长效白蛋白融合人生长激素JR-142的药代动力学和药效学:一项随机化、安慰剂对照的1期研究

IF 1.6 4区 医学 Q4 CELL BIOLOGY Growth Hormone & Igf Research Pub Date : 2022-12-01 DOI:10.1016/j.ghir.2022.101500
Yasuko Owada , Mika Okazaki , Toshiaki Ikeda , Ryuji Yamamoto , Kohtaro Minami , Kenichi Takahashi , Tohru Hirato , Yoko Mita , Tatsuyoshi Yamamoto , Kazunori Tanizawa , Hiroyuki Sonoda , Yuji Sato
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引用次数: 0

摘要

目的:在生长激素缺乏症患者的临床开发中,JR-142是一种通过与改性血清白蛋白融合而延长半衰期的长效生长激素。我们进行了一项1期研究,以调查每周一次皮下给药JR-142的安全性、耐受性、药代动力学(PK)和药效学(PD)概况。该研究包括两部分:开放标签单次递增给药研究(第一部分)和随机、安慰剂对照、评估盲的多次递增给药研究(第二部分)。设计共纳入31名健康的日本男性受试者。在第一部分中,其中7人接受单次皮下注射JR-142,剂量分别为0.15 mg/kg (n = 1)、0.25 mg/kg (n = 2)、0.5 mg/kg (n = 2)或1.0 mg/kg (n = 2)。在第二部分中,其他24名参与者(每组6人)每周皮下注射一次0.25 mg/kg、0.5 mg/kg、1.0 mg/kg或安慰剂,持续四周。测定血浆JR-142和血清胰岛素样生长因子-1 (IGF-1)浓度用于PK和PD评估。安全性根据不良事件(ae)、实验室检查和其他措施进行评估。结果JR-142诱导血浆JR-142最大浓度(Cmax)和血浆浓度-时间曲线下面积(AUC0-τ)从时间0到τ呈剂量依赖性增加。在血清IGF-1浓度中观察到类似的剂量-反应关系。三种剂量JR-142最后一次给药一周后,所有IGF-1的低谷水平都保持良好,而IGF-1的峰值浓度仍然轻度升高。没有观察到严重的不良反应,实验室测试,包括抗药物抗体的评估,没有发现重大的安全问题。结论1周皮下注射JR-142在一定剂量范围内产生了正的剂量依赖性PK和PD谱。在4周给药期后观察到药物积累,但没有引起安全性问题,表明JR-142在健康受试者中耐受性良好。在IGF-1浓度方面观察到的PD谱也呈阳性,我们相信本研究的令人鼓舞的结果值得在GHD患者的进一步临床试验中得到证实。该临床研究在日本大阪的一个研究地点进行,其机构审查委员会于2019年5月9日审查并批准了JR-142的临床研究和非临床数据。本研究遵循已批准的研究方案、1964年赫尔辛基宣言(2013年修订)和良好临床实践进行。
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Pharmacokinetics and pharmacodynamics of once-weekly administration of JR-142, a long-acting albumin-fused human growth hormone: A rondemized, placebo-controlled phase 1 study

Objective

Under clinical development for patients with growth hormone deficiency, JR-142 is a long-acting growth hormone with a half-life extended by fusion with modified serum albumin. We conducted a Phase 1 study to investigate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of once-weekly subcutaneous administrations of JR-142. The study consisted of two parts: an open-label single ascending dosing study (Part 1), and a randomized, placebo-controlled, assessor-blinded multiple ascending dosing study (Part 2).

Design

A total of 31 healthy Japanese male participants were enrolled. In Part 1, seven of them received a single subcutaneous injection of JR-142 each at dosages of 0.15 mg/kg (n = 1), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 2), or 1.0 mg/kg (n = 2). In Part 2, one weekly subcutaneous injection of JR-142 at 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg or a placebo were given for four weeks to each of the other 24 participants (six in each group). Plasma JR-142 and serum insulin-like growth factor-1 (IGF-1) concentrations were measured for PK and PD assessments. Safety was evaluated on the basis of adverse events (AEs), laboratory tests, and other measures.

Results

JR-142 induced dose-dependent increases in the maximum plasma JR-142 concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to τ (AUC0-τ). A similar dose-response relationship was observed in serum IGF-1 concentrations. All trough IGF-1 levels were well sustained one week after the final administrations of JR-142 at the three dosages, while the peak concentrations of IGF-1 remained mildly elevated. No serious AEs were observed, and laboratory tests, including assessment of anti-drug antibodies, uncovered no significant safety issues.

Conclusions

Once-weekly subcutaneous injections of JR-142 produced positive dose-dependent PK and PD profiles over the dosage range. Drug accumulation was observed after the four-week administration period but did not raise safety concerns, indicating that JR-142 is well-tolerated in healthy participants. The PD profiles observed in terms of IGF-1 concentrations were also positive, and we believe the encouraging results of this study warrant substantiation in further clinical trials in patients with GHD.

Ethics

This clinical study was conducted at one investigational site in Osaka, Japan, where the clinical study and the non-clinical data of JR-142 were reviewed and approved by its Institutional Review Board on 9th May 2019. The study was conducted in compliance with the approved study protocol, the Declaration of Helsinki, 1964, as revised in 2013, and Good Clinical Practice.

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来源期刊
Growth Hormone & Igf Research
Growth Hormone & Igf Research 医学-内分泌学与代谢
CiteScore
3.30
自引率
0.00%
发文量
38
审稿时长
57 days
期刊介绍: Growth Hormone & IGF Research is a forum for research on the regulation of growth and metabolism in humans, animals, tissues and cells. It publishes articles on all aspects of growth-promoting and growth-inhibiting hormones and factors, with particular emphasis on insulin-like growth factors (IGFs) and growth hormone. This reflects the increasing importance of growth hormone and IGFs in clinical medicine and in the treatment of diseases.
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