Active Lupus Nephritis

Primary Objective: • To assess the efficacy of Orelvo (voclosporin) compared with placebo in achieving renal response after 24 weeks of therapy in subjects with active lupus nephritis (LN) Secondary Objective: • To assess the safety, tolerability, and efficacy of Orelvo over 52 weeks compared with placebo in subjects with active LN

Orelvo (voclosporin)

Orelvo (voclosporin)

softgel capsule

7.9

Primary Endpoint:
Renal response at Week 24 will be adjudicated by the Clinical Endpoints Committee
based on the following parameters:
• UPCR of ≤0.7 mg/mg, and
• eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR
of >20%, and
• Received no rescue medication for LN (see Section 7.8, Prohibited Therapy
and Concomitant Treatment), and
• Received ≤10 mg/day prednisone from Weeks 16 through 24.
Subjects who withdraw from the study prior to the Week 24 assessment will be
defined as non responders.
Secondary Endpoints:
• Time to UPCR of ≤0.7 mg/mg.
• Partial renal response as defined by 50% reduction from baseline in UPCR
at Weeks 24 and 52.
• Time to 50% reduction in UPCR from baseline.
• Renal response at Week 52 (based on definition of primary endpoint).
• Duration of UPCR ≤0.7 mg/mg.
• Change from baseline in UPCR at each time point.
• Change from baseline in serum creatinine, urine protein, and eGFR.
• Change from screening in immunology parameters (complement 3 (C3), C4, and anti-double-stranded DNA).
• Renal response with low-dose steroids (defined as renal response in the presence of corticosteroids of ≤2.5 mg between Weeks 16 to 24 and Weeks 36 to 52).
• Change from baseline in health-related quality of life at Weeks 12, 24, and 52.
• Health Resource Utilization at Weeks 24 and 52.
• Change from baseline in the Safety of Estrogens in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity (SELENA-SLEDAI) Index score at Weeks 24 and 52.

1. Written informed consent before any study-specific procedures are performed.
2. Male or female subjects with a minimum age of 18 (or legal age of consent
if >18 years) to 75 years of age, inclusive, at the time of screening (Visit 1).
3. Previous diagnosis of systemic lupus erythematosus (SLE) according to the
American College of Rheumatology criteria
4. Subjects with evidence of active nephritis, defined as follows:
Kidney biopsy result within 2 years prior to screening indicating Class III,
IV-S or IV-G (alone or in combination with Class V) LN with a doubling or
greater increase of urine protein creatinine ratio (UPCR) within the last
6 months to a minimum of ≥1.5 mg/mg at screening.
OR
Kidney biopsy result within 6 months prior to screening indicating Class III,
IV-S or IV-G (alone or in combination with Class V) LN with a UPCR of
≥1.5 mg/mg at screening.
OR
Kidney biopsy result within 6 months prior to screening indicating Class V LN
and a UPCR of ≥2 mg/mg at screening.
A biopsy can be performed during screening, if not available. The above
criteria must be fulfilled at baseline.
5. In the opinion of the Investigator, subject requires high-dose corticosteroids and
immunosuppressive therapy.
6. Subject is willing to take oral MMF for the duration of the study, either by
continuing current MMF therapy or by initiating it on or before the Baseline
Visit.
7. Women of childbearing potential must have a negative serum pregnancy test at
screening and a negative urine pregnancy test at baseline. Two effective forms
of contraception must be used simultaneously unless abstinence is the chosen
method. Subjects must use effective contraception during the study

1. Subjects unable or unwilling to give written informed consent and/or to comply
with study procedures.
2. Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney
Disease Epidemiology Collaboration equation of ≤45 mL/minute/1.73 m2 at
screening confirmed before randomization.
3. Currently taking or known need for any of the medications listed in Section 7.8,
Prohibited Therapy and Concomitant Treatment at screening or during the study.
This includes prohibited medications prior to screening as specified in
Section 7.8.1, Prohibited Medications.
4. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or
expected to require dialysis during the study period.
5. A previous kidney transplant or planned transplant within study treatment
period.
6. Any known hypersensitivity or contraindication to MMF, mycophenolic acid, cyclosporine, corticosteroids or any components of these drug products.
7. Current or medical history of:
• Congenital or acquired immunodeficiency.
• In the opinion of the Investigator, clinically significant drug or alcohol abuse
within 2 years prior to screening.
• 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 test are allowed.
• Lymphoproliferative disease or previous total lymphoid irradiation.
• Severe viral infection (e.g., cytomegalovirus, hepatitis B virus, hepatitis C
virus) within 3 months of screening; or known HIV infection. Severe viral
infection is defined as active disease requiring antiviral therapy.
• Active tuberculosis (TB), or known history of TB/evidence of old TB if not taking prophylaxis with isoniazid
8. 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 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 ≥2.5 times the upper limit of normal) at screening and, if abnormal at
screening, then confirmed that the levels have returned to <2.5 times upper
limit of normal before randomization.
• Chronic obstructive pulmonary disease or asthma requiring oral steroids.
• Bone marrow insufficiency unrelated to active 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.
9. Any overlapping autoimmune condition for which the condition or the treatment
of the condition may affect the study assessments or outcomes (e.g., scleroderma
with significant pulmonary hypertension; any condition for which additional
immunosuppression is indicated). Overlapping conditions for which the
condition or treatment is not expected to affect assessments or outcomes (e.g.,
Sjögren’s syndrome) are not excluded.
10. No vaccines using live organisms, virus or bacterial, are allowed during
screening and while taking the study treatment.
11. Other major physical or psychiatric illness or major traumatic injury within
6 months prior to screening that may affect study conduct or interfere with study
assessments or outcome.
12. Any other medical condition which, in the Investigator’s judgment, may be
associated with increased risk to the subject or may interfere with study
assessments or outcomes.
13. Subjects who are pregnant, breast feeding or, if of childbearing potential, not
using adequate contraceptive precautions.
14. Participation in another interventional clinical study within 4 weeks prior to
screening and/or receipt of investigational drugs within 4 weeks or 5 half-lives
of the drug (whichever is longer) prior to screening.
15. Subjects randomized and treated in a previous voclosporin clinical study.