Insmed Incorporated, 202/206 North, Bridgewater, NJ, 08807, USA.
Insmed Incorporated, 202/206 North, Bridgewater, NJ, 08807, USA.
Pulm Pharmacol Ther. 2020 Dec;65:102002. doi: 10.1016/j.pupt.2021.102002. Epub 2021 Feb 15.
Treprostinil (TRE) is a prostanoid analog pulmonary vasodilator drug marketed with subcutaneous, intravenous (i.v.), oral, and inhaled routes of administration for the treatment of pulmonary arterial hypertension (PAH). Due to its short half-life, TRE requires either continuous infusion or multiple dosing, which exacerbates its side effects. Therefore, a long-acting prostanoid analog that maintains the positive attributes of TRE but has fewer TRE-related side effects could be of clinical benefit. In this report, we describe the discovery, preclinical development, and biology of the TRE ester prodrug, treprostinil palmitil (TP), which is formulated in a lipid nanoparticle (LNP) for administration as a nebulized inhaled suspension (TPIS). In screening assays focused on the conversion of prodrug to TRE, TP (16 carbon alkyl chain) had the slowest rate of conversion compared with short-alkyl chain TRE prodrugs (i.e., 2-8 carbon alkyl chain). Furthermore, TP is a pure prodrug and possesses no inherent binding to G-protein coupled receptors including prostanoid receptors. Pharmacokinetic studies in rats and dogs demonstrated that TPIS maintained relatively high concentrations of TP in the lungs yet had a low maximum plasma concentrations (C) of both TP and, more importantly, the active product, TRE. Efficacy studies in rats and dogs demonstrated inhibition of pulmonary vasoconstriction induced by exposure to hypoxic air or i.v.-infused U46619 (thromboxane mimetic) over 24 h with TPIS. Cough was not observed with TPIS at an equivalent dose at which TRE caused cough in guinea pigs and dogs, and there was no evidence of desensitization to the inhibition of pulmonary vasoconstriction in rats with repeat inhaled dosing. TPIS was also more efficacious than i.v.-infused TRE in a sugen/hypoxia rat model of PAH to inhibit pulmonary vascular remodeling, an effect likely driven by local activities of TRE within the lungs. TPIS also demonstrated antifibrotic and anti-inflammatory activity in the lungs in rodent models of pulmonary fibrosis and asthma. In a phase 1 study in healthy human participants, TPIS (referred to as INS1009) had a lower plasma TRE C and fewer respiratory-related side effects at equimolar doses compared with inhaled TRE. We have now formulated TP as an aerosol powder for delivery by a dry powder inhaler (referred to as treprostinil palmitil inhalation powder-TPIP), and as an aerosol solution in a fluorohydrocarbon solvent for delivery by a metered dose inhaler. These options may reduce drug administration time and involve less device maintenance compared with delivery by nebulization.
曲前列尼尔（TRE）是一种前列环素类似物肺血管扩张剂药物，以皮下、静脉（i.v.）、口服和吸入途径上市，用于治疗肺动脉高压（PAH）。由于其半衰期短，TRE 需要连续输注或多次给药，这会加剧其副作用。因此，一种长效前列环素类似物，既能保持 TRE 的积极属性，又能减少 TRE 相关副作用，可能具有临床益处。在本报告中，我们描述了 TRE 酯前药曲前列尼尔棕榈酸酯（TP）的发现、临床前开发和生物学特性，该前药被制成脂质纳米颗粒（LNP），作为雾化吸入悬浮液（TPIS）给药。在以转化为 TRE 为重点的筛选试验中，TP（16 个碳烷基链）的转化速度最慢，与短烷基链 TRE 前药（即 2-8 个碳烷基链）相比。此外，TP 是一种纯前药，与包括前列腺素受体在内的 G 蛋白偶联受体没有内在结合。在大鼠和狗的药代动力学研究中，TPIS 维持了肺中相对较高浓度的 TP，但最大血浆浓度（C）均较低，无论是 TP 还是更重要的活性产物 TRE。在大鼠和狗的功效研究中，TPIS 抑制了暴露于低氧空气中或静脉内输注 U46619（血栓烷模拟物）引起的肺动脉收缩，作用持续 24 小时。在相当于 TRE 引起豚鼠和狗咳嗽的剂量下，用 TPIS 没有观察到咳嗽，并且在重复吸入给药时，没有对抑制肺动脉收缩的脱敏迹象。TPIS 在舒根/低氧大鼠 PAH 模型中也比静脉内输注 TRE 更有效，抑制肺血管重塑，这一作用可能是由于 TRE 在肺部的局部活性所致。TPIS 在肺纤维化和哮喘的啮齿动物模型中还表现出抗纤维化和抗炎活性。在健康人类参与者的 1 期研究中，与吸入 TRE 相比，TPIS（称为 INS1009）具有较低的血浆 TRE C 和较少的呼吸相关副作用，剂量相等。我们现在已经将 TP 制成干粉吸入器（称为曲前列尼尔棕榈酸酯干粉吸入剂-TPIP）的干粉，以及氟碳溶剂中的气雾剂溶液，用于计量剂量吸入器。与雾化相比，这些选择可能会减少药物给药时间，并减少设备维护。
