PMID- 36113378 OWN - NLM STAT- MEDLINE DCOM- 20221116 LR - 20221222 IS - 1532-2238 (Electronic) IS - 1096-6374 (Linking) VI - 67 DP - 2022 Dec TI - 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. PG - 101500 LID - S1096-6374(22)00057-0 [pii] LID - 10.1016/j.ghir.2022.101500 [doi] AB - 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 (C(max)) and the area under the plasma concentration-time curve from time 0 to tau (AUC(0-tau)). 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. CI - Copyright (c) 2022 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Owada, Yasuko AU - Owada Y AD - Medical Corporation Heishinkai OPHAC Hospital, Osaka, Japan. FAU - Okazaki, Mika AU - Okazaki M AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: okazaki-m@jp.jcrpharm.com. FAU - Ikeda, Toshiaki AU - Ikeda T AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: ikeda-t@jp.jcrpharm.com. FAU - Yamamoto, Ryuji AU - Yamamoto R AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: yamamoto-ryu@jp.jcrpharm.com. FAU - Minami, Kohtaro AU - Minami K AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: minami-k@jp.jcrpharm.com. FAU - Takahashi, Kenichi AU - Takahashi K AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: takahasi@jp.jcrpharm.com. FAU - Hirato, Tohru AU - Hirato T AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: hirato-t@jp.jcrpharm.com. FAU - Mita, Yoko AU - Mita Y AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: mita@jp.jcrpharm.com. FAU - Yamamoto, Tatsuyoshi AU - Yamamoto T AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: t-yamamoto@jp.jcrpharm.com. FAU - Tanizawa, Kazunori AU - Tanizawa K AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: tanizawa-k@jp.jcrpharm.com. FAU - Sonoda, Hiroyuki AU - Sonoda H AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: sonoda-h@jp.jcrpharm.com. FAU - Sato, Yuji AU - Sato Y AD - JCR Pharmaceuticals, Hyogo, Japan. Electronic address: sato-yuji@jp.jcrpharm.com. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial DEP - 20220908 PL - Scotland TA - Growth Horm IGF Res JT - Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society JID - 9814320 RN - 12629-01-5 (Human Growth Hormone) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 9002-72-6 (Growth Hormone) RN - 0 (Albumins) SB - IM MH - Humans MH - Male MH - *Human Growth Hormone MH - Insulin-Like Growth Factor I MH - *Dwarfism, Pituitary/drug therapy MH - Growth Hormone MH - Double-Blind Method MH - Albumins MH - Dose-Response Relationship, Drug OTO - NOTNLM OT - Growth hormone deficiency OT - IGF-1 OT - Long-acting human growth hormone OT - Plasma drug concentration OT - Weekly administration COIS- Declaration of Competing Interest This clinical study was fully sponsored by JCR Pharmaceuticals, Co., Ltd. Yasuko Owada was an investigator for the studies sponsored by JCR Pharmaceuticals, Co., Ltd. (formerly Japan Chemical Research, Co., Ltd. ) in 2012, 2018, and 2019. Mika Okazaki, Toshiaki Ikeda, Ryuji Yamamoto, Kohtaro Minami, Kenichi Takahashi, Tohru Hirato, Yoko Mita, Tatsuyoshi Yamamo, Kazunori Tanizawa, Hiroyuki Sonoda and Yuji Sato are employed by JCR Pharmaceuticals, Co., Ltd., of which Hiroyuki Sonoda is a board member. EDAT- 2022/09/17 06:00 MHDA- 2022/11/18 06:00 CRDT- 2022/09/16 18:28 PHST- 2022/04/14 00:00 [received] PHST- 2022/08/30 00:00 [revised] PHST- 2022/09/03 00:00 [accepted] PHST- 2022/09/17 06:00 [pubmed] PHST- 2022/11/18 06:00 [medline] PHST- 2022/09/16 18:28 [entrez] AID - S1096-6374(22)00057-0 [pii] AID - 10.1016/j.ghir.2022.101500 [doi] PST - ppublish SO - Growth Horm IGF Res. 2022 Dec;67:101500. doi: 10.1016/j.ghir.2022.101500. Epub 2022 Sep 8.