IgA nephropathy (IgAN), previously known as Berger’s disease, is a serious, progressive autoimmune disease that results in chronic inflammation of the kidney. Up to 50% of those diagnosed with IgAN will progress to end-stage renal disease (ESRD). IgAN is the most common cause of glomerulonephritis. Glomerulonephritis refers to one of several kidney diseases characterized by inflammation of either the glomeruli or the small blood vessels in the kidneys impairing the kidney’s ability to filter waste and excess water from the blood. Glomerulonephritis is the largest disease-related cause of end-stage renal disease (ESRD) after diabetes and is responsible for 25-30% of all annual ESRD cases.
With IgAN affecting approximately 140,000 people in the United States and 200,000 people in Europe, it is the most common form of glomerulonephritis in the Western world. IgAN is considered a rare disease in the United States and Europe. Higher prevalence rates have been observed in China, Singapore, Japan and Hong Kong. In China, IgAN has long been the leading cause of ESRD and the prevalence rate is estimated to be 2 million. The higher prevalence seen in Asian countries is presumed to be a result of a genetic predisposition among Asian people.
There are an estimated 2 million patients suffering from ESRD worldwide. 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 125,157 patients newly diagnosed in 2016 alone. In order to survive, patients with ESRD require on-going dialysis or a kidney transplant. ESRD patients constitute 1% of the US Medicare population, but accounts for 7% 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 percent per year. After one year of treatment, those on dialysis have a 20–25% mortality rate and the 5-year survival rate is 35%.
At present, there are no approved treatments for IgAN. Physicians are currently using a variety of approaches in an attempt to treat the symptoms of IgAN, i.e.reduce blood pressure and suppress the pathologic immune system response in an attempt to slow the progression of kidney disease. There is clear need for new treatments that can improve eGFR (blood flow through the kidney filters) and reduce protein albuminuria (marker of kidney damage) in this patient group.
DM199 is a recombinant, or synthetic, form of the KLK1 protein also known as a serine protease. KLK1 is a naturally occurring protein produced by the body and is a critical protein used by the body to maintain healthy, stable blood flow. The action of KLK1 as an agent to lower blood pressure was first recognized more than 100 years ago. In the century since its discovery, scientists have learned that KLK1 plays an essential role in maintaining kidney health and normal function. Further, low levels of KLK1 have been associated with the progression of CKD.
DM199 was created as a protein replacement therapy. In the case of IgAN, we believe DM199 may preserve and possibly improve kidney function. We believe that DM199 may act on the following inter-related mechanisms in the kidney to promote better overall function, stable blood flow and ultimately may protect the kidney from further damage.
- Increasing renal blood flow and filtration by dilating the renal arteries and reducing pressure;
- Reducing inflammation, oxidative stress and fibrosis;
- Reducing kidney injury and levels of proteinuria; and
- Increase production of T-regs to suppress pathologic immune response.
As a serine protease, we believe DM199’s mechanism of action is believed to modulate many different biological functions in the kidney. DM199 is believed to release bradykinin-mediated nitric oxide and prostaglandins (PGE2 and PGI2-cAMP) in the kidney. Nitric oxide and prostaglandins are believed to work synergistically to improve renal blood flow in a healthy, or physiological, manner. These signaling molecules dilate the renal arteries (afferent & efferent arterioles) to improve blood flow at lower pressures, and are believed to reduce inflammation, oxidative stress and fibrosis. DM199 treatment has been shown to increase Tregs in an animal model of autoimmune diabetes. This potential action of DM199 may make it particularly well-suited for dampening the autoimmune component of IgAN. Tregs are immune cells that are believed to help to fight against autoimmunity in multiple diseases, including IgAN.
DiaMedica is currently sponsoring a 30 patient, Phase 2 trial of DM199 in confirmed IgAN subjects. This proof-of-concept trial will be conducted at approximately 5 sites in the United States. Under the current protocol, patients will receive DM199 as a subcutaneous injection twice per week for three months. The study analysis is designed to evaluate changes in eGFR (blood flow through the kidney), protein albuminuria (renal filtration ability) and biomarkers related to IgAN.
To learn more about the IgA nephropathy study, or if you are interested in participating, please visit clinicaltrials.gov.