An exploratory study assessing the ability of biomarkers measured at 8 weeks to predict clinical response over 24 and 48 weeks in subjects taking voclosporin 23.7 mg twice daily (BID) in combination with standard of care in patients with active lupus nephritis

Voclosporin is a novel calcineurin inhibitor (CNI) intended for use in the prevention of organ graft rejection and for the treatment of autoimmune diseases. The aim of the current development program is to investigate whether voclosporin added to the standard of care treatment in active Lupus Nephritis (LN) is able to reduce disease activity, as measured by a reduction in proteinuria. The background therapy will be mycophenolate mofetil (MMF) 2 g daily, initial treatment with IV methylprednisolone followed by a reducing course of oral corticosteroids. Patients with active, flaring LN will be eligible to enter the study. They are required to have a diagnosis of LN according to established diagnostic criteria (American College of Rheumatology) and clinical and biopsy features suggestive of active nephritis. Efficacy will be assessed by the ability of the drug combination to reduce the level of proteinuria while demonstrating an acceptable safety profile.

Key Inclusion Criteria:

• Diagnosis of systemic lupus erythematosus (SLE) according to the American College of Rheumatology criteria (1997; see Appendix 6).
• Kidney biopsy within 24 months prior to screening with a histologic diagnosis of lupus nephritis International Society of Nephrology/Renal Pathology Society Classes III, IV-S or IV-G, (A) or (A/C); or Class V, alone or in combination with Class III or IV.
• Laboratory evidence of active nephritis at screening, defined as: Class III, IV-S or Class IV-G (proteinuria ≥1000 mg/24 hours when assessed by 24 hour urine collection, defined by a urine protein/creatinine ratio (UPCR) of ≥1.0 mg/mg assessed in a first morning void urine specimen). Class V, alone or in combination with Class III or IV, (proteinuria ≥1,500 mg/24 hours when assessed by 24 hour urine collection, defined by a UPCR of ≥1.5 mg/mg assessed in a first morning void urine specimen).

Key Exclusion Criteria:

• Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation of ≤45 mL/min/1.73 m2 at screening
• Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to require dialysis during the study period.
• A previous kidney transplant or planned transplant within study treatment period.
• Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. Subjects with cervical dysplasia that is cervical intraepithelial neoplasia 1, but have been treated with conization or loop electrosurgical excision procedure, and have had a normal repeat Papanicolaou smear test (PAP) are allowed.
• Lymphoproliferative disease or previous total lymphoid irradiation.
• Severe viral infection (such as Cytomegalovirus (CMV), Hepatitis B virus (HBV), Hepatitis C virus (HCV)) within 3 months of screening; or known human immunodeficiency virus infection.
• Active tuberculosis (TB), or known history of TB/evidence of old TB if not taking prophylaxis with isoniazid.
• Other known clinically significant active medical conditions, such as:
• Severe cardiovascular disease including congestive heart failure, history of cardiac dysrhythmia or congenital long QT syndrome. QT interval duration corrected for heart rate using method of Fridericia (QTcF) exceeding 480 msec in the presence of a normal QRS interval (<110 msec) at time of screening will result in exclusion.
• Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or bilirubin greater than 2.5 times the upper limit of normal) at screening and confirmed before enrollment.
• Chronic obstructive pulmonary disease or asthma requiring oral steroids.
• Bone marrow insufficiency unrelated to active systemic lupus erythematosus (SLE) (according to Investigator judgment) with white blood cell count <2,500/mm3; absolute neutrophil count <1.3 × 103/μL; thrombocytopenia (platelet count <50,000/mm3).
• Active bleeding disorders.
• Current infection requiring IV antibiotics.