Povetacicept for IgA Nephropathy and Primary Membranous Nephropathy

Abstract

Introduction

Povetacicept is an inhibitor of B-cell activating factor (BAFF) and A proliferation–inducing ligand (APRIL), 2 cytokines central to the pathogenesis of autoimmune glomerulonephritis. Both BAFF and APRIL promote B-cell and plasma cell survival and function. APRIL primarily supports plasma cell survival and function, whereas BAFF regulates early pathogenic B-cell development, activates pathogenic T cells and innate immune cells, and contributes to mesangial cell proliferation and podocyte injury.

Methods

Our phase 1 and 2, open-label study evaluated povetacicept in adult participants with IgA nephropathy (IgAN) or primary membranous nephropathy (pMN), all with estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min per 1.73 m². The primary objective was safety. Secondary objectives included change from baseline in urine protein-to-creatinine ratio (UPCR), eGFR, galactose-deficient IgA1 (Gd-IgA1) (IgAN), antiphospholipase A2 receptor autoantibody (aPLA2R; pMN), and clinical remission (with hematuria resolution for IgAN).

Results

Povetacicept was administered subcutaneously every 4 weeks (Q4W) to 54 participants with IgAN (21 received 80 mg, 33 received 240 mg) and 10 with pMN (all received 80 mg). In this interim analysis, participants with IgAN on 80 mg had a 64% mean 24-hour UPCR decrease (95% confidence interval: –76 to –48) from baseline (1.3 g/g to 0.5 g/g; 65% with UPCR < 0.5 g/g) with stable eGFR at week 48. Early decline in Gd-IgA1 at week 12 (57%), continued at week 48 (77%). Approximately 90% achieved hematuria resolution and 53% achieved clinical remission. Efficacy outcomes were similar with 240 mg povetacicept. Participants with pMN had an 82% mean 24-hour UPCR decrease (95% confidence interval: –92 to –60) from baseline (3.8 g/g to 0.7 g/g) with stable eGFR. Early decline in aPLA2R at week 12 (73%), continued at week 48 (83%) with 100% in immunologic remission (40% achieved complete remission; 100% achieved partial remission). Povetacicept was generally safe and well-tolerated for IgAN and pMN.

Conclusion

Povetacicept had substantial, sustained UPCR reductions with stable eGFR, significant Gd-IgA1 reductions, hematuria resolution, clinical remission, with favorable safety in IgAN. Similar results were observed in pMN. By inhibiting both BAFF and APRIL, povetacicept targets the underlying cause of disease and has potential to provide a significant therapeutic advancement for autoimmune glomerular diseases.

Graphical abstract

Autoantibody-mediated glomerular diseases, such as IgAN and pMN, are characterized by immune system dysfunction leading to kidney injury. In these diseases, pathogenic B cells generate harmful autoantibodies targeting kidney tissues. The survival and function of these pathogenic B cells, as well as plasma cells, are heavily dependent on 2 cytokines BAFF and APRIL, both of which are central in the pathogenesis of autoimmune glomerulonephritis.¹ While APRIL’s function is primarily limited to promoting survival of plasma cells and their function,² BAFF exerts broader effects, including regulating early pathogenic B-cell development, activating pathogenic T cells and innate immune cells. BAFF contributes to mesangial cell proliferation and podocyte injury, further exacerbating glomerular damage.¹ Importantly, the survival of B cells and plasma cells is responsible for the production of pathogenic molecules, including Gd-IgA1 and anti-Gd-IgA1 autoantibodies in IgAN,¹ as well as anti-PLA2R autoantibodies in pMN.³

IgAN, the most common primary glomerulonephritis worldwide, develops through several interconnected pathogenic mechanisms, commonly described by the 4-hit hypothesis model.^1,4 The initial event involves aberrant production of IgA, driven by mucosal immune dysregulation that results in Gd-IgA1. Circulating levels of Gd-IgA1 are associated with disease activity, proteinuria, risk of disease progression, reflecting its key pathogenic role in disease pathogenesis. Subsequently, the body produces antiglycan autoantibodies directed against N-acetylgalactosamine residues on Gd-IgA1. These antibodies bind with Gd-IgA1 to form circulating immune complexes, which represent the third step in pathogenesis. Ultimately, these complexes deposit within the renal mesangium, activating complement pathways and local cells, triggering inflammation, matrix expansion, podocyte disruption, and leading to clinical manifestations such as proteinuria, hematuria, and progressive kidney failure.

In contrast, pMN, a less prevalent immune-mediated glomerulonephritis, is primarily driven by circulating autoantibodies targeting podocyte antigens such as PLA2R, present in approximately 70% of cases.5, 6, 7 Clinically, pMN presents with nephrotic-range proteinuria (> 3.5 g/d), hypoalbuminemia, edema, hyperlipidemia, and less frequently thromboembolic events and declining renal function. No approved therapies currently exist for pMN, and management relies on off-label immunosuppressive regimens.⁸

Current therapies for IgAN have limitations. Standard nonimmunosuppressive proteinuria-lowering therapies (e.g., renin-angiotensin system inhibitor, sodium glucose cotransporter 2 inhibitors, and endothelin receptor antagonist), lipid control, lifestyle modifications, and steroids and immunosuppressive therapies targeting downstream processes (e.g., complement inhibitors), do not ameliorate the root cause of the disease, are only modestly effective, and have significant side effects. There are no approved therapies for pMN; immune suppression treatments for pMN considered as standard-of-care are used off-label.⁸

In both IgAN and pMN, reduced kidney function and proteinuria are strongly associated with increased morbidity and mortality. Substantial reductions and/or disappearance of Gd-IgA1 in IgAN or aPLA2R in pMN firmly precede and predict subsequent proteinuria reduction, which in turn is strongly correlated with improved clinical outcomes.^9,10 Serum levels of BAFF and APRIL have been reported to be significantly higher in patients with IgAN than in controls.11, 12, 13, 14, 15 Increased serum BAFF levels have been correlated with histopathologic indicators of the severity of renal damage, such as mesangial hypercellularity and segmental glomerulosclerosis,^11,12 whereas increased APRIL serum levels induce hyperproduction of Gd-IgA1.13, 14, 15 We hypothesized that dual inhibition of BAFF and APRIL may address the underlying causes of these autoimmune diseases by disrupting pathways for autoantibody and autoantigen production, while preserving immature B cells required for adaptive immunity.

Povetacicept is a variant transmembrane activator and calcium-modulating ligand interactor crystallizable fragment fusion therapeutic specifically engineered to fully inhibit BAFF and APRIL ensuring potent, durable inhibition of both cytokines at clinically relevant doses with high tissue penetration. This represents a novel approach to provide B cell control and treat the underlying cause of IgAN and pMN. Nonclinical studies demonstrate that povetacicept binds to human BAFF and APRIL with high affinity and potently inhibits B-cell differentiation in vitro, leading to superior inhibition of B-cell differentiation, survival, and maturation, and antibody production in mice compared with wild type transmembrane activator and calcium-modulating ligand interactor crystallizable fragment therapeutics.¹⁶ A first-in-human study evaluating the proof-of-mechanism of povetacicept in healthy adults demonstrated the safety and tolerability of povetacicept at doses up to 960 mg and dose-dependent coverage of BAFF and APRIL of 2 to ≥4 weeks.¹⁷ Herein, we report interim results from a phase 1 and 2 study evaluating the effects of povetacicept in participants with autoantibody-mediated glomerular diseases, including IgAN and pMN.

Methods

Study Design

Our phase 1 and 2, open-label, dose-escalation study (Study AIS-D03) is currently ongoing in the United States, South Korea, and Australia; this study is registered at clinicaltrials.gov as NCT05732402. This study is evaluating the safety and efficacy of povetacicept in participants with autoantibody-associated glomerular diseases, IgAN, pMN, lupus nephritis, and antineutrophil cytoplasm antibody–associated vasculitis. All participants received povetacicept for an initial 24-week period. Eligible participants had the option to participate in additional 28-week and 52-week extensions (for up to a total of 104 weeks of treatment). Interim efficacy results through week 48 and all safety data through the data cutoff date of June 13, 2025, are provided to evaluate the potential of povetacicept as a treatment for autoimmune glomerular diseases. Therefore, this interim analysis was performed after participants with IgAN had 48 weeks of treatment (Supplementary Figure S1). Because this is an open-label study, this interim analysis was not prespecified in the statistical analysis plan.

Participants

Adults (aged ≥ 18 years) with autoantibody-associated glomerular disease (IgAN, pMN, lupus nephritis, or antineutrophil cytoplasm antibody–associated vasculitis) and eGFR ≥ 30 ml/min per 1.73 m² were eligible. For participants with IgAN, a biopsy-confirmed diagnosis within 10 years and proteinuria measured as UPCR ≥ 0.5 g/g were required. For participants with pMN, a historical biopsy-confirmed diagnosis, proteinuria measured as UPCR ≥ 1.0 g/g, and a positive aPLA2R (defined as ≥ 14 RU/ml) or a positive thrombospondin type 1 domain-containing 7A autoantibody were required. All participants with pMN were required to have inadequate reduction in proteinuria despite optimal supportive care for ≥ 12 weeks. Background immunosuppressive treatment was prohibited except for optional, stable calcineurin inhibitor use in persons with pMN. Full eligibility criteria are listed in the Supplementary Material.

Povetacicept Treatment

Enrolled participants in the IgAN cohort received povetacicept 80 mg or 240 mg administered subcutaneously Q4W, whereas participants in the pMN cohort received povetacicept 80 mg administered subcutaneously Q4W. Dose levels were selected based on safety, pharmacokinetics, and pharmacodynamics of povetacicept in the first-in-human study.¹⁷ Once 4 participants with IgAN or 3 participants with pMN received povetacicept 80 mg Q4W for 12 weeks, all available safety data were reviewed by a Safety Monitoring Committee before escalation to povetacicept 240 mg was allowed in the IgAN cohort. Dose escalation was not implemented in the pMN cohort.

End Points and Assessments

The primary objective was to evaluate the safety of povetacicept. The evaluation of safety was determined from the incidence of treatment-emergent adverse events, including clinically significant abnormalities in clinical laboratory assessments (including serum Ig levels), physical examination findings, vital signs, and electrocardiograms in participants with IgAN and with pMN.

Secondary objectives included efficacy of povetacicept. Efficacy end points included the change from baseline in 24-hour UPCR, change from baseline in spot UPCR, change from baseline in eGFR, and remission or renal response, which was defined differently for each disease incorporating disease-specific precedent. Clinical remission in IgAN was defined as 24-hour UPCR < 0.5 g/g, negative hematuria, and eGFR < 25% reduction from baseline.^8,18,19Hematuria resolution, defined using dipstick measured hematuria as a decrease to negative or small levels of urine blood in participants with baseline urine blood of moderate or large, was monitored in IgAN. In pMN, complete clinical remission was defined as 24-hour UPCR < 0.5 g/g and overall clinical remission was defined as those who achieved either complete or partial clinical remission. Partial clinical remission was defined as 24-hour UPCR reduction from baseline > 50% and < 3.5 g/g.

Pharmacodynamics end points included change from baseline in Gd-IgA1 for IgAN and change from baseline in aPLA2R and immunologic remission in pMN. Immunologic remission was defined as aPLA2R < 14 RU/ml. Details on end points and assessments for the study are listed in the Supplementary Material.

Statistical Analysis

All efficacy analyses were performed on all participants who received any amount of povetacicept and had ≥ 1 postbaseline efficacy assessment. All safety analyses were performed on all subjects who received any amount of povetacicept. All analyses are summarized by descriptive statistics; no hypothesis testing was performed.

Results

Participant Characteristics

Fifty-four participants with IgAN received ≥1 dose of povetacicept; 21 participants received povetacicept 80 mg Q4W and 33 participants received povetacicept 240 mg Q4W. The demographics and baseline characteristics are summarized in Table 1. Participants in the 80 mg cohort were predominantly female (67%), Asian or White (48% each), and were of a mean (± SD) age of 47.6 ± 11.7 years. Mean (± SD) baseline 24-hour UPCR was 1.3 ± 0.7 g/g and mean (± SD) baseline eGFR was 76.9 ± 34.0 ml/min per 1.73 m². Participants in the 240 mg cohort were predominantly male (55%), Asian or White (55% and 42%, respectively) and were of a mean (± SD) age of 45.1 ± 12.1 years. Mean (± SD) baseline 24-hour UPCR was 1.2 ± 0.8 g/g and mean (± SD) baseline eGFR was 63.5 ± 29.5 ml/min per 1.73 m². The 80 mg and 240 mg dose cohorts were generally similar in age, time since biopsy, previous immunosuppression, presence of hematuria at baseline, racial background, and proteinuria threshold at baseline.

Table 1.

Demographics and baseline characteristics for participants with IgAN

Parameter	Povetacicept 80 mg Q4W N = 21	Povetacicept 240 mg Q4W N = 33
Age (yrs); mean (SD)	47.6 (11.7)	45.1 (12.1)
Sex, n (%)
Male	7 (33)	18 (55)
Female	14 (67)	15 (45)
Race; n (%)
Asian	10 (48)	18 (55)
White	10 (48)	14 (42)
Other	1 (5)	1 (3)
Time since diagnosis (yrs); median (min, max)	2.1 (0.2, 23.3)	4.0 (0.2, 18.7)
Time since biopsy (yrs); mean (SD)	2.3 (2.7)	3.0 (3.0)
ACEi/ARB use; n (%)	18 (86)	33 (100)
SGLT2i use; n (%)	6 (29)	15 (45)
Prior immunosuppression usea; n (%)	4 (19)	5 (15)
24-hour UPCR (g/g); mean (SD)	1.3 (0.7)	1.2 (0.8)
24-hour UPCR >1.5 g/g; n (%)	5 (24)	8 (24)
eGFR (ml/min per 1.73 m2)b; mean (SD)	76.9 (34.0)	63.5 (29.5)
Hematuria positive by dipstick; n (%)	14 (67)	24 (73)
Hematuria moderate or large; n (%)	11 (52)	19 (58)
Gd-IgA1 (ng/ml); mean (SD)	9068 (4324)	7251 (3606)

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; Gd-IgA1, galactose-deficient IgA1; IgAN, IgA nephropathy; N, total number of subjects in the cohort; n, number of participants in the subset; Q4W, every 4 weeks; SGLT2i, sodium-glucose cotransporter-2 inhibitor; UPCR, urine protein-creatinine ratio.

^aPrior immunosuppression use includes use of corticosteroids.

^beGFR was determined using the Chronic Kidney Disease-Epidemiology Collaboration 2021 equation without adjustment for race.

Ten participants with pMN received ≥ 1 dose of povetacicept 80 mg Q4W (Table 2). Participants with pMN were predominantly male (80%), White or Black/African American (40% each), and were of a mean (± SD) age of 58.2 ± 18.1 years. Mean (± SD) baseline 24-hour UPCR was 3.8 ± 1.9 g/g and mean (± SD) baseline eGFR was 78.1 ± 24.9 ml/min per 1.73 m². Among the 10 participants with pMN dosed, 6 had nephrotic range proteinuria (baseline 24-hour UPCR

Table 2.

Demographics and baseline characteristics for participants with pMN

Parameter	All participants povetacicept 80 mg Q4W N = 10	UPCR ≥ 3.5 g/g subseta povetacicept 80 mg Q4W N = 6
Age (yrs); mean (SD)	58.2 (18.1)	63.5 (21.6)
Sex, n (%)
Male	8 (80)	4 (67)
Female	2 (20)	2 (33)
Race; n (%)
Black or African American	4 (40)	3 (50)
White	4 (40)	1 (17)
Asian	2 (20)	2 (33)
Time since diagnosis (yrs); median (min, max)	1.3 (0.3, 9.0)	0.9 (0.3, 2.9)
Time since biopsy (yrs); mean (SD)	1.7 (2.4)	0.7 (0.8)
ACEi/ARB use; n (%)	10 (100)	6 (100)
SGLT2i use; n (%)	3 (30)	1 (17)
Prior immunosuppression useb; n (%)	1 (10)	1 (17)
24-hour UPCR (g/g); mean (SD)	3.8 (1.9)	5.0 (1.4)
eGFR (ml/min per 1.73m2)c; mean (SD)	78.1 (24.9)	71.9 (28.0)
Anti-PLA2R autoantibody (RU/mL); mean (SD)	139.5 (92.1)	178.3 (40.6)

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; N, total number of subjects in the cohort; n, number of participants in the subset; PLA2R, phospholipase A2 receptor; pMN, primary membranous nephropathy; Q4W, every 4 weeks; SGLT2i, sodium-glucose cotransporter-2 inhibitor; UPCR, urine protein-creatinine ratio.

^aSubset of participants with nephrotic range proteinuria at baseline (24-hour UPCR ≥ 3.5 g/g).

^bPrior immunosuppression use includes use of corticosteroids.

^ceGFR was determined using the Chronic Kidney Disease-Epidemiology Collaboration 2021 equation without adjustment for race.

≥ 3.5 g/g). In this subset, the mean (± SD) baseline 24-hour UPCR was 5.0 ± 1.4 g/g and mean (±SD) baseline eGFR was 71.9 ± 28.0 ml/min per 1.73 m².

At the time of the interim data cut, 17 participants in the IgAN 80 mg cohort, 30 participants in the IgAN 240 mg cohort, and 5 participants in the pMN 80 mg cohort completed the week 48 study visit (Supplementary Figure S1).

Efficacy Outcomes With Povetacicept Treatment in IgAN

Treatment with povetacicept resulted in clinical improvements, including reductions in proteinuria, stabilization of eGFR, reduction of Gd-IgA1, hematuria resolution, and clinical remission in participants with IgAN. The reduction from baseline in 24-hour UPCR at week 48 (geometric mean ± geometric standard error) was −64% ± 20% (95% confidence interval: −76% to −48%) in the 80 mg cohort and −56% ± 16% (95% confidence interval: -68%, -40%) in the 240 mg cohort (Figure 1). Similar reductions from baseline in spot UPCR were also observed (Supplementary Figure S2). eGFR remained stable through 48 weeks of treatment with povetacicept. The change from baseline in eGFR (mean ± standard error) for the 80 mg cohort was 3.3 ± 3.1 ml/min per 1.73 m² at week 48. Similarly, for the 240 mg cohort, mean ± standard error change from baseline in eGFR was 3.2 ± 2.5 ml/min per 1.73 m² at week 48 (Figure 2).

Figure 1.

Percent change from baseline in 24-hour urine protein-to-creatinine ratio for participants with IgA nephropathy. Error bars indicate standard error. BL, baseline; Q4W, every 4 weeks; W, week.

Figure 2.

Change from baseline in estimated glomerular filtration rate for participants with IgA nephropathy. Estimated glomerular filtration rate was determined using the Chronic Kidney Disease-Epidemiology Collaboration 2021 equation without adjustment for race. Error bars indicate standard error. BL, baseline; Q4W, every 4 weeks; W, week.

Treatment with povetacicept resulted in early reduction of Gd-IgA1, the autoantigen implicated as the cause of disease in IgAN. Reductions from baseline Gd-IgA1 (mean ± standard error) were −57% ± 4% at week 12 and −77% ± 4% at week 48 in the 80 mg cohort and −59% ± 6% at week 12 and −77% ± 2% at week 48 in the 240 mg cohort (Figure 3).

Figure 3.

Percent change from baseline in galactose-deficient IgA1 for participants with IgA nephropathy. Error bars indicate standard error. BL, baseline; Q4W, every 4 weeks; W, week.

Hematuria resolution was achieved by week 48 in the majority of participants in the 80 mg cohort (90%) and the 240 mg cohort (94%). In addition, clinical remission was achieved by 9 of 17 participants (53%) at week 48 in the 80 mg cohort and 10 of 29 participants (34%) at week 48 in the 240 mg cohort (Table 3).

Table 3.

Clinical remission and hematuria resolution for participants with IgAN

Visit; n/m (%)	Povetacicept 80 mg Q4W N = 21	Povetacicept 240 mg Q4W N = 33	Povetacicept 80 mg Q4W N = 21	Povetacicept 240 mg Q4W N = 33
	Clinical remissiona		Hematuria resolutionb
Week 12	3/20 (15)	1/33 (3)	5/10 (50)	8/19 (42)
Week 24	6/19 (32)	4/31 (13)	10/11 (91)	11/18 (61)
Week 36	8/18 (44)	11/30 (37)	10/11 (91)	14/18 (78)
Week 48	9/17 (53)	10/29 (34)	9/10 (90)	17/18 (94)

IgAN, IgA nephropathy; m, number of evaluable participants; N, total number of subjects in the cohort; n, number of participants in the subset; Q4W, every 4 weeks; UPCR, urine protein-to-creatinine ratio.

^aClinical remission is defined as 24-hour UPCR < 0.5 g/g, negative hematuria, and < 25% reduction in estimated glomerular filtration rate from baseline.

^bHematuria resolution is defined as a decrease to negative/small levels of urine blood in subjects with baseline urine blood of moderate or large.

Efficacy Outcomes With Povetacicept Treatment in pMN

Treatment with povetacicept resulted in clinical improvements, including reductions in proteinuria, stabilization of eGFR, reductions in aPLA2R, and clinical remission in participants with pMN. For all participants with pMN, the reduction from baseline in 24-hour UPCR was −82% ± 34% (geometric mean ± geometric standard error; 95% confidence interval: −92% to −60%) at week 48. In the subset of participants who had baseline 24-hour UPCR ≥ 3.5 g/g, the reduction from baseline in 24-hour UPCR was −85% ± 40% at week 48 (Figure 4). Similar reductions from baseline in spot UPCR were observed (Supplementary Figure S3). eGFR remained stable through 48 weeks of treatment with povetacicept. The change from baseline in eGFR was −0.3 ± 3.4 ml/min per 1.73 m² at week 48. In the subset of participants who had baseline 24-hour UPCR ≥ 3.5 g/g, the change from baseline in eGFR was 2.2 ± 2.2 ml/min per 1.73 m² at week 48 (Figure 5).

Figure 4.

Percent change from baseline in 24-hour UPCR for participants with primary membranous nephropathy. Error bars indicate standard error. BL, baseline; Q4W, every 4 weeks; UPCR, urine protein-to-creatinine ratio; W, week.

Figure 5.

Change from baseline in estimated glomerular filtration rate for participants with primary membranous nephropathy. eGFR was determined by using the Chronic Kidney Disease-Epidemiology Collaboration 2021 equation without adjustment for race. Error bars indicate standard error. BL, baseline; Q4W, every 4 weeks; SE, standard error; UPCR, urine protein-to-creatine ratio; W, week.

Early reductions from baseline in aPLA2R (mean ± standard error), a key biomarker of disease in pMN, were −73% ± 6% at week 12 and −83% ± 9% at week 48. In the subset of participants with pMN who had baseline 24-hour UPCR ≥ 3.5 g/g, reductions from baseline in aPLA2R were −84% ± 5% at week 12 and −98% ± 2% in the subset at week 48. There was 100% immunologic remission in all participants with pMN (Figure 6 and Table 4).

Figure 6.

Percent change from baseline in anti–phospholipase A2 receptor autoantibody for participants with primary membranous nephropathy. Error bars indicate standard error. BL, baseline; Q4W, every 4 weeks; W, week.

Table 4.

Clinical and immunologic remission for participants with pMN

Visit; n/m (%)	Povetacicept 80 mg Q4W
	All N = 10	Subsetan = 6	All N = 10	Subsetan = 6	All N = 10	Subsetan = 6
	Complete remissionb		Overall remissionc		Immunologic remissiond
Week 12	1/9 (11)	0/6	3/9 (33)	1/6 (17)	4/9 (44)	1/5 (20)
Week 24	1/9 (11)	0/5	4/9 (44)	3/5 (60)	6/9 (67)	3/5 (60)
Week 36	0/8	0/5	2/8 (25)	2/5 (40)	5/8 (63)	2/4 (50)
Week 48	2/5 (40)	1/3 (33)	5/5 (100)	3/3 (100)	4/4 (100)	2/2 (100)

m, number of evaluable participants; N, total number of subjects in the cohort; n, number of participants in the subset; PLA2R, phospholipase A2 receptor; pMN, primary membranous nephropathy; Q4W, every 4 weeks; UPCR, urine protein-creatinine ratio.

^aThe subset includes participants with nephrotic range proteinuria at baseline (24-hour UPCR ≥ 3.5 g/g).

^bComplete remission is defined as 24-hour UPCR < 0.5 g/g.

^cOverall remission is defined as complete remission and partial remission, which is defined as 24-hour UPCR reduction from baseline > 50% and < 3.5 g/g.

^dImmunologic remission is defined as anti-PLA2R autoantibody < 14 RU/ml.

Overall remission was achieved by all 5 participants (100%) at week 48, with complete remission achieved by 2 of 5 participants (40%). In the subset of participants who had baseline 24-hour UPCR ≥ 3.5 g/g, overall remission was achieved by all 3 participants (100%) at week 48 and complete remission was achieved by 1 of 3 participants (33%) at week 48 (Table 4).

Safety of Povetacicept

Povetacicept was generally safe and well-tolerated at repeat doses of 80 and 240 mg Q4W for up to 104 weeks of treatment. The majority of adverse events were mild or moderate in severity across cohorts; there were no life-threatening adverse events or deaths. There were no serious adverse events related to povetacicept (Table 5). Common adverse events occurring in ≥ 5% of participants with IgAN and pMN are summarized in Supplementary Table S1.

Table 5.

Overview of safety for participants with IgAN and participants with pMN

Participants; n (%)	IgAN Povetacicept 80 mg Q4W n = 21	IgAN Povetacicept 240 mg Q4W n = 33	pMN Povetacicept 80 mg Q4W n = 10
Any AEs	16 (76)	27 (82)	8 (80)
Grade 1/mild	6 (29)	7 (21)	4 (40)
Grade 2/moderate	9 (43)	19 (58)	2 (20)
Grade 3/severe	1 (5)a	1 (3)b	2 (20)c,d
Grade ≥ 4/life-threatening, death	0	0	0
AEs related to povetacicept	6 (29)	10 (30)	3 (30)
AEs leading to discontinuation of povetacicept	0	1 (3)b	2 (20)c,d
SAEs	1 (5)e	1 (3)b	1 (10)c
SAEs related to povetacicept	0	0	0
Any infection AE	9 (43)	21 (64)	2 (20)
AEs of interest
Severe (grade ≥ 3) infection	0	1 (3)b	1 (10)c
Severe hypogammaglobulinemiaf	1 (5)	4 (12)	1 (10)d
Malignancy	1 (5)a	0	0
Administration-related reactiong	3 (14)	4 (12)	2 (20)
Acute kidney injury	0	2 (6)	0

AE, adverse event; IgAN, IgA nephropathy; pMN, primary membranous nephropathy; Q4W, every 4 weeks; SAE, serious adverse event.

^aGrade 3 event of carcinoma was not related to povetacicept, which led to discontinuation of povetacicept by the investigator.

^bGrade 3 event of urinary tract infection was not related to povetacicept, which resulted in the participant discontinuing povetacicept, per protocol.

^cGrade 3 event of pneumonia was not related to povetacicept; treatment was withdrawn per protocol.

^dGrade 3 nonserious event of hypogammaglobulinemia was related to povetacicept; treatment was withdrawn per protocol.

^eGrade 1 event of dermatitis was not related to povetacicept; resolved following treatment.

^fDefined as IgG < 300 mg/dl for participants with IgAN and IgG < 150 mg/dl for participants with pMN.

^gAdministration-related reaction includes injection site reactions.

In the IgAN 80 mg cohort, there were no adverse events that led to discontinuation of povetacicept. There was 1 participant with a serious adverse event of mild dermatitis that was considered not related to povetacicept by the investigator, which resolved following treatment. In the IgAN 240 mg cohort, there was 1 participant with a serious adverse event of severe urinary tract infection that was considered not related to povetacicept by the investigator, which resulted in the participant discontinuing povetacicept, per protocol. There were no other participants who discontinued povetacicept in this cohort.

In the IgAN cohorts, where eligibility required IgG ≥ 700 mg/dl, severe hypogammaglobulinemia (< 300 mg/dl) was observed in 1 participant in the 80 mg cohort (highest severity of 274 mg/dl) and 4 participants in the 240 mg cohort (highest severity of 249 mg/dl) (Table 5). All these events occurred after 48 weeks of povetacicept treatment. None of these severe hypogammaglobulinemia events were associated with serious or severe infections (including no zoster and respiratory events) or led to discontinuation of povetacicept; i.v. Ig were not administered for these events. One participant in the 240 mg cohort had a grade 2 event of COVID-19 that coincided with their hypogammaglobinemia event, which resolved despite IgG < 300 mg/dl.

There was 1 participant with IgAN in the 80 mg cohort who had a malignancy (Table 5). This participant had a significant history of breast cancer in situ and melanoma approximately 11 years and 8 years, respectively, before participation and was negative for malignancies for 5 years before enrolling in this study. At 20 weeks, an adverse event of malignancy (diagnosis of invasive ductal breast cancer) occurred, which led to discontinuation of povetacicept.

In pMN, there was 1 participant with a serious adverse event of severe pneumonia that was considered not related to povetacicept by the investigator but resulted in the participant discontinuing povetacicept, per protocol. In addition, 1 participant had nonserious, asymptomatic severe hypogammaglobulinemia, defined as IgG < 150 mg/dl (80 mg/dl at the time of event; 601 mg/dl at baseline), which met the criteria for discontinuation from povetacicept per protocol. This event was not associated with infection (including no zoster or respiratory events) and was considered by the investigator to be related to povetacicept; i.v. Ig was not administered for this event. There were no other participants who had serious adverse events, discontinued from povetacicept, or had severe hypogammaglobulinemia in this cohort.

Discussion

In this open-label, phase 1 and 2 clinical study to assess safety and efficacy of povetacicept, a dual BAFF and APRIL inhibitor in participants with the autoimmune glomerular diseases IgAN and pMN, treatment with povetacicept led to early, substantial, and sustained improvements in measures of disease activity and kidney function. Furthermore, povetacicept was generally safe and well-tolerated at repeat doses of 80 mg and 240 mg subcutaneously Q4W for up to 104 weeks of treatment. Rates of serious adverse events, severe infection, hypogammaglobulinemia, and administration-related reactions, including injection site reactions, were low. Notably, the cases of severe hypogammaglobulinemia were not associated with any severe or serious infections. Most of these occurred after 48 weeks of treatment with povetacicept and none required i.v. Ig treatment. In addition, vaccination requirements are required per protocol, as well as exclusion of participants with recent serious infections or other types of immune deficiencies; IgG levels were rigorously monitored during the study, all of which helped to minimize the risk of infection.

In IgAN, treatment with povetacicept 80 mg subcutaneously Q4W at 48 weeks showed a continuous trend in proteinuria reduction to a substantial 64% reduction on top of maximally-tolerated proteinuria-reducing therapy, the largest reported reduction among therapies that are approved or in late-stage development for IgAN.20, 21, 22 A sustained improvement of eGFR of + 3.3 ml/min per 1.73 m², which achieved the treatment target of eGFR < 1 ml/min per 1.73 m² decline in the Kidney Disease Improving Global Outcomes 2024 guideline was observed. The speed, depth, and durability of improvements in key markers of disease activity (Gd-IgA1, UPCR) and kidney function (eGFR) are evidence of robust B-cell control and offer the potential to substantially improve disease trajectory and patient outcomes. In particular, reductions in Gd-IgA1 levels precede the reduction in UPCR, suggesting that Gd-IgA1 can be an early indicator of clinical improvement in IgAN. In addition, near complete resolution of hematuria, a disease activity marker in IgAN independent of proteinuria and prognostic factor for kidney function was observed; collectively, 53% of participants achieved clinical remission, a quiescent state of IgAN defined as stable kidney function with minimal proteinuria and hematuria. The observed benefits reflect targeting drivers of nephron loss, in line with Kidney Disease: Improving Global Outcomes guidance,^8,23 and therefore constitute a therapeutic effect distinct from routine proteinuria reduction with therapies that do not target the root cause of disease.

There are no approved therapies for pMN. Povetacicept targets pMN at its origin by rapid and robust reduction of its pathogenic autoantibody, evidenced by achieving 100% immunologic remission (aPLA2R < 14 RU/ml) in this study. The speed, depth, and durability of B-cell control in pMN with povetacicept is evidenced by contrasting with data from the MENTOR study, where immunologic response (aPLA2R < 40 RU/ml) was achieved in 66% and 30%, respectively, in rituximab and cyclosporine treated patients at 12 months.²⁴ Immunologic remission predicts treatment response, which implies povetacicept has strong potential to offer superior efficacy. Furthermore, in individuals at moderate-to-high risk of accelerated decline in renal function, generally defined by a UPCR ≥ 3.5 g/g, who are recommended to receive immune suppression by Kidney Disease: Improving Global Outcomes, improvements in proteinuria and remission rates at week 48 were larger than those reported for existing off-label standard-of-care immune suppression or therapies in late phase development for pMN.25, 26, 27, 28

This is the first demonstration of clinical data through 48 weeks of treatment for 2 autoimmune-mediated glomerular diseases and illustrates the potential for povetacicept across B-cell mediated diseases. Povetacicept is a potent dual BAFF and APRIL antagonist, which leads to B-cell control and reductions in antibodies or autoantibodies and autoreactive B cells,^16,29,30 suppressing the formation of pathogenic immune complexes, without the need for cytotoxic B-cell depletion. Compared with therapies for IgAN in other classes, povetacicept works upstream in the causal pathway.²³ Off-label standard-of-care therapies for pMN have limited efficacy, likely related to their mechanisms of action. For example, anti-CD20 therapies do not directly target the autoantibody-secreting plasmablasts and plasma cells because these differentiated B cells do not express CD20, and calcineurin inhibitors are primarily effective at inhibiting T-cell–dependent B-cell activity but are ineffective at inhibiting T-cell–independent B-cell responses, which are important mediators of autoimmune diseases such as pMN. Cyclophosphamide, though effective at eliminating autoreactive B cells, is myeloablative and therefore mediates substantial adverse effects. Compared with classic B-cell depletion, BAFF and APRIL inhibition represents a new paradigm for treatment of B-cell autoimmune–mediated glomerular disease through B-cell control.

This study had several strengths. The study was conducted in 3 countries and had a substantial proportion of participants considered moderate-to-high risk for accelerated decline in renal function based on disease-specific norms. Drop-out through week 48 was minimal. Although participants with pMN were required to have positive autoantibodies for enrollment (e.g., aPLA2R), parallel efficacy in IgAN suggests that the mechanism of action of povetacicept is reasonably likely to improve disease in pMN regardless of whether the causative autoantibody is known.

Limitations of this study include the open-label and uncontrolled design. The study was not powered for statistical comparisons; therefore, all comparisons are qualitative without testing statistical significance. Comparisons between povetacicept and other therapies may be affected by definitions chosen for categorical outcome measures which, although similar, are not standardized across studies. For participants with IgAN, dose-level assignment was not randomized, which may introduce residual confounding because of imbalance in baseline characteristics and impact comparisons in outcomes between dose levels.

In this phase 1 and 2 study, clinical efficacy and safety results provided initial evidence that the targeted inhibition of BAFF and APRIL with an engineered, highly potent inhibitor, povetacicept, reduced proteinuria, stabilized eGFR, achieved high levels of clinical remission, and substantially improved disease-associated antigen and autoantibody levels in 2 B-cell autoimmune-mediated glomerular diseases. These data support the use of povetacicept across B-cell autoimmune–mediated glomerular diseases and the ongoing phase 3 trials of povetacicept for the treatment of IgAN (RAINIER study) and pMN (OLYMPUS study), where povetacicept is being developed for convenient subcutaneous self-administration in a small-volume autoinjector.

Appendix

List of AIS-D03 RUBY-3 Study Group

Hemant Kulkarni of Linear Clinical Research; Inwhee Park of Ajou University School of Medicine; Dong Ki Kim of Seoul National University Hospital; James Tumlin of Georgia Nephrology Research; Rania K. El Fekih of Brigham and Women's Hospital; Yong Kyu of Lee Ilsan Hospital, Department of Nephrology; Sung Gyun Kim of Hallym University Sacred Heart Hospital; Eun Young Lee of Soonchunhyang University Cheonan Hospital; Sang-Woong Han of Hanyang University Guri Hospital; Frank Cortazar of New York Nephrology Vasculitis and Glomerular Center; Arvind Madan of CTR Oakwater, LLC; Rajesh Yalavarthy of Western Nephrology; Eugenia Pedagogos of Western Health Sunshine Hospital (Public Institution); Sreedhar Mandayam of Prolato Clinical Research Center; Angus Ritchie of Concord Repatriation General Hospital; Ju-Young Moon of Kyung Hee University Hospital at Gangdong; and Alexander Nimri of Arizona Kidney Disease and Hypertension Center, Thomas Office.

Disclosure

AM consulted for MNK and Amgen; received research funding from Alpine Immune Sciences, AstraZeneca, Bayer, Cara Therapeutics, and Chinook Therapeutics; received honoraria from Amgen and Novartis; and participated in speaker bureaus for MNK, Otsuka, AstraZeneca, Bayer, and Amgen. RY has received research funding from Alpine Immune Sciences, Vera Therapeutics, PathalysPharma, AstraZeneca, Natera, Cara Therapeutics, and CinCorPharma. JM received research funding from Vertex Pharmaceuticals. SM received research funding from Travere Therapeutics, Novartis, Omeros, Roche, Vertex Pharmaceuticals, Alexion, AstraZeneca, Equillium, BioMarin Pharmaceutical, BeiGene, Otsuka, Pfizer, Sanofi, and Horizon; received honoraria from Calliditas Therapeutics, Travere Therapeutics, Novartis, Alexion, Bayer, and Otsuka; participated on speakers bureaus for Otsuka and Calliditas; serves as CEO of ProlatoClinical Research Center, and has other interests or relationships with UNICEF USA and the Mandayam Family Foundation. FC has consulted for and received honoraria from Amgen, Travere Therapeutics, Tenet Medicines, Aurinia Pharmaceuticals, and Calliditas Therapeutics; and participated on speaker bureaus for Amgen, Aurinia Pharmaceuticals, Calliditas Therapeutics, and Travere Therapeutics. SGK has consulted for Alpine Immune Sciences, AstraZeneca, Billy, GSK, Alexion, and Bayer; received research funding from FibroGen, GSK, JW Pharmaceutical Corporation, VALOR, Alexion, Roche, and Bayer; received honoraria from GSK, Bayer, Alpine Immune Sciences, and Alexion; and has an advisory or leadership role in the Korean Society of Nephrology. JT has consulted for NephroNetClinical Trials Consortium, Mallinckrodt Pharmaceuticals, Lilly, Relypsa, AstraZeneca, Alexion, Alpine Immune Sciences, Vera Therapeutics, Vertex Pharmaceuticals, HIBAR Microsciences LLC, Calliditas Therapeutics, Travere Therapeutics, and Argenyx; received research funding from NephroNetClinical Trials Consortium, Mallinckrodt Pharmaceuticals, Johnson & Johnson, La Jolla Pharmaceutical Company, AbbVie, ZS Pharmaceuticals, Achillion Pharmaceuticals, Relypsa, Epizon Pharma, Gilead Sciences, AstraZeneca, Akebia Therapeutics, Vera Therapeutics, Alpine Immune Sciences, Horizon, Novartis, and Argenyx; received honoraria from Mallinckrodt Pharmaceuticals, Genentech, Alexion, Genzyme, AstraZeneca, Aurinia Pharmaceuticals, Bayer, Alpine Immune Sciences, and Calliditas Therapeutics; has patents or royalties from HIBAR Microsciences LLC; has an advisory or leadership role at Achillion Pharmaceuticals, Relypsa, EpizonPharma, Gilead Sciences, KBP Biosciences, Alexion, Bayer, ChemoCentryx, Aurinia Pharmaceuticals, Vera Therapeutics, and Novartis; and participated in speakers bureaus for Mallinckrodt Pharmaceuticals, La Jolla Pharmaceutical Company, Alexion, AstraZeneca, Aurinia Pharmaceuticals, Bayer, Calliditas Therapeutics, and Travere Therapeutics. AE, HT, JL, YC, JS, OE are employees of Vertex Pharmaceuticals and may own stock options at the company. All the authors declared no competing interests.

Supplementary Material

Supplementary File (PDF)

Supplementary Methods. Supplementary References. Figure S1. CONSORT flow diagram. Figure S2. Percent change from baseline in spot UPCR for participants with IgAN. Figure S3. Percent change from baseline in spot UPCR for participants with pMN. Table S1. Common AEs occurring in ≥ 5% of participants with IgAN and pMN.