Gillies Hunter, Niven Ralph, Dake Benjamin T, Chakinala Murali M, Feldman Jeremy P, Hill Nicholas S, Hoeper Marius M, Humbert Marc, McLaughlin Vallerie V, Kankam Martin
Aerovate Therapeutics, Waltham, MA, USA.
Washington University School of Medicine, St Louis, MO, USA.
ERJ Open Res. 2023 Mar 13;9(2). doi: 10.1183/23120541.00433-2022. eCollection 2023 Mar.
Oral imatinib has been shown to be effective, but poorly tolerated, in patients with advanced pulmonary arterial hypertension (PAH). To maintain efficacy while improving tolerability, AV-101, a dry powder inhaled formulation of imatinib, was developed to deliver imatinib directly to the lungs.
This phase 1, placebo-controlled, randomised single ascending dose (SAD) and multiple ascending dose (MAD) study evaluated the safety/tolerability and pharmacokinetics of AV-101 in healthy adults. The SAD study included five AV-101 cohorts (1 mg, 3 mg, 10 mg, 30 mg, 90 mg) and placebo, and a single-dose oral imatinib 400-mg cohort. The MAD study included three AV-101 cohorts (10 mg, 30 mg, 90 mg) and placebo; dosing occurred twice daily for 7 days.
82 participants (SAD n=48, MAD n=34) were enrolled. For the SAD study, peak plasma concentrations of imatinib occurred within 3 h of dosing with lower systemic exposure compared to oral imatinib (p<0.001). For the MAD study, systemic exposure of imatinib was higher after multiple doses of AV-101 compared to a single dose, but steady-state plasma concentrations were lower for the highest AV-101 cohort (90 mg) compared to simulated steady-state oral imatinib at day 7 (p=0.0002). Across AV-101 MAD dose cohorts, the most common treatment-emergent adverse events were cough (n=7, 27%) and headache (n=4, 15%).
AV-101 was well tolerated in healthy adults, and targeted doses of AV-101 significantly reduced the systemic exposure of imatinib compared with oral imatinib. An ongoing phase 2b/phase 3 study (IMPAHCT; clinicaltrials.gov identifier NCT05036135) will evaluate the safety/tolerability and clinical benefit of AV-101 for PAH.
口服伊马替尼已被证明对晚期肺动脉高压（PAH）患者有效，但耐受性较差。为了在提高耐受性的同时保持疗效，开发了伊马替尼的干粉吸入制剂AV-101，以便将伊马替尼直接输送到肺部。
这项1期、安慰剂对照、随机单剂量递增（SAD）和多剂量递增（MAD）研究评估了AV-101在健康成年人中的安全性/耐受性和药代动力学。SAD研究包括五个AV-101队列（1毫克、3毫克、10毫克、30毫克、90毫克）和安慰剂，以及一个400毫克单剂量口服伊马替尼队列。MAD研究包括三个AV-101队列（10毫克、30毫克、90毫克）和安慰剂；每天给药两次，持续7天。
共纳入82名参与者（SAD组48名，MAD组34名）。在SAD研究中，伊马替尼的血浆峰值浓度在给药后3小时内出现，与口服伊马替尼相比，全身暴露较低（p<0.001）。在MAD研究中，与单剂量相比，多次服用AV-101后伊马替尼的全身暴露更高，但与第7天模拟的口服伊马替尼稳态相比，最高AV-101队列（90毫克）的稳态血浆浓度更低（p=0.0002）。在AV-101 MAD剂量队列中，最常见的治疗中出现的不良事件是咳嗽（n=7，27%）和头痛（n=4，15%）。
AV-101在健康成年人中耐受性良好，与口服伊马替尼相比，AV-101的靶向剂量显著降低了伊马替尼的全身暴露。一项正在进行的2b期/3期研究（IMPAHCT；clinicaltrials.gov标识符NCT05036135）将评估AV-101治疗PAH的安全性/耐受性和临床益处。
