Long-term safety of lumacaftor–ivacaftor in children aged 2–5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study

Abstract Introduction Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) affect the quantity and/or function of CFTR protein reaching the cell surface. Ivacaftor, a CFTR potentiator that enhances chloride transport, increases the channel-open probability of normal and dysfunctional CFTR. Initially approved for people with CF (pwCF) with G551D-CFTR gating mutations, ivacaftor demonstrated clinical benefit in pwCF with other gating mutations and certain residual function mutations, including R117H-CFTR, in clinical studies. We evaluated the long-term safety and efficacy of ivacaftor in pwCF aged 6 years and older with non-G551D-CFTR ivacaftor-responsive mutations. Methods Efficacy and safety data from a phase 3, multicenter, open-label, extension study for participants from Study 110 (R117H-CFTR mutations), Study 111 (non–G551D-CFTR gating mutations), and Study 113 (n-of-1 pilot study in participants with residual CFTR function) were analyzed. Following washout from the randomized parent study, participants received oral ivacaftor 150 mg once every 12 h for 104 weeks. Results Forty-one of 121 participants completed treatment through 104 weeks; 59 participants who did not complete the extension study continued treatment with commercial ivacaftor. The most common adverse events were pulmonary exacerbation (46.3%) and cough (33.9%). Most treatment-emergent adverse events were mild/moderate in severity and consistent with manifestations of CF or the ivacaftor safety profile. Rapid, durable improvement occurred across all efficacy endpoints. Conclusions Ivacaftor was generally safe and well tolerated with no new safety concerns for up to 104 weeks in pwCF with ivacaftor-responsive mutations. The pattern of improvement across efficacy endpoints was durable and generally consistent with parent-study outcomes. Trial Registration NCT01707290

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172 A Phase 3, Multicenter Study to Assess the Long-Term Safety, Tolerability, and Efficacy of Olanzapine/Samidorphan in Patients with Schizophrenia

CNS Spectrums ◽

10.1017/s1092852920000887 ◽

2020 ◽

Vol 25 (2) ◽

pp. 309-310

Author(s):

Sergey Yagoda ◽

Christine Graham ◽

Adam Simmons ◽

Christina Arevalo ◽

Yansong Cheng ◽

...

Keyword(s):

Clinical Laboratory ◽

Study Drug ◽

Term Treatment ◽

Extension Study ◽

Open Label ◽

Phase 3 ◽

Long Term Treatment ◽

Open Label Extension ◽

Clinically Significant

Abstract:Background: ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM), is in development for the treatment of schizophrenia and is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. We report the safety, tolerability, and efficacy of OLZ/SAM in patients with schizophrenia in a phase 3, 52-week, open-label extension study.Methods:Patients aged 18–70 years who completed a previous phase 3, 4-week, inpatient acute efficacy study were switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Study assessments included adverse events (AEs), weight, clinical laboratory testing, and Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S) scores.Results:281 patients were enrolled; 277 (mean age, 41.4 years) received ≥1 dose of study drug, and 183 (66.1%) completed the extension study. The most common reasons for discontinuation were withdrawal by patient (15.5%), loss to follow-up (6.9%), and AEs (5.8%). AEs were reported in 136 (49.1%) patients; most were mild in severity. The most common AEs were increased weight (13.4%), somnolence (8.3%), nasopharyngitis (4.0%), and headache (4.0%). Mean weight increase from baseline in patients completing 52 weeks of treatment was 1.86 kg, a 2.79% increase. No clinically significant changes in mean laboratory parameters were observed. Mean (SD) changes from baseline to week 52 in PANSS total score and CGI-S score were –16.2 (15.41) and –0.9 (0.92), respectively (both P<0.001).Discussion:OLZ/SAM was generally well tolerated with a safety profile that supports long-term treatment. During this 52-week extension study, there were improvements in schizophrenia symptoms.Funding Acknowledgements:This study was funded by Alkermes, Inc.

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