The trial met its primary objective of demonstrating a statistically significant reduction in urine protein creatinine ratio, UPCR or proteinuria, after 9 months with significant continued improvement at 12 months compared to placebo. A key secondary endpoint was also reached, and Nefecon was generally well tolerated. Based on these results, Calliditas plans to file for accelerated approval with the US FDA in Q1 2021 followed by a submission for conditional approval with the European Medicines Agency in H1 2021.
The pivotal, global Phase 3 NefIgArd trial consists of two parts.
Part A, which serves as the basis for potential regulatory submissions and approvals, was designed to provide data on the efficacy and safety of Nefecon. Patients with biopsy-confirmed primary IgA Nephropathy (IgAN), over or at 18 years of age and with a total urine protein of ≥ 1g / day, were eligible to take part in the trial. In the lead up to the trial, the patients had to be on optimized and stable renin-angiotensin system, or RAS inhibitor, treatment for at least 3 months, and remained on RAS blockade throughout the trial. Patients were randomized into either oral placebo or a once-daily 16 mg oral dose of Nefecon. After receiving 9 months of daily double-blind treatment, there was a two-week tapering, during which patients on drug received a once-daily 8mg oral dose of Nefecon and patients in the placebo arm continued to receive oral placebo. Following tapering, there was a 10-week follow-up where no trial drug was administered and during which blinding remained in place.
The primary endpoint for the trial is the effect of Nefecon on UPCR over 9 months compared to placebo, which is calculated from measured 24-hour urine samples. The analysis included 199 patients. The primary endpoint analysis showed a 31% mean reduction in the 16 mg arm versus baseline, with placebo showing a 5% mean reduction versus baseline, resulting in a 27% mean reduction at 9 months of the 16 mg arm versus placebo. The key secondary endpoint, eGFR, showed a treatment benefit of 7% versus placebo at 9 months, reflecting stabilization in the treatment arm and a 7% decline of eGFR in the placebo arm. This reflected an absolute decline of 4.04 ml/min/1.73m2 in the placebo group over 9 months compared to a 0.17 ml/min/1.73m2 decline in the treatment group.
Part B is designed to be a confirmatory post-market approval observational trial to confirm long-term renal protection. This trial consists of 360 patients, where recruitment of the 160 patients required, in addition to the 200 patients from Part A, is ongoing. Calliditas expects to complete recruitment of these patients in Q4 2020 or Q1 2021, depending on the impact of COVID-19.
Nefecon is a patented oral formulation of a potent and well-known active substance – budesonide – for targeted release. The formulation is designed to deliver the drug to the Peyer’s patch region of the lower small intestine, where the disease originates, as per the predominant pathogenesis models. Nefecon is derived from the TARGIT technology, which allows for the substance to pass through the stomach and intestine without being absorbed, and to be released in a pulse like fashion only when it reaches the lower small intestine.
Nefecon has been granted orphan drug designation for the treatment of IgA nephropathy in the United States and the EU.
IgA nephropathy (IgAN) – also known as Berger’s disease – is the most common form of glomerulonephritis, a chronic inflammatory condition of the kidney, in the Western world. IgA nephropathy is a serious autoimmune, progressive disease and up to 50 percent of patients diagnosed with IgAN will progress to end-stage renal disease (ESRD) within ten to twenty years, a disease state requiring dialysis or kidney transplant, which represents a significant health economic burden as well as a material impact on patients’ quality of life.
IgAN is an orphan disease, designated as an orphan indication in both the US and Europe. IgAN affects approximately 130,000–150,000 people in the US and about 200,000 people in Europe.