Symptoms and impacts of familial chylomicronemia syndrome: a qualitative study of the patient experience.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare, hereditary, metabolic disorder. FCS causes high levels of triglycerides in the blood, which can lead to abdominal pain, xanthomas, and acute pancreatitis (AP). Volanesorsen, along with adherence to a very low-fat diet is used to reduce triglyceride levels in individuals with FCS. We aimed to understand the symptoms of FCS and their impact on health-related quality of life (HRQoL). METHODS: Interviews were conducted with individuals with genetically confirmed FCS in the UK and Spain, some of whom had been treated with volanesorsen. Interview guides were developed with input from a patient advocacy group to explore the symptoms, impacts and management of FCS. Interviews were conducted by telephone and were recorded and transcribed. Data were analyzed using thematic analysis and saturation was recorded. RESULTS: Seventeen interviews were conducted with individuals with FCS (aged 27-68 years), thirteen of whom were currently/previously treated with volanesorsen. Episodes of AP were the most impactful reported symptom, resulting in severe abdominal pain, nausea, vomiting, fever, bloating and appetite loss. Other symptoms and functional issues included abdominal pain, gastrointestinal symptoms, impaired cognitive function and fatigue. These had an impact on work, social activities, relationships and psychological wellbeing. These symptoms and impacts were illustrated in a conceptual model, including management strategies. The challenges of managing a low-fat diet and experience with volanesorsen were discussed. CONCLUSION: Individuals with FCS experience a range of interrelated symptoms and functional limitations which impact their broader HRQoL. Treatments which alleviate symptoms and reduce the incidence of AP episodes have the potential to improve the HRQoL of these individuals.

Orphan drugs revisited: cost-effectiveness analysis of the addition of mifamurtide to the conventional treatment of osteosarcoma.

INTRODUCTION: Mepact(®) (mifamurtide) is the first drug approved for the treatment of high-grade resectable non-metastatic osteosarcoma in patients aged 2-30 in the last 20 years. It follows a randomized clinical trial showing a statistically-significant and clinically-relevant decrease in the risk of death without compromising safety. AIM: This study assessed the cost-effectiveness and budget impact of mifamurtide. METHODS: The economic evaluation was done on a hypothetical cohort of young patients under the age of 30 with high-grade, non-metastatic, resectable osteosarcoma. Standard chemotherapy without mifamurtide was used as comparator. A Markov model was adapted using Spanish costs and the results of the INT-0133 Phase III study. The analysis has been carried out from the perspective of the Spanish National Health Service, with a time horizon of up to 60 years in the base analysis. RESULTS: The observed greater efficacy of mifamurtide in the trial translates into a gain of 3.03 (undiscounted) and 1.33 (discounted) quality-adjusted life years at an additional cost of €102,000. The estimated budgetary impact of using mifamurtide in 10-100% of the potential population would cost €671,000 and €6.7 million respectively. CONCLUSION: The cost per quality-adjusted life years gained with mifamurtide in Spain is in the low band (<€100,000) of the iCERs obtained by other orphan drugs and would have a limited and affordable cost in Spain.

Selective inhibition of an apicoplastic aminoacyl-tRNA synthetase from Plasmodium falciparum.

The resistance of malaria parasites to available drugs continues to grow, and this makes the need for new antimalarial therapies pressing. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes and well-established antibacterial targets and so constitute a promising set of targets for the development of new antimalarials. Despite their potential as drug targets, apicoplastic ARSs remain unexplored. We have characterized the lysylation system of Plasmodium falciparum, and designed, synthesized, and tested a set of inhibitors based on the structure of the natural substrate intermediate: lysyl-adenylate. Here we demonstrate that selective inhibition of apicoplastic ARSs is feasible and describe new compounds that that specifically inhibit Plasmodium apicoplastic lysyl-tRNA synthetase and show antimalarial activities in the micromolar range.

Annexin A6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity.

Annexin A6 is a calcium-dependent membrane-binding protein that interacts with signalling proteins, including the GTPase-activating protein p120GAP, one of the most important inactivators of Ras. Since we have demonstrated that annexin A6 inhibits EGF- and TPA-induced Ras signalling, we investigated whether modulation of Ras activity by annexin A6 was mediated via altered subcellular localization of p120GAP. First, we exploited our observation that high-density lipoproteins (HDL) can activate the Ras/MAP kinase pathway. Expression of annexin A6 caused a significant reduction in HDL-induced activation of Ras and Raf-1. Annexin A6 promoted membrane binding of p120GAP in vitro, and plasma membrane targeting of p120GAP in living cells, both in a Ca(2+)-dependent manner, which is consistent with annexin A6 promoting the Ca(2+)-dependent assembly of p120GAP-Ras at the plasma membrane. We then extended these studies to other cell types and stimuli. Expression of annexin A6 in A431 cells reduced, while RNAi-mediated suppression of annexin A6 in HeLa cells enhanced EGF-induced Ras and Erk activation. Importantly, the enhancement of Ras activation following RNAi-mediated reduction in p120GAP levels was more marked in annexin A6-expressing A431 cells than controls, indicating that the effect of annexin A6 on Ras was mediated via p120GAP. Finally, we demonstrated that annexin A6 promotes plasma membrane targeting of p120GAP in A431 cells in response to a variety of stimuli, resulting in colocalization with H-Ras. These findings demonstrate an important role for annexin A6 in regulating plasma membrane localization of p120GAP and hence Ras activity.