LJPC-401 is La Jolla’s proprietary formulation of synthetic human hepcidin. Hepcidin, an endogenous peptide hormone, is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in vital organs, such as the liver and heart, where it can cause significant damage and even result in death. Pre-clinical studies have shown that increasing hepcidin, through either synthetic hepcidin injection or genetic induction, results in improved iron storage in heart, liver and endocrine glands. La Jolla is developing LJPC-401 for the potential treatment of iron overload, which occurs as a result of hereditary hemochromatosis (HH), a genetic deficiency of hepcidin, or as a result of frequent blood transfusions required to treat diseases such as beta thalassemia and sickle cell disease (SCD).

In a phase I study with patient with iron overload, 15 patients received sub-cutaneous doses at escalating levels from 1 mg to 20 mg. No dose-limiting toxicities were observed at any dose level. LJPC-401 demonstrated a dose-dependent, statistically significant reduction in serum iron with maximum iron reduction at 8 hours and durable effect observed through the last day on Day 7.

La Jolla reached agreement with the EMA on a pivotal study design in beta thalassemia patients suffering from iron overload. La Jolla plans to initiate a clinical trial in beta-thalassemia in mid-2017.

Mechanism of Action

Hepcidin is an endogenous 25-amino-acid peptide (2.7 kDa) with four disulphide bonds and is a hormone secreted by the liver and is the insulin of iron metabolism. Its main function is to control iron homeostasis by dictating how iron is used and absorbed in the body, as well as how excess iron is stored in various organs.

The target for hepcidin is ferroportin – the only clearly identified iron transporter from cellular stores to plasma. It does this by binding to and causing internalization and degradation of the cellular iron exporter ferroportin, thereby inhibiting iron release into plasma from storage sites in enterocytes, splenic macrophages and hepatocytes. Through this integrated system, plasma concentration of iron is maintained at 10 to 30 micromolar despite large fluctuations in dietary intake.

La Jolla’s novel formulation of synthetic human hepcidin, like endogenous hepcidin, works by binding to and causing internalisation and degradation of the cellular iron exporter ferroportin, thereby inhibiting iron release into plasma from storage sites in enterocytes, macrophages and hepatocytes.

Iron Overload

Iron is an essential element for the normal functioning of mammalian physiology. Major organ systems do not tolerate either a lack of or excess of free iron in the serum, therefore requiring a tight physiological control. Multiple organs including the liver, heart, spleen, duodenum, bone marrow, and blood components (macrophages and erythrocytes) are involved in the tight regulation of iron levels. Over time, patients with significant iron overload may experience end-stage organ damages due to iron built up in the organs. Some of the most common complications include liver cirrhosis, endocrine disturbances such as diabetes, reproductive issues, and cardiac problems which might be fatal.

Hereditary hemochromatosis (HH) is a disease caused by a genetic deficiency in hepcidin that results in excessive iron accumulation. HH is the most common genetic disease in Caucasians and causes liver cirrhosis, liver cancer, heart disease and/or failure, diabetes, arthritis and joint pain. Beta thalassemia and SCD are genetic diseases of the blood that can cause life-threatening anemia and usually require frequent and life-long blood transfusions. These blood transfusions cause excessive iron accumulation in the body, which is toxic to vital organs, such as the liver and heart. In addition, the underlying anemia causes excessive iron accumulation independent of blood transfusions.