The Emerging Landscape of Alternative Pathway Complement Inhibitors

Dysregulation of the complement system can induce or exacerbate a wide range of disorders—from age-related macular degeneration (AMD) to rare, complement-mediated renal diseases and prothrombotic hematologic disorders—and contributes to excessive inflammation and tissue damage.^1-3 The current landscape of approved therapeutics targeting the complement system involves inhibitors of the classical and terminal pathways.^4-8 Alternative pathway-targeting therapeutics explore novel means of treating many complement-mediated diseases.^9-20 Some of these agents are highly selective for the alternative pathway, leaving the classical and lectin pathways intact; this could result in a lower infection risk compared with use of other complement inhibitors.^4-6,9,19,21 This article reviews the current landscape of therapeutics targeting the complement system and the emerging drugs targeting the alternative pathway to treat a wide range of diseases.

The Role of the Complement System

The complement system is a set of proteins that plays a central role in innate immunity, adaptive immune responses, and normal tissue homeostasis.^1,22 The classical, lectin, and alternative pathways activate the complement system via distinct mechanisms.¹ Upon activation on certain plasma and cell surfaces following recognition of danger signals, the complement system proteins are cleaved in a cascade-like fashion into bioactive components.^1,22 These actions ultimately lead to the direct lysis of pathogens, pathogen phagocytosis by immune cells, and assembly and stimulation of inflammatory cells.¹ Regulation of adaptive cellular immune responses and clearance of dead/dying cells and immune complexes from circulation are also functions of the complement system.¹ The ability to distinguish pathogens from host cells and control unwanted complement activation against the host are key to the regulation and homeostasis of the complement system.¹

Impact of Complement System Dysregulation

A network of proteins acts to regulate the complement system and protect the host from complement-mediated tissue damage.¹ Dysregulation of the complement system contributes to excessive inflammation and tissue damage and induces or exacerbates a wide range of disorders including various chronic renal disorders, prothrombotic hematologic diseases, and ocular conditions.^1,2 Table 1 lists many of the diseases and conditions in which the pathogenic role of the complement system has been at least partially elucidated in human or animal studies.^{1-5,7,9,22-41}

Complement system dysregulation results from a deficiency or overactivation of 1 or more regulatory proteins.^1,2 Regulatory protein deficiencies can be genetic or acquired.^1,2,25,42 Adverse activation of the complement system can occur following exposure to high levels of a pathogen, damage-associated stimuli, or foreign surfaces.² Uncontrolled conditions (eg, ischemia/reperfusion, sepsis, neurodegenerative disorders) can overwhelm regulatory proteins, resulting in excessive inflammation and complement-mediated tissue damage.¹

The Role of the Alternative Pathway

Identification of immune complexes and pattern recognition signals trigger the classical and lectin pathways, respectively; however, under normal physiological conditions, the alternative pathway is the dominant complement surveillance method.^22,43 The alternative pathway activates the complement system via the tick-over mechanism, in which low levels of complement protein 3 (C3) are constantly activated into C3b, which can deposit on any surface, ensuring prompt detection of pathogens or irritants.^22,43 The classical, lectin, and alternative pathways converge at the level of the C3 convertase, with C3 being a central component to the complement system (Figure).^22,43,44

Under normal physiological conditions, C3b is inactivated by complement regulators, preventing damage to healthy host tissue.²² Complement regulators are mostly absent from pathogens and cell debris; when C3b binds to pathogens and cell debris, the activation of C3 will amplify as a positive feedback loop, with the alternative pathway C3 convertase C3bBb being generated by factors B, D, and properdin.²² The alternative pathway is key to the amplification loop of the complement system, as any C3b deposited by 1 of the 3 pathways can activate C3bBb of the alternative pathway.¹ Factors B, D, and properdin are unique to the alternative pathway, with each playing a role in its activation and subsequent complement system amplification.^22,43,45 Additional regulators (eg, factors H and I) also play a role in complement amplification.⁴³

Burden of Alternative Pathway Dysregulation

Given the key role of the alternative pathway in the amplification of the complement system, its dysregulation has been implicated in several diseases, including AMD, C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), and antineutrophil cytoplasmatic autoantibody-associated vasculitis.^1,3,23,25,29 The alternative pathway is also an important contributor to the pathogenesis of conditions such as paroxysmal nocturnal hemoglobinuria (PNH), immunoglobulin (Ig) A nephropathy, lupus nephritis, membranous nephropathy, and antiglomerular basement membrane glomerulonephritis.^{9,22,24,26-28,30,31} Involvement of the alternative pathway has also been associated with conditions such as rheumatoid arthritis, asthma, ischemic stroke, and periodontal disease.^32,33,36,37

AMD

AMD is a disorder of the macula distinguished by drusen (yellow lesions at the basement membrane level of the retinal pigment epithelium [RPE]) or other RPE alterations.⁴⁶ Abnormalities of the RPE may include hypopigmentation, hyperpigmentation, or geographic atrophy, which is an advanced form of AMD involving the center of the fovea.⁴⁶ Activation of the alternative complement pathway has been implicated in the pathogenesis of AMD, with levels of complement proteins (eg, C3, factors B and D) increasing with disease progression.²³

AMD affects an estimated 1.75 million US adults 40 years and older.^46,47 Patient visual acuity may range from normal to severely impaired.⁴⁶ The results of 2 observational studies of patients with geographic atrophy secondary to AMD demonstrated that the lesion area caused by geographic atrophy substantially increased and visual function deteriorated over a 2-year period.⁴⁸ AMD is associated with a considerable economic burden in the United States; annual direct medical costs have been estimated to be $575 million (2004 US$).⁴⁹ Additionally, because of the accompanying visual impairment, patients are at risk for falls and fractures, which can add to the cost of care.^50,51

PNH

PNH is a rare, acquired hematopoietic stem cell disorder characterized by chronic hemolysis.^24,52 Somatic mutations in the PIGA gene lead to deficiencies in the complement inhibitory proteins CD55 and CD59, resulting in chronic complement-mediated hemolysis of affected erythrocytes.²⁴ The alternative pathway, with its constant low-level activation state, contributes to the chronic nature of the hemolysis.²⁴ Intravascular hemolysis resulting in moderate to severe anemia is a common clinical manifestation.²⁴ In this setting, anemia also may be a result of bone marrow failure.²⁴ Extravascular hemolysis of erythrocytes that survived intravascular hemolysis may also be present in patients treated with complement 5 (C5) inhibitors.²⁴ Thrombosis, particularly venous thrombosis, also may occur in patients with PNH.²⁴ Fatigue, dyspnea, hemoglobinuria, and abdominal pain are common symptoms of PNH.⁵³

PNH is associated with considerable health care resource utilization (HCRU) and high costs, particularly among the many patients who depend upon red blood cell (RBC) transfusions.^53,54 An analysis of 2014-2019 HCRU and cost data from IBM MarketScan Research Databases found that, among 151 patients 12 years and older being treated for PNH with eculizumab, those who were transfusion dependent had significantly higher all-cause direct medical costs than did those who were not. The adjusted per patient per year cost difference between those with 1 or more claims for blood transfusion within 6 months on or after the eculizumab treatment date (n = 55) and those who had no such claims (n = 96) was $247,848 (95% CI: $87,350-$445,161; P = .004) (2020 US$).⁵⁴

Renal Effects

IgA nephropathy, a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD), is the most common form of primary glomerular disease globally.²⁵ In the United States, the incidence rate has been reported to be up to 2.3 per 100,000 persons/year.⁵⁵ The underlying pathogenesis of IgA nephropathy is thought to involve complement activation leading to the formation of pathogenic immune complexes that result in mesangial deposition and glomerular injury.²⁶ Factor H and activation of the lectin and alternative pathways also occur.²⁶ The disease usually follows a slow, progressive course, with about 30% of affected patients developing ESRD within 25 years of initial presentation. Current management of IgA nephropathy focuses on supportive care to slow disease progression.²⁵ More than half of affected patients in the United States have stage 3 or higher CKD at the time of diagnosis.⁵⁵ Although limited information is available on the economic burden associated with IgA nephropathy in the United States, the US Centers for Disease Control and Prevention found that Medicare costs for patients with CKD were $87.2 billion in 2019; Medicare costs for patients with ESRD totaled an additional $37.3 billion.^55,56

C3G

C3G is a rare, complement-mediated, membranoproliferative glomerulonephritis characterized by C3-dominant fragment deposition resulting from alternate pathway dysregulation.^3,25 Patients may present with hematuria, kidney insufficiency, and a variable degree of proteinuria.⁵⁷ Renal outcomes are often poor; results from a study of renal biopsies archived at the University of Utah Department of Pathology from 2005 to 2015 showed that, of 9 patients with C3G (age, ≥ 49 years) who had follow-up of at least 1 year, about half (n = 4) developed ESRD requiring chronic hemodialysis. Disease recurrence following kidney transplantation was also reported in 1 patient.⁵⁷ The optimal treatment strategy for patients with C3G remains unclear, with current management focusing on supportive measures, and, in the case of moderate to severe disease, immunosuppression.²⁵

Membranous Nephropathy

Membranous nephropathy is a kidney disorder associated with nephrotic syndrome, often caused by antibodies against the M-type phospholipase A2 receptor.²⁵ The resulting subepithelial immunoglobulin deposits and activation of complement via the lectin and/or alternative pathway lead to injury of the glomerular basement membrane.⁹ Although spontaneous remission of membranous nephropathy may occur, some patients are at risk of progressive kidney function loss that results in ESRD.^25,58 Supportive therapy is the primary treatment for patients with membranous nephropathy and proteinuria, whereas immunosuppressive therapy is reserved for those at risk of progressive kidney injury.²⁵

In a 2019 study of 2012-2015 US commercial health insurance claims data for patients with idiopathic membranous nephropathy (N = 2689), 16% of patients had ESRD, 10% underwent dialysis, and 3.5% received a kidney transplant.⁵⁸ Costs associated with dialysis and kidney transplant (ie, outpatient hospital use and ESRD facility use) were the primary drivers of the HCRU differences seen between the 5% of patients who constituted the high-cost cohort (HCC) and the remaining 95% of patients (non high–cost cohort [NHCC]).⁵⁸ The HCC incurred 43.7% of total 1-year cost for all patients, which included hospitalization, emergency department, pharmacy prescription, and outpatient (outpatient hospital use, ESRD facility use, and office visits) costs paid by the patient and the commercial insurance plan. Mean per-patient 1-year costs for the HCC and NHCC were $401,608 and $27,154, respectively.⁵⁸

aHUS

aHUS is a very rare form of thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury resulting from endothelial cell damage involving the kidney vasculature.^25,42 The disease is often caused by genetic or acquired functional defects in complement regulatory proteins that lead to dysregulation of the alternative complement pathway at the surface of endothelial cells.^25,42 Prior to the introduction of complement inhibitors, the prognosis for patients with aHUS was poor, with most developing ESRD within 2 years of diagnosis.⁴² Current complement inhibitors offer the potential to prevent the progressive loss of kidney function, yet the clinical and treatment-related burdens associated with the disease remain substantial.^42,59,60

A 2022 modeling study estimated treatment costs for a population of patients in the United States with aHUS who were treated with the C5 complement inhibitors eculizumab or ravulizumab (n = 100). Results of the analysis demonstrated that annualized discounted treatment costs over a lifetime for adults and their caregivers, including lost productivity costs, could exceed $210,000 (2020 US$). Limitations of the study included its assumptions regarding patient characteristics, treatment patterns, travel times, and level of caregiver support.⁶⁰

Lupus Nephritis

Lupus nephritis is an immune complex-mediated glomerulonephritis that can develop in patients with the autoimmune disorder systemic lupus erythematosus (SLE).²⁵ Activation of different components of the complement system, including the alternative pathway, are thought to occur in lupus nephritis.^22,27,28 The prevalence of lupus nephritis among patients with SLE varies depending upon disease severity, with 1 study reporting rates of 8% for patients with mild SLE and 34% for patients with moderate/severe SLE between 2009 and 2016.⁶¹ The prevalence of ESRD among patients with lupus nephritis was 10.5% in a retrospective study of 2007-2019 Optum medical and pharmacy claims data for patients who received a diagnosis of SLE, had evidence of lupus nephritis, and had and at least 1 inpatient admission or at least 2 outpatient admissions separated by at least 30 days between January 2015 and December 2019 (N = 21,251). Additionally, all-cause medical costs for patients with lupus nephritis almost doubled during active disease periods (ie, during relapses or flares) compared with low disease–activity periods (mean, $4777/month vs mean, $2523/month; 2020 US$).⁶² Patients with ESRD had a mean monthly all-cause medical cost of $18,084, mainly driven by inpatient visit costs.⁶²

Myasthenia Gravis

Myasthenia gravis is a neuromuscular disorder in which an abnormal autoimmune, antibody-mediated response affects the neuromuscular junction, resulting in muscle weakness and fatigue.⁶³ Deposition of the terminal complement complex C5b-9, also known as the membrane attack complex, at the neuromuscular junction is thought to play a role in the pathogenesis of generalized myasthenia gravis.^4,5 In 2015, the prevalence of myasthenia gravis in the United States was estimated to be 14 to 20 cases per 100,000 people; the disorder remains underdiagnosed, however, and the prevalence is likely higher.⁶⁴ Patients with myasthenia gravis often report ocular involvement, ptosis, general fatigue, and weakness of arms, legs, hands, or fingers.⁶⁵ Many patients report moderate to severe symptoms despite receiving chronic treatment.⁶⁵

A study of Symphony Health Integrated Dataverse data identified US adults with at least 2 medical and/or pharmaceutical claims associated with myasthenia gravis between January 2014 and December 2019 (N = 41,490). Cost analysis of HCRU related to these claims estimated that patients with generalized myasthenia gravis with exacerbation events (N = 4355) had standardized 12-month mean all-cause (2018 US$) costs of $43,734 and direct costs for disease treatments of $21,550.⁶⁶

Current Treatment Landscape and Unmet Needs

The current landscape of approved therapeutics targeting the complement system is dominated by inhibitors of the classical and terminal pathways.^4-8 In 2007, eculizumab became the first complement inhibitor to receive FDA approval.⁶⁷ A second complement inhibitor, ravulizumab, was approved in 2018 and a few other agents have been approved more recently.^5-8 In addition, several other drugs targeting the classical and terminal pathways are being developed.^22,68,69

Eculizumab and ravulizumab are injectable terminal complement inhibitors that block the activity of C5, preventing the formation of the C5b-9 terminal complement complex.^4,5 These agents inhibit intravascular hemolysis mediated by the terminal complement in patients with PNH and complement-mediated thrombotic microangiopathy in patients with aHUS.^4,5 Both agents also are approved for the treatment of adults with generalized myasthenia gravis who harbor antiacetylcholine receptor antibodies.^4,5 Eculizumab also is approved for the treatment of adults with neuromyelitis optica spectrum disorder who harbor anti–aquaporin-4 antibodies.⁴ Both agents are under investigation as treatments for patients with one of several other diseases that may involve complement dysregulation including hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (eculizumab) and dermatomyositis (ravulizumab).^70,71

Pegcetacoplan is an injectable C3 inhibitor approved for the treatment of adults with PNH.⁶ This agent acts proximally in the complement system, regulating both C3b-mediated extravascular hemolysis and terminal complement–mediated intravascular hemolysis in PNH.⁶ In a phase 3 trial (NCT03500549), pegcetacoplan led to superior hemoglobin (Hb) level improvements compared with eculizumab in patients with PNH and baseline Hb levels less than 10.5 g/dL despite treatment with eculizumab.⁷² This agent is currently under investigation as treatment for patients with geographic atrophy secondary to AMD, cold agglutinin disease, and other diseases.⁷³

Sutimlimab is an injectable classical complement pathway inhibitor that blocks the activity of C1, inhibiting hemolysis in patients with cold agglutinin disease.⁷ This agent was approved in 2022 to decrease RBC transfusion requirements due to hemolysis in adults with cold agglutinin disease.⁷ Phase 1 trials of this agent have been conducted in patients with chronic immune thrombocytopenia (NCT03275454) and with 1 of 3 other complement-mediated diseases (bullous pemphigoid, warm autoimmune hemolytic anemia, or ESRD) (NCT02502903).^74,75

Avacopan is an oral C5a receptor antagonist that blocks the neutrophil activation and migration mediated by C5a.⁸ Avacopan was approved in 2021 in combination with standard-of-care (SOC) therapy for adults with severe active ANCA–associated vasculitis.⁸ Phase 2 trials of avacopan have been conducted for patients with C3G (NCT03301467), hidradenitis suppurativa (acne inversa) (NCT03852472), and IgA nephropathy (NCT02464891).^76-78

Limitations of Current Therapeutics

Despite demonstrated benefits in various complement-mediated diseases, use of inhibitors targeting the classical/lectin and terminal pathways is associated with limitations.^4-6,79,80 Some patients with PNH remain anemic and still require transfusions despite treatment with a C5 or C3 inhibitor.^72,80

An additional key limitation of these agents is the increased risk of infections resulting from blockage of the terminal complement pathway, which plays a key role in immune surveillance.^2,4-6 The prescribing information for eculizumab, ravulizumab, and pegcetacoplan all carry boxed warnings concerning the potential for serious and potentially life-threatening meningococcal infections.^4-6 The prescribing information for pegcetacoplan also specifically warns about the potential for serious infections caused by encapsulated bacteria (eg, Streptococcus pneumoniae, Neisseria meningitidis, Hemophilus influenzae type B).⁶ Patients should receive a meningococcal vaccine at least 2 weeks before initiating therapy with any of these agents; however, the risk of serious infection is not eliminated by vaccination.^4-6

Due to the risk for serious infections, eculizumab, ravulizumab, and pegcetacoplan are available only via a REMS (Risk Evaluation and Mitigation Strategy) program, which ensures that prescribers counsel patients on associated risks and that prevention strategies are in place.^4-6 Although they do not carry a boxed warning, the prescribing information for sutimlimab and avacopan include warnings about the potential for serious infections.^7-8 Use of sutimlimab may increase susceptibility to serious infections caused by encapsulated bacteria; pneumonia and urinary tract infections were the most common serious infections reported in patients treated with avacopan.^7-8

Emerging Therapeutics Targeting the Alternative Pathway

Emerging agents targeting the alternative pathway of the complement system employ novel means of treating both rare diseases (eg, PNH, complement-mediated renal disorders) and more common conditions (eg, AMD).^9-20 Preclinical data suggest that some of these agents are highly selective for the alternative pathway, leaving the classical and lectin pathways intact, which could lower infection risk compared with C3 and terminal complement inhibitors.^4-6,9,19,21

Iptacopan

Iptacopan (LNP023) is an oral small-molecule factor B inhibitor that was granted Breakthrough Therapy Designation (BTD) by the FDA for the treatment of PNH in 2020.^9,81 At that time, iptacopan also was granted Rare Pediatric Disease Designation for C3G.⁸¹ Based on the results of in vivo and in vitro studies, iptacopan is considered to be a highly potent factor B inhibitor capable of blocking the activation of the alternative pathway at the level of the C3 convertase.⁹ In addition, this agent is highly selective for factor B without having any inhibitory effects on factor D or blocking activation of the classical or lectin complement pathways.⁹ In the United States, iptacopan is being studied in patients with PNH, C3G, AMD, aHUS, primary IgA nephropathy, lupus nephritis, and idiopathic membranous nephropathy.^10-16

The BTD of iptacopan for PNH was based on positive interim results from two phase 2 studies that evaluated the safety, efficacy, pharmacokinetics, and pharmacodynamics of iptacopan in 2 patient populations. The first trial (NCT03896152) assessed outcomes in patients with PNH and active hemolysis who were complement treatment-naïve, whereas the second trial (NCT03439839) studied iptacopan in patients with PNH and active hemolysis despite treatment with SOC anticomplement agents.^81-83

NCT03896152 was a 2-cohort, open-label, proof-of-concept study across centers in Korea, Taiwan, Malaysia, and Singapore, in patients with PNH and active hemolysis and no prior complement inhibitor treatment within 3 months of enrollment.⁸² Based on data from 12 evaluable patients, all participants experienced reductions in serum lactate dehydrogenase (LDH) levels of at least 60% by week 12 compared with baseline, meeting the primary end point of the trial.⁸² This improvement corresponded with hematologic benefit including clinically meaningful improvement in mean Hb levels, and all but 1 patient (with preexisting myelodysplastic syndrome)remained transfusion-free until at least week 12.⁸² None of the patients experienced serious or severe infectious events.⁸²

In NCT03439839, an open-label, single-arm, phase 2 proof-of-concept trial in Europe, iptacopan was evaluated as an add-on treatment to SOC anti-C5 treatment with eculizumab in 10 patients with PNH and signs of active hemolysis despite use of eculizumab.⁸³ After 13 weeks of treatment with iptacopan, all patients experienced improvements in LDH levels (a marker of active hemolysis), with reductions of 34% to 81% compared with baseline levels.⁸³ Additionally, significant improvements from baseline in Hb levels were observed in all patients in the absence of RBC transfusions (P < .0001).⁸³ Data from follow-up demonstrated that 7 patients were able to discontinue eculizumab and continue iptacopan monotherapy while maintaining a hematologic response for at least 3 months.⁸³ All patients were vaccinated against N meningitidis, H influenzae, and S pneumoniae infection, and no serious infectious events were reported.⁸³

Results from the phase 3 APPLY-PNH trial (NCT04558918) were recently presented at the 64th ASH Annual Meeting and Exposition on December 13, 2022, in New Orleans, Louisiana.⁸⁴ Patients (N = 97) were randomly assigned 8:5 to either receive iptacopan monotherapy (200 mg twice daily) or to continue SOC regimen of either eculizumab or ravulizumab for 24 weeks. More than half of the patients (64.9%) had previously received treatment with eculizumab and 35.1% had received treatment with ravulizumab (mean treatment duration: 4 years). Iptacopan monotherapy achieved both primary end points and showed superiority vs SOC. A total of 85% of the patients treated with iptacopan (51/60) experienced an Hb increase from baseline of at least 2 g/dL and 70% (42/60) achieved an Hb of at least 12 g/dL, irrespective of RBC transfusions, compared with none of the patients on SOC (0/35) (P < .0001 for both). No deaths or treatment discontinuations occurred. Patients treated with iptacopan more frequently reported headache (16.1% vs 2.9%) or diarrhea (14.5% vs 5.7%) and less frequently experienced infestations/infections (38.7% vs 48.6%) or clinical breakthrough hemolysis (3.5% vs 17.1%) than did those treated with SOC.⁸⁴ The ongoing phase 3 APPOINT-PNH trial (NCT04820530) is examining the safety and efficacy of iptacopan 200 mg twice daily as a monotherapy in patients who are naïve to complement inhibitor therapy.⁸⁵

Iptacopan also was investigated in an open-label, 2-cohort phase 2 study of patients with C3G (NCT03832114). Results presented at the American Society of Nephrology 2021 Annual Meeting showed that primary end points were met in both cohorts.^86,87 Patients with C3G who had received kidney transplant (native C3G; n = 16) experienced a 45% reduction in proteinuria (measured by 24-hour urinary protein-to-creatine ratio) from baseline (P = .0003). Patients with C3G who had previously received kidney transplant, and for whom data were available (n = 7), experienced a significant reduction in C3 protein deposits (obtained from kidney biopsy at week 12 compared with baseline) compared with baseline (P = .0313).⁸⁷ The phase 3 APPEAR-C3G trial (NCT04817618), currently in the recruiting stage, will evaluate the efficacy and safety of iptacopan compared with placebo and SOC therapy in adults with native C3G.^11,88

Iptacopan therapy also demonstrated positive results in patients with IgA nephropathy.⁸⁹ A phase 2 trial (NCT03373461) met its primary end point by demonstrating a significant dose-response reduction of proteinuria in patients treated with iptacopan (n = 87) vs placebo (n = 25) in patients with IgA nephropathy after 90 days of treatment (P = .038).^89,90 The phase 3 APPLAUSE-IgAN (NCT04578834) trial is currently recruiting patients; investigators will evaluate the safety and efficacy of iptacopan in patients with primary IgA nephropathy receiving background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy.¹⁵

IONIS-FB-L_RX

IONIS-FB-L_RX, an antisense oligonucleotide targeting complement factor B production by hepatocytes, is being studied for the treatment of geographic atrophy secondary to AMD and of primary IgA nephropathy.^91,92 The results of a phase 1 trial (NCT03101878), found that multiple-dose subcutaneous administration of IONIS-FB-L_RX was associated with dose-dependent reductions of factor B plasma levels of up to 72% in healthy individuals (N = 54).⁹¹ These results led to current recruiting for the adaptive design, double-masked, placebo-controlled, phase 2 GOLDEN study of IONIS-FB-L_RX in patients with geography atrophy secondary to AMD.^91,93 In NCT04014335, a phase 2 trial, among patients with primary IgA nephropathy, treatment with IONIS-FB-L_RX was associated with positive changes in 24-hour urinary protein level at 29 weeks compared with baseline, meeting the trial’s primary end point.^92,94 Based on these findings, plans for a phase 3 trial evaluating IONIS-FB-L_RX in patients with IgA nephropathy are underway.⁹²

Lampalizumab

Lampalizumab is an antigen-binding fragment that targets factor D, blocking activation of the alternative pathway at the level of C3 convertase.^45,95 In the MAHALO phase 2 trial (NCT01229215), patients with geographic atrophy due to AMD (N = 129) were randomly assigned to receive intravitreal lampalizumab or sham injections.⁹⁵ After 18 months, patients given lampalizumab monthly experienced a 20% reduction in the mean change in progression of geographic atrophy area compared with patients in the pooled sham group (80% CI, 4%-37%; P = .117), meeting the prespecified significance level for this proof-of-concept study.⁹⁵

Lampalizumab was subsequently evaluated in Chroma (NCT02247479) and Spectri (NCT02247531), 2 identically designed, phase 3, randomized, multicenter trials in adult patients (aged ≥ 50 years) with bilateral geographic atrophy secondary to AMD and no prior or current evidence of choroidal neovascularization.⁹⁶ A total of 906 patients in Chroma and 975 patients in Spectri were randomly assigned to different cohorts to receive lampalizumab or sham injections.⁹⁶ The primary end point of adjusted mean change in geographic atrophy lesion area from baseline to 48 weeks was 1.93 to 2.09 mm² across all groups in the 2 studies.⁹⁶ Robustness assessments for this end point failed to demonstrate a benefit of lampalizumab over sham therapy.⁹⁶ In clinical subgroup analyses, no consistent benefit in any of the subgroups was demonstrated for lampalizumab over sham.⁹⁶ Because these two phase 3 trials failed to meet their primary end point, FDA approval for the use of lampalizumab in this setting is no longer being pursued.⁹⁷

Danicopan

Danicopan (ALXN2040) is an oral, small-molecule, factor D inhibitor being studied in patients with PNH and in those with geographic atrophy due to AMD.^18,19,98,99 In 2019, based on positive phase 2 (NCT03472885) trial data, danicopan was granted BTD by the FDA for the treatment of PNH as an add-on therapy to a C5 inhibitor.^100,101 Danicopan was previously evaluated in patients with C3G, but phase 2 data demonstrated suboptimal clinical response with incomplete inhibition of the alternative pathway; thus, this agent is no longer being studied for this indication.¹⁰² Phase 1 safety, pharmacokinetic, and pharmacodynamic studies of danicopan have been completed in patients with hepatic or renal impairment (NCT03555539 and NCT04935294), although results are not currently available.^103,104 A phase 2 trial evaluating danicopan in geographic atrophy due to AMD (NCT05019521) currently is recruiting participants.⁹⁸

An international, single-arm, dose-finding, phase 2 trial (NCT03053102) evaluated danicopan in 10 patients with hemolytic PNH who were not receiving treatment with a complement inhibitor.¹⁰⁵ The trial met its primary efficacy end point, with all patients demonstrating a significant reduction in mean LDH level from baseline to day 28 (P < .001).¹⁰⁵ Danicopan was associated with an improvement in anemia, with mean Hb values increasing from 9.8 g/dL at baseline to 10.9 g/dL at day 28 and 11.5 g/dL at day 84 (all P < .005).¹⁰⁵ Benefits also were observed in patient-reported outcomes, with the mean Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score among patients improving by 9 and 13 points at day 28 and 84, respectively (P < .05).¹⁰⁵ No severe infectious events were reported in this trial.¹⁰⁵

A different multicenter, open-label, phase 2 trial (NCT03472885) evaluated danicopan as add-on therapy in 12 patients with PNH who had an inadequate response to eculizumab.¹⁸ Findings after 24 weeks of danicopan treatment demonstrated a significant increase in mean Hb value from baseline, with a mean increase of 2.4 g/dL (P = .0001).¹⁸ This improvement was observed by the second week in most patients and was sustained for the duration of the study.¹⁸ Although no change in the mean LDH level was noted, favorable results in other laboratory markers (eg, mean absolute reticulocyte counts, total bilirubin, direct bilirubin) were observed.¹⁸ Additionally, a clinically meaningful decrease in the number of patients requiring RBC transfusion was noted during the 24 weeks of treatment.¹⁸ Patient-reported outcomes also improved from baseline in patients treated with danipocan and included in the efficacy analysis (n = 11), with improvements in FACIT–Fatigue score noted at week 24 (P = .0191).¹⁸ One serious adverse event (ie, pneumonia from viral bronchitis) was reported in a patient with history of neutropenia, although it was deemed to be unlikely related to danicopan treatment.¹⁸

The ongoing, phase 3 ALPHA trial (NCT04469465) is evaluating danicopan vs placebo as add-on treatment to a C5 inhibitor (eculizumab or ravulizumab) in patients with PNH with clinically evident extravascular hemolysis (Hb ≤ 9.5 g/dL and absolute reticulocyte count ≥ 120 x 10⁹/L).⁹⁹ Based on a prespecified interim analysis, add-on danicopan was associated with results superior to those of placebo, with the trial meeting its primary end point of improved Hb levels from baseline to week 12.¹⁷ Additionally, add-on danicopan was associated with improvements over placebo in key secondary end points, such as avoidance of transfusion and change in the FACIT–Fatigue score from baseline.¹⁷

Vemircopan

Vemircopan (ALXN2050) is an oral factor D inhibitor that inhibits the alternative pathway in a near complete and sustained manner, as demonstrated in two phase 1 studies of healthy volunteers (NCT05047458 and NCT05047484).^102,106-109 This agent is currently being studied in patients with lupus nephritis, IgA nephropathy, PNH, and generalized myasthenia gravis.^110-112 A randomized, multicenter, placebo-controlled, phase 2 trial (NCT05097989) currently in the recruiting stage will evaluate vemircopan as an add-on treatment to SOC background therapy in adults with either lupus nephritis or IgA nephropathy.¹¹⁰ A randomized, placebo-controlled, phase 2 trial evaluating vemircopan in patients with generalized myasthenia gravis (NCT05218096) also is currently recruiting.¹¹² Outside the United States, this agent is being studied as monotherapy in an ongoing phase 2 trial of patients with PNH (NCT04170023); it includes those who are treatment-naïve, those who have had an inadequate response to eculizumab, and those who previously received danicopan.¹¹¹ In an interim analysis, among patients who had completed 12 weeks of vemircopan 120 mg monotherapy twice daily (n = 9), mean (SD) Hg increased by 3.9 g/dL (1.11 g/dL); no serious or treatment-emergent adverse events (TEAE) of grade 3 or higher, discontinuations, or deaths were reported, and headache–the most common TEAE–occurred in 36.4% of patients.¹¹³

BCX9930

BCX9930 is an oral factor D inhibitor that has demonstrated complete suppression of the alternative pathway and blockage of both erythrocyte hemolysis and accumulation of C3 fragments on PNH erythrocytes in preclinical studies.¹¹⁴ In a phase 1/2 trial (NCT04330534), BCX9930 treatment was associated with greater than 99% suppression of the alternative pathway among both healthy individuals and patients with C3G.¹¹⁵ The ongoing phase 2 REDEEM-1 and REDEEM-2 trials will evaluate BCX9930 monotherapy among patients with PNH and residual anemia despite treatment with a C5 inhibitor and those not receiving complement inhibitor therapy, respectively (NCT05116774 and NCT05116787).^116,117 Outside the United States, BCX9930 is being evaluated in an ongoing, open-label, proof-of-concept, phase 2 trial (RENEW; NCT05162066) among patients with C3G, IgA nephropathy, or membranous nephropathy.¹¹⁸

GT005

GT005 is an investigational, 1-time gene therapy that works by increasing production of the factor I protein, leading to decreased levels of key downstream proteins associated with complement system activation.²⁰ The ongoing phase 1/2 FOCUS trial (NCT03846193) is evaluating the safety, dose response, and efficacy of a single subretinal injection of GT005 administered to genetically defined patients with macular atrophy due to AMD.¹¹⁹ Interim data from 13 patients demonstrated that most patients (n = 11) experienced significant increases in levels of factor I compared with baseline (P = .002). Significant average decreases of 46% were observed for vitreous levels of Ba protein in 11 patients and C3 breakdown proteins in all 13 patients, compared with baseline (both P = .001).²⁰ Investigators on the phase 2 HORIZON (NCT04566445) and EXPLORE (NCT04437368) trials are currently recruiting; each will evaluate 2 doses of a single subretinal injection of GT005 in patients with geographic atrophy secondary to AMD.^120,121

CLG561

CLG561, an antiproperdin antigen-binding fragment that inhibits activation of the alternative pathway, was studied in patients with geographic atrophy.^122,123 A phase 2, proof-of-concept study (NCT02515942) evaluated intravitreal injection of CLG561 as monotherapy and with LFG316, vs sham injections, in 114 patients with geographic atrophy.¹²³ After 12 injections administered every 28 days, treatment with CLG561 failed to show efficacy for the primary outcome of change in geographic atrophy lesion size from baseline.¹²³

These alternative pathway–targeting therapeutics under development are included in Table 2.^{9-16,18-20,22,45,81,85,91,93-95,97-100,106,107,110-112,115-123,125,126}

Conclusions

Complement system dysregulation is associated with a wide range of diseases.^1-3 Currently available complement inhibitors have demonstrated treatment benefits in various diseases; still, their use is associated with limitations, including lack of response in certain patients and an increased risk of infections.^{4-6,72,79,80,124} Alternative pathway­–targeting therapeutics are a promising novel strategy to treat many complement-mediated diseases.^9-20 Some of these agents are highly selective for the alternative pathway; by leaving the classical and lectin pathways intact, their use could result in a lower infection risk compared with other complement inhibitors.^4-6,9,19,21 Several ongoing trials are exploring the role of these promising agents in various diseases.^{10-16,98,99,120,121}

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