Hepcidin is a small peptide which acts as iron regulatory hormone. The name ‘hepcidin’ is taken from the place of synthesis in hepatocytes (hep), whereas cidin denotes its antimicrobial activity. Liver is the key organ that secrete hepcidin and regulates iron hormone. Hepcidin was initially observed in human urine sample and in human blood ultrafiltrate as a small bactericidal peptide (defensin and cathelicidin) and now it is known as liver–expressed antimicrobial peptide. Hepcidin is encoded by HAMP, 19q13 gene, which is expressed in the liver, heart, lungs, brain, spinal cord, intestine, macrophages and several other organs. The mode of action of hepcidin activity depends on the interaction between hepcidin and ferroportin. Ferroportin is expressed on the surface of reticulo-endothelial macrophages, hepatocytes, duodenal enterocytes and placenta cells. It is the only known mammalian cellular iron exporter. Binding of Hepcidin with ferroportin causes its internalization and degradation in endo lysosomes, which in turn blocks the iron transport through ferroportin.
The hepcidin antagonist pipeline has more than 10 drugs. In pipeline analysis, drugs are analyzed on the basis of route of administration and molecule type. The pipeline is also analyzed on the basis of monotherapy and combination therapy, and different clinical phases including Phase III, Phase II, Phase I and Pre-clinical stage.
Phase III clinical trial known for the comparison of new treatments with the standard treatment in which the safety, efficacy and side effects of new intervention is compared with the already existing treatment. The Phase III clinical trial takes around 2-3 years to complete and the total number of participants vary from 100-1,000. In Hepcidin antagonist, there are 3 drugs in phase III clinical trial. For instance, Luspatercept, a phase III drug candidate of Celgene Corporation is being developed in collaboration with Acceleron Pharma, Inc., for the treatment of anemia with myelodysplastic syndromes and anemia associated with beta thalassaemia.
NOX-H94 is a phase II drug candidate of NOXXON Pharma N.V. The drug candidate is an anti-hepcidin single-stranded structured L-RNA oligonucleotide conjugated to 40kDa polyethylene glycol. Phase II clinical trial is the second phase that answer safety, efficacy and dosing of the new intervention. It takes around 2 years to complete and between 100 – 120 patients participate in the Phase II trial.
PRS 080, a phase I/II drug candidate is under development by Pieris Pharmaceuticals, Inc. for the treatment of anemia. The drug candidate is an hepcidin antagonist, which can restore iron utilization and erythropoiesis. The company mentioned that the compound has successfully shown a favorable safety profile in healthy volunteers and is expected to complete a multi-dose trial by mid of 2017. In Phase I clinical trial, safety of the new intervention is determined. The trial takes around 1-2 years to complete and the total number of volunteers participating in the trial vary between 15 – 30.
ABT-207, a pre-clinical drug candidate of AbbVie Inc. is being developed for the treatment of anemia of inflammation. ABT-207 is a humanized antibody that inhibits repulsive guidance molecule C and thus downregulate hepcidin. Pre-clinical study is also known as animal study. It is done before testing a drug in people to find out the toxicity profile of the drug. Pre-Clinical study is of two types, including In vitro and In vivo.
Pipeline analysis provides description about the key companies developing hepcidin antagonist drugs. Some of the key players actively involved in the research and development are Celgene Corporation, Akebia Therapeutics, Inc., FibroGen, Inc., Noxxon Pharma AG and Tolero Pharmaceuticals, Inc.