Overview of Nefecon– Calliditas’ lead product candidate

Proposed mechanism of action

Nefecon is an investigational product that has not been approved by regulatory authorities in any jurisdiction.
Edsbäcker S et al. Gastroenterology 1993;104:A695; Fellstrom BC et al. Lancet 2017;389:2117; Smith AC et al. J Am Soc Nephrol 2006;17:3520; Watts P et al. Expert Opin Drug Deliv 2005;2:159

Nefecon is a patented novel, investigational oral formulation of a potent and well-known active substance – budesonide – for targeted release.1 The formulation is designed to deliver the drug to the ileum where the Peyer’s patches are concentrated and where IgA nephropathy is thought to originate.1-3

Nefecon utilizes a two-step enteric technology, which allows the drug to pass through the stomach and intestine without being absorbed, with the active substance released in a sustained way only when it reaches the ileum, where the majority of Peyer’s patches are concentrated.3,4

Nefecon’s optimized dose and release profile is intended to have a local effect.  Another advantage of using this active substance is that it has very low bioavailability – around 90% of the budesonide is inactivated in the liver before it reaches the systemic circulation.5 This means that a high concentration can be applied locally where needed limiting systemic exposure and side effects.

Calliditas is currently sponsoring a large global Phase 3 trial of Nefecon in IgA nephropathy.6,7

Clinical trial program

NEFIGAN – our Phase 2b trial

Nefecon was investigated in the 150-patient Phase 2b NEFIGAN study (NCT01738035), which involved leading clinicians at 62 sites across ten countries in Europe.1,8 This study is still the largest phase 2 double-blind study ever conducted with an experimental product in patients with IgAN. NEFIGAN was a double-blind, placebo-controlled Phase 2b trial, in which patients with IgAN at risk of end-stage renal disease (ESRD) were randomized to receive either Nefecon 8 mg/day or 16 mg/day or placebo, each on top of optimized renin–angiotensin system (RAS) blockade, the current standard of care therapy to lower blood pressure.

NEFIGAN achieved its primary endpoint of a reduction in proteinuria for the Nefecon 16 mg/day cohort versus placebo. After 9 months of treatment, the urine protein-creatinine ratio (UPCR) in patients in the placebo cohort exhibited an increase in proteinuria of 2.7%, whereas patients in the Nefecon 16 mg/day cohort exhibited statistically significant and clinically meaningful reductions in proteinuria of 27.3%.1 As measured by estimated glomerular filtration rate (eGFR), the NEFIGAN trial showed a clinical benefit. Patients treated with Nefecon exhibited stabilization of eGFR, whereas patients administered with placebo continued to show a deterioration of eGFR.

The trial findings supported Nefecon’s ability to counteract a decline in kidney function.

NefIgArd – our Phase 3 trial

Calliditas is currently conducting a global pivotal Phase 3 clinical trial (NCT03643965) in IgAN with Nefecon.6,7,9

NefIgArd is our double-blind, placebo-controlled, two-part clinical trial in IgAN, designed to evaluate the efficacy, safety and tolerability of Nefecon 16 mg/day in patients with primary IgAN at risk of progressing to ESRD.6 Top line results of the first part (Part A) of the study were announced in November 2020.10 The second part of the study (Part B) is continuing.

Part A is the pivotal efficacy and safety trial expected to form the basis for submission of a New Drug Application, or NDA, to the Food and Drug Administration (FDA) and a Marketing Authorization Application, or MAA, to the European Medicines Authority (EMA). The primary endpoint of Part A was the decrease in proteinuria in the first 200 randomized and dosed patients, the same endpoint used in the completed NEFIGAN trial.1,6 In addition, a secondary endpoint of Part A is the difference in kidney function between Nefecon treated and placebo patients as measured using eGFR.

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 (p=0.0005) 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 (p=0.0029). Nefecon was generally well-tolerated and consistent with the known safety profile of budesonide.11

References

  1. Fellstrom BC, Barratt J, Cook H et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet 2017;389:2117–2127.
  2. Cornes JS. Peyer’s patches in the human gut. Proc R Soc Med 1965;58:716.
  3. Van Kruiningen HJ, West AB, Freda BJ, Holmes KA. Distribution of Peyer’s patches in the distal ileum. Inflamm Bowel Dis 2002;8:180–185.
  4. Watts P, Smith A. TARGIT technology: coated starch capsules for site-specific drug delivery into the lower gastrointestinal tract. Expert Opin Drug Deliv 2005;2:159–167.
  5. Edsbacker S, Andersson T. Pharmacokinetics of budesonide (Entocort EC) capsules for Crohn’s disease. Clin Pharmacokinet 2004;43:803-821.
  6. Barratt J, Rovin BH, Cattran D et al. Why target the gut to treat IgA nephropathy? KI Reports 2020;5:1620–1624.
  7. Calliditas Therapeutics AB. Efficacy and safety of Nefecon in patients with primary IgA (immunoglobulin A) nephropathy (Nefigard). 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT03643965 [accessed 28 April 2020].
  8. Calliditas Therapeutics AB. The effect of NEFECON® in patients with primary IgA nephropathy at risk of developing end-stage renal disease (NEFIGAN). 2015. Available at: https://clinicaltrials.gov/ct2/show/NCT01738035 [accessed 22 October 2020].
  9. Calliditas Therapeutics AB. Surrogate marker and design of Calliditas Therapeutics’ IgA nephropathy phase 3 study agreed with the FDA. 2017. Available at: https://www.calliditas.se/en/surrogate-marker-and-design-of-calliditas-therapeutics-iga-nephropathy-phase-3-study-agreed-with-the-fda-2271/ [accessed 15 May 2020].
  10. Calliditas Therapeutics AB. Calliditas Therapeutics to host conference call on positive topline results from pivotal phase 3 NefIgArd trial. 2020. Available at: https://www.calliditas.se/en/calliditas-therapeutics-to-host-conference-call-on-positive-topline-results-from-pivotal-phase-3-nefigard-trial-3312/ [accessed 16 November 2020].
  11. Calliditas Therapeutics AB. Calliditas Announces Positive Topline Results from Pivotal Phase 3 NefIgArd Trial. 2020. Available at: https://www.calliditas.se/en/calliditas-announces-positive-topline-results-from-pivotal-phase-3-nefigard-trial-3310/ [accessed 16 November 2020].