LUPKYNIS Voclosporin 7.9 mg Capsule, 180-count — NDC 75626-001-02 (Billing 75626-0001-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action LUPKYNIS is a calcineurin-inhibitor immunosuppressant. The mechanism of voclosporin suppression of calcineurin has not been fully established. Activation of lymphocytes involves an increase in intracellular calcium concentrations that bind to the calcineurin regulatory site and activate calmodulin binding catalytic subunit and through dephosphorylation activates the transcription factor, Nuclear Factor of Activated T-Cell Cytoplasmic (NFATc).

The immunosuppressant activity results in inhibition of lymphocyte proliferation, T-cell cytokine production, and expression of T-cell activation surface antigens. Studies in animal models also support a non-immunological role for calcineurin inhibition in kidney function to stabilize actin cytoskeleton and stress fibers in podocytes leading to increased podocyte integrity in glomeruli.

12.2Pharmacodynamics Calcineurin inhibition Concentration-dependent calcineurin inhibition, measured as the percent of maximum calcineurin inhibition, was observed after oral administration of voclosporin twice daily in healthy volunteers. There is little or no lag time between the time to maximum drug concentration and the time to maximum calcineurin inhibition. Voclosporin inhibits calcineurin in a dose-dependent manner up to a maximum dose of 1.0 mg/kg.

Cardiac Electrophysiology In a randomized, placebo- and active-controlled (moxifloxacin 400 mg), single dose study with parallel study design, dose-dependent QT prolonging effect was detected with LUPKYNIS in the dose range of 0.5–4.5 mg/kg (up to 9-fold coverage of the therapeutic exposure). Dose-dependent QT prolongation effect was observed with a time to maximum QTc increase occurring at 4–6-hour postdose across different dose levels. The maximum mean placebo-adjusted changes of QTcF from baseline after LUPKYNIS 0.5 mg/kg, 1.5 mg/kg, 3.0 mg/kg, and 4.5 mg/kg dose were 6.4 msec, 17.5 msec, 25.7 msec, and 34.6 msec, respectively.

In a separate, randomized, placebo-controlled, crossover study in 31 healthy subjects, an absence of large mean increases (i.e., >20 msec) was observed following 7 days of treatment with LUPKYNIS at 0.3, 0.5 and 1.5 mg/kg twice daily (approximately 6-fold coverage of the therapeutic exposure). The mechanism for the QT prolonging effect as observed in the single-dose and multiple-dose studies is unknown.

12.3Pharmacokinetics The whole blood voclosporin pharmacokinetics increase in a greater than dose-proportional manner over the therapeutic range. With a twice daily dosing regimen, voclosporin achieves steady-state after 6 days and the accumulation is approximately 2-fold. Absorption The median T max of voclosporin is 1.5 hours (1 to 4 hours) when administered on an empty stomach.

Effect of Food Co-administration of voclosporin with food decreased both the rate and extent of absorption: with either low- or high-fat meals, C max and AUC of voclosporin were reduced by 29% to 53% and 15% to 25%, respectively. Distribution The apparent volume of distribution (V ss /F) of voclosporin is 2,154 L. Protein binding of voclosporin is 97%.

Voclosporin partitions extensively into red blood cells and distribution between whole blood and plasma is concentration- and temperature-dependent. Elimination The mean apparent clearance at steady-state (CL ss /F) of voclosporin is

63.6L/h, and mean terminal half-life (t 1/2 ) is approximately 30 hours (24.9 to 36.5 hours). Metabolism Voclosporin is predominantly metabolized by CYP3A4. Voclosporin is the major circulating component and the pharmacologic activity is mainly attributed to the parent molecule.

A major metabolite in human whole blood represented 16.7% of total exposure and is about 8-fold less potent than the parent molecule. Excretion Following single oral administration of radiolabeled voclosporin 70 mg, 92.7% of the radioactivity was recovered in feces (including 5% as unchanged voclosporin), and 2.1% was recovered in urine (including… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action LUPKYNIS is a calcineurin-inhibitor immunosuppressant. The mechanism of voclosporin suppression of calcineurin has not been fully established. Activation of lymphocytes involves an increase in intracellular calcium concentrations that bind to the calcineurin regulatory site and activate calmodulin binding catalytic subunit and through dephosphorylation activates the transcription factor, Nuclear Factor of Activated T-Cell Cytoplasmic (NFATc).

The immunosuppressant activity results in inhibition of lymphocyte proliferation, T-cell cytokine production, and expression of T-cell activation surface antigens. Studies in animal models also support a non-immunological role for calcineurin inhibition in kidney function to stabilize actin cytoskeleton and stress fibers in podocytes leading to increased podocyte integrity in glomeruli.

12.3Pharmacokinetics The whole blood voclosporin pharmacokinetics increase in a greater than dose-proportional manner over the therapeutic range. With a twice daily dosing regimen, voclosporin achieves steady-state after 6 days and the accumulation is approximately 2-fold. Absorption The median T max of voclosporin is 1.5 hours (1 to 4 hours) when administered on an empty stomach.

Effect of Food Co-administration of voclosporin with food decreased both the rate and extent of absorption: with either low- or high-fat meals, C max and AUC of voclosporin were reduced by 29% to 53% and 15% to 25%, respectively. Distribution The apparent volume of distribution (V ss /F) of voclosporin is 2,154 L. Protein binding of voclosporin is 97%.

Voclosporin partitions extensively into red blood cells and distribution between whole blood and plasma is concentration- and temperature-dependent. Elimination The mean apparent clearance at steady-state (CL ss /F) of voclosporin is

63.6L/h, and mean terminal half-life (t 1/2 ) is approximately 30 hours (24.9 to 36.5 hours). Metabolism Voclosporin is predominantly metabolized by CYP3A4. Voclosporin is the major circulating component and the pharmacologic activity is mainly attributed to the parent molecule.

A major metabolite in human whole blood represented 16.7% of total exposure and is about 8-fold less potent than the parent molecule. Excretion Following single oral administration of radiolabeled voclosporin 70 mg, 92.7% of the radioactivity was recovered in feces (including 5% as unchanged voclosporin), and 2.1% was recovered in urine (including 0.25% as unchanged voclosporin). Specific Populations There were no clinically significant differences in the pharmacokinetics of voclosporin based on age (18 to 66 years), sex, race (Caucasian, Black, Asian, other), or body weight (37 to 133 kg).

Patients with Renal Impairment Voclosporin C max and AUC were similar in volunteers with mild (CL Cr 60 to 89 mL/min as estimated by Cockcroft-Gault) and moderate (CL Cr 30 to 59 mL/min) renal impairment compared to volunteers with normal renal function (CL Cr ≥90 mL/min). The C max and AUC increased 1.5- and 1.7-fold, respectively, in volunteers with severe renal impairment (CL Cr <30 mL/min). The effect of end-stage renal disease (ESRD) with or without hemodialysis on the pharmacokinetics of voclosporin is unknown.

Patients with Hepatic Impairment Voclosporin C max and AUC increased approximately 1.5- to 2.0-fold in volunteers with mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of voclosporin is unknown. Drug Interaction Studies Effect of Other Drugs on LUPKYNIS The effect of co‑administered drugs on the exposure of voclosporin is shown in Table 2.

Table 2: Change in Pharmacokinetics of Voclosporin in the Presence of Co-administered Drugs Notes: CI = Confidence interval; CYP = Cytochrome P450; P-gp = P-glycoprotein; QD = once daily; TID = every 8 hours. 1 Ratios for C max and AUC compare co-administration of the medication with voclosporin vs. administration of voclosporin alone. Co-administered Drug Regimen of Co-administered Drug Ratio (90% CI) 1 C max AUC Ketoconazole (strong CYP3A4 inhibitor) 400 mg QD for 9 days 6.45 (5.02, 8.29) 18.55 (15.89, 21.65) Verapamil (moderate CYP3A4 and strong P-gp inhibitor) 80 mg TID for 10 days 2.08 (1.89, 2.28) 2.71 (2.56, 2.87) Rifampin (strong CYP3A4 inducer) 600 mg QD for 10 days 0.32 (0.28, 0.37) 0.13 (0.11, 0.15) Moderate CYP3A inhibitors: Co-administration of multiple doses of fluconazole or diltiazem is predicted to increase voclosporin C max and AUC 0-12 approximately 2- and 3-fold, respectively.

Weak CYP3A inhibitors: Co-administration of multiple doses of fluvoxamine and cimetidine is predicted to have minimal effects on voclosporin C max and AUC 0-12. Moderate CYP3A inducers: Co-administration of multiple doses of efavirenz is predicted to decre… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Calcineurin inhibition Concentration-dependent calcineurin inhibition, measured as the percent of maximum calcineurin inhibition, was observed after oral administration of voclosporin twice daily in healthy volunteers. There is little or no lag time between the time to maximum drug concentration and the time to maximum calcineurin inhibition. Voclosporin inhibits calcineurin in a dose-dependent manner up to a maximum dose of 1.0 mg/kg.

Cardiac Electrophysiology In a randomized, placebo- and active-controlled (moxifloxacin 400 mg), single dose study with parallel study design, dose-dependent QT prolonging effect was detected with LUPKYNIS in the dose range of 0.5–4.5 mg/kg (up to 9-fold coverage of the therapeutic exposure). Dose-dependent QT prolongation effect was observed with a time to maximum QTc increase occurring at 4–6-hour postdose across different dose levels. The maximum mean placebo-adjusted changes of QTcF from baseline after LUPKYNIS 0.5 mg/kg, 1.5 mg/kg, 3.0 mg/kg, and 4.5 mg/kg dose were 6.4 msec, 17.5 msec, 25.7 msec, and 34.6 msec, respectively.

In a separate, randomized, placebo-controlled, crossover study in 31 healthy subjects, an absence of large mean increases (i.e., >20 msec) was observed following 7 days of treatment with LUPKYNIS at 0.3, 0.5 and 1.5 mg/kg twice daily (approximately 6-fold coverage of the therapeutic exposure). The mechanism for the QT prolonging effect as observed in the single-dose and multiple-dose studies is unknown.

14 CLINICAL STUDIES The safety and efficacy of LUPKYNIS were investigated in Study 1 (NCT03021499), a 52-week, randomized, double-blind, placebo-controlled trial in patients with a diagnosis of systemic lupus erythematosus and with International Society of Nephrology / Renal Pathology Society (ISN/RPS) biopsy-proven active Class III or IV LN (alone or in combination with Class V LN) or Class V LN. Patients with Class III or IV LN (alone or in combination with Class V LN) were required to have a urine protein to creatinine (UPCR) ratio of ≥1.5 mg/mg; patients with Class V LN were required to have a UPCR of ≥2 mg/mg.

A total of 357 patients with LN were randomized in a 1:1 ratio to receive either LUPKYNIS 23.7 mg twice daily or placebo. Patients in both arms received background treatment with MMF and corticosteroids as follows: Oral MMF at a target dose of 2 g/day (1 g twice a day). (Patients not already receiving MMF were started on MMF 500 mg twice a day with escalation to MMF 1 g twice a day after the first week.) Dose increases up to 3 g/day were allowed.

Intravenous (IV) methylprednisolone on Day 1 and Day 2 at a dose of 500 mg/day (body weight ≥45 kg) or 250 mg/day (body weight <45 kg) followed by a reducing taper of oral corticosteroids [oral prednisone 25 mg/day (body weight ≥45 kg) or 20 mg/day (body weight <45 kg); tapered to achieve a target dose of 2.5 mg/day by Week 16]. Throughout the study, patients were prohibited from using immunosuppressants (other than MMF and hydroxychloroquine/chloroquine) and from changing/commencing angiotensin II receptor blockers (ARBs) or angiotensin converting enzyme (ACE) inhibitors.

Patients with baseline eGFR ≤45 mL/min/1.73 m 2 were not enrolled in this study. Dosage was adjusted based on eGFR and BP in a pre-defined dosage adjustment protocol. Dosage adjustments should follow the dosage recommendations [see Dosage and Administration ( 2.3 )] .

The median age of patients was 31 years (range 18 to 72). The proportion of women was 88%. Approximately 36.1% were White, 9.5% were Black, 30.5% were Asian, 1.1% were American Indian or Alaska Native, and 22.7% were multiple race or other.

Approximately 32.5% were Hispanic or Latino. The mean (SD) daily dose of voclosporin was 41.3 (±9.7) mg/day. The mean (SD) daily dose of MMF was 1.9 (±0.4) g/day; 9% received >2 but ≤3 g/day of MMF.

The mean (SD) daily dose of IV methylprednisolone (on Day 1 was 495 (±90) mg/day and Day 2 was 487 (±55) mg/day). The mean (SD) starting oral corticosteroid dose (Day 3) was 22.8 (±4.8) mg/day; approximately 81% received ≤2.5 mg/day of oral corticosteroids at Week 16. The distribution by kidney biopsy class was Class III or IV (60.8%), Class III or IV in combination with Class V (24.9%), and Class V (14.3%).

Mean (SD) eGFR on entry was 91 (±30) mL/min/1.73 m 2 . Mean (SD) UPCR on entry was 4.0 (±2.5) mg/mg. The primary efficacy endpoint was the proportion of patients achieving complete renal response at Week 52.

Complete renal response was defined as follows (both must be met): UPCR of ≤0.5 mg/mg, and eGFR ≥60 mL/min/1.73 m 2 or no confirmed decrease from baseline in eGFR of >20% or no treatment- or disease-related eGFR-associated event (defined as blood creatinine increased, creatinine renal clearance decreased, glomerular filtration rate decreased, serum creatinine increased, renal impairment, renal failure, or renal failure acute) at time of assessment. In order to be considered a responder, the patient must not have received more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 44 through 52.

Patients who received rescue medication or withdrew from the study were considered non-responders. A higher proportion of patients in the LUPKYNIS arm than the placebo arm achieved complete renal response at Week 52 (Table 4). Table 4: Complete Renal Response at Week 52 (Study 1) CI = Confidence interval; eGFR = Estimated glomerular filtration rate; UPCR = Urine protein to creatinine… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year mouse carcinogenicity study, administration of voclosporin at oral doses of 3, 10, or 30 mg/kg/day resulted in an increased incidence of malignant lymphoma in high dose females (7.5 times the MRHD on an AUC basis) and a dose-responsive trend for increase in malignant lymphoma in males. Malignant lymphoma was considered drug related in mice. In a 2-year rat carcinogenicity study, oral administration of voclosporin at doses up to 1.25 mg/kg/day in males and 2.5 mg/kg/day in females (doses that result in approximately similar drug exposures in rats) resulted in no statistically significant increases of tumor incidences.

In a 39-week oral toxicology study with monkeys, malignant lymphomas occurred at a dose of 150 mg/kg/day (approximately 4- and 7-times MRHD based on AUC for male and female animals, respectively). [At this dose, monkeys experienced high levels of immunosuppression as indicated by maximum calcineurin inhibition levels (E max ) of greater than 80%.] Voclosporin was not mutagenic or clastogenic in a standard battery of genetic toxicity studies that included the in vitro bacterial reverse mutation assay, in vitro Chinese hamster ovary cell chromosomal aberration assay, and in vivo rat micronucleus assay.

Voclosporin had no effect on fertility at doses up to 25 mg/kg/day in male and female rats (16- and 9-times MRHD based on AUC, respectively).