DESIGN OF A PHASE 2b/3 ADAPTIVE, RANDOMIZED, ACTIVE‑CONTROLLED TRIAL (OLYMPUS) EVALUATING POVETACICEPT IN PRIMARY MEMBRANOUS NEPHROPATHY

Primary membranous nephropathy (pMN) is characterized by immune system dysfunction where pathogenic B cells generate harmful autoantibodies targeting proteins in the kidney, most commonly PLA2R. Survival and function of pathogenic B cells and plasma cells are dependent on 2 cytokines, BAFF and APRIL, both central to the pathogenesis of pMN. APRIL is involved in promoting plasma cell survival and function; BAFF exerts overlapping as well as distinct effects to APRIL, including regulating early B cell development and activating T cells and innate immune cells. BAFF also contributes to mesangial cell proliferation and podocyte injury, further exacerbating glomerular damage. There are no therapies specifically approved for pMN.

Povetacicept, a dual inhibitor, is specifically engineered to potently inhibit BAFF and APRIL, with enhanced target affinity and superior tissue penetration, offering effective B cell control. In the ongoing Ph1/2 trial (RUBY-3), treatment with povetacicept 80mg SC Q4W resulted in mean 24hr urine protein to creatinine ratio (UPCR) reduction of 82% (95%CI:60%,92%) from baseline and stable estimated glomerular filtration rate (eGFR) at Wk48 (n=5). Early and substantial decline in anti-PLA2R autoantibodies was seen at Wk12 (73%) and continued at Wk48 (83%) with 100% (4/4) achieving immunologic remission. At Wk48, 40% (2/5) achieved complete remission; 100% (5/5) achieved partial remission. Povetacicept was generally safe and well tolerated; majority of adverse events were mild or moderate in severity. These transformative results support further evaluation of povetacicept.

This Ph2b/3 adaptive, randomized, active-controlled trial (OLYMPUS) in adults with pMN will evaluate 2 povetacicept doses (80mg and 240mg SC Q4W) in Ph2b to select a Ph3 dose to evaluate the efficacy and safety of the selected dose compared to tacrolimus. Adults (18 to 75 yrs) with biopsy-confirmed pMN, UPCR ≥3.5g/g and eGFR ≥40mL/min/1.73m2 may be eligible to enroll. In Ph2b, ~20 participants will be randomized to receive 1 of 2 povetacicept doses. Ph3 dose recommendation by an independent data monitoring committee will occur when Ph2b participants complete at least 12wks (based on review of totality of available data, including change from baseline in anti-PLA2R autoantibody through Wk12). Ph3 will begin after Ph2 enrollment is complete. In Ph3, ~156 participants will be randomized 2:1 to povetacicept or tacrolimus for 104 weeks.

The primary endpoint for Ph3 is proportion of participants with complete clinical remission (CR) definition 1 (24hr UPCR <0.5g/g and stable eGFR [≤15% reduction from baseline]) at Wk104. The secondary efficacy endpoints for Ph3 are: proportion of participants with CR definition 2 (24hr UPCR <0.3g/g and stable eGFR) at Wk104 and proportion of participants with overall clinical remission (24hr UPCR <3.5g/g and ≥50% reduction from baseline and stable eGFR) at Wk104. The final analysis will be performed when ~156 participants who receive at least 1 dose of povetacicept or tacrolimus in Ph3 complete Wk104. Safety will be evaluated.

Povetacicept demonstrated transformational efficacy in reducing proteinuria and stabilizing renal function in pMN and was generally safe and well tolerated in Ph1/2. The OLYMPUS trial will further evaluate the efficacy and safety of povetacicept for pMN.