Orkambi in patients with severe disease — Bumps in the road to CFTR modulation

Horsley, Alex; Barry, Peter J.

doi:10.1016/j.jcf.2017.04.008

Cited by 5 publications

(5 citation statements)

References 9 publications

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“…More recently, combinations of a folding "corrector" and a channel potentiator significantly increased F508del CFTR surface expression and activity (Van Goor et al 2009. This drug combination was approved by the Food and Drug Administration (FDA) in 2015, and even with some positive outcomes the effects in patients have shown limited efficacy and give rise to unwanted side effects (Horsley and Barry 2017). Improved corrector-potentiator combinations will undoubtedly be forthcoming.…”

Section: Uromodulinmentioning

confidence: 99%

Chaperoning Endoplasmic Reticulum–Associated Degradation (ERAD) and Protein Conformational Diseases

Needham

Guerriero

Brodsky

2019

Cold Spring Harb Perspect Biol

111

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Misfolded proteins compromise cellular homeostasis. This is especially problematic in the endoplasmic reticulum (ER), which is a high-capacity protein-folding compartment and whose function requires stringent protein quality-control systems. Multiprotein complexes in the ER are able to identify, remove, ubiquitinate, and deliver misfolded proteins to the 26S proteasome for degradation in the cytosol, and these events are collectively termed ERassociated degradation, or ERAD. Several steps in the ERAD pathway are facilitated by molecular chaperone networks, and the importance of ERAD is highlighted by the fact that this pathway is linked to numerous protein conformational diseases. In this review, we discuss the factors that constitute the ERAD machinery and detail how each step in the pathway occurs. We then highlight the underlying pathophysiology of protein conformational diseases associated with ERAD.

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Section: Uromodulinmentioning

confidence: 99%

Chaperoning Endoplasmic Reticulum–Associated Degradation (ERAD) and Protein Conformational Diseases

Needham

Guerriero

Brodsky

2019

Cold Spring Harb Perspect Biol

111

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“…Lung transplantation is the ultimate treatment option for end-stage cystic fibrosis pulmonary disease despite maximal therapy [6]. New treatments including CFTR-modulators, ought to be tested [19]. If lung transplant candidates stabilise clinically, conditions for transplantation, when finally required, improve.…”

Section: Original Articlementioning

confidence: 99%

First experience in Switzerland in Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease enrolled in a lumacaftor-ivacaftor therapy trial – preliminary results

2018

Swiss Med Wkly

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Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease tolerated LUM/IVA, although RAEs occurred early and were severe. This positive finding was probably due to the stepwise dose increases. There was clinical benefit mainly from reduction in AER and stabilisation of lung function. We propose that all suitable Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease should have a trial of LUM/IVA treatment in experienced centres.

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“…The original Phase 3 studies excluded individuals with a baseline percent predicted (pp) FEV 1 <40% at screening and reported that fewer than 10% of individuals experienced adverse respiratory effects such as chest tightness and dyspnoea . Subsequent real‐world reports in such individuals have demonstrated a much higher incidence (up to 50%) of adverse respiratory effects severe enough to result in rates of discontinuation of therapy of up to 30% . The lack of a protective effect of bronchodilators prior to dosing and the inability of such therapy to always reverse the fall in FEV 1 has resulted in greater caution in initiating lumacaftor/ivacaftor therapy, especially in people with severe lung disease.…”

Section: Cftr Modulator Therapymentioning

confidence: 99%

“…13 Subsequent real-world reports in such individuals have demonstrated a much higher incidence (up to 50%) of adverse respiratory effects severe enough to result in rates of discontinuation of therapy of up to 30%. 18 The lack of a protective effect of bronchodilators prior to dosing and the inability of such therapy to always reverse the fall in FEV 1 has resulted in greater caution in initiating lumacaftor/ivacaftor therapy, especially in people with severe lung disease. Initial dosing is often given under supervision or in conjunction with a course of intravenous antibiotics if there are clinical concerns.…”

Section: Ivacaftor-lumacaftormentioning

confidence: 99%

Cystic fibrosis: novel therapies, remaining challenges

Coulthard

2018

Pharmacy Practice and Res

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Developments in the treatment of cystic fibrosis (CF) over the past 50 years have seen survival extend from death in the first decade of life to an expected median survival now approaching 50 years of age. Adults with CF now outnumber children, a dramatic shift if one considers that many adult CF clinics were only established in the 1980s. Together with speciality multidisciplinary clinics, new medicines and their aggressive application have played a pivotal role in this achievement. Although there is still no clinically available cure, novel therapies targeting the underlying basic defects have resulted in major beneficial clinical outcomes and quality of life for those living with CF, albeit at significant cost. Although this review concentrates on currently available novel pharmacological therapies, the important role of potential ‘cures’, such as gene therapy, must not be overlooked. The complex drug interactions of the new agents, the need for detailed patient education and research opportunities in CF in general support the role of the specialist pharmacist in CF clinics.

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Orkambi in patients with severe disease — Bumps in the road to CFTR modulation

Cited by 5 publications

References 9 publications

Chaperoning Endoplasmic Reticulum–Associated Degradation (ERAD) and Protein Conformational Diseases

Chaperoning Endoplasmic Reticulum–Associated Degradation (ERAD) and Protein Conformational Diseases

First experience in Switzerland in Phe508del homozygous cystic fibrosis patients with end-stage pulmonary disease enrolled in a lumacaftor-ivacaftor therapy trial – preliminary results

Cystic fibrosis: novel therapies, remaining challenges

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