Mutation-specific Therapy for the Long QT Syndrome

Description

The congenital Long QT Syndrome (LQTS) is a life-threatening condition characterized by a prolonged QT interval on the electrocardiogram, and an increased risk of life-threating arrhythmias in otherwise healthy individuals. Typically, the heart is structurally normal and the electric abnormality present in these patients is due to mutations in genes encoding ion channel subunits or proteins modulating ion-channel function. The investigators will specifically study the LQT2 variant which is the second most common form of LQTS (30-35% of all LQTS cases), a rare condition present in approximately 1 in 7.500-8.000 live births characterized by loss-of-function mutations in the KCNH2 gene (hERG) which result in a reduction of the potassium current IKr, pivotal for ventricular repolarization. Four different mutation classes define the molecular mechanisms impairing hERG. Among these, almost 50% are class 2 mutations that determine hERG trafficking defects, with the consequent lack of expression of these essential ion channels on the cardiomyocyte membrane.

According to clinical severity current therapies for LQT2 include -blockers, left cardiac sympathetic denervation and an implantable cardioverter defibrillator (ICD). However, ICD implantation, is not devoid of complications and often, the pain and fear associated with ICD shocks lead to electrical storms with multiple recurrent shocks. Furthermore, there are concerns about the long-term impact of implanting an ICD in young LQTS patients, likely to live another 7 to 8 decades after initial device implantation and who would be subjected to multiple procedures for generator replacement and lead revisions/extractions with frequent complications. There is a clear and unmet need for additional therapeutic strategies and implementation of gene-specific therapy could represent a quite important step for improving the clinical management of these pts.

Lumacaftor (LUM) is a drug developed and currently indicated for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. By acting as a chaperone, LUM corrects protein folding and trafficking defects of mutant and misfolded CFTR channels, restoring their cell surface expression. In its commercial formulation - brand name Orkambi - it is combined with ivacaftor (IVA), an enhancer of the CFTR protein function. The recommended dose is two tablets (each tablet containing LUM 200 mg/ IVA 125 mg) taken orally every 12 hours for a total daily dose of LUM 800 mg/ IVA 500 mg.

The investigators recently demonstrated that LUM can rescue in vitro the LQTS phenotype observed in human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) from patients with LQT2 Class 2 mutations (PMID: 29020304) and in these same two patients Orkambi administrated for 7 days at the same dosage approved for cystic fibrosis showed to reduce their QTc (PMID: 30753398).

With the present phase II clinical trial (MAST2) 20 LQT2 patients will be enrolled (see inclusion and exclusion criteria). Patients will be admitted to hospital for a maximum of 7 days (minimum in-hospital stay based on evidence of QTc shortening) while beta-blocker therapy will continue at the current dose. Orkambi will be administered at the dose approved for cystic fibrosis [Orkambi (Lumacaftor 200 mg/Ivacaftor 125 mg) 2 tablets twice a day for a total daily dose of 800 mg of Lumacaftor and 500 mg of Ivacaftor] and blood exams will be performed at day 1, 3, 5 and 7. During the entire period continuous ECG monitoring through both telemetry and 12-lead 24-hr Holter monitoring will be performed and QTc length and morphology will be analysed. Independently of the result the patient will be discharged without Orkambi as a chronic therapy. Therefore, the drug will be administered orally for a maximum of 7 days.

In case of side effects a reduction of the dose will be considered and according to the specific problem the possibility of an interruption will be evaluated. Furthermore, as an additional "stopping rule" the patient can freely decide to withdraw from the study in any moment even during the Hospitalization phase.

Compliance will be strictly monitored as the drug will be assumed in Hospital in front of the nurse twice a day for the maximum of 7 days. Placebo will not be used.

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