Protocol for treatment of lupus nephritis

Abstract

To provide a method for treating a proteinuric kidney disease.SOLUTION: There is provided a method comprising administering a predetermined daily dosage of effective amounts of voclosporin over a projected treatment period of at least 24 weeks. The method further comprises: (a) assessing an estimated Glomerular Filtration Rate (eGFR) of a subject at at least a first time point and a second time point on different days within the treatment period; and (b) (i) when 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 dosage by units of 7.9 mg BID or discontinuing the administration of voclosporin to the subject; (ii) when the eGFR of the subject decreases by less than the target % between the first and second time points, continuing to administer the same predetermined daily dosage of voclosporin to the subject.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. patent application Ser. No. 15 / 835,219, filed Dec. 7, 2017, and the benefit under 35 U.S.C. § 119(e) of U.S. provisional patent application Ser. No. 62 / 505,734, filed May 12, 2017, and U.S. provisional patent application Ser. No. 62 / 541,612, filed Aug. 4, 2017, the contents of which are incorporated herein by reference in their entireties.

[0002] Technical Field The present invention relates to the treatment of lupus nephritis and other proteinuric kidney diseases with voclosporin. More particularly, the present invention relates to the pharmacodynamic dosing of subjects according to improved treatment protocols. [Background technology]

[0003] Lupus nephritis (LN) is one of many proteinuric kidney diseases, in which renal inflammation is caused by systemic lupus erythematosus (SLE), affecting up to 60% of SLE patients. LN is a debilitating and costly disease, often resulting in kidney failure requiring dialysis or kidney transplantation and often leading to death. In fact, patients with renal failure have a 60-fold increased risk of premature death compared with the general population of SLE patients. The clinical sign of LN is leakage of blood proteins into the urine, and the disease can be diagnosed by many factors, including the urinary protein-to-creatinine ratio (UPCR). A UPCR greater than 0.5 mg / mg indicates an active state of the disease. Furthermore, specific markers in the blood, such as complement 3 (C3), complement 4 (C4), and anti-dsDNA antibodies, can also be used to diagnose the condition.

[0004] The standard of care for LN has not been very successful. It involves the use of mycophenolate mofetil (MMF) or intravenous cyclophosphamide. These treatments result in partial remission in approximately 50% of cases, and complete remission in fewer than 10% of subjects. Therefore, there is a clear need for therapies that improve these outcomes.

[0005] Voclosporin is an analog of cyclosporin A that has been found to be useful in the treatment of autoimmune diseases and as an immunosuppressant during organ transplantation.

[0006] A mixture of the E and Z isomers of voclosporin is described in U.S. Patent No. 6,998,385. A mixture containing a predominantly E isomer is described in U.S. Patent No. 7,332,472. The '472 patent describes a number of indications, including glomerulonephritis, that can be treated with a mixture of isomers of voclosporin. However, although some animal studies are described, no human protocols are disclosed.

[0007] Various formulations of voclosporin mixtures are also described in US Patent Nos. 7,060,672; 7,429,562; and 7,829,533.

[0008] In October 2016, an abstract was published from a clinical study conducted on behalf of Aurinia Pharmaceuticals. The abstract presented data from 24 weeks of voclosporin 23.7 mg twice daily in combination with mycophenolate mofetil (MMF) and reduced-dose corticosteroids in subjects with lupus nephritis (LN). Inclusion criteria for this study were a urine protein-to-creatinine ratio (UPCR) of ≥ 1.0 mg / mL or ≥ 1.5 mg / mL, depending on renal biopsy classification, and a serum creatinine level of 45 mol / min / 1.73 m / s. 2The protocol included assessment of estimated glomerular filtration rate (eGFR) and serologic evidence of LN. Results of this protocol showed complete or partial remission in the majority of subjects.

[0009] Furthermore, subjects who achieved a 25% or greater reduction in UPCR at 8 weeks were shown to be more likely to maintain benefit throughout the 24- or 48-week protocol.

[0010] A news release from Aurinia Pharmaceuticals on March 1, 2017, described the results of a more extensive clinical study that included mycophenolate mofetil (MMF) and reduced-dose corticosterone, but used a higher dose of 39.5 mg twice daily in addition to voclosporin at 23.7 mg twice daily. The results of this study showed that many patients achieved complete or partial remission at 24 and 48 weeks. The lower dose of 23.7 mg twice daily (BID) appeared to be more effective than the higher dose of 39.5 mg twice daily (BID).

[0011] Data on the predictability of success for complete remission (CR) based on various criteria measured after 8 weeks of treatment with voclosporin 23.7 bid with MMF-1 and steroid taper were presented by the inventors at the 12th International Congress on Systemic Lupus Erythematosus (SLE) held on March 27, 2017. These criteria included UPCR (a decrease of less than 25% was considered indicative of ineffectiveness) and normalization of complement 3 and complement 4 (C3 and C4) and anti-dsDNA. However, the criteria for normalization of C3, C4, and anti-dsDNA were not disclosed.

[0012] Early studies of lupus treatment with cyclophosphamide, but not voclosporin, suggested normalization of C4 as a marker (Dall'Era, M. et al Arth. Care and Res. (2011) 63:351-357).

[0013] It has now been found that modifying the protocols disclosed in these publications by providing a pharmacodynamic dosing schedule based on individual patient response can produce favorable results, including a reduction in the number and severity of side effects. Furthermore, lower doses of voclosporin, i.e., 15.8 mg voclosporin twice daily or 7.9 mg voclosporin twice daily, are effective. Summary of the Invention

[0014] Disclosure of the Invention Thus, the present invention provides improved protocols for the treatment of lupus nephritis and other proteinuric kidney diseases that utilize evaluation of parameters related to individual subject response. The present invention provides personalized protocols for the treatment of proteinuric kidney diseases, including protocols using low doses of voclosporin. The voclosporin used is preferably a mixture of more than about 80% E isomer and less than about 20% Z isomer, more preferably a mixture of more than about 90% E isomer and less than about 10% Z isomer. The protocols employ daily doses of voclosporin over a planned period of 24, 48, 52, or more weeks, in which voclosporin is administered twice daily (BID). Suitable dosages include 39.5 mg, 31.6 mg, 23.7 mg, 15.8 mg, 7.9 mg, and other amounts in 7.9 mg increments. Lower doses demonstrate superior results compared to the higher dose of 39.5 mg; each of these doses is administered twice daily. Low doses of 15.8 mg or 7.9 mg administered twice daily are effective. The protocol preferably further includes administering to the subject an effective amount of MMF and / or an effective amount of a corticosteroid, typically prednisone, at decreasing dose levels throughout the study period.

[0015] Although the protocol of the present invention has been confirmed to be effective for lupus nephritis, such results indicate that the same protocol can be used to treat proteinuric kidney diseases in general, including diabetic nephropathy, nephrotic syndrome (i.e., renal parenchymal renal failure), nephritic syndrome, toxic lesions of the kidney, glomerular diseases such as membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS), IgA nephropathy (i.e., Berger's disease), IgM nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, minimal change disease, hypertensive nephrosclerosis, and interstitial nephritis.

[0016] One side effect of treatment with voclosporin is an undesirable decrease in estimated glomerular filtration rate (eGFR). One inventive protocol is designed to reduce the occurrence of this undesirable side effect by adjusting the dose according to the subject's response.

[0017] Accordingly, in one aspect, the present invention relates to a pharmacodynamic method for treating proteinuric kidney disease, comprising administering to a subject diagnosed with said disease an effective amount of voclosporin at a predetermined daily dose for a planned treatment period of at least 24 weeks, said pharmacodynamic method further comprising: (a) assessing the subject's estimated glomerular filtration rate (eGFR) at least at a first and a second time point on different days during the treatment period; and (b)(i) if the subject's eGFR decreases by more than a target % between the first and second time points to less than a predetermined value, reduce the daily dose by 7.9 mg BID or discontinue administration of voclosporin to the subject; (ii) continuing to administer the same prescribed daily dose of voclosporin to the subject if the subject's eGFR decreases below the target % between the first and second time points; The compound comprises:

[0018] In one particular embodiment, the present invention includes a pharmacodynamic method of treating lupus nephritis, comprising administering to a subject diagnosed with lupus nephritis an effective amount of voclosporin at a predetermined daily dose for a planned treatment period of at least 24 weeks, said pharmacodynamic method further comprising: (a) assessing the subject's estimated glomerular filtration rate (eGFR) at least at a first and a second time point on different days during the treatment period; and (b)(i) the subject's eGFR is 60 mL / min / 1.73 m between the first and second time points; 2 If there is a 30% or greater decrease in serum creatinine to a value below 100mg / mL, discontinue administration of voclosporin to the subject; (ii) the subject's eGFR is 60 ml / min / 1.73 m between the first and second time points; 2 If there is a 20% to 30% decrease in serum vasoconstriction to a value below 500 mg / kg / day, administer a reduced dose of voclosporin to the subject; (iii) continuing to administer the same prescribed daily dose of voclosporin to the subject if the subject's eGFR decreases by 20% or less between the first and second time points; The compound comprises:

[0019] 60mL / min / 1.73m as mentioned above 2 Although an eGFR of 90 mL / min / 1.73 m is commonly used, 2 , 75 or 70mL / min / 1.73m 2 Higher values ​​such as 50 mL / min / 1.73 m 2 , 55mL / min / 1.73m 2 Lower values ​​such as .gtoreq..times ...

[0020] The pharmacodynamic method can utilize a third time point following the first and second time points, where the target percent reduction is again measured and treatment can be reversed if the percent reduction compared to the first time point is below the target percent, or a further dose reduction can be indicated if the percent reduction exceeds the target percent indicated at the second time point.

[0021] A second embodiment relates to the use of blood pressure as an index rather than eGFR. In this second embodiment, the present invention relates to a pharmacodynamic method for treating lupus nephritis, comprising administering to a subject diagnosed with lupus nephritis an effective amount of voclosporin at a predetermined daily dose for a planned treatment period of at least 24 weeks, said pharmacodynamic method further comprising: (a) measuring the subject's blood pressure (BP) at least at a first time point during the treatment period; and (b) if the subject has a systolic or diastolic BP component value >130 / 80, discontinue administration of voclosporin to the subject or administer a reduced dose of voclosporin to the subject; The compound comprises:

[0022] In this case, additional time points for measuring BP may be utilized, and if both components of the subject's blood pressure are below 130 / 80, administration of the prescribed daily dose of voclosporin may be resumed.

[0023] Thus, elevated blood pressure measurements are another unwanted side effect of treatment, which can be used as a basis for dosage adjustments.

[0024] It has also been found that the efficacy of the protocol can be evaluated after only a portion of the treatment period has elapsed. This can be done instead of or in addition to the above protocol. Therefore, since continuing an ineffective treatment is generally undesirable, evaluation can be performed earlier than the planned end of the protocol, and if the treatment is not found to be effective, the treatment can be terminated. In this case, such termination may be useful, since the administration of immunosuppressants is generally not recommended unless some benefit is achieved.

[0025] For example, the evaluation may involve measuring UPCR at a first and second time point, which are early time points in the protocol; the first time point is determined at the beginning of the protocol; and if UPCR does not decrease by a predetermined amount, for example, 15%, 20%, 25%, or 35%, at the second time point, the administration of voclosporin to the subject is discontinued. UPCR can be measured by standard techniques, for example, using the first morning void or a 24-hour urine sample. This evaluation can be supplemented or replaced by evaluation of blood C3 and C4 concentrations. Failure to treat to normalize C3 / C4 concentrations indicates failure. When using a combination of these factors, the rule for discontinuing treatment is that if neither success criterion is met, i.e., if the subject does not show a satisfactory decrease in UPCR at the second time point and does not show normalization of C3 / C4 at the second time point, treatment is discontinued. Alternatively, either criterion can be used alone.

[0026] Alternatively, if the subject appears to be in complete remission, continued treatment may not be necessary.

[0027] In any of the above protocols, a single dose of MMF and reduced-dose corticosteroids are preferably also administered during the treatment period. Typically, MMF is administered at a level of 2 grams per day, and oral corticosteroids are administered at a daily dose tapered from 20-25 mg / day to 2.5 mg / day over 16 weeks. The reduced doses are then continued for the duration of the study. These protocols are illustrated in Figure 1.

[0028] In all cases, subjects suitable for this treatment should be screened for the following before the method is administered to the subject: (a) the subject's urinary protein / creatinine ratio (UPCR) is ≥ 1.5 mg / mg or ≥ 1 mg / mg, depending on the kidney biopsy, preferably measured in the first morning void; and (b) The subject has a blood glucose level of ≥ 45 mL / min / 1.73 m as measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or other appropriate method, such as the Modification of Diet in Renal Disease (MDRD) Study equation. 2 have an eGFR of; If the determinations in subparagraphs (a) and (b) are positive, the subject is considered suitable to undergo the protocol.

[0029] Furthermore, lowering the dosage level of voclosporin has been shown to be effective.

[0030] Therefore, in another aspect, the present invention relates to a method for treating lupus nephritis, comprising administering to a subject diagnosed with lupus nephritis an effective amount of voclosporin in a predetermined daily dose, wherein the effective amount is 15.8 mg BID or 7.9 mg BID. Surprisingly, these low doses have been found to be effective in the majority of patients, especially when treatment is extended beyond 24 weeks. A dose of 31.6 mg BID (4 capsules) may also be employed. Pharmacodynamic dosing may also be applied in these cases.

[0031] It is also beneficial and part of the present invention to evaluate subjects treated with the protocol at the end of the treatment period to determine whether a complete or partial remission has occurred. Further evaluation at some point after the end of treatment is included to assess whether the remission achieved by the end-of-treatment measurement is maintained. Such evaluations can also be performed at intermediate points during treatment to determine whether the dosage can be reduced. In an exemplary embodiment, used for illustrative purposes only, the dosage of voclosporin 23.6 mg BID can be reduced to 15.8 mg or 7.9 mg BID based on such results.

[0032] Efficacy assessment can be based on the urinary protein / creatinine ratio (UPCR), where a ratio of ≤0.5 mg / mg indicates a complete response; alternatively, or additionally, an eGFR of ≥60 mL / min / 1.73 m 2 or no decline of 20% or more from baseline in eGFR. Other indicators of complete response include no need for rescue medication such as intravenous steroids, cyclophosphamide, or the need for ≦10 mg of prednisone for more than 3 consecutive days or more than 7 days total. Such assessments can be made at any time during treatment. [Brief explanation of the drawings]

[0033] [Figure 1] FIG. 1 graphically illustrates the design of a protocol for the treatment of lupus nephritis with voclosporin onto which the pharmacodynamic treatment of the present invention is superimposed. [Figure 2] Figure 2 is a bar graph showing a comparison of complete response (CR) at 48 weeks and partial response (PR) at 48 weeks for low dose compared with high dose voclosporin (VCS). Percent PR includes percent CR. DETAILED DESCRIPTION OF THE INVENTION

[0034] As discussed above, the pharmacodynamic protocols of the present invention involve tailoring the administration of voclosporin to a subject's specific physiological endpoints. As previously mentioned, voclosporin is preferably administered against a background of MMF administration and corticosteroid administration.

[0035] In general, the treatment protocol underlying the present invention has demonstrated dramatically superior results to current standard therapies, with complete remission rates approaching 50%, compared with the significantly lower levels achieved using current standard therapies, and even higher partial remission rates after 48 weeks; here, the partial remission rate (PR) includes subjects who achieved a complete remission (CR). As shown below, low-dose voclosporin was more effective than high-dose voclosporin in comparable protocols, with complete remission achieved in 49% of subjects in the low-dose group compared with 40% in the high-dose group.

[0036] Of critical importance to the present invention is the pharmacodynamic dosing of the voclosporin component, which is essential because the drug's effects may be too strong and / or have undesirable side effects, or results may indicate a lack of efficacy; therefore, the dosage is reduced or discontinued to allow homeostasis to re-establish the appropriate set of physiological parameters.

[0037] The protocol is designed to cover a treatment period of at least 24 weeks and can be extended for longer periods, such as 48 or 52 weeks. The regimen includes a daily dose of the voclosporin component, typically administered twice daily, but can be varied to once daily, three times daily, or four times daily, based on patient response and convenience. By way of example, the protocol will be described below with respect to a 23.7 mg twice-daily (BID) dose; of course, if the voclosporin formulation is administered four times daily, the dose will be reduced by half with each administration, and if it is administered only once daily, the once-daily dose will be double the 23.7 mg BID dose.

[0038] Furthermore, for the pharmacodynamic protocol of the present invention, the dose can be any combination of the 7.9 mg base unit, and thus can be 7.9 mg, 15.8 mg, 31.6 mg, or 39.5 mg, rather than just the exemplified 23.7 mg.

[0039] The indicated dose, e.g., 23.7 mg (or other specified dose), may vary slightly, usually by ±10%; alternatively, 23.7 mg may be specified between 21 mg and 26 mg BID. This is due to inconsistencies in pharmaceutical manufacturing, and the ideal dose is the specified dose, e.g., 23.7 mg BID. Equivalent variations apply to alternate doses and differential adjustments.

[0040] Adjustment based on eGFR: One important parameter used to assess the desirability of dose reduction is eGFR using the CKD-EPI equation or other appropriate method. Chronic kidney disease is defined as a kidney failure rate of ≤60 mL / min / 1.73 m for ≥3 months with or without renal damage. 2 The eGFR is defined as the eGFR of the patient with a blood glucose level below 100 mg / mL / min. As mentioned above, further decline in eGFR is a potential negative side effect during treatment. If the decline is too severe, the protocol should be modified in accordance with the prescription instructions of the present invention. Typically, a baseline eGFR is established at the beginning of the protocol or at some "first time point" during the protocol. If the decline exceeds a target percentage (usually 20%-45% compared to the first time point), a dose reduction is indicated, including a reduction to zero or discontinuation of treatment. If the decline falls below the target percentage, maintenance of treatment at the same level is indicated. In addition to indications that treatment should be reduced or terminated based on a decline in eGFR, a decline below a predetermined value also indicates the need to modify treatment. This predetermined value is typically 50-90 mL / min / 1.73 m. 2 The range is.

[0041] As mentioned above, a baseline eGFR is established at the start of or during treatment. This is usually done on the first day of treatment, before any protocol-based drug is administered. This baseline is used as a reference for adjusting the dosage. However, the first time point can be any time selected during the protocol.

[0042] In one exemplary protocol, at a second time point (which can be any treatment day) following the first time point, eGFR is determined to be <60 ml / min / 1.73 m from baseline. 2 Subjects who experience a 30% or greater decline in eGFR to the 23.7 mg BID level (or a higher cutoff, if appropriate) should discontinue treatment until a repeat study can be performed. However, if the decline is confirmed to be not due to contributory factors (e.g., a high baseline eGFR; addition or change of a nonsteroidal anti-inflammatory drug, angiotensin-converting enzyme inhibitor, or angiotensin 2 blocker; or concurrent dehydration), treatment should be withheld until a third time point is determined, usually within 48 hours. If a 30% or greater decline is not maintained, treatment should be ramped back down to two-thirds or one-third of the original dose, increasing to the 23.7 mg BID level as tolerated.

[0043] For convenience, the 23.7 mg dose is administered orally in the form of three capsules containing 7.9 mg each. Thus, it is easy to provide two-thirds of the standard dose by administering only two of the three capsules at any one time.

[0044] For the second time point, in this exemplary protocol, eGFR ≤ 60 ml / min / 1.73 m 2 Subjects who achieve a 20% or greater reduction in blood glucose to 23.7 mg BID, but a less than 30% reduction compared to baseline, will not discontinue treatment, but will have their dose reduced, preferably in 7.9 mg increments. Again, assessments showing recovery of baseline values ​​at any subsequent additional time point during the treatment period indicate that the original dose level of 23.7 mg BID can be resumed.

[0045] Blood pressure-based adjustment A surrogate parameter that can be used to determine the pharmacodynamic dosage is blood pressure. Because voclosporin can increase blood pressure to undesirable levels, if at any time during treatment, either component of the subject's blood pressure, i.e., systolic or diastolic, is ≥ 130 / 80, treatment should be reduced, preferably by 7.9 mg increments. If at a subsequent time point, both components of blood pressure fall below 130 / 80, treatment can be restored to the original level.

[0046] Adjustment based on decrease in UPCR and / or normalization of C3 / C4 Appropriate criteria for early assessment of the probability of success, i.e., the probability of achieving complete or partial remission by the end of the planned protocol, have been identified. These criteria allow for earlier discontinuation of treatment if the subject is highly unlikely to benefit from continuing the dosing schedule. These criteria are a decrease in UPCR and normalization of C3 / C4. These can be used in combination or alternatively. It has been found that early measurements in a 24-week or 48-week protocol with a high probability of success can be used to determine whether treatment with voclosporin should be continued; such findings are applicable to much longer-term protocols. For example, if UPCR does not decrease by a sufficient amount early in the regimen or if C3 / C4 does not normalize early in the regimen, it can be concluded that improvement over a long-term treatment period is unlikely. The application of these criteria in an exemplary study is shown in detail in Example 3.

[0047] However, the rules for stopping treatment are based on a decline in UPCR or normalization of C3 / C4, taken alone or in combination. If a combination is used, failure of both criteria will indicate termination of treatment. The decision is based on the values ​​of sensitivity, specificity, and positive and negative predictive values ​​shown in the table in Example 3. These terms are defined in the Examples.

[0048] By way of example only, such an assessment can be made approximately 8 weeks after the start of the regimen; a time frame of 6 to 10 weeks can be used as the number of weeks close to 8 weeks. If a reduction in UPCR of, for example, 25% or less is not achieved, the subject is unlikely to benefit from further treatment, and the protocol is discontinued. As shown in the examples, this can be complemented by an assessment of C3 / C4 normalization; if this is done, it is desirable to perform both assessments at the same early time point.

[0049] Adjunctive treatment The voclosporin treatment of the present invention is complemented with MMF and reduced dose corticosteroids.

[0050] For example, with regard to corticosteroids, subjects weighing 45 kg or more will receive 0.5 grams of methylprednisolone intravenously on days 1 and 2 of the study, with oral corticosteroid therapy initiated on day 3. Subjects weighing less than 45 kg will receive only half of these doses.

[0051] For oral prednisone, the starting oral dose is 20 mg / day for subjects weighing less than 45 kg and 25 mg / day for subjects weighing 45 kg or more. This dose is tapered according to the protocol shown in Table 1.

[0052] [Table 1]

[0053] In contrast to corticosteroid tapering, the same dose of MMF is maintained throughout the study, administered twice daily before meals with a glass of water. Typically, individual doses are 1 gram, for a total dose of 2 grams per day, although subjects may alternatively receive 500 mg four times daily.

[0054] low dose In addition to the pharmacodynamic protocol described above, Applicant has found that significantly lower doses than expected are effective in many subjects, and as a result, methods for treating lupus nephritis in subjects, with or without pharmacodynamic adjustments, can be based on either a 15.8 mg BID or 7.9 mg BID dosage level. The 7.9 mg unit is dictated by the availability of capsules containing the 7.9 mg dose level, which provides a convenient platform for modifying the dosage.

[0055] Thus, a further aspect of the present invention is a method for treating lupus nephritis using a theoretically adjusted dose or a fixed dose of 15.8 mg BID or 7.9 mg BID, in which the above-mentioned background administration of MMF and corticosteroids is included in the protocol, as is the case with high-dose voclosporin.

[0056] General factors In all cases, subjects are evaluated for treatment success both at the completion of treatment and during subsequent extension periods. Typical treatment duration is at least 24 weeks, with 48 weeks or longer being preferred. Reassessments after completion of treatment periods of 1-2 weeks or longer are also employed. Subjects are evaluated for complete or partial remission. Complete remission (CR) is defined as: confirmed protein / creatinine ratio ≤ 0.5 mg / mg and eGFR ≥ 60 mL / min / 1.73 m 2 or confirmation that there is no decrease of 20% or more from baseline in eGFR. Partial response is defined as a 50% decrease from baseline in UPCR.

[0057] By establishing a pharmacodynamic dosing regimen, the efficacy of the protocol in treating lupus nephritis is maximized while undesirable side effects are minimized.

[0058] The length of the treatment protocol in all cases varies from at least 8 weeks, for example, 12, 16, 24, 48, or 52 weeks or more, and even up to 60 weeks, including the stop points between the levels mentioned above. For example, treatment protocols of 10, 11, 15, 20, 29, 31, 36, 43, 51, or 55 weeks can be employed and are within the scope of the present invention. The above evaluations are performed not only at the end of the protocol but also at appropriate time points or time periods thereafter. These time points generally range from 1-2 weeks to 4-5 months after the end of administration, with intervening time intervals also being within the scope of the present invention.

[0059] This statement regarding time intervals applies to the pharmacodynamic treatment protocols of the present invention regardless of the underlying dosage level.

[0060] The following examples are intended to illustrate but not limit the invention. [Example]

[0061] Example 1 48-week study of LN treatment The subjects enrolled in this study were divided into three groups. Eighty-eight subjects were in the control group and received 2 g / day of MMF and oral corticosteroids (i.e., tapered doses of prednisone, as shown graphically in Figure 1) starting at 20–25 mg / day and gradually tapering to 2.5 mg / day after 12 weeks. (Some subjects received lower doses of MMF due to gastrointestinal issues.) The 89 subjects in the low-dose group received this background treatment but also received three capsules containing 7.9 mg of voclosporin twice daily (i.e., 23.7 mg). The voclosporin used in this study contained more than 90% E isomer. The third group of 88 subjects received the same background treatment but also received five 7.9 mg capsules twice daily (i.e., 39.5 mg). The study was conducted over 48 weeks, with safety evaluated at 24 weeks.

[0062] Subjects were screened prior to participation in the study by determining: (a) a urinary protein-to-creatinine ratio (UPCR) >1.5 mg / mg as measured on the first morning void; and (b) an eGFR >45 ml / min / 1.73 m as measured by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). 2 Subjects were evaluated at 24 and 48 weeks, and then at 50 weeks.

[0063] As shown in Figure 2, low-dose administration achieved better results than high-dose voclosporin administration. After 48 weeks of treatment, 49% of low-dose subjects achieved a complete remission compared with 40% of high-dose subjects. In the same study, after 24 weeks of treatment, 32.6% of low-dose patients achieved a complete remission (CR), compared with 19.3% of the control group, while only 27% of high-dose patients achieved a CR. At 24 weeks, 70% of low-dose patients and 66% of high-dose patients achieved a partial remission (PR), compared with 49% of the control group.

[0064] In this example, CR is a composite endpoint including efficacy, safety, and low-dose steroids: UPCR ≤ 0.5 mg / mg (confirmed); eGFR > 60 ml / min / 1.73 m 2 or within 20% of baseline; steroids ≤ 10 mg / day; no rescue medication.

[0065] PR is a composite endpoint including safety and efficacy: a 50% reduction in UPCR from baseline and no use of rescue medication.

[0066] To determine the effectiveness of the pharmacodynamic protocol (in which the dose is reduced or discontinued depending on whether or not there is an indicator of a decrease in eGFR experienced as a side effect), these three groups of patients were evaluated after 24 and 48 weeks of treatment regarding whether their treatment was modified according to the protocol of the present invention. In all three groups, patients were evaluated according to the criteria set forth in the exemplary protocol above; i.e., each patient's eGFR was measured immediately before and at a second time point at least one day after administration of the first dose of voclosporin; and (i) the subject's eGFR is 60 mL / min / 1.73 m between the first and second time points; 2 If there is a 30% or greater decrease in serum creatinine to a value below 100mg / kg, discontinue administration of voclosporin to the subject or reduce the dose; (ii) the subject's eGFR is 60 mL / min / 1.73 m between the first and second time points; 2 If the blood pressure drops by 20% to 30% to a value below 100mg / kg, administer a reduced dose of voclosporin to the subject; (iii) If the subject's eGFR decreases by 20% or less between the first and second time points, continue to administer the same prescribed daily dose of voclosporin to the subject.

[0067] The results are shown in Tables 2 and 3 below. Table 2 shows the rates of complete response (CR) or partial response (PR) after 24 weeks for patients without and with dose reduction, and Table 3 shows these values ​​after 48 weeks.

[0068] [Table 2]

[0069] [Table 3]

[0070] In this study, CR was defined as UPCR ≤ 0.5 mg / mg; eGFR > 60 mL / min / 1.73 m 2or within 20% of baseline; ≤10 mg / day steroids; and no rescue medication. PR was defined as a 50% reduction in UPCR from baseline and no rescue medication.

[0071] As shown in Table 2, 12.5% ​​of placebo patients, 43.8% of low-dose patients, and 53.4% ​​of high-dose voclosporin patients underwent dose reductions during treatment. The proportion of patients experiencing a complete response at 24 weeks was not affected by pharmacodynamic dosing in either dose group. The proportion experiencing a partial response was similar, although this improved with partial dose reduction in the high-dose group. Table 3 shows similar results at 48 weeks, although a higher proportion of patients underwent dose reductions. Again, this did not demonstrate a dramatic impact on overall response.

[0072] Example 2 Low-dose protocol During the course of a clinical study similar to that in Example 1, it was observed that most subjects showed substantial remission with a dose that was almost immediately reduced to 15.8 mg of voclosporin administered twice daily (BID). Accordingly, Applicant analyzed these data and concluded that a dosing protocol providing 15.8 mg or 7.9 mg of voclosporin BID was effective, regardless of the pharmacodynamic profile of the protocol.

[0073] Each capsule contains 7.9 mg of voclosporin, so one capsule is equivalent to 7.9 mg of voclosporin, two capsules are equivalent to 15.8 mg of voclosporin, three capsules are equivalent to 23.7 mg of voclosporin, etc. A significant number of subjects achieved complete or partial remission even when the dose was reduced to 7.9 mg of voclosporin twice daily very early in treatment. Similar results were obtained with the 15.8 mg twice daily dose.

[0074] Example 3 Predictability based on initial responses The study reported in Example 1 determined the predictability of outcomes based on markers at early time points. These results are shown in Tables 4-12.

[0075] The study described in Example 1 provided data to determine whether markers assessed at various time points during treatment predict a final favorable outcome or indicate that continued treatment is likely to be futile. This is important because it is undesirable to expose patients to unnecessary treatment, even if the treatment is relatively safe. These data are presented in the table below.

[0076] Based on these data, we determined the sensitivity and specificity of each marker assessment, and their corresponding positive and negative predictive values, for whether patients would achieve a partial response (PR) after the 48-week treatment protocol. A PR is defined as at least a 50% decrease in proteinuria (i.e., UPCR). This includes subjects who achieved a complete response (CR).

[0077] Sensitivity is defined as the probability that a subject who shows a PR at 48 weeks will have a favorable outcome for the marker at a specified early time point. In the table below, this is the ratio of the number of subjects who showed a favorable marker outcome (early decline or normalization) to the total number of subjects who showed a PR at 48 weeks.

[0078] Specificity is defined as the probability that a subject without a PR at 48 weeks will have an unfavorable result for the marker at a specified early time point. In the table below, this is the ratio of the number of subjects with an unfavorable marker result (no early decline or normalization) to the number of all subjects without a PR at 48 weeks.

[0079] Positive predictive value is defined as the probability that a subject with a favorable marker result at an early time point will have a PR at week 48. In the table below, this is the ratio of the number of subjects with a favorable marker result who achieved a PR at week 48 to the total number of subjects with a favorable marker result (the "yes" column in the early decline column).

[0080] Negative predictive value is defined as the probability that a subject with an unfavorable marker result at an early time point will not have a PR at week 48. In the table below, this is the ratio of the number of subjects without a PR at week 48 with an unfavorable marker result to the total number of subjects with an unfavorable marker result (column "No" early decline).

[0081] An ideal marker would exhibit a value of 100 for all of these, but this is generally unattainable. Values ​​as high as possible are desirable.

[0082] Based on the results of these tables, the protocol of the present invention is designed to stop treatment at the earliest time when the above parameters are most favorable, but at a reasonable time before the 48-week endpoint. (Obviously, the closer to the endpoint, the more favorable the indicators, but the benefit of stopping treatment is correspondingly less.)

[0083] [Table 4] JPEG2025163248000006.jpg113125

[0084] [Table 5] JPEG2025163248000008.jpg113125

[0085] [Table 6] JPEG2025163248000010.jpg113125

[0086] [Table 7] JPEG2025163248000012.jpg110125

[0087] [Table 8] JPEG2025163248000014.jpg112125

[0088] Thus, for example, results at 8 or 12 weeks appear to be predictive of ultimate outcome, and if there is not a >15% reduction in UPCR at that time, it would be beneficial to discontinue treatment.

[0089] For completeness, Tables 9a and 9b show similar results for the early 8-week time point when extending the protocol to 24 or 48 weeks, using a 25% reduction in UPCR as the baseline.

[0090] [Table 9]

[0091] Another criterion for efficacy is the normalization of blood C3 and / or C4 concentrations. Normal C3 concentrations are 90 mg / dl or higher, and C4 concentrations are 16 mg / dl or higher. Subjects receiving the treatment of the present invention generally have concentrations lower than these values. Normalization of C3 is defined as an increase in the subject's C3 level from less than 90 mg / dl to above that level, or a 25% increase from baseline (less than 90), and normalization of C4 is defined as an increase in the subject's C4 level from less than 16 mg / dl to above that level, or a 25% increase from baseline (less than 16).

[0092] Tables 10-12 provide data for these criteria similar to the data in Tables 4-9 for UPCR.

[0093] [Table 10]

[0094] [Table 11]

[0095] [Table 12]

[0096] Similar calculations are performed for the combined UPCR and C3 / C4 results at week 12 in Tables 13-17. In these tables, data from the 12-week determinations in Tables 4-8 are matched with data from the 12-week time point in Table 12.

[0097] The decision to discontinue or continue treatment is made based on the demonstrated levels of sensitivity, specificity, positive predictive value, and negative predictive value.

[0098] [Table 13]

[0099] [Table 14]

[0100] [Table 15]

[0101] [Table 16]

[0102] [Table 17]

[0103] Example 4 Low-dose corticosteroids Applicant has also found that corticosteroid dosage can be effectively reduced, even to 4 mg / day or less, compared to "standard of care," as shown in Tables 18 and 19.

[0104] [Table 18]

[0105] [Table 19] (Addendum) (Appendix 1) 1. A pharmacodynamic method for treating proteinuric kidney disease, comprising administering to a subject diagnosed with said disease an effective amount of voclosporin at a predetermined daily dose for a planned treatment period of at least 24 weeks, and further comprising: (a) assessing the subject's estimated glomerular filtration rate (eGFR) at least at a first and a second time point on different days during the treatment period; and (b)(i) if the subject's eGFR decreases by more than a target % below a predetermined value between the first and second time points, reducing the daily dose by 7.9 mg BID or discontinuing administration of voclosporin to the subject; (ii) continuing to administer the same prescribed daily dose of voclosporin to the subject if the subject's eGFR decreases below the target % between the first and second time points; The method comprising: (Appendix 2) 2. The method of claim 1, wherein the first time point is immediately before starting the protocol. (Appendix 3) The predetermined value is 50 to 90 ml / min / 1.73 m 2 The method according to claim 1, wherein the range is (Appendix 4) 2. The method of claim 1, wherein the target % is in the range of 20 to 45%. (Appendix 5) The predetermined value is approximately 60 ml / min / 1.73 m 2 The method according to Appendix 3, (Appendix 6) 5. The method of claim 4, wherein the target % is about 30%. (Appendix 7) prior to performing the method on the subject, (a) determining that the subject has a urinary protein / creatinine ratio (UPCR) of ≥ 1 mg / mg as measured in a first morning void or 24-hour urine sample; and (b) The subject's eGFR, as measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), is ≥ 45 ml / min / 1.73 m 2 determining that it is; further comprising identifying the subject suitable for the method by In this case, if conditions (a) and (b) are met, the subject is identified as being suitable for the method. (Appendix 8) 8. The method of any one of appendixes 1-7, wherein the predetermined daily dose is 39.5 mg voclosporin BID, 31.6 mg voclosporin BID, 23.7 mg voclosporin BID, 15.8 mg voclosporin BID, or 7.9 mg voclosporin BID. (Appendix 9) 10. The method of any one of claims 1 to 7, wherein the method further comprises evaluating the subject for renal function at some point after completion of the treatment period by assessing eGFR. 10. The method of claim 9, wherein the method further comprises evaluating the subject for efficacy by assessing the protein / creatinine ratio (UPCR) at a time point after the end of the treatment period. (Appendix 11) 8. The method of any one of claims 1 to 7, wherein the method further comprises administering to the subject an effective amount of mycophenolate mofetil (MMF). (Appendix 12) 8. The method of any one of claims 1-7, further comprising administering to the subject an effective amount of a corticosteroid. (Appendix 13) 8. The method of any one of claims 1-7, wherein the treatment period is at least 48 weeks. (Appendix 14) 8. The method of any one of claims 1-7, further comprising measuring the subject's eGFR at a third time point, and resuming administration of the predetermined daily dose of voclosporin if the eGFR measured at the third time point differs from the eGFR measured at the first time point by less than a target %. (Appendix 15) 15. The method of claim 14, wherein the target % is 20 to 45%. (Appendix 16) 16. The method of claim 15, wherein the target % is about 30%. (Appendix 17) 1. A pharmacodynamic method for treating proteinuric kidney disease, comprising administering to a subject diagnosed with proteinuric kidney disease an effective amount of voclosporin at a predetermined daily dose for a planned treatment period to an end point, and further comprising: (a) measuring the subject's urinary protein to creatinine ratio (UPCR) at a first time point before the treatment period and at a second time point after the start of the treatment period but before the end of the treatment period, and determining a decrease in the UPCR between the first and second time points; and (b) discontinuing administration of voclosporin to the subject if the subject's UPCR does not show a decrease by at least a predetermined amount at said second time point, and continuing said administration if the UPCR does show a decrease by said predetermined amount; The method comprising: (Appendix 18) 18. The method of claim 17, further comprising measuring the concentration of C3 / C4 in the subject's blood at the first and second time points, determining whether the concentration of C3 / C4 is normalized at the second time point, and if so, reinstating or continuing administration of voclosporin to the subject, or maintaining the discontinuation if normalization does not occur. (Appendix 19) 19. The method of claim 17 or 18, wherein the method further comprises administering to the subject an effective amount of mycophenolate mofetil (MMF). (Appendix 20) 19. The method of claim 17 or 18, further comprising administering to the subject an effective amount of a corticosteroid. (Appendix 21) 19. The method of claim 17 or 18, wherein the predetermined daily dose is 39.5 mg voclosporin BID, 31.6 mg voclosporin BID, 23.7 mg voclosporin BID, 15.8 mg voclosporin BID, or 7.9 mg voclosporin BID. (Appendix 22) A method for treating proteinuric kidney disease, comprising administering to a subject diagnosed with lupus nephritis an effective amount of voclosporin at a predetermined daily dose for a planned treatment period of at least 8 weeks, wherein the effective amount is 15.8 mg or 7.9 mg of voclosporin BID.

Claims

1. 1. A pharmacodynamic method for treating proteinuric kidney disease, comprising administering to a subject diagnosed with said disease an effective amount of voclosporin at a predetermined daily dose for a planned treatment period of at least 24 weeks, and further comprising: (a) assessing the subject's estimated glomerular filtration rate (eGFR) at least at a first and a second time point on different days during the treatment period; and (b)(i) if the subject's eGFR decreases by more than a target percentage below a predetermined value between the first and second time points, reducing the daily dose by 7.9 mg BID or discontinuing administration of voclosporin to the subject; (ii) continuing to administer the same prescribed daily dose of voclosporin to the subject if the subject's eGFR decreases below the target percentage between the first and second time points; The method comprising:

2. 2. The method of claim 1, wherein the first time point is immediately before starting the protocol.

3. The predetermined value is 50 to 90 ml / min / 1.73 m 2 The method of claim 1, wherein the range is

4. 2. The method of claim 1, wherein the target % is in the range of 20-45%.

5. The predetermined value is approximately 60 ml / min / 1.73 m 2 The method of claim 3, wherein

6. 5. The method of claim 4, wherein the target percentage is about 30%.

7. prior to performing the method on the subject, (a) determining that the subject has a urinary protein / creatinine ratio (UPCR) of ≧1 mg / mg as measured in a first morning void or a 24-hour urine sample; and (b) the subject's eGFR is ≥ 45 ml / min / 1.73 m as measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2 determining that further comprising identifying the subject suitable for the method by The method of claim 1, wherein the subject is identified as suitable for the method if conditions (a) and (b) are met.

8. 8. The method of any one of claims 1-7, wherein the predetermined daily dose is 39.5 mg voclosporin BID, 31.6 mg voclosporin BID, 23.7 mg voclosporin BID, 15.8 mg voclosporin BID, or 7.9 mg voclosporin BID.

9. 8. The method of any one of claims 1-7, wherein the method further comprises assessing the subject for renal function at some point after completion of the treatment period by assessing eGFR.

10. 10. The method of claim 9, wherein the method further comprises evaluating the subject for efficacy by assessing the protein / creatinine ratio (UPCR) at a time point after the end of the treatment period.

11. 8. The method of any one of claims 1 to 7, wherein the method further comprises administering to the subject an effective amount of mycophenolate mofetil (MMF).

12. 8. The method of any one of claims 1 to 7, further comprising administering to the subject an effective amount of a corticosteroid.

13. 8. The method of any one of claims 1 to 7, wherein the treatment period is at least 48 weeks.

14. 8. The method of any one of claims 1-7, further comprising measuring the subject's eGFR at a third time point, and resuming administration of the predetermined daily dose of voclosporin if the eGFR measured at the third time point differs from the eGFR measured at the first time point by less than a target percentage.

15. 15. The method of claim 14, wherein the target percentage is 20-45%.

16. 16. The method of claim 15, wherein the target percentage is about 30%.

17. 1. A pharmacodynamic method for treating proteinuric kidney disease, comprising administering to a subject diagnosed with proteinuric kidney disease an effective amount of voclosporin at a predetermined daily dose for a planned treatment period to an end point, and further comprising: (a) measuring the subject's urinary protein-to-creatinine ratio (UPCR) at a first time point before the treatment period and at a second time point after the start of the treatment period but before the end of the treatment period, and determining a decrease in the UPCR between the first and second time points; and (b) discontinuing administration of voclosporin to the subject if the subject's UPCR does not demonstrate a decrease by at least a predetermined amount at said second time point, and continuing said administration if the UPCR demonstrates a decrease by said predetermined amount; The method comprising:

18. 18. The method of claim 17, further comprising measuring the concentration of C3 / C4 in the subject's blood at the first and second time points, determining whether the concentration of C3 / C4 is normalized at the second time point, and if normalization occurs, reinstating or continuing administration of voclosporin to the subject, or maintaining the discontinuation if normalization does not occur.

19. 19. The method of claim 17 or 18, wherein the method further comprises administering to the subject an effective amount of mycophenolate mofetil (MMF).

20. 19. The method of claim 17 or 18, further comprising administering to the subject an effective amount of a corticosteroid.

21. 19. The method of claim 17 or 18, wherein the predetermined daily dose is 39.5 mg voclosporin BID, 31.6 mg voclosporin BID, 23.7 mg voclosporin BID, 15.8 mg voclosporin BID, or 7.9 mg voclosporin BID.

22. A method for treating proteinuric kidney disease, comprising administering to a subject diagnosed with lupus nephritis an effective amount of voclosporin at a predetermined daily dose for a planned treatment period of at least 8 weeks, wherein the effective amount is 15.8 mg or 7.9 mg of voclosporin BID.

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