INSPIRE: Final Results from a Phase 3, Open-Label, Pivotal Study to Evaluate the Safety and Tolerability of LIQ861 in Pulmonary Arterial Hypertension

A dry-powder inhaled formulation of treprostinil (LIQ861) produced using PRINTÂ® technology offers a substantial advantage over current nebulized therapy. Treprostinil is a synthetic prostacyclin analogue that is currently approved for inhalation administration to patients with pulmonary arterial hypertension (PAH) via nebulized TyvasoÂ® inhalation solution. LTI-101 was a phase 1, placebo-controlled, double-blind, randomized, single-center study that evaluated the ascending single-dose pharmacokinetics (PK) of LIQ861 in healthy subjects. Six sequential, escalating doses (25, 50, 75, 100, 125, and 150 mcg) were studied to investigate treprostinil exposure from LIQ861 inhalation. Subjects (n=57) were randomly assigned in a 3:1 ratio to receive a single dose of either LIQ861 (n=43) or placebo (n=14); 56 subjects completed all protocol-defined assessments. Following single-dose administration, treprostinil exposure from LIQ861 increased proportionally across the dose range studied, and the PK profile of treprostinil administered as LIQ861 was similar to prior reports of inhaled treprostinil. All doses of LIQ861 were generally well-tolerated with no deaths, serious adverse events, or dose-limiting toxicities. The most frequently reported treatment-emergent adverse events (TEAEs) related to study drug administration were coughing and throat irritation, which are common to dry-powder formulations. Treatment-related TEAEs were reported more frequently at higher dose levels; however, all were assessed as mild in severity. We conclude that the PK profile of treprostinil using a dry-powder inhaled formulation increased in proportion to dose as anticipated and was similar to earlier reports of inhaled, nebulized treprostinil (TyvasoÂ®). Based on these results, a phase 3 study (INSPIRE; Clinicaltrials.gov Identifier NCT03399604) evaluating the long-term safety and tolerability of LIQ861 in patients with PAH was initiated.

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“…Interim safety and tolerability results are consistent with those reported for this phase 1 PK trial. 46 …”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and tolerability of LIQ861, a novel dry‐powder formulation of treprostinil

et al. 2020

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“…To overcome these shortcomings researchers, have evaluated numerous strategies to develop alternative therapies, including prodrug chemical modification of TRE [ 6 , 7 ], liposomal encapsulation [ 8 , 9 ], new devices [ 10 ], and particle engineering via modern manufacturing techniques [ 11 , 12 ]. Furthermore, to increase convenience and improve patient compliance, there have been preclinical efforts to develop inhaled TRE therapies that utilize pressurized metered-dose inhalers [ 13 ] or dry powder inhalers [ 14 ]. We hypothesized that a prodrug formulation of TRE delivered by inhalation and designed to provide prolonged efficacy with potentially reduced adverse events following a simple administration procedure could provide a superior treatment option for PAH patients.…”

Section: Introductionmentioning

confidence: 99%

Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension

Plaunt

Islam

Macaluso

et al. 2021

IJMS

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Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.

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Comprehensive review on novel targets and emerging therapeutic modalities for pulmonary arterial Hypertension

Dhoble

Patravale

Weaver

et al. 2022

International Journal of Pharmaceutics

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INSPIRE: Final Results from a Phase 3, Open-Label, Pivotal Study to Evaluate the Safety and Tolerability of LIQ861 in Pulmonary Arterial Hypertension

Cited by 4 publications

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Pharmacokinetics and tolerability of LIQ861, a novel dry‐powder formulation of treprostinil

Pharmacokinetics and tolerability of LIQ861, a novel dry‐powder formulation of treprostinil

Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension

Comprehensive review on novel targets and emerging therapeutic modalities for pulmonary arterial Hypertension

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