Novartis Reports Final Phase III ALIGN Data for Vanrafia in IgA Nephropathy

Novartis Reports Final Phase III ALIGN Data for Vanrafia in IgA Nephropathy

By, Admin 16 February 2026

Novartis announced final results from the Phase III ALIGN study evaluating Vanrafia (atrasentan) in adults with IgA nephropathy (IgAN), showing a slowing in kidney function decline compared with placebo.

At Week 136 (four weeks after treatment cessation), the difference in eGFR change from baseline versus placebo was:

  • +2.39 ml/min/1.73m²
  • Two-sided p = 0.057

At the end of treatment (Week 132), the difference was:

  • +2.59 ml/min/1.73m²
  • Nominal two-sided p = 0.039

Interpreting the Data: Statistically Borderline, Clinically Directional

The primary long-term eGFR endpoint narrowly missed conventional statistical significance (p<0.05) at Week 136.

However:

  • Results at Week 132 reached nominal statistical significance
  • Benefits were also observed in a prespecified exploratory subgroup receiving SGLT2 inhibitors
  • Safety remained consistent with prior data

The 2–2.6 ml/min eGFR preservation over ~2.5 years suggests disease-modifying potential, though magnitude and statistical robustness will be debated.

Disease Context: Why This Matters?

IgA nephropathy:

  • Is a progressive autoimmune glomerular disease
  • Causes proteinuria and chronic inflammation
  • Leads up to 50% of patients with persistent proteinuria to kidney failure within 10–20 years

Standard care typically includes:

  • Renin–angiotensin system (RAS) inhibitors
  • Increasingly, SGLT2 inhibitors

Despite these, residual progression risk remains high.

Mechanism and Positioning

Vanrafia is a highly selective endothelin A (ETA) receptor antagonist. The endothelin pathway:

  • Promotes inflammation and fibrosis
  • Drives proteinuria and structural kidney damage

Unlike dual endothelin receptor blockers associated with hepatotoxicity and REMS requirements, Vanrafia:

  • Is ETA-selective
  • Does not require a REMS program
  • Is once-daily oral
  • Can be added without titration

Liver monitoring remains recommended.

Competitive and Portfolio Context

Novartis is building a multi-asset IgAN portfolio that includes:

  • Fabhalta
  • Investigational zigakibart

This positions the company across:

  • Complement pathway inhibition
  • Endothelin blockade
  • Potential future combination strategies

The IgAN landscape also includes emerging competitors targeting complement, B cells, and other inflammatory mediators.

The strategic question becomes:

Will endothelin blockade become foundational background therapy alongside RAS and SGLT2 inhibition?

Clinical Significance vs Regulatory Interpretation

Key considerations:

  • The 136-week p-value of 0.057 may invite scrutiny
  • The Week 132 result reached nominal significance
  • Longest follow-up among pivotal IgAN trials strengthens durability claims

Regulators will evaluate:

  • Totality of evidence
  • Consistency across endpoints
  • Clinical relevance of eGFR preservation
  • Safety differentiation

Strategic Takeaway

ALIGN reinforces Vanrafia’s potential as:

  • A foundational oral add-on therapy
  • A complementary mechanism to RAS and SGLT2 inhibition
  • A pillar within Novartis’ expanding kidney franchise

However, the borderline statistical result at final follow-up tempers the narrative.

Commercial success will likely depend on:

  • Label language
  • Physician confidence in long-term renal protection
  • Positioning within multi-drug regimens

For Novartis, the broader strategy is clear:

Build a multi-mechanism, disease-modifying IgAN platform aimed at delaying dialysis and transplantation.

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