Recombinant Alpha-1 Antitrypsin-Fc Fusion Protein INBRX-101 in Adults With Alpha-1 Antitrypsin Deficiency: A Phase 1 Study.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS

ACS Applied Bio Materials Pub Date : 2024-05-29 DOI:10.15326/jcopdf.2023.0469

Mark L Brantly, Brooks T Kuhn, Humam W Farah, Ravi Mahadeva, Alexandra Cole, Catherina L Chang, Cynthia D Brown, Michael A Campos, Jorge E Lascano, Erin K Babcock, Sharvari P Bhagwat, Teresa F Boyea, Carson A Veldstra, Vasily Andrianov, James L Kalabus, Brendan P Eckelman, Andrew G Veale

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引用次数: 0

Abstract

Background: Alpha-1 antitrypsin deficiency (AATD) is characterized by low alpha-1 antitrypsin (AAT) levels, predisposing individuals to lung disease. The standard of care, plasma-derived AAT (pdAAT), is delivered as weekly infusions to maintain serum AAT concentrations ≥11µM (≈50% of those in healthy individuals). INBRX-101, a recombinant human AAT-Fc fusion protein, was designed to have a longer half-life and achieve higher AAT levels than pdAAT.

Methods: In this phase 1 dose-escalation study (N=31), adults with AATD received 1 dose (part 1) or 3 doses (part 2) of 10 (part 1), 40, 80, or 120mg/kg INBRX-101 every 3 weeks (Q3W) via intravenous infusion. The primary endpoint was safety and tolerability. Secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of INBRX-101.

Results: INBRX-101 was well tolerated. Most treatment-emergent adverse events were grade ≤2. In part 2 (n=18; each dose, n=6), dose-related increases in serum functional AAT (fAAT) were observed; mean fAAT levels remained above the 21 µM target for up to 4 weeks after the final dose in the 120-mg/kg cohort. Antidrug antibodies had no meaningful impact on PK or PD. INBRX-101 was detected in pulmonary epithelial lining fluid (PELF) from all patients assessed (n=11), and PELF fAAT increased after dosing. PK/PD modeling projected steady-state serum fAAT ≥21µM at 120 mg/kg Q3W (average concentration ≈43µM; trough concentration ≈28µM) and Q4W (≈34µM; ≈21µM).

Conclusion: The favorable safety profile and ability to maintain serum fAAT levels >21µM with extended-interval dosing, support a phase 2 trial evaluating Q3W and Q4W dosing of INBRX-101.

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重组 Alpha-1 抗胰蛋白酶-Fc 融合蛋白 INBRX-101 在 Alpha-1 抗胰蛋白酶缺乏症成人中的应用：1 期研究。

背景：α-1抗胰蛋白酶缺乏症（AATD）的特点是α-1抗胰蛋白酶（AAT）水平低，易导致肺部疾病。标准治疗方法是每周输注血浆源性 AAT（pdAAT），以维持血清 AAT 浓度≥11µM（≈健康人的 50%）。INBRX-101 是一种重组人 AAT-Fc 融合蛋白，与 pdAAT 相比，它的半衰期更长，能达到更高的 AAT 水平：在这项 1 期剂量递增研究中（N=31），成人 AATD 患者每 3 周（Q3W）通过静脉输注接受 1 次剂量（第 1 部分）或 3 次剂量（第 2 部分）的 10（第 1 部分）、40、80 或 120 毫克/千克 INBRX-101。主要终点是安全性和耐受性。次要终点是INBRX-101的药代动力学（PK）、药效学（PD）和免疫原性：INBRX-101的耐受性良好。结果：INBRX-101的耐受性良好，大多数治疗中出现的不良反应≤2级。在第2部分（n=18；每个剂量，n=6）中，观察到血清功能性AAT（fAAT）与剂量相关的升高；在120毫克/千克的组群中，最后一次给药后长达4周，平均fAAT水平仍高于21微摩尔的目标值。抗药抗体对 PK 或 PD 没有明显影响。所有接受评估的患者（n=11）的肺上皮内衬液（PELF）中都检测到了INBRX-101，用药后肺上皮内衬液中的fAAT有所增加。PK/PD模型预测，120毫克/千克Q3W（平均浓度≈43µM；谷值浓度≈28µM）和Q4W（≈34µM；≈21µM）时，稳态血清fAAT≥21µM：结论：INBRX-101良好的安全性以及延长给药间隔时间后血清fAAT水平仍能保持在21µM以上的能力，支持对INBRX-101的Q3W和Q4W给药进行2期试验评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Applied Bio Materials Chemistry-Chemistry (all)

CiteScore

9.40

自引率

2.10%

发文量

464