Vertex has announced positive data from a pre-specified week 36 interim analysis of the ongoing phase 3 Rainier trial of povetacicept, an engineered fusion protein and dual inhibitor of the BAFF (B cell activating factor) and APRIL (a proliferation inducing ligand) cytokines, in immunoglobulin A nephropathy (IgAN).
The trial met its primary objective. In the interim analysis population, patients treated with povetacicept achieved a 52.0% reduction from baseline in urine protein to creatinine ratio (UPCR) at week 36, with a statistically significant and clinically meaningful 49.8% UPCR reduction compared to placebo (P<0.0001). The reduction in proteinuria was consistent across all pre-specified subgroups.
The trial also met its secondary objective. For the first secondary endpoint, patients treated with povetacicept demonstrated a 77.4% reduction from baseline in serum galactose deficient IgA1 (Gd-IgA1) compared to an increase of +9.1% in the placebo group, yielding a reduction of 79.3% compared to placebo (P<0.0001).
For the second secondary endpoint, in patients with baseline haematuria, 85.1% achieved haematuria resolution in the povetacicept treatment group compared to 23.4% in the placebo group, resulting in haematuria resolution of 61.7% compared to placebo (P<0.0001).
Povetacicept was generally safe and well tolerated. Most adverse events (AEs) were mild to moderate. There were no serious adverse events (SAEs) related to povetacicept and no deaths in the trial. There were no opportunistic infections, and no discontinuations due to infections. As expected, anti-drug antibodies (ADAs) were observed; these ADAs had no impact on efficacy or the risk profile.
Treatment discontinuations (for any reason) were 8.8% in the placebo group and 3.8% in the povetacicept group, and trial discontinuations (for any reason) were 1.5% in the placebo group and 0.8% in the povetacicept group in this interim analysis population.
Trial design, population characteristics and efficacy results
Rainier is a global phase 3 randomised, double-blind, placebo-controlled pivotal trial of povetacicept 80 mg administered subcutaneously every four weeks versus placebo on top of standard of care.
A total of 605 patients were randomised in the trial, N=557 are in the main cohort, of which N=199 are in the interim analysis population, and N=48 patients are in an exploratory cohort.
These patients are representative of real world IgAN patients at risk of kidney disease progression. The median time from diagnosis of IgAN to randomization in the main cohort was approximately 3.8 years and the trial patients had high rates of background supportive care, with 97.8% of patients on angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARBs), and 67.7% of patients on sodium-glucose co-transporter 2 (SGLT2) inhibitors, the latter representing the highest percentage in recently completed IgAN trials.
For the interim analysis, the trial’s primary endpoint is percent change from baseline in 24-hour UPCR, and the two alpha-controlled secondary endpoints are percent change from baseline in serum Gd-IgA1 and the proportion of patients to achieve haematuria resolution, all at week 36.
Exploratory endpoints for this interim analysis included the proportion of patients with 24-hour UPCR <0.5 g/g, in line with the most recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines.
