Impact of Lumacaftor-Ivacaftor on body composition in adults with severe cystic fibrosis lung disease Susannah King1,2 Elyssa Williams2, Judy Allen-Graham2, Felicity Finlayson2, Denise Clark2, Audrey Tierney1,2,4, Tom Kotsimbos2,5, Dominic Keating2, Brenda Button2,3, John Wilson2,5 1Nutrition and Dietetics Department, Alfred Health, Melbourne 2Cystic Fibrosis Service, Department of Allergy, Immunology and Respiratory Medicine, Alfred Health Melbourne 3Physiotherapy Department, Alfred Health, Melbourne 4Dietetics and Human Nutrition, LaTrobe University, Melbourne, 5Department of Medicine, Monash University, Alfred Hospital, Melbourne

Susannah King, PhD Presenter Disclosure No relationships exist in relation to this presentation

Genetic modulators and nutritional status Ivacaftor associated with ↑ weight /BMI in clinical trials (3kg / 1BMI unit) ↑ fat-free mass (FFM) and fat mass at 3 months (Tierney et al, Alfred cohort (n=20)1 Lumacaftor-Ivacaftor (F508del homozygous): clinical trials (≥ 12 y, FEV1 40-90%)2 Modest ↑BMI (0.4 units) Patients with severe lung disease: excluded from these clinical trials Managed access program (MAP): F508del homozygous, ≥12 years FEV1 <40% predicted (or >40% but rapid decline or LTx listing)

Body composition in CF Body composition abnormalities are prevalent in CF ↓Fat-free mass (FFM)  lower FEV1%, ↑IL-6, recurrent pulmonary exacerbations3-6 Interventions aimed at improving nutritional status Traditionally monitor weight gain Cannot assume tissue composition – FFM vs fat mass Body composition is emerging as a relevant patient-centred outcome Preservation of function in the face of declining health Impact of clinical and exercise interventions Severe CF lung disease: paucity of data on LUM-IVA on weight & body composition

Body composition assessment: Bioelectrical impedance analysis (BIA) Tetrapolar, multi-frequency BIA Measures resistance to electric current Uses a range of frequencies: Measures both Total body water (TBW) and Extracellular water (ECW) From TBW + ECW => Intracellular water (ICW) From TBW = > FFM From weight and FFM => fat mass Quick, non-invasive High precision & reproducibility More accessible than DXA SECAR mBIA Images from SECA and Alfred Health

Aim To evaluate changes in body composition in adults with CF with FEV1<40% predicted over six months of treatment with Lumacaftor-Ivacaftor via the Managed Access Program at The Alfred CF Service, Melbourne, Australia Retrospective evaluation Design

Methods: the cohort 30 adults with baseline FEV1<40% predicted commenced Lumacaftor-Ivacaftor under the MAP Standard dosing: 400mg LUM, 250 IVA, 12hourly with fat and PERT N=5: ceased prior 6mo 3 not tolerating 2 lung Tx N=3: not yet at 6mo On Lumacaftor-Ivacaftor for ≥6 months: N=22 N=2 had 1 BIA measurement missing Body composition measurement (BIA) at baseline and 6 months N=20 50% male mean±SD age 34.1±8.9 years mean±SD FEV1 33.3±6.1% predicted mean±SD BMI 19.8±2.2kg/m2

Methods: body composition Body composition using SECA mBIA monitored routinely before and during Lumacaftor-Ivacaftor treatment Baseline and 6-month measurements extracted Changes in weight, FFM, fat mass, TBW, ICW, ECW Clinically important change in weight and FFM: ≥5% gain or loss Statistical analysis: Paired t-tests 0 vs 6 months Pearson’s correlations and multiple regression: explore relationships between body composition variables

results

Results: weight change Mean ∆weight: +2.2±3.9kg (p=0.02) Range: -4.6kg to +10.3kg Mean % ∆weight: +4.6±6.8% (p=0.009) ∆Weight n (%) Lost ≥5% 1 (5%) Stable within 5% 10 (50%) Gained ≥5% 9 (45%) Red bars show mean weight

Results: fat mass change Mean ∆fat mass: +2.1±2.6kg (p=0.02) Range: -3.9kg to +6.2kg Red bars show mean fat mass

Results: fat-free mass change Mean ∆FFM: +0.5±3.2kg (p=0.34) Range: -3.7kg to +5.2kg Mean % ∆FFM: +1.5±5.9% (p=0.28) ∆FFM n (%) Lost ≥5% 2 (10%) Stable within 5% 14 (70%) Gained ≥5% 4 (20%) Red bars show mean FFM

BMI profile Mean ↑BMI 0.93±1.3 kg/m2 (p=0.006) P=0.03

Correlates of ∆s in body composition Baseline BMI: significantly negatively correlated with ∆weight & ∆FFM, but not ∆fat mass Gender, age and baseline FEV1%: no correlation with: ∆weight, ∆FFM (or % changes) or ∆fat mass

Multiple regression analysis => Interpret tissue composition of weight ∆s: Change in weight significantly and independently associated with Change in fat mass (p<0.0001) Change in intracellular water (p=0.002) Not change in extracellular water Where changes in FFM are seen, the underlying change in TBW is predominantly intracellular reflects ∆ in body cell mass not extravascular fluid changes: ie FFM gain ≠ oedema ∆FFM vs ∆ICW r = 0.90 p<0.0001

Summary and Discussion In a cohort of adults with severe CF lung disease receiving LUM-IVA for 6 mo Overall significant gains in weight and fat mass Reduction in % with BMI <18.5 Hubert et al (France)7 LUM-IVA in FEV1<40% No change in BMI in 3 months FFM increases not explained by extravascular fluid retention Reflected increase in body cell mass (ICW)

Discussion: Possible mechanisms ? Direct anabolic effect of LUM-IVA ? Correction of CF defect in electrolyte transport at cellular level8 ? Mediation via pulmonary effects ? Modification of proinflammatory cytokine response – IL6 ? Ameliorate anorectic effects of severe lung disease ? Alterations in GI function impacting on nutrient absorption and E0 balance ? Via other clinical effects: exercise capacity ? Improved adherence to other CF treatments “opportunity” of LUM-IVA

Limitations Future directions Not a controlled clinical trial: cannot directly attribute changes to the medication cannot control for confounders such as adherence to other CF therapies Quantitative dietary intake not available – intake vs absorption vs metabolism Explore mechanisms for nutritional status changes on LUM-IVA treatment Integrate with evaluation of other clinical parameters Incorporate body composition into clinical practice and trial design in CF Monitor nutritional status, evaluate interventions Future directions

Acknowledgements Managed access program for Lumacaftor-Ivacaftor Alfred CF team members implementing and monitoring MAP References Tierney A, et al. J Cyst Fibr. 2016;14:S50. Wainwright CE, et al. New England Journal of Medicine. 2015;373(3):220-31 King SJ, et al. Nutr. 2010;26(7-8):753-9. 4. Ionescu AA, et al. Am J Resp Crit Care Med. 2002;165(4):495-500. 5. King SJ, et al. Clin Nutr. 2014;33(1):150-5. 6. Alicandro G, et al. J Cyst Fibr. 2013;13(3):328-34. 7. Hubert D et al, Journal of Cystic Fibrosis 16: 388-391 8. Holland AE, et al. Chest. 2003;124(2):490-3. .