Overview of NEFECON – Calliditas’ lead product candidate

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.

The combination of dose and optimized release profile is required to be effective in patients with IgA nephropathy, as shown in a large Phase 2b study, completed by the company. In addition to its potent local effect, another advantage of using this active substance is that it has very low bioavailability, i.e. around 90% of it is inactivated in the liver before it reaches the systemic circulation. This means that a high concentration can be applied locally where needed but with only very limited systemic exposure and side effects. Another example where this approach has proven to be successful is in asthma treatment where budesonide is successfully used to locally treat the airways and lung tissue.

Calliditas is now sponsoring a large global Phase 3 trial of NEFECON in IgA nephropathy.

Development program

Completed studies

Efficacy in IgA nephropathy patients was initially assessed in a multi-center 16-patient, open-label, Phase 2a (NCT00767221) study in which patients received 8 mg NEFECON for six months, followed by a three-month follow-up. Patients in this study had a mean reduction in proteinuria of 23 per cent at end of treatment with a further reduction to 40 per cent two months after end of treatment; and an increase in eGFR of 8 per cent.

NEFECON was subsequently investigated in a 150 patient Phase 2b (NCT01738035) study that involved leading clinicians at 62 sites across ten countries in Europe. This study is still the largest completed double-blind study ever conducted with an experimental product in IgA nephropathy patients. It is also the only successful randomized, placebo-controlled Phase 2b study to date.

The study had three treatment arms, 8mg, 16mg NEFECON and placebo. Patients had biopsy-confirmed IgA nephropathy and were on optimized blood pressure control. NEFECON or placebo was administered, as oral capsules, once a day for nine months. During that time, treatment with RAS blockade continued (inhibition of the renin-angiotensin system).

At the end of nine months, the patients were followed for an additional three months. The primary endpoint was reduction in proteinuria as measured by the urine protein creatinine ratio (UPCR). This endpoint was achieved during a planned interim analysis after the first 90 patients had completed nine months of treatment. The 16 mg and 8 mg patients had a reduction in UPCR of 27.3 and 21.5 per cent, respectively, while the placebo treated patients had an increase of 2.7 per cent.

Significant differences in eGFR between the NEFECON and placebo treated groups were also observed. Patients in the placebo group experienced a 9.8 per cent decrease in eGFR during the nine months of treatment while the 16 mg NEFECON group had an increase of 0.6 per cent and the 8 mg NEFECON group had a decrease of 0.9 per cent There were no severe adverse events such as severe infections or significant impact on the metabolic system (blood pressure, weight gain, diabetes etc.), which are typical side systemic effects of systemic glucocorticosteroid treatment.

The trial findings supported NEFECON’s ability to counteract a decline in kidney function and potentially also promote a slight improvement. This suggests that NEFECON with its attractive efficacy / safety profile may have an important disease-modifying activity which could help delay onset of dialysis or potentially remove the need for such treatment. If confirmed in the Phase 3 study, the benefit / risk profile may enable clinicians to treat patients with earlier stage disease to regain and stabilize the existing kidney function.

Phase 3 study design

The planned randomized double-blind and placebo-controlled Phase 3 study will have a substantially similar
design to the completed Phase 2b study. The study is divided into a treatment part (“Part A”) and a long term observational part (“Part B”). Up to 450 patients with biopsy-confirmed IgA nephropathy and on optimal or highest tolerable blood pressure medication will be randomized in this study across 15–20 countries including, e.g., Australia and selected countries in North America and Europe. In the first part of the study, Part A, the patients will receive orally either 16 mg NEFECON or placebo, once daily for 9 months, on the background of optimized RAS treatment, and then be followed for three months. Subsequently, the patients will continue into Part B, which is an observational long-term follow up period where the patients’ renal function as measured by eGFR will be followed and measured. The data from the study will be analyzed in two parts.

The first analysis will be conducted after the first 200 randomized patients have completed Part A. The primary endpoint will be reduction in proteinuria and will form the basis for accelerated approval in the United States and conditional approval in the EU. This will, based on positive data, enabling marketing and commercialization of the drug in the United States and EU, after the expected processing time for a New Drug Application (NDA) and Marketing-Authorisation Application (MAA) with the FDA and the EMA, respectively.

The Part B study analysis is designed to validate proteinuria as a surrogate marker and is event based. An event is defined as a relevant reduction in eGFR from baseline and we expect less events in the Nefecon treated group. The company may choose to conduct an interim read out of Part B following the completed treatment of all 450 patients.

Other potential indications

Calliditas has identified two potential follow-on indications for Nefecon, based on its localized delivery in the intestine and resulting first passage though the liver. These are autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC).