Rusfertide Analog-PN23114 As a Hepcidin Mimetic Provides Efficacy Benefits in Conjunction with Phlebotomy in Mouse Model for Hereditary Hemochromatosis

Hepcidin deficiency in hereditary hemochromatosis (HH) leads to hyperabsorption of dietary iron and primary iron overload (Nemeth E., Science 2004). Therapeutic phlebotomy is used to reduce organ iron-overload in HH patients. However, persistent high transferrin-saturation (TSAT%) may result in toxic labile iron that can deposit in organs, leading to tissue damage and subsequent organ dysfunction. Additionally, newly diagnosed patients with severe iron overload require frequent phlebotomies during the induction phase of therapy that can last for many months, during which TSAT% levels may continue to be high even when serum ferritin levels are reduced. Rusfertide is a hepcidin mimetic peptide that has demonstrated potential benefit in reducing the need for therapeutic maintenance phlebotomy in a Phase 2 trial with hemochromatosis subjects who have previously required chronic phlebotomies to reduce and maintain ferritin and liver iron values within normal range (Kowdley KV, AASLD Hepatology 2021).

To evaluate the potential benefits of co-treatment of hepcidin mimetic during induction phase of clinical management, we evaluated additive effects of PN23114 in combination with phlebotomy in HJV^-/- mouse model for HH (129S-Hjvtm1Nca/J; Andrews NC, J Clin Invest. 2005). PN23114 is an analog of rusfertide with a single amino acid change and with similar pharmacokinetic and pharmacodynamic characteristics. Male HJV^-/- mice at 8-12 weeks of age were treated with either PN23114 (7.5 mg/kg, TIW), phlebotomy (~0.3mL blood drawn, QW), or combination of both for a total of 46 days. We found that all three treatment strategies reduced iron concentrations in both heart and kidney, as compared to a baseline group that was terminated at start of study. None of the treatments were able to reduce liver iron but all three prevented further iron deposition in the liver as compared to baseline. It's possible that the length of phlebotomy treatment is not sufficient to result in iron removal from liver. Treatment with PN23114 redistributed the excess iron into spleen and duodenum, thereby significantly elevating spleen iron concentration, while co-treatment of PN23114 and phlebotomy did not result in marked iron sequestration in spleen. Serum ferritin was reduced in all three treatment groups, the group that received the PN23114 and phlebotomy co-treatment showed the largest reduction. Serum iron was normalized with PN23114 treatment and with co-treatment with PN23114 and phlebotomy. Phlebotomy treatment was not able to lower serum iron to normal levels.

Our data overall indicate that combining hepcidin mimetic treatment along with phlebotomy may be more effective in quickly lowering TSAT% and labile iron, and thereby quickly reversing tissue iron deposition in specific organs. Titration of rusfertide to the desired clinical effect may be effective in combination with phlebotomy during the induction phase of clinical management to reduce the frequency and duration of phlebotomy treatment as well as lower the lingering high TSAT% levels.

Taranath:Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dion:Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company. Bhandari:Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu:Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company.