背景:遗传性血色素沉着症蛋白(HFE)相关血色素沉着症,由铁调素生产不足引起的遗传性铁超负荷疾病,导致铁的过度吸收和组织器官损伤,并接受一线治疗性静脉切开术治疗。我们的目的是调查rusfertide的疗效和安全性,铁调素的肽模拟物,HFE相关血色素沉着病患者。
方法:这个开放标签,多中心,概念验证2期试验在美国和加拿大的9个学术和社区中心进行.在筛选前至少6个月,患有HFE相关血色病的成年人(年龄≥18岁)接受稳定的治疗性静脉切开术方案(维持期),并且每月静脉切开术频率至少为0·25(例如,在12个月内至少进行3次静脉切开术或在15个月内至少进行4次静脉切开术),每月少于1次静脉切开术,血清铁蛋白低于300ng/mL,血红蛋白超过11·5g/dL,有资格。患者在每周一次10mg的计划静脉切开术的7天内开始皮下rusfertide治疗24周。可以调整Rusfertide剂量和给药时间表以将血清转铁蛋白铁饱和度(TSAT)维持在40%以下。在Rusfertide治疗期间,当血清铁蛋白和TSAT值超过患者个体在放血前的血清铁蛋白和TSAT值时,研究者应考虑是否需要进行放血.没有预设主要终点或测试层次结构。预先确定的疗效终点包括静脉切开术频率的变化;实现静脉切开术独立性的患者比例;血清铁的变化,TSAT,血清转铁蛋白,血清铁蛋白,和通过MRI测量的肝铁浓度(LIC);以及治疗引起的不良事件(TEAE)。在意向治疗人群中使用配对t检验进行了静脉切开率和LIC的关键疗效分析,定义为接受任何研究药物并接受治疗前和至少一次剂量后测量的所有患者。我们在安全性分析中纳入了所有接受至少一剂rusfertide的参与者。该试验已结束并完成,并已在ClinicalTrials.gov注册,NCT04202965。
结果:在2020年3月11日至2021年4月23日之间,对28例患者进行了筛查,其中16例(10例[63%]男性和6例[38%]女性)入组。16个纳入静脉切开术终点分析,14个纳入LIC终点分析。12例(75%)患者完成24周的医治。与研究前24周(2·31次静脉造血[95%CI1·77至2·85];p<0·0001)相比,在Rusfertide治疗24周期间,平均静脉造血次数显著减少(0·06次静脉造血[95%CI-0·07至0·20];在治疗期间,16例患者中有15例(94%)无静脉切开术。意向治疗人群中14例患者的平均LIC在筛选时为每克肝干重1·4毫克铁(95%CI1·0至1·8),在治疗结束时为每克肝干重1·1毫克铁(95%CI0·9至1·3)(p=0·068)。筛查时平均TSAT为45·3%(95%CI33·2至57·3),预处理放血后36·7%(24·2至49·2),首次服用Rusfertide后24小时21·8%(15·8至27·9),治疗结束时40·4%(27·1至53·8),在治疗期间为32·6%(25·0至40·1)。平均血清铁为24·6μmol/L(95%CI18·6至30·6),20·1μmol/L(14·8至25·3),11·9μmol/L(9·2至14·7),22·5μmol/L(15·9至29·1),在这些相同的时间点和19·0μmol/L(15·3至22·6),分别。平均血清铁蛋白为83·3μg/L(52·2至114.4),65·5μg/L(32·1至98·9),62·8μg/L(33·8至91·9),150·0μg/L(86·6至213.3),和94·3μg/L(54·9至133.6)在这些相同的时间点,分别。血清转铁蛋白浓度仅有微小变化。12(75%)患者至少有一个TEAE,其中最常见的是注射部位疼痛(5例[31%]患者).所有TEAE的严重程度均为轻度或中度,除了胰腺腺癌的严重不良事件,被认为是严重的,与治疗无关,并且在开始rusfertide治疗21天后预先存在并诊断。
结论:Rusfertide在没有静脉切除术的情况下可以防止铁的再积累,并且可能是某些血色素沉着病患者的可行治疗选择。
背景:主角治疗剂。
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.