From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2
Key result
Lumacaftor-ivacaftor shortens QTc by ~28 ms in two LQT2 patients with trafficking defects.
- n=2
Why the study?
After Lumacaftor rescued the hERG trafficking defect in patient-derived iPSC-CMs, investigators tested whether Lumacaftor + Ivacaftor could shorten the QTc in the same two LQT2 patients.
Does Lumacaftor + Ivacaftor shorten QTc in patients with long QT syndrome Type 2 and a hERG trafficking defect?
Population
Two LQT2 patients with a hERG trafficking defect
Comparison
Lumacaftor + Ivacaftor vs baseline
Design
Two-patient study with blind QTc measurements
Authors
Discussion
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Member takes
Implication
Should not alter LQT2 management; leaves open a potential role for LUM+IVA in larger trials.
Key Points
- This research aims to evaluate the clinical efficacy of Lumacaftor + Ivacaftor in shortening QTc in patients with Long QT Syndrome Type 2.
- Administration of half dose of Lumacaftor + Ivacaftor on Day 1, followed by full dose for 7 days.
- Continuous 12-lead Holter ECG monitoring for QTc measurements during treatment.
- Treatment effects were evaluated in terms of changes in QTc values pre-and post-treatment.
- QTc significantly shortened in Patient 1 from 551 ± 22 ms to 523 ± 35 ms and in Patient 2 from 472 ± 21 ms to 449 ± 20 ms in lead V6.
- Percentage of QTc values in lower tertile increased in both patients; in V6 from 33% to 68% for Pt1 and 33% to 76% for Pt2.
- Diarrhea was noted as a side effect more in Patient 1 than Patient 2.
Study Design
Type
Case Report (n=2)
Blinding
Single-blind (outcome assessment)
Structured PICO
Does Lumacaftor + Ivacaftor shorten QTc in patients with long QT syndrome Type 2 and a hERG trafficking defect?
P
Population
2 patients with long QT syndrome Type 2 (LQT2) and a hERG trafficking defect
I
Intervention
Lumacaftor + Ivacaftor (half dose on Day 1, followed by full dose LUM 800 mg + IVA 500 mg for 7 days)
C
Comparator
Baseline (1 day of baseline recordings prior to treatment)
O
Outcome
QTc shortening measured by continuous 12-lead Holter ECGsurrogate
Lumacaftor + Ivacaftor successfully shortened the QTc interval in two patients with LQT2, providing first-in-human translation of in vitro iPSC-CM drug repurposing results.
Limitations
- Small sample size (2 patients), requiring validation in more patients before clinical translation.
- Extremely small sample size (n=2)
- Requires validation in more patients before clinical translation
Cite This Study
Schwartz et al. (2019) conducted a case report in Long QT syndrome Type 2 (n=2). Lumacaftor + Ivacaftor vs. Baseline was evaluated on QTc interval. Lumacaftor + Ivacaftor significantly shortened the QTc interval in two LQT2 patients with a trafficking defect (e.g., from 551 to 523 ms in V6 for Patient 1).