QP | LYRIC Trial

LYRIC-HF Study Design

Lumacafter Yields Reversal of Impaired Cerebral Blood Flow in Heart Failure Patients

The study is utilizing MRI and cognitive testing to quantify cerebral blood flow abnormalities, detect injury, and meaningful cognitive and functional outcomes.

Repositioning an existing cystic fibrosis drug with favourable safety profile
Short 30-day treatment period with active vs. placebo arms
Cerebral MRI scans and cognitive tests pre- and post-treatment
60 stable heart failure patients with reduced ejection fraction (HFrEF ≤40) on standard-of-care
Participants recruited by their circle of care team in Toronto

The Principal Investigator of the LYRIC-HF trial is leading cardiologist, Dr. Kim Connelly, who is running the study at Unity Health Toronto, St. Michael's Hospital, in collaboration with recruiting centre, the University Health Network, Peter Munk Cardiac Centre.

Cognitive impairment in Heart Failure

Heart failure (HF) affects more than 64 million people worldwide, with an estimated 25%-75% developing cognitive impairment (CI).

For those living with the condition, CI directly worsens HF outcomes, affecting decision making, ability to recognize worsening symptoms, practicing self-care, adhering to complex treatment regimens, and increasing reliance on caregivers. CI compounds economic and clinical burden, being a known driver of re-hospitalization, disability and mortality rates.
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Despite its high toll, there are currently no approved therapies specifically indicated for the prevention or treatment of CI associated with HF, making this a high unmet medical need.

CI in HF often occurs in the domains of complex attention, executive function, learning and memory, language, perceptual-motor function, social cognition and emotional well-being.

Research Background

This study builds on preclinical evidence that impaired cerebral autoregulation, managed at the microvascular (resistance) artery level, is a therapeutic target for cerebral blood flow management and maintenance of cognitive health.

CBF autoregulation normally maintains constant blood flow to the brain tissues despite fluctuations in blood pressure, and is managed at the microvascular level by cerebral resistance artery myogenic tone. In HF, this mechanism is altered and leads to persistently high cerebral artery tone, which constricts the vessel, and reduces adequate CBF to the tissues that is associated with the development of cognitive decline.

Program

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 in patients.

Pre-Clinical

QP’s nonclinical pharmacology studies in mouse models of heart failure and subarachnoid hemorrhage confirmed that CFTR 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

Phase 1 - Bioequivalence and Food-Effect

Lumacaftor Trial in Healthy Volunteers
NCT05968612

QP’s Phase 1 study tested comparative bioavailability of its investigational lumacaftor mono-substance tablet in comparison to the commercial product, Orkambi® (lumacaftor/ivacaftor combination tablet) in 39 healthy adult volunteers.

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.

Phase 2a - Efficacy and Safety

LYRIC Proof-of-Concept Trial in HF Patients

The purpose of this study is to establish proof-of-concept for repositioning lumacaftor, a drug with an established safety profile, to stabilize CFTR and restore cerebral blood flow in heart failure patients, thereby improving cognitive function.

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.

The LYRIC-HF trial will target microvascular dysfunction, an unaddressed driver of heart failure progression and cognitive impairment.