Synthetic Hepcidin Options Safe in Patients With Iron Disorders, But Efficacy Data Still Preliminary

Two studies presented at the 23rd Congress of the European Hematology Association examined the safety and pharmacokinetics of two synthetic hepcidin options for the treatment of hereditary blood disorders associated with iron overload: PTG-300 and LJPC-401.

Hepcidin is secreted by the liver and acts as “the master regulator of serum iron concentrations,” explained one study’s lead author Ashutosh Lal, MD, of the UCSF Benioff Children’s Hospital in San Francisco. “Several disorders of iron overload, such as hereditary hemochromatosis and beta-thalassemia major, are associated with reduced hepcidin secretion, [and] there is considerable interest in augmenting endogenous hepcidin for the management of iron overload.”


LJPC-401 is a synthetic endogenous human hepcidin that mimics the natural hepcidin hormone. Dr. Lal and colleagues evaluated its safety in a phase I study of 18 patients (7 with hemoglobinopathies and 11 with hemochromatosis), who had the following disorders and medical histories:

  • transfusion-dependent anemia
  • iron chelation therapy within 6 months prior to enrollment
  • serum ferritin >1,000 μg/L
  • hemochromatosis requiring phlebotomy at least once every 2 months

Patients received subcutaneous LJPC- 401 at doses of either 1 mg, 5 mg, 10 mg, 20 mg, or 30 mg. If the final patient in each dose group did not experience any drug-related toxicity within three days of injection, the researchers escalated doses.

Treatment-emergent adverse events (TEAEs), immunogenicity, and physical and laboratory assessments were used to evaluate safety related to drug administration.

Most patients (n=16; 88.9%) reported TEAEs, with four events reported as moderate and 34 reported as mild in severity. There were no differences in the rates of TEAEs across dose groups. The following AEs were the most frequently reported during and following treatment:

  • injection-site reactions (66.7%)
  • nausea (11.1%)
  • increased alanine aminotransferase (11.1%)
  • decreased appetite (11.1%)
  • hypoesthesia (11.1%)

In their pharmacokinetic analysis, the investigators found that the maximum serum concentration at 24 hours after administration increased with each dose level increase, with the peak serum drug concentrations occurring approximately two to four hours following all doses. Doses up to LJPC-401 20 mg were associated with a greater reduction in serum iron concentrations, but the reduction at 30 mg was lower than that at 20 mg. Researchers observed a significant dose response across all cohorts (p=0.0478).

While these findings are preliminary, ongoing studies are exploring the drug’s iron-regulating effects in larger, longitudinal analyses. “There was a significant effect on serum iron, but further studies should examine changes in tissue iron concentrations and non–transferrin bound iron,” Dr. Lal explained.

The findings of LJPC-401, a synthetic endogenous human hepcidin, represent the first insight into the investigational therapy’s effects on iron metabolism. “These data will pave a way for future studies and clinical trials to evaluate clinical application of synthetic hepcidin in several clinical conditions including iron overload anemias, hemochromatosis, and myelodysplastic syndromes (MDS),” co-author and presenter Vip Viprakasit, MD, DPhil, from the Mahidol University in Bangkok, Thailand, commented.

“Complications secondary to iron overload are the chief cause of morbidity in thalassemia and hereditary hemochromatosis,” Dr. Lal added. “If it is shown in subsequent studies that treatment with synthetic hepcidin can reduce the toxic forms of iron, decrease gastrointestinal iron absorption or control abnormal tissue distribution of iron, then it would be an important therapeutic advance in this group of patients.”


The injectable hepcidin mimetic PTG-300 is also under development for the treatment of various blood disorders, including chronic anemia, iron overload, beta-thalassemia, MDS, and ineffective erythropoiesis.

In a study presented by Richard Shames, MD, of Protagonist Therapeutics in Newark, California, researchers assessed the safety and preliminary efficacy of PTG-300 in 62 men who had no recent history of oral iron, transfusion, or blood donation and had normal baseline hematologic parameters.

Participants were randomized to receive either placebo or subcutaneous PTG-300 in cohorts of 10 subjects (8 received single doses of PTG-300 1 to 40 mg; 2 received placebo) or six subjects (5 received a single dose of PTG-300 80 mg or two doses of 40 mg over two weeks; 1 received placebo).

One week after dosing, investigators found that, compared with placebo, PTG- 300 treatment resulted in a dose-related decline in serum iron stores, with average iron levels decreasing by 60 percent from baseline levels (p values not provided). In the single-dose group, the treatment’s impact on reducing iron values plateaued at 20 mg, and these effects persisted for up to 72 hours at higher dose levels.

Patients who received repeated 40 mg doses of PTG-300 also appeared to experience reductions in iron levels, including a small decline in mean hemoglobin and reticulocytosis at 480 hours after dosing (p values not reported).

No dose-limiting toxicities or serious AEs occurred in either the single-dose or repeated-dose groups. During treatment, the most commonly reported AEs included:

  • injection-site reactions
  • transient erythema without systemic Effects
  • upper-respiratory infections
  • headache

“PTG-300 demonstrated marked and sustained dose-related effects on iron distribution consistent with known activities of hepcidin and pre-clinical studies of PTG-300,” the authors concluded. “This first-in-human study establishes pharmacodynamics-based proof of concept and provides a range of doses that could be evaluated in the treatment of iron-loading anemias, such as beta-thalassemia and MDS.”

Both studies are limited by small populations and limited-duration of follow-up.


  1. Lal A, Piga A, Viprakasit V, et al. A phase 1, open-label study to determine the safety, tolerability, and pharmacokinetics of escalating doses of LJPC-401 (synthetic human hepcidin) in patients with iron overload. Abstract #S894. Presented at the 23rd Congress of the European Hematology Association, June 16, 2018; Stockholm, Sweden.
  2. Nicholls A, Lickliter J, Tozzi L, et al. Hepcidin mimetic PTG-300 induces dose-related and sustained reductions in serum iron and transferrin saturation in healthy subjects. Abstract #S895. Presented at the 23rd Congress of the European Hematology Association, June 16, 2018; Stockholm, Sweden.