Real Life Evaluation of the Multi-organ Effects of Lumacaftor/Ivacaftor on F508del Homozygous Cystic Fibrosis Patients.

Introduction Cystic fibrosis (CF) is a genetic multisystem disease that is characterized by pancreatic insufficiency (PI) and chronic airway infections associated with loss of lung function, repeated pulmonary exacerbations (PEx), and ultimately, respiratory failure. F508del, the deletion of a single amino acid, is the most common mutation that causes CF. In July 2015, the U.S. Food and Drug Administration approved the combination Lumacaftor/Ivacaftor (Orkambi®, Vertex pharmaceuticals) for use in patients with CF homozygous for the F508del mutation. Briefly, this combination of a corrector (Lumacaftor) and potentiator (Ivacaftor) partially restores the activity of the membranous CF transmembrane regulator (CFTR) protein. Lumacaftor improves the processing of F508del CFTR and its transport to the cell surface, while Ivacaftor increases the probability for the channel to be open and its transport of chloride. In clinical trials, treatment with Lumacaftor-Ivacaftor (LUM-IVA) in individuals homozygous for F508del led to an increase in lung function, weight, and a significant reduction in the frequency of PEx and CF-related hospitalizations.

Extra-pulmonary complications are common in CF. Of these, CF-related diabetes (CFRD) is one of the worst prognostic factors. In people with gating mutations responsive to Ivacaftor, treatment was associated with an improvement in insulin secretion after glucose challenge.

Another important extra-pulmonary complication is CF bone disease (CFBD), characterized by low bone mineral density. Osteopenia and fractures are noted among 50-75% of patients diagnosed with CF. The reasons for those pathologies are malabsorption of fat soluble vitamins, a complex abnormality of sex hormone composition, primary CFTR dysfunction, chronic infection and inflammation, and low levels of bone-building exercise resulting from advanced respiratory compromise. It is well known that growth and sexual development is delayed in CF patients, due in part to nutritional deficiencies and the severity of their chronic lung disease. These delays are accompanied by low levels of sex hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).

The aim of the current study was to evaluate endocrine pancreatic function, bone metabolism and respiratory changes through the first year of LUM-IVA treatment in adult patients.

Materials and methods Study design and participants The study was a prospective, single center, observational real-world study on F508del homozygous adult CF patients, who commenced treatment with LUM-IVA and were followed for a year. Pregnant and nursing females; solid organ or hematological transplant recipients; alcohol or drug abusers; patients with an acute upper or lower respiratory infection, and those with PEx or changes in therapy for pulmonary disease within 28 days before Day 1 (first dose of study drug) were excluded.

All subjects received 400 mg Lumacaftor /250 mg Ivacaftor (LUM-IVA) fixed-dose combination film coated tablets for oral administration every12 hours. All participants remained on their pre-study stable CF medication regimen through the year. They were followed in the CF Center at Carmel Medical Center, Haifa, Israel between 2016 and 2019. The institutional board reviewed and approved the study protocol. All patients provided written informed consent.

Study period Screening period was from day -28 through day -1. Treatment period was from day 1 (first dose of study drug) through 12 months ± 7 days. Five clinic visits were carried out on day 1 and at weeks 12, 24, 36 and 48 (± 7 days).

At screening (V0) and at 12 months (V5) the patients underwent a sweat test, Oral glucose tolerance test (OGTT) in patients without CF related diabetes (CFRD), chest computed tomography (CT) and a bone density evaluation using Dual-energy x-ray absorptiometry (DEXA). Evaluations performed during each visit included: recording of CF-related symptoms, treatments, physical examination, vital signs, body mass index (BMI) measurements, pulmonary function tests (PFT), laboratory tests, sputum culture and disease-specific quality of life evaluation using the Cystic Fibrosis Questionnaire-Revised (CFQR).

Study assessments The primary endpoint was the absolute change from baseline through 12 months in the percentage of predicted Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and forced expiratory flow between 25-75 (FEF25-75). Spirometry was performed in accordance with the American Thoracic Society/ European Respiratory Society (ATS/ERS ) Task Force, using a KoKo® spirometer (n-Spire Healthcare, Inc., Longmont CO, USA).

Key secondary endpoints included the absolute and relative change from baseline through 12 months in (1) metabolic factors, including BMI, OGTT (75g of glucose were ingested orally, and glucose, insulin \& c-peptide were examined at the time of ingestion, 1 hour and 2 hours later), Albumin and HbA1C; (2) bone health factors including parathyroid hormone (PTH), Alkaline phosphatase, , Phosphor, and Calcium levels; A, D, E vitamin levels, Urine Ca/Cr ratio; and DEXA scans (3) Hormonal factors including; luteinizing hormone (LH), follicle stimulating hormone (FSH), Testosterone and Estradiol levels; and (4) evaluation of CFTR function through concentration of sweat chloride Additional evaluations included (1) chest CT scans that were performed and scored using the Bhalla scoring method by a radiologist-investigator (the total score ranges from 9 to 25, with a higher score indicating more severe structural lung changes); (2) The patient-reported CFQ-R respiratory domain score (scores range from 0 to 100, with higher scores indicating a better quality of life and 4 points considered to be a minimal clinically important difference) (3) safety parameters (electrolytes, liver and kidney function test, coagulation function) and (3) pulmonary exacerbations (PEx). A PEx was defined as a deterioration in respiratory symptoms that led to a change in treatment. Each PEx was counted as a separate event, and the number of PEx in the year prior to commencing treatment with LUM-IVA was compared to PEx in the year on the treatment. We documented: number of exacerbations, oral vs. intravenous antibiotic treatment, hospitalizations, presence of fever >38°C, laboratory parameters (white blood cells count [WBC], absolute neutrophil count [ANC], C-reactive protein [CRP] at PEx start in hospitalized patients), sputum culture results and time to next PEx.