Haemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, and University of the Witwatersrand, Johannesburg, South Africa.
Catalyst Biosciences, San Francisco, CA, USA.
Haemophilia. 2021 Jul;27(4):574-580. doi: 10.1111/hae.14315. Epub 2021 May 6.
Phase 2b study to assess efficacy, safety, thrombogenicity, immunogenicity and tolerability with 28 days of daily dosing of subcutaneous (SQ) dalcinonacog alfa as prophylaxis for haemophilia B (HB).
Adult males with a confirmed diagnosis of congenital HB (factor IX [FIX] activity <2%) received daily dalcinonacog alfa 100 IU/kg SQ until day 28. The primary efficacy endpoint was the number of participants who achieved a steady-state FIX activity level ≥12%. Tolerability, thrombogenicity and immunogenicity were study safety endpoints.
Of 6 participants who received study drug, one discontinued the study on day 7 due to injection-site reactions (ISR). Of the 5 participants completing the study, FIX activity level exceeded 12% in 3 participants at day 7, increasing to 4 participants on days 14, 21 and 28 and all 5 at day 29. Pharmacokinetic findings (including mean alpha and beta half-life of 5.3 days and 3.9 days, respectively, and mean residence time of 6.2 days) supported prolonged effects. Thrombogenicity markers remained normal throughout prophylactic injections or showed some initial increases followed by decreases with continued dosing. Two participants had anti-drug antibodies to dalcinonacog alfa at study end, none had neutralizing antibody. Two participants had ISR, both resolved. Reports of redness, swelling, tenderness or pain among the first 3 participants prompted dose-splitting for the last 3 participants, leading to fewer ISR.
Subcutaneous dalcinonacog alfa is effective in raising FIX levels into the mild haemophilia range, comparable to intravenous extended half-life FIX clotting factors.
评估皮下(SC)给予 dalcinonacog alfa 每日一次、连续 28 天治疗作为乙型血友病(HB)预防的疗效、安全性、血栓形成、免疫原性和耐受性的 2b 期研究。
确诊为先天性 HB(因子 IX [FIX] 活性 <2%)的成年男性接受每日 100IU/kg SC 达比加群 alfa 治疗直至第 28 天。主要疗效终点为达到稳定状态 FIX 活性水平≥12%的参与者人数。耐受性、血栓形成和免疫原性是研究安全性终点。
6 名接受研究药物的参与者中,1 名因注射部位反应(ISR)于第 7 天退出研究。5 名完成研究的参与者中,3 名在第 7 天、4 名在第 14、21 和 28 天、所有 5 名在第 29 天的 FIX 活性水平超过 12%。药代动力学发现(包括分别为 5.3 天和 3.9 天的平均 alpha 和 beta 半衰期,以及 6.2 天的平均停留时间)支持延长作用。整个预防性注射过程中,血栓形成标志物保持正常,或在继续给药时最初增加后减少。研究结束时,2 名参与者有针对达比加群 alfa 的抗药物抗体,均无中和抗体。2 名参与者出现 ISR,均已解决。前 3 名参与者出现发红、肿胀、压痛或疼痛的报告,促使最后 3 名参与者进行剂量分割,从而减少 ISR 的发生。
皮下给予达比加群 alfa 可有效提高 FIX 水平至轻度血友病范围,与静脉给予延长半衰期 FIX 凝血因子相当。