Iptacopan (Fabhalta) has demonstrated a clinically meaningful reduction in proteinuria in patients with IgA nephropathy, according to interim results from the phase III APPLAUSE-IgAN study. The trial's findings, presented at the American Society of Nephrology Kidney Week meeting, suggest a potential new treatment avenue for this rare kidney disorder.
The study, which included an initial cohort of 250 randomized patients, revealed that iptacopan led to a 38.3% reduction (95% CI 26.0-48.6, P < 0.001) in the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio (UPCR) compared to placebo at month 9. Dana V. Rizk, MD, of the University of Alabama at Birmingham, highlighted that this reduction is likely to translate to important clinical benefits for kidney function. The results were simultaneously published in the New England Journal of Medicine.
Complement Pathway Biomarker Changes
Further analysis of the data showed significant changes in complement pathway biomarkers. Urinary sC5b-9 levels, a marker of complement activation in the kidneys, decreased by a median of 97.6% in the iptacopan arm, reaching levels comparable to those in healthy volunteers. In contrast, the placebo group saw a median increase of 47% by month 9. Plasma sC5b-9 also decreased with iptacopan (-17.2% vs -2.1% with placebo), while C4 serum levels remained relatively stable in both groups (-2% vs -3.8%, respectively).
These changes are consistent with the drug's mechanism of action as a selective alternative pathway inhibitor. Specifically, the study reported the following median changes from baseline:
- Bb plasma: -21.1% with iptacopan vs 2.1% with placebo
- Wieslab serum: -89.4% vs 0%
- C3 serum: 16.4% vs -4.3%
Accelerated Approval and Future Considerations
Iptacopan received accelerated FDA approval in August 2024 as the first complement inhibitor indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid progression (UPCR of 1.5 g/g or above). The drug functions by inhibiting factor B in the alternative complement pathway.
Julie R. Ingelfinger, MD, NEJM deputy editor, noted that while the initial results are promising, it remains to be seen whether iptacopan can slow or halt the decline of kidney function in these patients. Data on the estimated glomerular filtration rate (eGFR) at the trial's completion in 2025 will be crucial for traditional approval.
The interim analysis included the first 250 patients from the main trial, which comprised 222 patients in the iptacopan group and 221 in the placebo group. Patients received 200 mg of oral iptacopan or placebo twice daily for 24 months, alongside supportive therapy. The average age of participants was 39, with 47.6% being women and 51.2% from Asia. The average eGFR was 62.7±26.0 mL/min/1.73 m2 in the iptacopan group and 65.5±26.7 mL/min/1.73 m2 in the placebo group. The median 24-hour UPCR was 1.81 in the iptacopan group and 1.87 in the placebo group.
Additional Findings and Safety Profile
The study also found that hematuria was no longer present at month 9 in 38.7% of the iptacopan group compared to 16.3% of the placebo group. Subgroup analyses showed consistent treatment effects across various stratifications, including sex, geographic region, baseline UPCR and eGFR, SGLT2 inhibitor use, hematuria level, MEST-C score, and prior use of glucocorticoids or immunosuppressants.
The rates of severe adverse events (AEs) and AEs leading to discontinuation were similar between the two groups (3.2% vs 3.2% and 2.7% vs 2.7%, respectively). The most common AEs in the iptacopan group included COVID-19 infection (14%), upper respiratory tract infection (9%), nasopharyngitis (5%), headache (4.1%), and hypertension (1.8%). No deaths or meningococcal infections were reported in either group.
The iptacopan label includes a boxed warning about an increased risk of infections caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b. Patients are advised to be up to date on their vaccinations for these bacteria at least 2 weeks before starting treatment.
