Targeting trafficking defects in long QT syndrome type 2: a phase 2 clinical study with patient-specific cellular validation

A major component of long QT syndrome (LQTS) is LQT2 due to pathogenic variants in KCNH2, which frequently cause trafficking defects. Despite progress in therapeutic management, there is an unmet clinical need for mechanism-targeted therapies. It has been previously shown, using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), that lumacaftor (LUM), currently used for cystic fibrosis, can partially correct hERG trafficking. A single-arm phase 2 study was conducted to determine whether LUM could shorten QTc in LQT2 patients with trafficking defects.

Sixteen adult patients with genetically confirmed trafficking-defective KCNH2 variants were enrolled. Participants were admitted to hospital and received LUM for 7 days under continuous telemetry. QTc was quantified on serial electrocardiograms and 12-lead Holter recordings. For mechanistic correlation, hiPSC-CMs were generated from the first five participants with distinct genetic variants and assessed for hERG maturation and trafficking.

Overall, lumacaftor produced a significant QTc shortening (P < .001). The per-patient change averaged 31 ± 21 ms. Patients with baseline QTc ≥500 ms exhibited the most substantial effect, with 75% achieving reductions ≥40 ms. No ventricular arrhythmias occurred, and adverse effects were primarily gastrointestinal and self-limited. In hiPSC-CMs, LUM restored hERG trafficking in three out of five variants, mirroring the clinical observations.

Short-term LUM therapy is safe and yields a significant QTc shortening in LQT2 patients with a trafficking defect. Concordance between cellular and clinical findings reinforces the value of a mechanism-based, variant-informed approach and supports the feasibility of trafficking-correction strategies within a precision-medicine framework for inherited arrhythmia syndromes.