Safety and Efficacy of Combination Belimumab and Voclosporin in the Treatment of Proliferative Forms of Lupus Glomerulopathy: Synergy Trial

Inclusion Criteria

• •1. Signed Informed Consent Form
• •2. Age 18-80 years at time of signing Informed Consent Form
• •3. Ability to comply with the study protocol, in the investigator's judgment
• •4. A diagnosis of SLE by any one of the following criteria: European League Against Rheumatism/ American College of Rheumatology/Systemic Lupus International Collaborating Clinics (EULAR/ACR/SLICC)
• •• At least one positive ANA defined as a \>1:80 titer or a positive anti-ds-DNA within the last 3 years will be accepted.
• •5. ISN/RPS 2003 Class III, Class IV, Class III/V or Class IV/V Lupus Nephritis diagnosed and meet one of these criteria:
• •i) A new diagnosis of LN (kidney biopsy current by SOC), or ii) A previous diagnosis of LN that has been treated, responded, but has flared (If diagnostic biopsy was \>24 months before SCREENING, a SOC repeat biopsy will be required for trial entry or by Medical Monitor approval if the last biopsy was less than 36 months prior to screening), or iii) A current diagnosis of LN confirmed by SOC kidney biopsy within the last 24 months prior to screening, or by Medical Monitor approval if the last biopsy - was less than 36 months prior to screening, who has been treated with MMF + glucocorticoids
• •6. UPCR must be \>750 mg/gm from a 24 hour urine collection during screening. If the UPCR does not exceed 750 mg/gm, it may be repeated once during the screening period.
• •7. Resting systolic blood pressure \<150 mm Hg and resting diastolic blood pressure \<90 mm Hg.
• •Note: If the blood pressure is \>150/90 at screening it can be repeated twice in the screening period and if it is \<150/90 upon repeat the subject is eligible for study enrollment.
• •8. Subject must be on maximum tolerated ACEi or ARB therapy as adjudicated by the site PI for ≥4 weeks prior to randomization.
• •Note: Patients with confirmed ACEi or ARB intolerance defined as persistent cough, anaphylaxis, or angioedema will be eligible and treatment with another protein-lowering anti-hypertensive encouraged (See #9).
• •9. Use of other protein-lowering agents, including non-dihydropyridine calcium channel blockers, sodium-glucose transporter 2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRA), will be allowed provided dosing has been stable for ≥4 weeks prior to randomization.
• •Note: Titration of the above antihypertensive agents will NOT be allowed following randomization without Sponsor approval. Control for changes in blood pressure will be accomplished using non-protein lowering agents (e.g. Amlodipine, Nifedipine, or Hydralazine).
• •10. EGFR \>30 ml/min/1,73m2 will be required for kidney biopsies obtained \>3.0 months from the start of drug administration.
• •EGFR\> 20 mls/min/1.73 m2 will be allowed for renal biopsies obtained \<3.0 months from start of study drug administration provided interstitial fibrosis/tubular atrophy and/or global glomerulosclerosis \<65%, and in the judgement of the PI the decrease in eGFR is due to ATN that is reversible.
• •Note: All patients will interstitial fibrosis/tubular atrophy and/or global glomerulosclerosis \>65% will be excluded from the trial Note: If a patient underwent a renal biopsy within 6 months of randomization and found to have a eGFR between 20-30 ml/min/1,73m2, the site will consult with the study Medical Monitor(s) to determine eligibility.
• •Note: The rationale for this is to allow patient to that have low eGFR with intense and active inflammation.
• •11. Eligible patients will have adequate hematologic parameters defined below as:
• •1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
• •2. Absolute lymphocyte count (ALC) ≥ 1.0 x 109/L. Note: If count is between .5 x 109/L and 1.0 x 109/L , the site will consult with the study Medical Monitor(s) to determine eligibility.
• •3. Platelet count \> 75 x 109/L
• •4. Hemoglobin \> 8.5 g/dL
• •12. Subjects must be taking Belimumab prior to Consent / Screening or start on Day 0 / Baseline (randomization to short-term MMF or MPA therapy or extended MMF or MPA therapy).
• •Note: If Belimumab therapy is expected for less than 12 months in duration post-randomization, please contact Sponsor for approval on a case-by-case basis.
• •13. Subjects of Child-Bearing Potential must use a highly effective method of contraception consistently and correctly during the study.
• •Highly effective methods of contraception have a failure rate of \<1% per year when used consistently and correctly.
• •The following methods of contraception are considered highly effective:
• •Combined hormonal (estrogen+progestin) contraception (oral, intravaginal, transdermal) associated with inhibition of ovulation.
• •Progestogen- or progestin-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation.
• •Intrauterine device.
• •Intrauterine hormone-releasing system.
• •Bilateral tubal ligation/occlusion/division.
• •Vasectomized partner (considered a highly effective birth control method provided that partner is the sole sexual partner of the study subject and that the vasectomized partner has received medical assessment of the surgical success).
• •Sexual abstinence: defined as refraining from intercourse which may result in pregnancy during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject.
• •Note: Subjects who are on oral contraceptive must also use additional barrier contraceptive methods, consistent with the approved prescribing information for MMF and MPA.