Novartis set to expand Vanrafia to IgA nephropathy after strong Phase III

Edited by Robert McTiernan··3 min read

Novartis announced positive results from the Phase III APPLAUSE-IgAN clinical trial evaluating Vanrafia (iptacopan) in patients with IgA nephropathy (IgAN). Vanrafia is an oral, proximal complement inhibitor targeting Factor B in the alternative pathway. The announcement represents a potential expansion of the iptacopan franchise into glomerular diseases, building on its existing regulatory footprint in hematology.

Trial specifics

The APPLAUSE-IgAN study is a multicenter, randomized, double-blind, placebo-controlled Phase III trial enrolling 470 adult patients with IgAN. Participants were randomized to receive either 200 mg of iptacopan twice daily or a placebo, in addition to supportive care consisting of maximally tolerated renin-angiotensin system (RAS) inhibition. The study utilized two primary endpoints to assess efficacy across different timeframes. The first primary endpoint, measuring the reduction in proteinuria at 9 months as determined by 24-hour urine protein-to-creatinine ratio (UPCR), was previously met. The newly released data focus on the second primary endpoint: the annualized total estimated glomerular filtration rate (eGFR) slope over 24 months.

The trial demonstrated a statistically significant and clinically meaningful reduction in the rate of kidney function decline for patients treated with iptacopan compared to placebo. Novartis reported that the safety profile of iptacopan in this population remained consistent with previously reported data, with no new safety signals identified. The double-blind portion of the study has concluded, and the data are expected to support global regulatory filings for full marketing authorization in this indication.

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Novartis stated that these results will be submitted to regulatory authorities globally, including the US FDA and the European Medicines Agency (EMA), to transition current accelerated or conditional approvals toward full approval. Shreeram Aradhye, President of Development and Chief Medical Officer at Novartis, noted that the data underscore the potential for iptacopan to provide a disease-modifying benefit by targeting the alternative complement pathway, which is a key driver of glomerular damage in IgAN.

Research context

Iptacopan is a small-molecule inhibitor of Factor B, a serine protease essential to the amplification loop of the alternative complement pathway. In IgAN, overactivation of this pathway leads to the deposition of immune complexes in the kidney’s mesangium, triggering inflammation and progressive fibrotic damage. By inhibiting Factor B, iptacopan seeks to halt this inflammatory cascade upstream of the terminal complement pathway. Vanrafia is currently unapproved for IgAN in many jurisdictions, though it received US FDA accelerated approval for the reduction of proteinuria in this indication in Q3 2024.

The IgAN therapeutic landscape has evolved rapidly, with several targeted therapies recently reaching the market or late-stage development. Key competitors include:

  • Calliditas Therapeutics’ Tarpeyo (budesonide), a delayed-release oral corticosteroid designed to release the drug in the ileum to target the mucosal immune system, which received full US FDA approval for IgAN in late 2023.
  • Travere Therapeutics’ Filspari (sparsentan), a first-in-class dual endothelin angiotensin receptor antagonist (DEARA) that received full US FDA approval in Q3 2024 based on the Phase III PROTECT study results.
  • Vertex Pharmaceuticals’ povetacicept, an antagonist of both BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand) being advanced into Phase III development following the acquisition of Alpine Immune Sciences.
  • Vera Therapeutics’ atacicept, a recombinant fusion protein that inhibits BAFF and APRIL, which is currently being evaluated in the Phase III ORIGIN trial.
  • Omeros Corporation’s narsoplimab, a human monoclonal antibody targeting MASP-2 in the lectin pathway of the complement system, which has faced regulatory delays following Phase III analysis.
  • Chinook Therapeutics’ (a Novartis company) atrasentan, an oral endothelin A receptor antagonist that met its primary proteinuria endpoint in the Phase III ALIGN study.