Lumacaftor is typically known in the context of cystic fibrosis, where it is approved in the combination drug, Orkambi^® (lumacaftor/ivacaftor) that targeted mutated CFTR-protein.

The QP team recently discovered an alternate use for lumacaftor as a cerebrovascular therapy and are now accelerating development of a microvascular targeted drug for proof-of-concept studies inpatients.

CFTR-correctors in animals

QP’s nonclinical pharmacology studies in mouse models of heart failure and subarachnoid hemorrhage confirmed thatCFTR plays an essential role mediating the inflammatory signals that compromise cerebral artery function.These findings established proof of principal for clinically testing CFTR correctors in patients.

QP selected lumacaftor for its existing safety profile and evidence of its effect on key disease parameters:
‣     Cerebral vessel tone
‣     cerebral blood flow
‣     neuronal health
‣     neurological deficits

Lumacaftor Trial in Healthy Volunteers
NCT05968612

QP’s Phase 1 study tested its investigational lumacaftor mono-substance tablet in comparison to the commercial product, Orkambi® (lumacaftor/ivacaftor combination tablet) in 39 healthy adult volunteers, with top-line results expected in Q2 2024.

QUESTIONS
‣ What area the PK properties of lumacaftor following oral dosing in healthy subjects taken with and without food?
‣ Are lumacaftor measures in blood comparable to that in the commercial product?

STUDY DESIGN
Phase 1 consists of a single-dose, randomized, open-label, three-way crossover, three-period, three-sequence, three-treatment, single-centre, bioequivalence and food-effect study. Subjects enrolled in this study we rerandomized receive a single oral dose of QP’s lumacaftor mono-substance tablet formulation under fasted and fed conditions to evaluate food-effect, and the commercial product, Orkambi^® (lumacaftor/ivacaftor combination tablet) under fed conditions.

LYRIC Proof-of-Concept Trial in HF Patients

HF is a multi-organ disease where the dysfunction of the heart causes collateral damage in other organ systems. HF is associated with a reduction in brain blood flow that causes ischemia and threatens the structural and functional integrity of the brain. One of the main clinical complications is cognitive impairment (CI), which affects about half of all HF patients, without any available treatments. The purpose of this study is to establish proof-of-concept for repurposing lumacaftor as a microvascular treatment for HF patients to improve CBF.

QUESTIONS
‣ Does lumacaftor increase CBF versus placebo in HFrEF patients at 1 month on perfusion MRI?
‣ Is lumacaftor safe and tolerable in stable HFrEF patients?
‣ Does lumacaftor improve symptoms of CI?

STUDY DESIGN
Phase 2 is a randomised, parallel group, placebo-controlled, double-blind, longitudinal, single treatment centre, proof-of-concept study to evaluate the efficacy and safety of Lumacaftor vs. placebo in 60 stable heart failure subjects with reduced ejection fraction (HFrEF) on optimal goal-directed medical therapy. Subjects enrolled in the trial will undergo a cerebral MRI to assess baseline CBF, and then be randomised to receive Lumacaftor or Placebo for 30 days. After treatment, a second MRI will take place. Cognitive function and patient-reported outcomes will be measured at baseline, 1 month and 3 months.