Novartis’s Iptacopan Secures IgAN Crown with Full Approval, Setting New eGFR Benchmark Amidst Rising Competition

Novartis' Fabhalta Gains Traditional FDA Approval for IgAN

Novartis announced that the US Food and Drug Administration (FDA) has granted traditional approval for Fabhalta (iptacopan) to slow kidney function decline in adults with primary IgA nephropathy (IgAN) at risk of disease progression. This approval, following an initial FDA accelerated approval in August 2024, was based on data from the Phase III APPLAUSE-IgAN study. Fabhalta demonstrated a statistically significant and clinically meaningful 48% slower annualized mean eGFR decline (-3.0 mL/min/1.73 m2/yr) compared to placebo (-5.7 mL/min/1.73 m2/yr) over two years, preserving kidney function. Clinically meaningful improvements in proteinuria were also observed as early as two weeks. Fabhalta is a first-in-class Factor B inhibitor targeting the alternative complement pathway, a key driver of inflammation associated with IgAN.

• The traditional FDA approval for Fabhalta (iptacopan) is based on robust data from the Phase III APPLAUSE-IgAN study, which showed a significant 48% reduction in the annualized mean decline of estimated glomerular filtration rate (eGFR) over two years. Patients treated with Fabhalta experienced an eGFR decline of -3.0 mL/min/1.73 m2/yr, compared to -5.7 mL/min/1.73 m2/yr for those on placebo, underscoring its role in preserving kidney function in adults with primary IgAN.
• Fabhalta is a first-in-class oral Factor B inhibitor that selectively targets the alternative complement pathway, a critical mechanism driving glomerular inflammation and kidney damage in IgAN. This targeted approach aims to reduce ongoing complement-mediated injury and slow disease progression, addressing the underlying cause of this chronic, immune-mediated kidney disease that can lead to kidney failure in a significant portion of patients.
• This traditional approval follows an initial FDA accelerated approval in August 2024 for the reduction of proteinuria in primary IgAN, reinforcing the drug's consistent efficacy profile. The APPLAUSE-IgAN study also confirmed Fabhalta's favorable safety profile, with the most common adverse events being abdominal pain, dizziness, and nausea. Due to an increased risk of serious infections from encapsulated bacteria, Fabhalta is available only through a Risk Evaluation and Mitigation Strategy (REMS) program.

The Persistent Challenges in Managing Progressive IgA Nephropathy

Despite being the most common primary glomerulonephritis worldwide, IgA nephropathy (IgAN) continues to lack a definitively established therapy, largely because its pathogenesis remains incompletely understood. This gap translates into substantial variability in clinical management, persistent disease progression in a meaningful proportion of patients, and guideline frameworks that are increasingly viewed as outdated relative to emerging evidence.

• Absence of established, evidence-based therapy: No definitive treatment standard exists for IgAN or related IgA vasculitis with nephritis (IgAV-N); the scarcity of rigorous clinical trials—particularly in pediatric populations—has led to wide variation in treatment approaches and suboptimal outcomes.

• Corticosteroid trade-offs: Corticosteroids remain a viable option and appear to mitigate risk associated with endocapillary proliferation, with transcriptomic data supporting a molecular basis for their efficacy in this subgroup. However, their protean cellular effects and significant toxicity require careful risk-benefit balancing, and their precise mechanism of action in modulating kidney injury remains poorly delineated. Notably, corticosteroid use has declined over time (e.g., in Denmark, 2002–2023), even as renin-angiotensin system inhibitors (RASi) remain the mainstay of treatment.

• Persistent proteinuria despite conservative management: A global survey of 869 patients (USA, China, Japan, France, Germany, Italy, Spain, UK) found that high-grade proteinuria (≥1 g/day) persisted across regions and treatment lines, even though most nephrologists adhered to conservative, guideline-consistent approaches. RASi (76.3%) and corticosteroids (42.8%) were the most commonly prescribed agents overall, with similar patterns in first-line settings.

• Suboptimal disease control: At the time of survey completion, 17.5% of nephrologists believed their patients' prescribed treatment was not achieving optimal disease control—underscoring a disconnect between guideline-based practice and real-world therapeutic adequacy.

• Long-term prognosis remains poor: Danish cohort data (2002–2023) show a 15-year risk of kidney failure with replacement therapy (KFRT) of 42.7% and 15-year all-cause mortality of 22.8%. Critically, there were no substantial improvements in 5-year KFRT or mortality risk over the two-decade study period, indicating stagnant prognosis despite evolving treatment patterns.

• Limitations of risk prediction tools: The International IgA Nephropathy Prediction Tool (IIgAN-PT) increasingly overestimates the risk of adverse renal outcomes in contemporary cohorts, complicating risk stratification and treatment decision-making.

• Outdated guideline frameworks: The KDIGO Controversies Conference (2017) concluded that most existing guideline recommendations—especially those addressing therapy—require revisiting by the guideline-updating Work Group, a need reaffirmed as of 2020.

• Diagnostic and disease heterogeneity: Highly variable clinical presentation and disease course often prolong and complicate the diagnostic pathway. This heterogeneity, combined with an evolving treatment landscape, creates significant challenges for both patients and healthcare providers throughout the clinical journey. Additional complexities include diagnostic classification issues for adult-onset IgA vasculitis and the need for age-inclusive clinical trial design.

• Emerging but still-maturing therapeutic pipeline: While landmark studies have reinforced the value of adding immunomodulatory drugs to supportive care for aggressive disease, and numerous novel agents with diverse mechanisms of action are in active development, these therapies are still being evaluated for their capacity to meaningfully slow or halt disease progression.

Fabhalta’s APPLAUSE-IgAN Data: Slowing Kidney Decline

Recent clinical investigations in IgA nephropathy (IgAN) continue to evaluate novel therapeutic approaches and refine existing treatment paradigms. Key studies have demonstrated the efficacy of B-cell targeted therapies like telitacicept, localized corticosteroids such as controlled-release budesonide, and combination strategies in specific patient populations, including pediatrics. The data highlight significant progress in reducing proteinuria and preserving kidney function.

Targeting Complement Activation: A New Era for IgAN Treatment

The pathogenesis of primary IgA nephropathy (IgAN) is best described by a "four-hit hypothesis," a sequential molecular cascade that drives disease development. The process is initiated by the production of galactose-deficient IgA1 (Gd-IgA1), characterized by aberrantly glycosylated O-glycans in the hinge region. These Gd-IgA1 molecules, believed to originate from B cells in mucosal-associated lymphoid tissues, act as autoantigens. This leads to the second hit: the generation of anti-Gd-IgA1 autoantibodies, which can be of either IgG or IgA isotypes. The binding of these autoantibodies to Gd-IgA1 results in the formation of pathogenic circulating immune complexes. The final step involves the deposition of these nephritogenic immune complexes within the glomerular mesangium, setting the stage for renal inflammation and injury.

Following deposition, these immune complexes trigger a damaging cellular response within the glomerulus. They activate resident mesangial cells, leading to their proliferation, the release of pro-inflammatory cytokines such as IL-6, and activation of the complement system. This cellular proliferation is partly driven by the enhanced expression of genes regulating the cell cycle, including the platelet-derived growth factor (PDGF)-EDG5 signaling pathway. PDGF upregulates the endothelial differentiation gene-5 (EDG5) receptor, which acts synergistically with its ligand, sphingosine 1-phosphate, to promote mesangial cell proliferation. This cascade of events results in the characteristic histopathological findings of IgAN, including mesangial hypercellularity and extracellular matrix expansion, which cause both glomerular and interstitial damage and ultimately lead to a progressive decline in kidney function.

The development of IgAN is also influenced by a complex interplay of genetic and regulatory factors. Genetic studies have identified specific susceptibility loci and copy number variants (CNVs) associated with the disease. For example, a loss-of-function CNV in a region of chromosome 3 containing the Toll-like receptor 9 (TLR9) gene has been linked to lower TLR9 expression and more rapid deterioration of renal function. Other candidate genes include Megsin (SERPINB7), which is predominantly expressed in the glomerular mesangium and upregulated in IgAN. Furthermore, non-coding RNAs are implicated in the disease process, playing important roles in regulating the expression of glycosyltransferases—the key enzymes responsible for the aberrant glycosylation of IgA1 that initiates the entire pathogenic sequence.