Stockholm, Sweden – June 4, 2017 (see press release). The Phase 2b trial (known as the NEFIGAN trial), was presented in a special session co-hosted by The Lancet by lead author Bengt Fellström, MD, PhD, Professor of Nephrology at Uppsala University Hospital and Principal Investigator of the NEFIGAN Trial.
Nefecon® is an investigational treatment for patients with primary IgAN at risk of developing ESRD. Nefecon® has successfully completed a randomized, placebo-controlled Phase 2b study in 149 primary IgAN patients (full analysis set) at risk of developing ESRD, under standardized rigorous blood pressure control with an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB). Nefecon® is an oral, targeted-release and locally acting formulation of the potent corticosteroid, budesonide, that down-regulates the disease process in the kidney through suppression of the gastrointestinal immune system thus exploiting the pivotal role the gastrointestinal tract plays in the overall immune response. These promising results indicate that treatment with Nefecon® may provide clinical benefits to primary IgAN patients at risk of progressing to ESRD, and provide an alternative to dialysis and transplantation. Nefecon® has received orphan drug designation in primary IgAN by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
The NEFIGAN trial was randomized, double-blinded, and placebo-controlled in male and female patients (aged >18 years) with primary IgAN and overt proteinuria considered at risk of progressing to end-stage renal disease (ESRD)1. The trial was conducted at 62 sites across 10 European countries between November 2012 and June 2015. Data from 149 patients constituted the final analysis set, from a total of 249 patients screened. Following a 6-month run-in phase (to optimize RAS blockade treatment), patients underwent a 9-month treatment phase in which they were randomized in a 1:1:1 ratio to receive Nefecon at 16 mg/day, 8 mg/day or placebo. The primary outcome of the Phase 2b clinical trial was assessed on the full analysis set (n=149), defined as all randomized patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement (modified intention-to-treat analysis). At nine months, mean urine protein to creatinine ratio (UPCR) decreased by -26.4% with Nefecon [p=0.0066] (-29.3% with 16 mg/day [p=0.009; p=NS], -23.7% with 8 mg/day [p=0.029]), vs. placebo. The effect was sustained throughout the follow-up; mean UPCR decreased by -32% from baseline at 12 months for 16 mg/day vs. a 0.5% increase for placebo. Over nine months, eGFR was stable with Nefecon but decreased 9.8% with placebo (Nefecon vs. placebo: p=0.001). Nefecon was well tolerated and the total incidence of treatment-emergent adverse events was similar across all treatment groups.
Immunoglobulin A (IgA) nephropathy (IgAN) is a chronic glomerular disease characterized histologically by the presence of mesangial deposits of IgA, which are often accompanied by IgG or IgM deposits and often by complement deposits. It is a slowly progressive disease, leading to end-stage renal disease (ESRD) in 20% to 40% of patients over 20 years. IgA nephropathy IgA Nephropathy is the most common primary glomerulonephritis worldwide2,3.
The presence of hypertension and low GFR at the onset are associated with more rapid progression and worse outcomes.2,3 Multiple studies have shown that proteinuria is a risk factor for progression of renal disease in patients with IgAN and other glomerular diseases. Furthermore, higher levels of proteinuria are associated with a more rapid decline in renal function and reduction in proteinuria with treatment, may lead to slowing of the rate of progression of kidney dysfunction.4
Several studies have shown the benefit of treatment with corticosteroids, given either as 6 monthly pulses of methylprednisolone or orally for 8 weeks. Inhibition of the renin-angiotensin system (RAS) pathway is also recommended 5,6. In addition to lowering blood pressure, it reduces proteinuria. Treatment recommendations for IgAN have recently been summarized in the Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines.6 Treatment of hypertension targeting a blood pressure (BP) <130/80 mmHg should slow the rate of progression of disease. Additionally, the guidelines recommend treatment using RAS blockade (as tolerated, with either an ACE inhibitor or an angiotensin receptor blocker [ARB]) to achieve a maximal reduction in proteinuria, when proteinuria is >1 g/24 h.6 Other supportive therapy, such as fish oil and statins, should be considered and have been associated with clinical benefits.
The novelty of the targeted release budesonide (Nefecon)® is the ability to target the distal ileum and block the immune mechanisms responsible for the development of circulating immune complexes, while reducing the adverse effects seen with systemic steroid treatment. The reduction in proteinuria is an acceptable endpoint for Phase 2 proof-of-concept studies in IgAN and other forms of GN. However, for Phase 3 registration studies, both the FDA and the EMA require assessment of time to doubling of serum creatinine or 50% reduction in eGFR or time to ESRD. To reach these endpoints, long treatment and follow-up times (24-36 months) are needed7. Recent studies suggest that reductions in eGFR less than 50% may be acceptable, but agreement of the agency is required before finalizing the design of the clinical trial.
- Fellström BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, Sørensen SS, Tsars V, Del Vecchio L; NEFIGAN Trial Investigators. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomized, placebo-controlled phase 2b trial. 2017 May 27;389(10084):2117-2127. doi: 10.1016/S0140-6736(17)30550-0. Epub 2017 Mar 28.(link)
- Canetta PA, Kiryluk K, Appel GB. Glomerular diseases: emerging tests and therapies for IgA nephropathy. Clin J Am Soc Nephrol 2014; 9: 617-25 (link).
- Rodrigues JC1, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol. 2017 Apr 3;12(4):677-686. doi: 10.2215/CJN.07420716. Epub 2017 Feb 3 (link).
- Reich HN, Troyanov S, Scholey JW, Cattran DC, for the Toronto Glomerulonephritis Registry. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol 2007; 18:3177-83 (link). doi:10.1681/ASN.2007050526.
- Lv J, Zhang H, Chen Y, et al. Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis 2009; 53:26-32 (link).
- KDIGO Clinical Practice Guideline for Glomerulonephritis. June 2012; 2(2). http://www.kidney-international.org (link).
- Formentini I, Bobadilla M, Haefliger C, Hartmann G, Loghman-Adham M, Mizrahi J, Pomposiello S, Prunotto M, Meier M. Current drug development challenges in chronic kidney disease (CKD)—identification of individualized determinants of renal progression and premature cardiovascular disease (CVD). Nephrol Dial Transplant; 27 (suppl 3), 2012, iii81–iii88, https://doi.org/10.1093/ndt/gfs270 (link)
Copyright © M. Loghman-Adham, MD