LJPC-401, a clinical-stage investigational product, 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. In healthy individuals, 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. La Jolla is developing LJPC-401 for the potential treatment of iron overload, which occurs as a result of primary iron overload diseases such as hereditary hemochromatosis (HH), or secondary iron overload diseases such as beta thalassemia, sickle cell disease (SCD) and myelodysplastic syndrome (MDS). The European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) has designated LJPC‑401 as an orphan medicinal product for the treatment of beta thalassemia intermedia and major and SCD.

In September 2016, La Jolla reported positive results from a Phase 1 study of LJPC-401 in patients at risk of iron overload suffering from HH, thalassemia and SCD. In this study, single, escalating doses of LJPC-401 were associated with a dose-dependent, statistically significant reduction in serum iron. LJPC-401 was well-tolerated with no dose-limiting toxicities. Injection-site reactions were the most commonly reported adverse event and were all mild or moderate in severity, self-limiting and fully resolved.

In September 2016, La Jolla reached agreement with the EMA on the design of a pivotal study of LJPC-401 for the treatment of beta thalassemia patients suffering from iron overload, a major unmet need in an orphan patient population. This study, also known as LJ401-BT01, was initiated in December 2017. If this study is successful, La Jolla anticipates filing an MAA for LJPC-401 in Europe. Also in December 2017, La Jolla announced the initiation of LJ401-HH01, a Phase 2 clinical study of LJPC‑401 in patients with HH. LJ401-HH01 is a multinational, multicenter, randomized, placebo-controlled, double-blind, Phase 2 study that is designed to evaluate the safety and efficacy of LJPC-401 as a treatment for HH.

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.