Nephrotic Syndrome

Nephrotic Syndrome (NS) is a condition associated with increased loss of protein into the urine resulting in tissue swelling and eventually development of edemas. The edemas can develop in the hands and feets, including the ancles, in the face often with puffiness around the eyes. Edema´s can even develop in the lungs where it is associated with dyspnoe (shortening of breath). The edemas is secondary to the urinary loss of proteins, as the protein loss reduces the protein (most importantly albumin) levels in the blood. When the albumin levels in blood is decreased a larger fraction of fluid in transferred from the blood to the tissues causing the formation of edemas.

Untreated or insufficient treated NS will in many cases be associated with hypercholesterolemia, increased risk for blood clots, increased risk for infections and can develop in to chronic kidney disease that is associated increased risk for development of cardiovascular diseases and risk for development of end stage kidney disease and thereby need for renal replacement therapy (dialysis).

The urinary protein loss is due to defects in the functional units in the kidneys called the glomeruli. The glomeruli´s is responsible for the filtration of the blood in order to get rid of excess of water, electrolytes and other smaller molecules though excretion into the urine. Under normal conditions macromolecules as plasma proteins will not be filtered, but a number of conditions affects the glomeruli´s with the result that lager amounts of proteins are lost into the urine.

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Nephrotic Syndrome is caused by a number of different diseases. In some diseases as minimal Change disease (the most common cause of NS in children) the protein loss is associated with a defect in a specialized cell in glomeruli called podocytes. The changes are so discrete that it can only be identified by use of electron microscopic examination of kidney tissue biopsies. Even though the changes are very discrete the loss of protein can be very severe and importantly symptoms can develop very fast. The aetiology behind minimal change disease is unknown

Membranous Nephropathy is another example of a disease, causing NS.  Membranous nephropathy (MN) is one of the most common causes of NS in adult. MN can be primary ie is the primary disease or it can be secondary to other diseases, including systemic lupus (often called Lupus Nephritis), cancer or seen following treatment with drugs.

Primary MN is considered an autoimmune disease, ie that it caused by an immune reaction induced within the body. It has recently been shown that a large fraction of patients with MN has circulating antibodies against a receptor in the glomeruli called the phospholipase A2 receptor and the antibodies found in circulation in the patients are called anti-PLA2R. These antibodies bind to the glomeruli, more specifically the podocytes and cause deposition of immune complexes in the glomeruli, whereby the glomeruli become leaky with the result that large amount of protein is lost in the urine.

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Nephrotic Syndrome can also be caused of other primary kidney diseases including focal segmental glomerulopathy (most common cause of NS in Afro Americans), C1q nephropathy and membranoproliferative glomerulonephritis.  Kidney affection following Diabetes Mellitus called diabetic glomerulosclerosis can also induce nephrotic syndrome.

Treatment of NS

First line treatment of NS is in most cases treatment with ACE-inhibitors, that in has shown to able to reduce proteinuria and in addition has the beneficial effect of reducing blood pressure. However, a large fraction of patients will have continued proteinuria and, in these cases, next line treatment is systemic administration of glucocorticoid and/or immunosuppressive treatment. Both glucocorticoid treatment and immunosuppressive treatment are associated with often treatment limiting side effects and will in some cases not have the wanted treatment effect. Consequently, there is a large unmet medical need for novel treatment option in patients with NS.

Targeting the melanocortin system in the kidneys.

Alpha-MSH, the endogen agonist to the melanocortin receptors, as well as a number of agonists to the melanocortin systems has shown effective in treatment of a number of experimental kidney diseases. Ischemia/reperfusion models, sepsis models, models of ureteral obstruction as well as models of Nephrotic syndrome.

In addition, ACTH derived therapy, both Synacthen used in European studies and ACHTAR gel in US-studies have shown to be effective in NS and very importantly have been reported to show effective in patients resistant to glucocorticoid treatment.  The current marked for ACTH derived therapy is dominated by ACHTAR gel which on the US market generate an annual revenue around 300 M US $ in NS. However, treatment of NS with ACHTAR Gel is limited to difficult to treat cases as ACTHAR Gel is associated with a number of unwanted side effects mainly related to the compounds ability to induce glucocorticoid release from the adrenal glands as from the compounds ability to induce skin pigmentation.

Very interestingly it has recently been reported that the treatment effect of melanocortin in NS is associated with MC1r mediated stabilization of the cytoskeleton in the podocytes, which seems to be mediated though the same pathway, ie ERK phosphorylation, stimulated by SynAct Pharma´s AP1189 compound.

Effects of AP1189 in NS

SynAct Pharma´s AAP189 compound has been tested in an animal model of NS, the Heymann Nephritis model in rats, which in many aspects mimic Membranous Nephropathy. In the model once daily oral dosing for four weeks significantly reduced proteinuria compared to pre-treatment levels, whereas time-controlled vehicle treated animals show unchanged high levels of proteinuria during the 4 weeks treatment period-

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In addition, in a head to head study with ACTH, the fractional albumin excretion showed to be lower in AP1189 treated animals than in the ACTH treated animals and in addition GFR (measure of kidney function) was significantly higher in the AP1189 treated animals than in the ACTH treated animals.

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Together these data suggest that AP1189 could have treatment effects in patients with NS

Clinical development of AP1189 in NS

SynAct Pharma is currently planning (February 17 2020) for submission of Phase 2 clinical trial in patients with membranous Nephropathy (MN) that will be setup as a 4 weeks once daily dosing with repeated 24-hours urine collection for determination of proteinuria and kidney function in MN patients with continued proteinuria despite treatment with ACE inhibitors. Details of the study will be published on clinicaltrial.gov once approval has been given.