1. 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

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

3. 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, FEV %)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)

4. 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

5. 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

6. 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

7. 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 ±8.9 years
mean±SD FEV ±6.1% predicted
mean±SD BMI ±2.2kg/m2

8. 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

9. results

10. 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

11. 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

12. 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

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

14. 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

15. 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

16. 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)

17. 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

18. 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

19. 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):
5. King SJ, et al. Clin Nutr. 2014;33(1):150-5.
6. Alicandro G, et al. J Cyst Fibr. 2013;13(3):
7. Hubert D et al, Journal of Cystic Fibrosis 16:
8. Holland AE, et al. Chest. 2003;124(2):490-3. .