the subject is classified as having a pure Class V LN if a renal biopsy from the subject exhibits:(a) significant glomerular capillary wall thickening in global distribution;(b) subepithelial fuchsinophilic deposits;(c) spikes in glomerular capillary wall indicator of membranous nephropathy; and / or(d) continuous subepithelial IgG deposits in the glomerular capillary wall.

40. The method of any of claims 1-39, wherein the subject is further assessed for a National Institutes of Health Activity Index (NIH-AI).

41. The method of claim 40, wherein the NIH-AI is assessed on a total score scale between 0 and 24, based on the sum of the scores of the following assessments:(a) Endocapillary hypercellularity on a scale of 0-3, with endocapillary hypercellularity in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(b) Neutrophils / karyorrhexis on a scale of 0-3, with neutrophils and / or karyorrhexis in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(c) Fibrinoid necrosis on a scale of (0-3) x 2, with fibrinoid necrosis in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(d) Hyaline deposits on a scale of 0-3, with wire loop lesions and / or hyaline thrombi in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(e) Cellular / fibrocellular crescents on a scale of (0-3) x 2, with cellular and / or fibrocellular crescents in <25% (1), 25%-50% (2), or >50% (3) of glomeruli; and(f) Interstitial Inflammation on a scale of 0-3, with interstitial leukocytes in <25%(1), 25%-50% (2), or >50% (3) in the cortex.

42. The method of any of claims 1-41, wherein the subject is further assessed for a National Institutes of Health Chronicity Index (NIH-CI).

43. The method of claim 42, wherein the NIH-CI is assessed on a total score scale between 0 and 12, based on the sum of the scores of the following assessments:(a) Total glomerulosclerosis score on a scale of 0-3, with global and / or segmental sclerosis in <25% (1), 25%-50% (2), or >50% (3) of glomeruli;(b) Fibrous crescents on a scale of 0-3, with fibrous crescents in <25% (1), 25%-50%(2), or >50% (3) of glomeruli;(c) Tubular atrophy on a scale of 0-3, with tubular atrophy in <25% (1), 25%-50% (2), or >50% (3) of the cortical tubules; and(d) Interstitial fibrosis on a scale of 0-3, with interstitial fibrosis in <25% (1), 25%- 50% (2), or >50% (3) in the cortex.

44. The method of any of claims 1-43, wherein the renal biopsy is assessed using light microscopy, immunofluorescence, and / or electron microscopy.

45. The method of any of claims 1-44, wherein the voclosporin is administered at a daily dose of between about 5 mg BID to about 50 mg BID.

46. The method of any of claims 1-45, wherein the voclosporin is administered at an initial daily dose of about 39.5 mg, about 31.6 mg, about 23.7 mg, about 15.8 mg, or about 7.9 mg BID.

47. The method of any of claims 1-46, wherein the voclosporin is administered at an initial daily dose of about 39.5 mg.

48. The method of any of claims 1-46, wherein the voclosporin is administered at an initial daily dose of about 23.7 mg.

49. The method of any of claims 1-46, wherein the voclosporin is administered at an initial daily dose of about 15.8 mg.

50. The method of any of claims 1-49, wherein the voclosporin is administered over a projected voclosporin 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 or longer.

51. The method of any of claims 1-50, wherein the method further comprises assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of the projected treatment period; and(i) if the eGFR of the subject decreases by more than a target % to below a predetermined value, between the first and second time points, reducing the daily dose by increment(s) of 7.9 mg BID or stopping the administering of voclosporin;(ii) if the eGFR of the subject decreases by less than the target %, between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

52. The method of claim 51, wherein the predetermined value is in the range of 50-90 ml / min / 1.73m2.

53. The method of claim 51 or 52, wherein the predetermined value is approximately 60 ml / min / 1.73m2.

54. The method of any of claims 51-53, wherein the target % is in the range of 20%- 45%.

55. The method of any of claims 51-54, wherein the target % is approximately 30%.

56. The method of any of claims 51-55, wherein:(i) if the eGFR of the subject decreases by > 30% to a value of below 60 mL / min / 1.73m2between the first and second time points, stopping the administering of voclosporin to the subject;(ii) if the eGFR of the subject decreases by between 20% to 30% to a value of below 60 ml / min / 1.73m2between the first and second time points, administering a reduced dosage of voclosporin to the subject; and(iii) if the eGFR of the subject decreases by < 20% between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

57. The method of any of claims 51-56, wherein the first time point is immediately preceding initiating the administration of voclosporin.

58. The method of any of claims 51-57, wherein the second time point is after the first time point and initiating the administration of voclosporin.

59. The method of any of claims 51-58, wherein the second time point is 8 weeks after initiating the administration of voclosporin.

60. The method of any of claims 51-59, wherein the method further comprises determining the eGFR of the subject at a third time point and if the eGFR is determined at the third time point to differ from the eGFR determined at the first time point by less than the target %, resuming administering the predetermined daily dosage of voclosporin.

61. The method of any of claims 51-60, wherein the method further comprises measuring urinary protein creatinine ratio (UPCR) of the subject at the first time point and the second time point and determining any reduction of the UPCR between the first and second time points, and if the UPCR of the subject fails to show a reduction of at least 25% at the second time point, discontinuing administering voclosporin to the subject.

62. The method of any of claims 51-61, wherein the method further comprises measuring the concentration of C3 or C4 in the blood of the subject at the first time point and the second time point, and determining whether the concentration of C3 or C4 is normalized at the second time point, and if normalization of C3 or C4 is found, reinstating the administering voclosporin to the subject.

63. The method of any of claims 1-62, wherein the method further comprises administering to the subject an effective amount of my cophenolate mofetil (MMF).

64. The method of any of claims 1-63, wherein the method further comprises administering to the subject an effective amount of a corticosteroid.

65. The method of any of claims 1-64, wherein the voclosporin is a mixture of at least 90% E isomer and not more than 10% Z isomer.

66. Voclosporin for use in the method of any of claims 1-65.

67. Use of voclosporin in the manufacture of a medicament according to the method of any of claims 1-65.

68. Use of voclosporin in the method of any of claims 1-65.

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