New Drug Monograph

By Lindsey Benavente, PharmD Dylan King, PharmD Candidate

Lupkynis (voclosporin) Aurinia Pharmaceuticals Inc. By:

Generic Name: Voclosporin

Brand Name: LupkynisTM

Classification: Calcineurin-inhibitor immunosuppressant

Indication: Approved for use in combination with a background immunosuppressive therapy regimen (mycophenolate mofetil and corticosteroids) in the treatment of active lupus nephritis in adults.

Contraindications: Voclosporin is contraindicated in patients concomitantly taking strong CYP3A4 inhibitors such as ketoconazole, itraconazole, and clarithromycin.

US Boxed Warning: Voclosporin increases the risk for developing serious infections and malignancies (e.g., lymphomas and particularly cancer of the skin) and can lead to hospitalization or death. The risk appears to be related to the intensity and duration of immunosuppression.

Pharmacology: Voclosporin is a calcineurin inhibitor that inhibits calmodulin activation leading to the prevention of Nuclear Factor of Activated T-Cell Cytoplasmic (NFATc) activation; thereby, inhibiting lymphocyte proliferation, T-cell cytokine production, and the expression of T-cell activation surface antigens.

Pharmacokinetics: The whole blood voclosporin pharmacokinetics increase in a greater than dose-proportional manner over the therapeutic range. With twice daily dosing, voclosporin achieves steady-state after 6 days and the accumulation is approximately 2-fold. Absorption Maximal absorption occurs within 1 to 4 hours when administered on an empty stomach. If taken with food, the rate and extent of absorption is reduced by 29% to 53% and 15% to 25% if taken with either low- or high-fat meals, respectively.

Distribution Voclosporin is 97% protein bound and has an apparent volume of distribution of 2,154 L. Distribution of voclosporin between whole blood and plasma is both concentration- and temperature-dependent.

Metabolism Voclosporin is primarily metabolized by CYP3A4 to a metabolite found to be about 8-fold less potent than the parent molecule.

Elimination Primarily excreted through the feces (92.7%), including 5% as unchanged. Voclosporin is excret-

ed minimally in the urine (2.1%), including 0.25% as unchanged. The mean apparent clearance at steady-state is 63.6 L/h, and mean terminal half-life is approximately 30 hours (24.9 to 36.5 hours).

Clinical Efficacy

A randomized, controlled double-blind study conducted by Rovin and colleagues evaluated the efficacy and safety of voclosporin compared to placebo in achieving remission in patients with active lupus nephritis. Study participants were between 18 to 75 years of age who met at least 4 American College of Rheumatology criteria for lupus and had active Class III, IV, or V lupus nephritis as determined by kidney biopsy within 6 months of screening. Two-hundred sixty-five patients on background therapy (mycophenolate mofetil plus low- to -medium dose corticosteroids) were randomized to receive placebo (low-dose, n = 44; high-dose, n = 44), lowdose voclosporin (23.7 mg twice daily, n = 89), or high-dose voclosporin (39.5 mg twice daily, n = 88). Baseline characteristics were similar among groups, with a majority of participants being Asian/Asian-Indian females with an average baseline eGFR of 99.8 mL/min/1.73 m2 .The primary endpoint was complete renal remission (CRR), defined as a decrease in UPCR to < 0.5 mg/mg in 2 consecutives, first morning void urine samples, plus an eGFR > 60 mL/min/1.73 m2 or no decrease in baseline eGFR by > 20% on 2 consecutive occasions, after 24 weeks of therapy. Secondary endpoints assessed the safety, tolerability, and efficacy of voclosporin compared to placebo after 48 weeks of therapy. After 24 weeks, patients receiving low-dose voclosporin were significantly more likely to reach CRR compared to placebo, as CRR was achieve by 32.6% (OR = 2.03; CI 1.01 – 4.05; p = 0.046) of patients compared to 19.3%. While not significantly higher than placebo, high-dose voclosporin resulted in a greater CRR rate, with CRR achieved by 27.3% of patients (OR = 1.59; 95% CI 0.78 – 3.27; p = 0.204). After 48 weeks, both low- and high-dose voclosporin resulted in significantly higher CRR, with CRR being achieved by 49.4% (OR = 3.21; 95% CI 1.68 – 6.13); P < 0.001) and 39.8% (OR = 2.01; 95% CI 1.09 – 4.02; p = 0.026) of patients, respectively, as compared to 23.9% in the placebo group. In evaluating the time it took to reach CRR, the median time for low-dose voclosporin was 19.7 weeks and 23.4 weeks for high-dose. Adverse events occurred more commonly in patients who received voclosporin, with any event reported in 92.1% and 96.6% of patients receiving low- and high-dose voclosporin, respectively, as compared to placebo with any adverse event reported in 85.2% of patients.

The most common adverse events reported by all treatment arms were infections and gastrointestinal disorders. Furthermore, in evaluating renal function, a change in eGFR greater than 10% was observed in 50.6% of patients receiving low-dose voclosporin and 62.5% of patients receiving high-dose voclosporin as compared to 17% of patients who received placebo. Ultimately, this study revealed low-dose voclosporin in combination with background therapy is superior to placebo in combination with background therapy in achieving CRR after both 24 and 48 weeks. Furthermore, while voclosporin was generally well tolerated, more patients receiving voclosporin experienced greater than a 10% change in eGFR, though the difference was not found to be statistically significant. A phase 3 study has been conducted by Arriens and colleagues and the results presented at the EULAR and ERA-EDTA annual meetings in 2020. This trial was a multicenter, randomized, double blind, placebo-controlled study comparing voclosporin plus background therapy to placebo plus background therapy, defined as IV methylprednisolone once daily on days 1 and 2 (0.5 g/day in patients > 45 kg and 0.25 g/day for patients < 45 kg). All patients then began a rapid taper of oral prednisone on day 3 beginning at 20 - 25 mg per day, decreased over time to 2.5 mg per day at week 16. In this study, 357 patients were randomized in a 1:1 fashion to receive voclosporin 23.7 mg twice daily or placebo. Patients included in the study had to have had a biopsy-proven active Class III or IV lupus nephritis and a urine protein to creatinine ratio > 1.5 mg/mg or Class V lupus nephritis with a UPCR > 2 mg/mg. The study was composed primarily by white females and the average eGFR on entry was 91 mL/min/1.73 m2. The primary endpoint was the proportion of patients who achieved CRR (following the same definition as the previous study) after 52 weeks of therapy defined as a compositeof UPCR of 0.5 mg/mg or less,eGFR of 60 mL/minor more or no confirmed eGFR decrease > 20% from baseline, no rescuemedication

administration, and no more than 10 mg prednisoneequivalent per day for 3 or more consecutive days or 7 or more days during weeks 44 - 52before the primary endpoint assessment. Secondary hierarchical endpoints were time to UPCR of 0.5 mg/mg or less, partial renal response (≥50% reduction from baseline UPCR) at weeks 24 and 52, time to 50% reduction in UPCR from baseline, and complete renal response at week 24 in order. One-hundred seventy-nine patients were randomized to receive voclosporin and 178 were randomized to placebo.

CRR at week 52 occurred in 40.8% of patients receiving voclosporin compared to 22.5% of those receiving placebo (OR = 2.7; 95 CI 1.6-4.3; p < 0.001). In evaluating disease-related eGFR-associated adverse events after 52 weeks, this was experienced by 82.1% of patients receiving voclosporin compared to 75.8% of patients receiving placebo (OR = 1.5; 95% CI 0.82.5). While more adverse events were associated with treatment, the difference was not statistically significant when compared to placebo. When evaluating secondary endpoints, 116 (65%) patients in the voclosporin group achieved an UPCR of 0.5 mg/mg or less during the study than in the placebo group (78 [44%]) and the time to reach this threshold was significantly shorter for the voclosporin group. A 50% reduction in UPCR from baseline during the study was achieved by 173 (97%) patients treated with voclosporin compared with 135 (76%) patients receiving placebo. The median time to achieve a 50% reduction in UPCR was significantly shorter for the voclosporin group than in the placebo group. Overall, for both primary and secondary endpoints the results seem to favor voclosporin over placebo and ultimately this study resulted in outcomes similar to the study previously discussed in that a higher proportion of patients in the voclosporin arm achieved CRR and reduced UPCR when compared to placebo.

Drug Interactions:

CYP3A4 Inhibitors: Voclosporin is extensively metabolized by CYP3A4; therefore, co-administration with strong-to-moderate CYP3A4 inhibitors increases voclosporin concentrations. Co-administration with ketoconazole, itraconazole, clarithromycin, and other strong CYP3A4 inhibitors is contraindicated. Co-administration with moderate CYP3A4 inhibitors such as verapamil, fluconazole, and diltiazem are not contraindicated; however, the dose of voclosporin should be reduced. Voclosporin should not be taken with any food or drink containing grapefruit. CYP3A4 Inducers: Voclosporin is extensively metabolized by CYP3A4; therefore, co-administration with strong or moderate CYP3A4 inducers can decrease voclosporin concentrations and its efficacy. The manufacturer suggests avoiding co-administration with strong-to-moderate CYP3A4 inducers.

P-gp Substrates: Voclosporin is a P-gp inhibitor, therefore when given concurrently with a P-gp substrate, voclosporin may increase the concentration and risk of adverse reactions associated with these substrates. voclosporin has been shown to be an OATP1B1 inhibitor. These interactions have not been studied clinically; however, it is important to monitor for possible adverse reactions and increased concentrations of OATP1B1 substrates when taken with voclosporin.

Immunizations: Voclosporin is an immunosuppressant and live attenuated vaccines should be avoided.

Adverse Effects: The most common adverse reactions to voclosporin are reduction in mean glomerular filtration rate (26%), hypertension (19%), diarrhea (19%), headache (15%), anemia (12%), cough (11%) and urinary tract infection (10%). Less common reactions include alopecia, hypertrichosis, gastrointestinal issues, fatigue, tremor, acute kidney injury, and renal insufficiency (1-10%). Prolonged QT intervals have been documented and appear to be dose-dependent; however, the frequency in which this adverse reaction occurs is not defined. Other reactions with unknown frequency include hyperkalemia, azotemia, hematologic/oncologic issues, infections, and CNS disturbances.

Pregnancy and Lactation:

While there is limited data to establish drug-related risks associated with voclosporin and pregnancy, it is recommended voclosporin be avoided in pregnant women due to its alcohol content (21.6 mg of dehydrated ethanol per capsule for a total of 129.4 mg/day). Animal studies have found that voclosporin is embryocidal and fetocidal in rats and rabbits at doses 15- and 1-times the maximum recom-

mended human dose (MRHD) of 23.7 mg twice daily. Furthermore, animal studies have linked voclosporin doses at 0.1 to 0.3-times the MRHD in rabbits to reduced placental and fetal body weight.

There is no available data from humans regarding the presence of voclosporin in breastmilk or its effects on lactation. In animal models, voclosporin was detected in the milk of lactating rats, indicating it would likely be present in human milk as well. The use of voclosporin is not recommended in lactating women, and breastfeeding should be avoided for at least 7 days after the last dose of voclosporin.

Dosing: The recommended starting dose for voclosporin in patients with normal renal function is 23.7 mg (3 capsules) twice a day taken on an empty stomach. It is important to stay as consistent as possible with at least 8-hours between doses. If a dose has been missed, the patient should be instructed to take the dose as soon as possible within 4-hours of the missed dose. If it has been > 4 hours, omit the missed dose and continue taking at scheduled time. Baseline eGFR must be established prior to treatment initiation and should be assessed every two weeks for the first month and every four weeks thereafter. If eGFR is < 45 mL/min/1.73m2 at baseline, voclosporin is not recommended as it has not been studied in these patients. However, if used in patients with severe renal impairment, the recommended starting dose is 15.8 mg twice daily. In patients with mild to moderate hepatic impairment (Child-Pugh A or Child-Pugh B), the recommended starting dose is also 15.8 mg twice daily. If at follow up visits eGFR is < 60 mL/min/1.73m2 and has decreased by 20-30% from baseline, the dose should be reduced by 7.9 mg twice a day. If the eGFR is still reduced from baseline by > 20% in two weeks after the initial dose reduction, reduce the dose again by 7.9 mg twice a day. If eGFR is < 60 mL/ min/1.73m2 and reduced from baseline by > 30%, discontinue and reassess eGFR in two weeks. Voclosporin may be re-initiated at 7.9 mg twice daily if eGFR returns to > 80% of baseline, and the dose can continue to be increased by 7.9 mg twice a day for each eGFR measurement > 80% of baseline, not to exceed the initial starting dose.

Storage: Store in the original packaging at room temperature (20oC to 25oC); may be stored briefly at 15oC to 30oC.

Dosages and Cost: Voclosporin is available as 7.9 mg capsules contained within a wallet consisting of four individual 3 x 5 blister strips (60 capsules) or carton containing three wallets (180 capsules). Cost has not yet been established.

Summary/Use in clinical practice

Voclosporin in addition to background immunosuppressive therapy (mycophenolate mofetil plus corticosteroids) is a viable option for treating patients with lupus nephritis. Lupus nephritis is a serious condition that without appropriate treatment can lead to permanent and irreversible damage to the kidneys. The standard of therapy is currently high-dose corticosteroids plus either mycophenolate mofetil or cyclophosphamide. Unfortunately, research has shown that after 6 to 12 months of therapy, only 10 to 40% of patients achieve CRR, indicating the need for a more efficient treatment regimen. Voclosporin is a next-generation calcineurin inhibitor similar to cyclosporine; however, it is more potent and is metabolized quicker, eliminating the need for drug level monitoring.

When compared to the current standard of treatment for lupus nephritis, treatment with voclosporin resulted in a higher proportion of patients reaching CRR. While an effective treatment, the use of voclosporin is associated with more adverse effects such as reduced eGFR, hypertension, and headache when compared to placebo. Prior to the initiation of voclosporin, it is important for providers to evaluate the patient’s renal function and their list of current medications. Voclosporin should not be taken concomitantly with potent CYP3A4 inhibitors, as these will increase voclosporin concentrations and the risk for adverse effects. Furthermore, it is important to counsel patients on the importance of staying consistent and separating doses by at least 8 hours and to take on an empty stomach to ensure absorption. The manufacturer suggests monitoring blood pressure every two weeks for the first month after initiating voclosporin, and as clinically indicated thereafter. If the patient experiences readings >165/105 mmHg or presents with hypertensive emergency, voclosporin should be discontinued and antihypertensive therapy initiated.

Voclosporin is relatively new and the most recent findings from Arriens and colleagues have yet