Kowdley Kris V, Modi Nishit B, Peltekian Kevork, Vierling John M, Ferris Christopher, Valone Frank H, Gupta Suneel
Liver Institute Northwest, Seattle, WA, USA; Elson S Floyd College of Medicine, Washington State University, Seattle, WA, USA.
Protagonist Therapeutics, Newark, CA, USA.
Lancet Gastroenterol Hepatol. 2023 Dec;8(12):1118-1128. doi: 10.1016/S2468-1253(23)00250-9. Epub 2023 Oct 17.
Hereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis.
This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965.
Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI -0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 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) at these same timepoints, respectively. Mean serum ferritin was 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 these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment.
Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis.
Protagonist Therapeutics.
遗传性血色素沉着症蛋白（HFE）相关的血色素沉着症是一种因铁调素生成不足导致的遗传性铁过载疾病，会导致铁吸收过多以及组织和器官损伤，一线治疗方法是放血疗法。我们旨在研究铁调素的肽模拟物鲁司特肽对HFE相关血色素沉着症患者的疗效和安全性。
这项开放标签、多中心、概念验证的2期试验在美国和加拿大的9个学术和社区中心进行。纳入年龄≥18岁、在筛查前接受稳定的放血治疗方案（维持期）至少6个月、放血频率至少为每月0.25次（例如，12个月内至少3次放血或15个月内至少4次放血）且每月放血次数少于1次、血清铁蛋白低于300 ng/mL且血红蛋白高于11.5 g/dL的HFE相关血色素沉着症成人患者。患者在计划放血的7天内开始皮下注射鲁司特肽，每周1次，剂量为10 mg，疗程24周。鲁司特肽的剂量和给药方案可进行调整，以维持血清转铁蛋白铁饱和度（TSAT）低于40%。在鲁司特肽治疗期间，当血清铁蛋白和TSAT值超过患者放血前的个体血清铁蛋白和TSAT值时，研究人员应考虑是否需要进行放血。未预先指定主要终点或测试层次。预先指定的疗效终点包括放血频率的变化；实现放血独立的患者比例；通过MRI测量的血清铁、TSAT、血清转铁蛋白、血清铁蛋白和肝脏铁浓度（LIC）的变化；以及治疗中出现的不良事件（TEAE）。放血率和LIC的关键疗效分析在意向性治疗人群中使用配对t检验进行，意向性治疗人群定义为所有接受任何研究药物且有治疗前和至少一次给药后测量值的患者。我们在安全性分析中纳入了所有接受至少一剂鲁司特肽的参与者。该试验已结束并完成，已在ClinicalTrials.gov注册，注册号为NCT04202965。
2020年3月11日至2021年4月23日期间，共筛选了28例患者，其中16例（10例[63%]男性和6例[38%]女性）入组。16例纳入放血终点分析，14例纳入LIC终点分析。12例（75%）患者完成了24周的治疗。与研究前24周相比，在24周的鲁司特肽治疗期间，放血的平均次数显著减少（0.06次放血[95%CI -0.07至0.20]），而研究前24周为2.31次放血[95%CI 1.77至2.85]；p<0.0001）。16例患者中有15例（94%）在治疗期间无需放血。意向性治疗人群中14例患者的平均LIC在筛查时为每克干肝重1.4 mg铁（95%CI 1.0至1.8），治疗结束时为每克干肝重1.1 mg铁（95%CI 0.9至1.3）（p=0.068）。平均TSAT在筛查时为45.3%（95%CI 33.2至57.3），预处理放血后为36.7%（24.2至49.2），首次注射鲁司特肽后24小时为21.8%（15.8至27.9），治疗结束时为40.4%（27.1至53.8），整个治疗期间为32.6%（25.0至40.1）。在这些相同时间点，平均血清铁分别为24.6 μmol/L（95%CI 18.6至30.6）、20.1 μmol/L（14.8至25.3）、11.9 μmol/L（9.2至14.7）、22.5 μmol/L（15.9至29.1）和19.0 μmol/L（15.3至22.6）。血清转铁蛋白浓度仅有轻微变化。12例（75%）患者至少发生1次TEAE，最常见的是注射部位疼痛（5例[31%]患者）。除1例胰腺腺癌严重不良事件外，所有TEAE均为轻度或中度，该严重不良事件被认为严重且与治疗无关，是在开始鲁司特肽治疗21天后诊断出的既往疾病。
鲁司特肽可在不放血的情况下防止铁重新蓄积，对于部分血色素沉着症患者可能是一种可行的治疗选择。
Protagonist Therapeutics公司。
