General Information

Lupkynis (voclosporin) is a calcineurin-inhibitor immunosuppressant.

Lupkynis is specifically indicated in combination with a background immunosuppressive therapy regimen for the treatment of adult patients with active lupus nephritis.

Lupkynis is supplied as a capsule for oral administration.  Lupkynis must be swallowed whole on an empty stomach. Administer consistently as close to a 12-hour schedule as possible, and with at least 8 hours between doses. If a dose is missed, instruct the patient to take it as soon as possible within 4 hours after missing the dose. Beyond the 4-hour time frame, instruct the patient to wait until the usual scheduled time to take the next regular dose. Instruct the patient not to double the next dose. Instruct patients to avoid eating grapefruit or drinking grapefruit juice while taking Lupkynis.

Dosage Recommendations:

• Before initiating Lupkynis, establish an accurate baseline estimated glomerular filtration rate (eGFR) and check blood pressure (BP). Use of Lupkynis is not recommended in patients with a baseline eGFR ≤45 mL/min/1.73 m2 unless the benefit exceeds the risk; these patients may be at increased risk for acute and/or chronic nephrotoxicity. Do not initiate Lupkynis in patients with baseline BP >165/105 mmHg or with hypertensive emergency.
• The recommended starting dose is 23.7 mg orally, twice a day.
• Use Lupkynis in combination with mycophenolate mofetil (MMF) and corticosteroids.

Please see drug label for dose modifications based on eGFR, as well as for patients with renal and hepatic impairment.

Monitor blood pressure every two weeks for the first month after initiating Lupkynis, and as clinically indicated thereafter. For patients with BP >165/105 mmHg or with hypertensive emergency, discontinue Lupkynis and initiate antihypertensive therapy.

If the patient has not experienced therapeutic benefit by 24 weeks, consider discontinuation of Lupkynis. 

Consider the risks and benefits of Lupkynis treatment beyond one year in light of the patient’s treatment response and risk of worsening nephrotoxicity.

Mechanism of Action

Lupkynis (voclosporin) 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.

Side Effects

Adverse effects associated with the use of Lupkynis may include, but are not limited to, the following:

• glomerular filtration rate decreased
• hypertension
• diarrhea
• headache
• anemia
• cough
• urinary tract infection
• abdominal pain upper
• dyspepsia
• alopecia
• renal impairment
• abdominal pain
• mouth ulceration
• fatigue
• tremor
• acute kidney injury
• decreased appetite

 The Lupkynis drug label comes with the following Black Box Warning: MALIGNANCIES AND SERIOUS INFECTIONS. Increased risk for developing serious infections and malignancies is associated with Lupkynis or other immunosuppressants that may lead to hospitalization or death.

Clinical Trial Results

The FDA approval of Lupkynis was based on the AURORA Phase 3 study and the AURA-LV Phase 2 study. In both studies, a total of 533 patients with LN were randomized to receive either Lupkynis 23.7 mg or placebo twice daily used with standard of care (SoC). All patients were dosed with concurrent MMF at a target dose 2 g/day. In both studies, initial treatment with intravenous (IV) methylprednisolone up to a cumulative dose of 1 g was administered on Days 1 and 2, and all patients received a subsequent taper of oral corticosteroids. The starting dose of oral prednisone was 20 mg/day for patients with a body weight of <45 kg and 25 mg/day for patients ≥45 kg. The dose of oral corticosteroid was tapered down to achieve a target dose of 2.5 mg/day by Week 16. The studies enrolled patients with LN of Class III or IV (alone or in combination with Class V) or pure Class V. Enrolled patients were required to have baseline eGFR >45 mL/min/1.73 m2.

In the Phase 3 AURORA study, at one year, Lupkynis plus SoC was more than two times as effective at achieving a complete renal response than the SoC alone. Patients in the study taking Lupkynis also achieved a 50 percent reduction in UPCR twice as fast as SoC, and a higher portion of Lupkynis-treated patients achieved a complete renal response at 24 weeks compared to patients receiving SoC. The study results were achieved using a protocol-defined steroid taper. Patients treated with Lupkynis showed improved response rates in all parameters across immunologically-active classes of LN studied.

In the phase 2 AURA-LV study, the primary endpoint was complete renal remission (CRR) at 24 weeks; the secondary endpoint was CRR at 48 weeks. Two hundred sixty-five subjects from 79 centers in 20 countries were recruited and randomized to treatment for 48 weeks. CRR at week 24 was achieved by 29 (32.6%) subjects in the low-dose Lupkynis group, 24 (27.3%) subjects in the high-dose Lupkynis group, and 17 (19.3%) subjects in the placebo group (OR=2.03 for low-dose Lupkynis versus placebo). The significantly greater CRR rate in the low-dose Lupkynis group persisted at 48 weeks, and CRRs were also significantly more common in the high-dose Lupkynis group compared to placebo at 48 weeks.