C3 Glomerulopathy: Novel Treatment Paradigms

Abstract

C3 glomerulopathy (C3G) is diagnosed by kidney biopsy, with immunofluorescence showing isolated or dominant C3 staining, indicating hyperactivity of the alternative complement pathway as the key driver of glomerular injury. Therefore, the lesion is defined by its complement-mediated pathogenesis as much as its histological pattern. As a bevy of complement-targeting agents are moving through development and clinical trials, we review the evolution in treatment paradigms for C3G. Here we survey the limited efficacy of noncomplement targeting therapy before focusing on the work being done on targeting various components of the complement cascade in aiming to provide disease-specific therapy.

C3G encompasses dense deposit disease and C3 glomerulonephritis, and is defined by its complement-mediated pathogenesis as much as its histological pattern. C3G results from a dysregulation in the alternative pathway (AP) of the complement system (Figure 1), which leads to the deposition of C3 fragments in the glomeruli, with trace or no presence of immunoglobulins.^1,2 Genetic or acquired abnormalities in 1 or more of the multiple components of the AP can lead to C3G.³ The clinical course includes proteinuria, hematuria, and progressive chronic kidney disease, with most patients reaching end-stage kidney disease within 2 decades of diagnosis.4, 5, 6

Figure 1.

Complement-directed drugs for C3G and their targets in the complement cascade. Pegcetacoplan inhibits the binding of C3 to C3bBb and thus the formation of C5 convertase. ARO-C3 reduces hepatic production of C3. Iptacopan and NM8074 inhibit the enzymatic activity of factor B. Danicopan inhibits factor D and thus the cleavage of factor B. KP104 is a dual drug that has a factor H component, inhibiting the activity of C3 convertase C3bBb, and an anti-C5 antibody component that inhibits C5 cleavage. Eculizumab inhibits the cleavage of C5 and thus the release of C5a and C5b. Avacopan inhibits the binding of C5a to its receptor C5aR1. Narsoplimab targets MASP2, inhibiting the cleavage of C4 and C2 in the lectin pathway. MASP1, mannose-binding lectin associated serine protease 1; MASP2, mannose-binding lectin associated serine protease 2; MBL, mannose-binding lectin; FB, factor B; FD, factor D; C5aR, C5a receptor 1; MAC, membrane attack complex.

⚡Proteolytic cleavage.

Current standard-of-care for C3G includes supportive measures for patients with mild disease and immunosuppression with mycophenolate mofetil (MMF) plus glucocorticoids for those with moderate to severe disease (>0.5–1 g/d of proteinuria, declining kidney function).^7,8 However, these nonspecific treatment approaches seem to have limited benefits among patients with C3G,^5,6,9,10 and complement blockade is expected to be the best strategy to explore in this population. To date, no complement inhibitor is approved for C3G, although eculizumab, a terminal complement blocker, is included in some clinical guidelines as a backup agent for patients with progressive disease who fail to respond to other therapies.^7,8

There are multiple reasons for the lack of an established optimal treatment for C3G. First, it is a rare entity, and often affecting pediatric population, making it difficult to carry out large randomized controlled trials; therefore, most evidence is based on retrospective analyses, case series, and observational studies. Second, the tests required to characterize genetic variants, complement functionality and complement-directed autoantibodies are costly and not generally available outside of the research setting. Lastly, comparing and interpreting these results is not straightforward because it also is a rather heterogenous disease in many aspects. In terms of disease drivers, abnormalities in complement genes are found in only 13% to 25% of patients, and the frequency of complement-targeting autoantibodies such as C3 nephritic factor (C3Nef) varies widely between populations, from 20% to 80%.^4,5,11 Clinical presentation classically includes low C3 levels; however, this is not true for about 30% to 50% of patients.^4,5,12 Histopathological definition has evolved, and earlier publications included patients with a membranoproliferative glomerulonephritis (MPGN); whereas now, other patterns of injury such as mesangial or endocapillary proliferative glomerulonephritis are recognized as C3G as well. Furthermore, many of the cited publications and ongoing clinical trials combine patients with C3G and immune complex-mediated MPGN (IC-MPGN) because the distinction between the 2 is questionable.¹³ Although the difference is based on the hypothesis that IC-MPGN results from classical complement pathway activation by deposited IC, many authors have reported a substantial involvement of the AP as seen by abnormalities in AP genes, autoantibodies, and biomarkers in serum and tissue.^5,14, 15, 16 Shifts from a diagnosis from IC-MPGN to C3G in repeat biopsies also support the idea that these 2 entities could be part of the same disease spectrum.^15,17

Despite these difficulties, there are multiple emerging therapies that have made their way into clinical trials for patients with C3G, all of them directed at the complement system at various levels (Table 1). In this review, we aim to present the current outlook for novel treatments of C3G.

Table 1.

Clinical trials of complement inhibitors in C3 glomerulopathy

Target in complement cascade	Mechanism of action	Drug	Type of inhibitor	Mode of administration	Pharmaceutical company	Clinical trial phase	Identification	Status	Potential indication in kidney diseases
C3	inhibition of the binding of C3 to C3bBb and thus of the cleavage of C3	Pegcetacoplan	Pegylated peptide	s.c.	Apellis	Phase 2 (n = 21)	NCT03453619 (DISCOVERY)	active, not recruiting	IgAN, LN, C3G, MN, DDD
						Phase 2 (n = 12)	NCT04572854 (NOBLE)	recruiting	Posttransplant recurrent C3 and IC-MPGN
						Phase 3 (n = 90)	NCT05067127 (VALIANT)	recruiting	C3G, IC-MPGN
						Phase 3 (n = 100)	NCT05809531 (VALE)	not yet recruiting	C3G, IC-MPGN
	reduction of production of C3	ARO-C3	RNAi	s.c.	Arrowhead	Phase 1/2a (n = 60)	NCT05083364	recruiting	C3G, IgAN
Factor B	inhibition of serine protease FB and thus of the cleavage of C3 and C5	Iptacopan (LNP023)	small molecule	Oral	Novartis	Phase 2 (n = 27)	NCT03832114	completed	C3G (native and posttransplant)
						Phase 2 (n = 94)	NCT03955445	recruiting	C3G
						Phase 3 (n = 83)	NCT04817618 (APPEAR-C3G)	recruiting	C3G
		NM8074	mAB	i.v.	NovelMed	Phase 1b/2a (n = 18)	NCT05647811	not yet recruiting	C3G
Factor D	inhibition of the cleavage of FB	Danicopan (ALXN2040)	small molecule	Oral	Alexion	Phase 2 (n = 13)	NCT03369236	completed	C3G
						Phase 2 (n = 22)	NCT03459443	terminateda	C3G, IC-MPGN
						Phase 2a (n = 6)	NCT03124368	completed	C3G, IC-MPGN
C5	inhibition of the release of C5a and C5b, and ultimately the formation of C5b9	Eculizumab	mAB	i.v.	Alexion	Phase 1 (n = 6)	NCT01221181	completed	C3G
C5a receptor	inhibition of the binding of C5a to its receptor	Avacopan (CCX168)	small molecule	Oral	ChemoCentryx	Phase 2 (n=57)	NCT03301467 (ACCOLADE)	completed	C3G
C3 convertase and C5	Factor H component: inhibition of C3 convertase. C5 antibody: inhibition of release of C5a and C5b	KP104	Bifunctional biologic	i.v. and s.c.	Kira	Phase 2 (n = 52)	NCT05517980	not yet recruiting	C3G, IgAN
MASP-2	inhibition of the cleavage of C4 and C2	Narsoplimab (OMS721)	mAB	i.v. and s.c.	Omeros	Phase 2 (n = 54)	NCT02682407	completed	IgAN, LN, C3G, MN

C3G, C3 glomerulopathy; DDD, dense deposit disease; IC-MPGN, immune complex-mediated membranoproliferative glomerulonephritis; IgAN, IgA nephropathy; i.v., intravenous; LN, lupus nephritis; mAB, monoclonal antibody; MN, membranous nephropathy; RNAi, RNA interference; s.c., subcutaneous.

^aTerminated because of inconclusive efficacy results. No safety findings were identified.

C3/C3 Convertase Axis Inhibition

An increase in AP C3 convertase formation and activity is the cornerstone of C3G pathogenesis, making this axis the main target for the development of new therapies.³ Inhibition at this level can also have a downstream effect and may help regulate an overactivation of the terminal pathway.

Different findings can point us to an altered function at the level of C3. C3NeFs, any autoantibody capable of stabilizing alternative C3 convertase activity, can be found in a large percentage of patients with C3G, especially among patients with dense deposit disease.^5,18,19 Pathogenic variants in complement genes have been identified in up to 20% to 25% of cases, although more modern analyses using stricter standards for pathogenicity have yielded far lower percentages of case (closer to 10%–15%). These variants mostly affect the activity of C3/C3 convertase axis, such as variants in the genes encoding for C3, C3 gene; factor B, CFB gene; factor H (FH), CFH gene; factor I, CFI gene; or rearrangements, duplications, and deletions in FH-related proteins, CFHR gene.^20,21 C3 serum levels, a biomarker of C3 convertase activation in the fluid phase, are low in 50% to 70% of patients with C3G.^4,5,22 Patients with normal serum C3 levels, in which convertase overactivation can occur in the tissue, may still benefit from C3 inhibition. Other biomarkers such as breakdown products of factor B and C3 could be of interest to better assess AP C3 convertase activation.

An upstream inhibition of the AP should allow the integrity of the classical and lectin pathways, which would potentially reduce the risk of infection by encapsulated bacteria that has been described with direct C5 inhibition.²³ C3 convertase inhibition could reduce the formation of opsonins (C3b, iC3b, and C3d), leading to a potential reduction in immune complex and pathogen removal, whereas a more AP-selective inhibition targeting factor B or factor D should not affect opsonization and terminal complement activity via the classical and lectin pathways.²⁴ However, complete genetic deficiency of factor B²⁵ and factor D²⁶ have been associated with infections by encapsulated bacteria. Prophylactic measures such as vaccination against Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae; and antibiotic use should be applied to patients receiving C3/AP inhibition.

Given the critical role of this proximal portion of the AP in the disease, many new drugs targeting the numerous components are being investigated (Figure 1, Table 1).

Pegcetacoplan

Pegcetacoplan is a subcutaneous, second-generation compstatin derivative. Compstatins comprise a family of peptides that selectively bind to C3, inhibiting access to C3 convertases, thereby blocking C3 cleavage from all 3 pathways.^27,28

A phase 2 clinical trial including patients with C3G, the DISCOVERY (NCT03453619), enrolled 21 participants with IgA nephropathy (IgAN), lupus nephritis, membranous nephropathy, and C3G. Results of the 8 patients in the C3G cohort were recently published.²⁹ All patients received pegcetacoplan for 48 weeks, with the option to continue treatment in an extension phase. During the treatment period, all 8 participants were concomitantly on renin-angiotensin-aldosterone system inhibition, 5 were also receiving MMF, and 3 were receiving corticosteroids. Proteinuria reduction, the primary end point, was 50.9%, from a mean 24h urine protein-to-creatinine ratio (UPCR) of 3.3 mg/mg at baseline to 1.2 mg/mg at week 48 in the intention-to-treat group (n = 7). Serum albumin levels normalized; and kidney function, starting at a mean estimated glomerular filtration rate (eGFR) of 102.4 ml/min per 1.73 m² at baseline, was stable throughout the study. Complement serum mean levels improved from baseline to week 48, with a 6-fold increase in C3 (from 44 to 243.1 mg/dl) and a 57.3% decrease of sC5b-9 (although it remained above normal range). No severe treatment-related adverse events or serious adverse events occurred.

Posttransplant recurrent C3G, which is expected in nearly all patients with C3G who undergo kidney transplant, will be represented in the NOBLE study (NCT04572854), a phase 2 trial designed to evaluate the safety and efficacy of pegcetacoplan in 12 patients with posttransplant C3G or IC-MPGN. The first portion of the study is a 12-week randomized controlled period with one arm receiving pegcetacoplan 1080 mg twice weekly and the other arm receiving no intervention. The primary outcome is the proportion of subjects with reduction in C3c staining on renal biopsy at the 12-week time point, after which all patients will be given pegcetacoplan until week 52.

The VAILANT trial (NCT05067127), a phase 3 study, is aiming to recruit 90 participants with native or recurrent C3G or IC-MPGN. Participants will be given pegcetacoplan (1080 mg for adults and adolescents ≥50 kg, dose reductions for adolescents <50 kg) twice weekly or a matched placebo for 6 months, followed by an open-label assignment of active therapy for all participants for another 6 months. Outcomes include proteinuria, renal function, and repeat biopsy findings at week 26, including changes in the activity score of the C3G histologic index score⁴ as well as C3c staining. The VALIANT trial will have an extension study, the VALE study (NCT05809531), to evaluate the agent’s long-term safety and efficacy in this population.

Iptacopan

Iptacopan (LNP023) is a first-in-class, oral small molecule that inhibits the enzymatic activity of factor B. Factor B is a key node in the AP: its breakdown product, Bb, is the component with proteolytical activity of the AP C3 convertase (C3bBb) and AP C5 convertase (C3bBb3b). Iptacopan is expected to have a suppressive effect on both convertases, resulting in an upstream and downstream regulation of the AP.³⁰

The results of a phase 2, open-label study using iptacopan in 27 patients with native (n = 16) or posttransplant C3G (n = 11), were recently published (NCT03832114).³¹ All patients received an 84-day (12-week) course of iptacopan, at a dose of 10 to 100 mg twice a day on days 1 to 21, and 200 mg twice a day on days 22 to 84. All patients in the native cohort were on maximally tolerated renin-angiotensin-aldosterone system inhibition, 5 were on concomitant treatment with MMF, and 3 were receiving glucocorticoids up to 7.5 mg/day of prednisolone. Proteinuria, the primary end point in this cohort, decreased from a mean 24h-UPCR of 401.9 g/mol to 220.1 g/mol at week 12 (45% reduction). The posttransplant cohort included patients at ≥90 days posttransplant, with a stable immunosuppression regimen (calcineurin inhibitors, n = 11; MMF n = 9; glucocorticoids, n = 9; azathioprine, n = 2; cyclophosphamide, n = 1) and no evidence of rejection. The primary end point for the posttransplant cohort was C3 deposit score (proteinuria was predominantly normal at baseline), which decreased significantly from baseline to day 84 by 2.5 (scale: 0–12). Kidney function remained stable throughout the study in both cohorts. Iptacopan treatment reduced sC5b-9 levels in plasma (from a mean of 1306 ng/ml to 398.8 ng/ml on day 84) and urine in the native cohort. In the posttransplant cohort, levels were comparable to healthy subjects at baseline, and remained stable. Both cohorts showed reductions in plasma Bb levels. All patients were vaccinated against N meningitidis, S pneumoniae and H influenzae prior to iptacopan treatment, and no infection by encapsulated bacteria were recorded.

Twenty-six of the 27 participants of this trial (16 with native C3G and 10 with posttransplant C3G) joined the extension study (NCT03955445) for long-term efficacy, safety, and tolerability of iptacopan. An interim analysis was performed after 12 months of treatment with iptacopan and presented in abstract form.³² Patients with native C3G showed a proteinuria reduction of 57%, an increase in eGFR by 6.83 ml/min per 1.73 m², and an increase in serum C3 by 253%. In patients with C3G in the allograft, eGFR was stable and serum C3 levels increased by 96%; proteinuria reduction was not assessed as median baseline proteinuria was already normal.

These preliminary results supported the rationale for a phase 3 study, the Alternative Complement Pathway Inhibition with Iptacopan for the Treatment of C3G trial (NCT04817618).³³ This randomized and placebo-controlled study, with an estimated enrollment of 83 adults and adolescents with native C3G,³³ will look at outcomes, including changes in UPCR, eGFR, activity score on renal biopsy and Functional Assessment of Chronic Illness Therapy-Fatigue score, as well as safety measurements, at 6 months and at 12 months, after an open-label 6-month phase of iptacopan treatment for all participants. As with the phase 2 iptacopan study, patients in the Alternative Complement Pathway Inhibition with Iptacopan for the Treatment of C3G trial have the open to enroll into an extension study after the 12-month study period.

Danicopan

Danicopan, formerly named ALXN 2040 or ACH 4471, is an orally administered small molecule that acts as a factor D inhibitor. Factor D is a serine protease that catalyzes the cleavage of factor B, therefore limiting production of AP C3 convertase C3bBb. It is produced mainly by adipose tissue, and circulating levels depend on kidney function, because it is filtered through the glomerulus and catabolized in the proximal renal tubule.³⁴ In vitro and in vivo studies showed that a very high level of factor D inhibition was needed to suppress the complement AP.³⁵

Danicopan was tested in 2 phase 2 studies. NCT03369236 included 13 patients with C3G and had a placebo-controlled 6-month period followed by an open-label extension period. NCT03459443 enrolled 22 patients with C3G or IC-MPGN and had a single-arm, open-label design. Data from patients from both studies were merged and published in 2 different articles. The first publication presented the baseline characteristics of 29 patients with C3G.³⁶ Systemic complement AP activation was confirmed by reduced levels of serum C3 and C5, elevated serum C5b-9 and normal C4. Renal function was inversely correlated with serum concentrations of Ba (a factor B breakdown product) and factor D; urine C5b-9 correlated with plasma sC5b-9 and proteinuria. AP activity biomarkers had a correlation with biopsy activity indices. The second article included all 35 patients and focused on clinical outcomes as well as pharmacokinetic or pharmacodynamic findings.³⁷ Optimal systemic concentrations of danicopan for complete and sustained inhibition of the AP were not reached, although there was evidence of suppressed AP activity shortly after drug administration. This resulted in limited and inconsistent clinical responses in participants.

These findings have led to the discontinuation of development of danicopan in C3G, whereas research studies for other complement-mediated conditions, such as paroxysmal nocturnal hemoglobinuria, are underway.

Vermircopan (ALXN2050, ACH-5228) is another orally active complement factor D inhibitor currently in development. Although it is currently not being studied among patients with C3G, there is a phase 2 clinical trial for patients with lupus nephritis and IgAN (NCT05097989).

NM8074

NM8074 is the first humanized monoclonal antibody targeting the C3/C3 convertase axis, and it does so by selectively binding Bb, blocking its catalytic activity, similar to iptacopan. This intravenous agent will be tested in a phase 1b/2a, open-label, dose-escalation study to evaluate the safety, efficacy, and immunogenicity in 18 adult patients with C3G (NCT05647811). Primary outcomes include change in UPCR, urinary albumin-to-creatinine ratio, eGFR, and incidence of adverse events. Phase 2 trials for NM8074 in paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy have also been registered.

ARO-C3

ARO-C3 is an RNA interference agent designed to reduce hepatic production of C3 and is currently being tested in a phase 1 study (NCT05083364) among healthy volunteers, followed by people with C3G and IgAN. This early study aims to recruit 60 participants with the purpose of evaluating the safety, tolerability, and pharmacokinetic or pharmacodynamic parameters. The company developing the drug shared the results of an interim analysis of the first part of the trial on healthy volunteers, showing an 88% mean reduction in serum C3 levels; a 91% mean reduction in AH50, a biomarker of AP hemolytic activity; along with a good safety profile.³⁸ The trial is still recruiting and moving forward to testing on participants with C3G and IgAN.

C5/C5 Convertase Inhibition

Terminal pathway activity seems to play a role in C3G phenotype, rather than the pathogenesis. C5 nephritic factors in C3G are usually found in conjunction with C3NeF, and are more prevalent among patients with C3 glomerulonephritis than those with dense deposit disease.³⁹ Similarly, patients with C3 glomerulonephritis show greater terminal activity than those with dense deposit disease when analyzing biomarkers for the C5 convertase activity such as low serum C5, elevated serum C5a and elevated soluble C5b-9.⁴⁰

The involvement of this axis in C3G has also been linked to disease severity. Intense deposition of C5b-9 in kidney biopsies has been correlated with renal function at diagnosis of C3G.⁶ In mice with FH deficiency, the addition of C5 deficiency caused a less severe phenotype, whereas the addition of C6 deficiency did not, pointing out a potential role not of the C5b-9 formation, but of the inflammation caused by anaphylatoxin C5a.⁴¹ Therefore, patients with evidence of terminal pathway activation should be especially suitable candidates for C5 inhibition.

As previously mentioned, direct C5 inhibition results in a higher risk of infection by encapsulated bacteria, notably N meningitidis, due to the blocking of C5b-9 (membrane attack complex [MAC]) generation.²³ Conversely, targeting C5a activity should maintain MAC formation and therefore pathogen lysis intact, with a milder repercussion on infection risk.

Eculizumab

Eculizumab laid the path for complement-targeting therapies. It was the first and only complement inhibitor available for treating glomerular diseases for many years. It is a humanized monoclonal antibody that targets an epitope of C5 involved in the binding to the AP C5 convertase, C3bBb3b, blocking the cleavage of C5 into C5a and C5b, and subsequently avoiding the formation of the MAC. First used as a therapy for paroxysmal nocturnal hemoglobinuria, eculizumab became a potential therapy for many other entities, as the role of complement in their pathophysiology gained recognition.

Eculizumab is currently available to treat C3G on an off-label basis, although, unlike in complement-mediated thrombotic microangiopathy (or atypical hemolytic uremic syndrome), the benefit of eculizumab in C3G appears to be somewhat limited.

The first clinical trial of eculizumab in patients with C3G, a proof-of-concept, open-label study included 6 participants with C3G who received intravenous infusions of eculizumab biweekly for 1 year. Whereas renal function or proteinuria improved in 4 participants, 2 experienced worsening renal function. Elevation of sC5b-9 was proposed as a potential predictor of response.⁴²

In another phase 2 open-label study, 10 patients with MPGN or C3 glomerulonephritis were given eculizumab for two 48-week periods, separated by a 12-week washout period. Suppression of the terminal pathway was achieved, measured by normalization of sC5b-9 in all patients. However, only 3 patients reached partial remission, and the other 7 were deemed nonresponders. The presence of C3NeFs was posed as a potential predictor for poor response.⁴³

Two retrospective studies have also contributed to the description of response to eculizumab among patients with C3G. A case series of 26 patients with C3G, 13 of them children or adolescents, reported that after a median time of 14 months of treatment, there was no response in 14 patients, 6 achieved partial response, and 6 achieved global response. Compared with the rest, the 6 patients with a global response had worse kidney function, a more rapidly progressive course and more extracapillary proliferation on kidney biopsy at baseline. The authors proposed that the response may have been a consequence of reduced glomerular inflammation via C5a inhibition, rather than the reduction of complement deposition.⁴⁴ In a recently published study, 11 of 14 included patients with C3G were given eculizumab for a median of 10 months. At the end of treatment, none of them experienced an improvement in eGFR, 6 had a stable renal function, and the other 5 had worsened.⁴⁵

Avacopan

Avacopan (CCX168), an orally administered small molecule, is a C5a receptor antagonist that inhibits the binding of C5a to its receptor C5aR1. C5a is a product of the cleavage of C5 and, through interacting with C5aR1, acts as a potent anaphylatoxin. It increases vascular permeability, induces oxidative bursting and release of proinflammatory cytokines in myeloid cells, and has a chemotactic effect on myeloid and lymphoid cells.⁴⁶ Because avacopan does not affect MAC formation, it potentially has less impact on the defense against microbes, especially encapsulated organisms, when compared to a global C5 inhibitor.

After showing positive results as an adjunctive therapy to standard-of-care induction therapy in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis, avacopan is being tested in other glomerular diseases, one of them C3G.⁴⁷ The ACCOLADE trial (NCT03301467), a phase 2, randomized, placebo-controlled trial has recently been completed. Fifty-two participants with C3G were assigned to receive avacopan (3 capsules twice daily) versus a matched placebo for 26 weeks, after which all participants received the study drug for another 26 weeks in the open-label phase. Preliminary results were presented in abstract form⁴⁸ and showed improvement in eGFR and proteinuria alongside a reduction of disease chronicity progression at week 26 in the patients receiving the study drug. However, the study’s primary outcome of changes in disease activity were no different between active and placebo arms. Reductions in disease chronicity progression were also observed at week 52 in patients that switched from placebo to avacopan.⁴⁸

Dual C3 and C5 Inhibition

KP104

KP104 is currently the first and only anticomplement therapy with a dual action, inhibiting both the C3 and C5 axis, to be tested in human trials. It is an anti-C5 immunoglobulin G4 monoclonal antibody that inhibits C5 cleavage, fused with 5 short consensus repeats of human FH, which blocks AP C3 convertase activity.

An open-label phase 2 trial (NCT05517980) is aiming to recruit 52 participants with C3G or IgAN to evaluate the efficacy, safety, and pharmacokinetic or pharmacodynamic of KP104. After determining the optimal biologic dose in stage 1 of the study, participants in stage 2 will receive this subcutaneous agent weekly or biweekly during a 48-week maintenance period. The primary outcome is change in UPCR at week 24, and secondary outcomes include change in eGFR at week 24 as well as pharmacokinetic or pharmacodynamic parameters and safety events at week 56.

Lectin Pathway Inhibition

The lectin pathway is activated when molecules such as mannose-binding lectin, collectins, or ficolins, recognize polysaccharides in the surface of pathogenic bacteria, antibodies, or immune complexes. They then form a trimolecular complex with mannose-binding lectin-associated serine protease 1 and 2, which cleaves C4 and C2 to form the lectin pathway C3 convertase (C4bC2b) (Figure 1).

The lectin pathway has been proposed as a contributing mechanism in different glomerular diseases such as membranous nephropathy and IgAN; however, the implication in C3G pathogenesis has not been well-established. In a minority of patients with C3G, a C4 nephritic factor, an autoantibody able to bind to and stabilize C4b2a, can be found.⁴⁹ Mannose-binding lectin-associated serine protease 1 and 3 have been shown to activate profactor D in the AP, although a deficiency of mannose-binding lectin-associated serine protease 1 or 3 did not reduce complement activation in an experimental model of C3G.⁵⁰

Narsoplimab

The only therapy currently being tested for lectin pathway inhibition in complement-mediated diseases is narsoplimab (OMS721), a human monoclonal antibody that targets mannose-binding lectin-associated serine protease 2. A phase 2 study aimed to include 54 participants with IgAN, membranous nephropathy, lupus nephritis and C3G (NCT02682407). Participants received intravenous or subcutaneous narsoplimab once weekly, and the outcome measures included safety profiling as well as changes in proteinuria, albuminuria and complement levels. Positive results in patients with IgAN were published, although there is no available data on the C3G cohort.⁵¹

With our current understanding of C3G pathophysiology, it is not clear that mannose-binding lectin-associated serine protease 2 inhibition will significantly block complement activation in C3G.

Experimental Therapies

Several agents have been studied in preclinical trials with positive in vitro and in vivo results in complement AP downregulation and glomerular deposit reduction.

Different experimental agents have targeted the complement AP at the level of C3. A small interfering RNA targeting liver C3 expression was used for 7 months in an experimental C3G model of mice with heterozygous deficiency of FH. After monthly administration for 7 months, there was proof of limitation of fluid-phase AP activation and reduction of glomerular C3d deposits.⁵² A recombinant complement receptor of the immunoglobulin superfamily was designed to bind C3b, thereby inhibiting the AP C3 and C5 convertases. Used on mice with sequence variants in the FH and properdin genes, this agent diminished the activity and consumption of plasma C3, factor B, and C5, as well as reduced proteinuria, hematuria, blood urea nitrogen, glomerular C3 fragments, C9 and fibrin glomerular deposition, and glomerulonephritis pathology scores.⁵³

Factor B, primarily of hepatic synthesis, has been the target of another small interfering RNA. Factor B silencing was used in mice with complete or partial loss of function of FH. The small interfering RNA did not achieve significant benefits in those with a homozygous deletion of FH, who showed a severe C3G phenotype, with almost complete C3 consumption and strong glomerular C3 deposition. However, among mice with a heterozygous deletion of FH, the ones resembling human C3G the most, it normalized circulating C3 levels and reduced glomerular C3 deposits.⁵⁴

Finally, attempts at exploiting the inhibitory role of FH have been tried with different therapies for over a decade. After the first demonstration of glomerular C3d deposit reduction administering human FH, more engineered and potent molecules are emerging, such as a recombinant mouse protein composed of domains from complement receptor 2 and complement receptor 2-FH, a synthetic fusion protein with regulatory domains of FH as well as FH-related protein 1, and homodimeric mini-FH constructs using FH short consensus repeats. These agents have shown in vitro and in vivo increases of plasma C3 levels as well as reductions in glomerular C3d and C5b-9 deposits.55, 56, 57

Challenges Ahead

Over the past decade, we have seen great advancements in our understanding of C3G as well as in the use and development of complement inhibitors; however, some major questions remain unanswered. Carefully conceived clinical trials have a key role to fill in those knowledge gaps.⁵⁸

Identifying which patients will benefit most from these therapies is one of them. Patients with a poor prognosis clearly constitute a population worth considering for novel therapies. Predictors of kidney failure known to date include proteinuria and kidney function at diagnosis, longitudinal change in proteinuria, presence of cellular or fibrocellular crescents and chronicity features in kidney biopsy, such as interstitial fibrosis or tubular atrophy and segmental sclerosis.^4,5,11,59, 60, 61 Baseline and repeat biopsies should be part of clinical trial protocols to try to consolidate these prognostic parameters and possibly establish a correlation between tissue findings and less invasive tests.

Elucidating the most suitable therapy for each patient also represents a challenge. With the variety of agents potentially emerging, finding the driver of the disease in each case through genetic testing and complement assays could be key to guide treatment. Ideally, abnormalities in different components of the AP could be specifically targeted. Complement biomarkers are needed and should be included in clinical trials to help us identify predictors of response to treatment and markers of treatment efficacy. In accordance with this etiological approach, some authors have reported a better response to immunosuppression with MMF and corticosteroids among patients with C3NeF compared with those with genetic causes.^9,22 Whether complement inhibition should be an additive or a substitute for classic immunosuppression is also up for debate.

Long-term safety is another concern, as previously explained, especially with an expected long duration of therapy in most cases. Reliable biomarkers could potentially help titrate anticomplement drugs according to disease activity in order to minimize exposure.

Conclusion

Complement inhibition is showing promising results in the treatment of C3G as well as other complement-mediated disorders. This strategy has the potential to provide patients with targeted therapy and possibly avoid the toxicity from nonspecific immunosuppressive agents such as corticosteroids. Nevertheless, some uncertainties and concerns need to be elucidated before we can confidently use these agents in patients with C3G, chief among them safety and long-term outcomes.

We know from experience using eculizumab that inhibiting the formation of MAC is associated with higher rates of infection by encapsulated bacteria, whereas the impact on opsonization and microorganism lysis with a more upstream AP inhibition is yet to be quantified. An interdisciplinary approach, including kidney biopsy phenotyping, genetic testing, and complement autoantibodies and function testing, can lead to the characterization of individual forms of C3G and subsequently to the selection of the best treatment choice. More accessible and noninvasive biomarkers of complement activity could additionally guide and monitor treatment response. Collaborative efforts need to keep growing to face the challenge of changing the natural course of this rare disease.

Disclosure

ASB has received consulting honoraria from Achillion/Alexion, Apellis, Catalyst, Chemocentryx/Amgen, Novartis, Silence, Visterra, and Q32. BTE declared no competing interests.