IgA nephropathy – Overview of the disease

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), a disease state requiring dialysis or kidney transplant.

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. Calliditas’ lead product candidate, Nefecon, has been granted orphan drug designation for the treatment of IgA nephropathy in the United States and the EU.

Pathogenesis, origins and disease mechanism of IgA nephropathy

The kidney is a complex organ and it´s functions include production of hormones, absorption of minerals, filtration of the blood and removal of waste products. According to the most predominant theory on disease origin and progression, IgA nephropathy is a disease that starts in the intestine and not in the kidney itself, i.e. the disease’s origin is in the ileum where the Peyer’s patches are located.

IgA is an antibody that plays a key role in the immune system by protecting the body from foreign substances such as bacteria and viruses. Patients with IgA nephropathy have elevated levels of IgA molecules lacking galactose units (a type of sugar). In IgA nephropathy patients, a combination of genetic predisposition, environmental and dietary factors is presumed to cause disease development and progression.

The galactose-deficient spot at the hinge region of the IgA molecule is immunogenic. It therefore attracts other antibodies, forming immune complexes that become stuck in the filtration membranes of the kidney, known as the glomeruli. The trapped immune complexes initiate an inflammatory response which damages the kidney and ultimately destroys the kidney’s filtration mechanism.

The first symptoms for IgA nephropathy are appearance of protein and/or blood in the urine (proteinuria and hematuria, respectively), indicating leakage through the damaged membranes in the kidney. The risk of ESRD is related to the level of proteinuria, which reflects the fact that as the kidney function deteriorates, waste products, of which creatinine is a marker, accumulates in the blood.

Creatinine levels in the blood are used to calculate the eGFR (estimated glomerular filtration rate), which is a measure of the kidney’s capacity to filter the blood. Hence, eGFR is a measure of renal function (the lower eGFR, the less renal function remains). As the disease progresses the eGFR deteriorates and a large proportion of the patients will eventually be afflicted by ESRD. A patient with ESRD will need dialysis or a renal transplant in order to survive.

Clinical symptoms, diagnosis and disease progression

The clinical course of IgA nephropathy can exist without any obvious signs or symptoms for an extended period of time. IgA nephropathy is often diagnosed either through routine health checks, or by the patient presenting symptoms such as visible hematuria or proteinuria. Calliditas estimates that the majority of patients are diagnosed when they exhibit symptoms or through routine health controls, while the remaining cohort is discovered at a much later point in time.

A patient journey typically begins within the primary care, culminating in diagnosis taking place at a nephrologist. The nephrologist’s standard diagnostic method for determining the underlying cause of the observed increased urine protein level is to perform a kidney biopsy followed by a histopathologic evaluation. The diagnosis of IgA nephropathy can then be determined from the histopathologic characteristics of the biopsy.

IgA nephropathy normally presents in the patient’s twenties or thirties and is more common in men than in women in the Western world, with patients following a variety of progression paths over several years. It results in deterioration of kidney function that in a significant part of the population eventually leads to ESRD.

ESRD is associated with significant risks of complications and considerable quality of life deterioration as well as an increased risk of premature death. Persistent proteinuria is a defined characteristic of patients progressing to ESRD. A decrease of proteinuria levels has shown to markedly reduce the risk of progression.

Prevalence and incidence


Prevalence measures how common a disease is in a population at a particular point in time. Calliditas therefore estimates the prevalence of IgA nephropathy in the US to between 130,000–150,000.

The estimated European prevalence is equivalent to approximately 4 in 10,000, resulting in an estimate of 200,000 people.

Beyond the US and Europe, high prevalence rates have been observed in China, Singapore, Japan, Australia and Hong Kong. In China, IgA nephropathy has long been the leading cause of ESRD, and the prevalence rate is estimated to be 2-3 times the prevalence rate in Europe. Even in Japan, lgA nephropathy has a much greater prevalence than in the Western world, with an estimate of at least 190,000 people. This higher prevalence in Asia is presumed to be a result of the interplay of a genetic predisposition, environmental, bacterial and dietary impact. In some geographic areas there are also general health screenings being performed which often impact diagnosis rates.


Incidence measures the rate of occurrence of new cases of a disease in a specified time period (usually a year). Calliditas estimates an annual incidence to be 2.5 per 100,00 resulting in around 6,000–7,000 new cases each year in the US.

The variability of estimated IgA nephropathy prevalence and incidence rates for IgA nephropathy between geographical regions is in Calliditas’ assessment partly due to varying clinical practice in performing kidney biopsy. A kidney biopsy is an invasive procedure and is not a requirement in all geographical regions for patients exhibiting elevated levels of proteinuria, but necessary to confirm the diagnosis of IgA nephropathy.

ESRD treatment options and burden on the healthcare system

IgA nephropathy is a significant burden on the healthcare system in the US. Glomerulonephritis is the largest disease-related cause of ESRD after diabetes, and is responsible for 25–30 per cent of all annual ESRD cases. Glomerulonephritis refers to several kidney diseases, usually affecting both kidneys, where the majority of the diseases are characterized by inflammation either of the glomeruli or of the small blood vessels in the kidneys.

IgA nephropathy is established as being the largest condition within glomerulonephritis. IgA nephropathy is hence a major cause of ESRD, causing a significant number of ESRD cases in the US each year. According to the US Renal Data System (“USRDS”) ESRD quarterly update in April 2018, the number of ESRD patients in the US amounted to 741,037 in the third quarter of 2017, with an incidence during 2016 of 125,157 patients.

There are an estimated 2 million patients suffering from ESRD worldwide. Patients that live with ESRD constitute 1 per cent of the US Medicare population, but account for 7 per cent of the Medicare budget. More than 100,000 patients in the US are on the kidney transplant list, but each year there are less than 20,000 available donor kidneys and the need for donor kidneys in the US is increasing at 8 per cent per year. After one year of treatment, those on dialysis have a 20–25 per cent mortality rate, with a 5-year survival rate of 35 per cent. Patients who receive transplants have, in comparison, a 3 per cent mortality rate after 5 years.

IgA nephropathy – A high unmet medical need

There are at present no approved treatments for IgA nephropathy. A variety of off label approaches are used to reduce the blood pressure and systemically suppress the immune system.

Against this background, Calliditas assesses that there is a clear need for new treatments showing both efficacy and safety in large randomized, controlled trials. The targeted release with Nefecon, focused on treating the source of the disease, with the potential to be disease modifying, provides a completely new method of treatment, which has shown to have the potential to be an efficacious and safe therapy to patients with IgA nephropathy in a large Phase 2b study involving 150 patients. The Company is sponsoring a global Phase 3 study.