The following is a summary of “Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial,” published in the December 2023 issue of Gastroenterology by Kowdley et al.

For a study, researchers sought to assess the efficacy and safety of rusfertide, a peptidic hepcidin mimetic, in treating Hereditary Haemochromatosis Protein (HFE)-related hemochromatosis. The hereditary iron overload disorder arises from inadequate hepcidin production, leading to excessive iron absorption, tissue damage, and organ injury. The standard treatment for the condition involves therapeutic phlebotomy. The objective was to evaluate the impact of rusfertide on patients with HFE-related hemochromatosis, particularly focusing on its efficacy and safety. Conducted as an open-label, multicentre, proof-of-concept phase 2 trial across nine academic and community centers in the USA and Canada, this study enrolled adults (≥18 years) with HFE-related hemochromatosis who were on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening. Eligible participants had a specific phlebotomy frequency criterion (at least 0.25 per month), serum ferritin levels below 300 ng/mL, and hemoglobin levels exceeding 11.5 g/dL. The trial involved a 24-week subcutaneous rusfertide treatment initiated within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses were modifiable to maintain serum transferrin iron saturation (TSAT) at less than 40%. Phlebotomy necessity during rusfertide treatment was considered based on individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was predetermined. 

Prespecified efficacy endpoints included changes in phlebotomy frequency, the proportion of patients achieving phlebotomy independence, alterations in various iron-related parameters (serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration [LIC] measured by MRI), and treatment-emergent adverse events (TEAEs). Key efficacy analyses for phlebotomy rate and LIC were executed using paired t-tests in the intention-to-treat population, defined as all patients who received any study drug and had pretreatment and at least one post-dose measurement. Safety analyses included all participants receiving at least one dose of rusfertide. Between March 11, 2020, and April 23, 2021, 28 patients were screened, and 16 individuals (63% men 38% women) were enrolled in the study. Among these, 16 participants were included in the analyses of phlebotomy endpoints, while 14 were considered for the liver iron concentration (LIC) endpoint. A noteworthy 75% (12 out of 16) of patients successfully completed the entire 24-week rusfertide treatment duration. During this period, the mean number of phlebotomies exhibited a significant reduction, with 0.06 phlebotomies (95% CI –0.07 to 0.20) compared to the 24 weeks pre-study (2.31 phlebotomies [95% CI 1.77 to 2.85]; P<0.0001). 94% (15 out of 16) of patients achieved a phlebotomy-free status. In the intention-to-treat population of 14 patients, the mean LIC at screening was 1.4 mg iron per g dry liver weight (95% CI 1.0 to 1.8), which decreased to 1.1 mg iron per g dry liver weight (95% CI 0.9 to 1.3) at the end of treatment (P=0.068). 

Transferrin saturation (TSAT) exhibited variations throughout the treatment duration, with values at screening (45.3%), 24 h after the pretreatment phlebotomy (36.7%), 24 h after the first dose of rusfertide (21.8%), at the end of treatment (40.4%), and over the entire treatment duration (32.6%). Similarly, serum iron levels fluctuated at different time points, with mean values of 24.6 μmol/L (95% CI 18.6 to 30.6), 20.1 μmol/L (14.8 to 25.3), 11.9 μmol/L (9.2 to 14.7), 22.5 μmol/L (15.9 to 29.1), and 19.0 μmol/L (15.3 to 22.6), respectively. Serum ferritin levels also showed variations, with mean values of 83.3 μg/L (52.2 to 114.4), 65.5 μg/L (32.1 to 98.9), 62.8 μg/L (33.8 to 91.9), 150.0 μg/L (86.6 to 213.3), and 94.3 μg/L (54.9 to 133.6) at the respective time points. Minimal changes were observed in serum transferrin concentration. Regarding safety, 75% of patients experienced at least one treatment-emergent adverse event (TEAE), with injection site pain being the most common (31% of patients). All TEAEs were of mild or moderate severity except for one severe adverse event involving pancreatic adenocarcinoma. Notably, the event, considered unrelated to treatment, was pre-existing and diagnosed 21 days after initiating rusfertide treatment. The findings suggested that rusfertide effectively prevented iron re-accumulation without phlebotomies. It indicated its potential as a viable therapeutic option for selected patients with hemochromatosis.

Source: sciencedirect.com/science/article/abs/pii/S2468125323002509