Nashville 31 st Oct 2019 2 Nov 2019 Laura Kinsey Lead Dietitian Manchester Adults Cystic fibrosis Centre l aurakinseymftnhsuk Nutritional management of patients with CF in the era of highly effective modulators ID: 1042658
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1. Highlights of the North American Cystic Fibrosis Conference,Nashville, 31st Oct 2019 – 2 Nov 2019Laura KinseyLead Dietitian Manchester Adults Cystic fibrosis Centrelaura.kinsey@mft.nhs.uk
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4. Nutritional management of patients with CF in the era of highly effective modulatorsWhat are modulatorsTriple therapy trial resultsWhat could be the nutritional implications
5. CFTR modulatorsCFTR potentiatorsIncrease channel opening at the cell surface and increase chloride transportImproved CFTR chloride transportCFTR correctorsHelp the CFTR fold properly so that it can move to the cell surface=
6. Different modulatorsIvacaftor(Kalydeko)2012Lumcaftor/Ivacaftor(Orkambi)2019Tezacaftor/ivacaftor(Symkevi)2019Elexacaftor/Tezacaftor/ivacaftor(Trikafta)Not yet available in the UKModulator TypePotentiatorCorrector + PotentiatorCorrector + PotentiatorCorrector + Corrector + PotentiatorTarget MutationG551D, “Gating Mutations”(5% of pop)F508 x2(around 50% pop)F508 x2(Some F508 heterozygotes) (around 50% pop)F508 + one minimal functionF508 x 2(90% pop)
7. Davies et al, 2018Increase in FEV1% of 13.8% over baseline for 200mg Vx445Increase in FEV1% of 11.0% over Tez/Iva after adding 200mg Vx445 (+4% from tez/iva already)Reduction in sweat chloride of 39.1 mmol/L from baseline for 200mg Vx445Reduction in sweat chloride of 39.6 mmol/L over Tez/Iva after adding 200mg Vx445
8. Triple therapy trials published 31st October 2019403 patientsF508del-MF115 trial sites, 13 countries25% 12-18yrMean FEV1 61%Placebo and active groups well matchedMean 98% adherenceAll 400 completers went on to open label study
9. Sustained improvement in FEV1: 14.3% vs placeboRapid rise in FEV1Sustained14.3%Many patients with large increase in FEV1
10. 63% reduction in pulmonary exacerbationsReduced by 63%Same for inpatient exacerbationsSame for all IV-treated exacerbations
11. BMI mean increase 1.04kg/m2Middleton et al., 2019 NEJM
12. Published in The Lancet 31st October 2019
13. DF/DF outcomes: TC vs Tez/IvaFEV1 improved +10% Sweat chloride improved -45.1mmol/LCFQ-R respiratory domain improved +17.4 pointsBMI increase 0.6 kg/m2 (p<0.001)Heijerman et al., 2019
14. Long term effects of modulators?No long term studies yet for triple therapy …can we draw from our experiences of Ivacaftor?
15. Long term effects of Ivacaftor1: Bessonova et al, Thorax 2018
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17. What we know about modulators and nutrition?Sig improvements in Wt and BMI with Ivacftor and triple (Borowitz et al, 2016, Rowe et al., 2014, Davies et al., 2016m Middleton et al. 2019, Heijerman etal., 2019)More modest effects with Lumacafor-ivacaftor (Mcnamara et al., 2019 and Ratjen et al. 2017)Not significant with Tez-iva (Taylor-Cousar et al., 2017)
18. Ivacaftor(Kalydeko)2012Lumcaftor/Ivacaftor(Orkambi)2019Tezacaftor/ivacaftor(Symkevi)2019Elexacaftor/Tezacaftor/ivacaftor(Trikafta)Modulator TypePotentiatorCorrector + PotentiatorCorretor + PotentiatorCorrector + Corrector + PotentiatorTarget MutationG551D, “Gating Mutations”(5% of pop)F508 x2(around 50% pop)F508 x2(Some F508 heterozygotes) (around 50% pop)F508 + one minimal functionF508 x 2(90% pop)Improvements in FEV110%3%4%14% F508 + one mutation10% F508 x2 (above 4%)Decrease in PE++++++++++Improvement in weight/BMI++++++++++
19. Weight gainWhy?Patients feel betterBecause they have less PELess hospital admissionIs it more than just this? Lets look beyond the lungs……
20. “The pancreas in CF is fibrotic +/- fatty infiltration at birth or in utero and nothing will cause it to function” True or false?
21. Improvement in faecal elastase in childrenDavies et la., 2016 KIWI age 2-5 years
22. ARRIVAL 12-24mthsRosenfield et al., 2019
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24. What about in adults?How many of you have had patients reduce/stop their PERT?
25. Other causes of improved GI symptoms and nutritionImprovement in bicarbonate secretion and changes in ph will have mutiple effects (Borowitz et al., 2015, Gelfond et al., 2017) :Improved effectiveness of PERTImproved effectiveness of any natural pancreatic enzymes present, aiding absorptionDecrease intestinal inflammation (Ooi et al, 2018)Changes in microbiota (ooi et al., 2018)Regulation of bile acid homeostasis
26. Decreased REE (Stallings et al, 2018)Pts with > 1 CFTR gating mutation evaluated pre- and post 3 months of Ivacaftor23 pts (5-61years), 70% PIGained 2.5+/- 2.2kg (p<0.001) with increased FFM (09+/-1.9kg, p<0.05) and FM 1.6+/- 1.5kg)REE% decreased by 5.5 +/- 12% (p< 0.05)Faecal calprotectin decrease by 30+/- 40ug/g stool (p<0.01)Improvements PI > PSCFA% increased sig in PI onlyFaecal elastase increased in PS but no change in PI Conclusions:Reduced REEReduced gut inflammationAnd improved fat malabsorption
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29. Is BMI good enough?Kapnadak et al 2019 (US)13.6% underweight, 28.8% overweight or obese30.3% primary concern was preventing weight lossMost commonly desired health-improvement resource was on-line CF nutrition and fitness informationAlvarex 2016 body composition FFM +ve assoc with lung functionAdiposity inversely assoc with lung function30% had normal weight obesity (NWO)Those with NOW had reduced FFM and reduced lung functionNutrition screening protocols that rely on BMI may require reassessment
30. “ don’t dig you grave with your own knife and fork”“ a high calorie diet can be healthy”
31. Is PI reversible in adults?Can patients stop their PERT?Can patients reduce their vitamins?At what point does weight gain become a negative factor? LBM Vs FMHow can we use body composition?Can patients reduce their salt tables?Can we use our experience in Ivacaftor to predict the impact of triple therapy?
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33. Lets get ready….Data collectionBody compositionGI symptomsFaecal elastaseVitamin levelsDietary intake? Faecal calprotectin Resources and servicesNutritional information for starting on modulatorsHealthy fatsLinks with psychological servicesDietetic services for weight management, resourcesSkillsResearch opportunitiesCollaboration
34. Thank youMy dietetic teamThe wider CF teamDr P BarryDr A HorsleyProf A JonesMy colleagues who I went with
35. https://videos.files.wordpress.com/pdupjf8m/daretodream-nacfc2019.mp4