Heterogeneity of weight gain after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis

doi:10.21203/rs.3.rs-2130790/v1

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Heterogeneity of weight gain after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis

https://doi.org/10.21203/rs.3.rs-2130790/v1

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published 17 Jun, 2023

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Background. The introduction of the novel therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been showed to be effective in weight gain in both clinical trials and real-world studies. However, this effect appears heterogeneous across patient subgroups and predictors of individual weight gain after treatment are still missing.

Methods. This was a multicenter, prospective cohort study enrolling 93 adults with CF at two major CF Centers in Italy. For the pourpose of this study, the cohort was divided into two groups according to median BMI change after 6 months of ETI treatment: ‘responders’ included patients with BMI increase ≥1 kg/m² and ‘poor responders’ those with BMI increase <1 kg/m².

Results. The median increase in BMI after six months of ETI was 1.0 kg/m²(0.4-1.7), in line with previous studies. We identified a correlation between BMI increase and both BMI before ETI initiation (r -0.392, P <0.001) and the duration of ETI treatment (r 0.293, P =0.006). BMI responders were more likely to have Phe508del/MF genotype (71% VS. 37%, P = <0.001), younger age at diagnosis (1 [0-4] VS. 5 [0-14] years, P =0.018), pancreatic insufficiency (92% VS. 77%, P =0.042) and CF-related diabetes (49% VS. 21%, P =0.006). Low BMI before ETI initiation (OR 0.75; 95% CI 0.64-0.0.92; P =0.005), pancreatic insufficiency (OR 5.08; 95% CI 1.34-19.28; P =0.017) and the previous use of earlier CFTR modulators (OR 3.41; 95% CI 1.21-9.57; P =0.020) were predictive factors for the status of BMI responder.

Conclusions. Our results might help to identify a subset of patients that might deserve both a targeted clinical approach and a translational characterization.

weight gain

response to treatment

personalized medicine

CFTR modulators

elexacaftor

overweight

adults

We reported heterogeneity in weight gain after 6 months of treatment with elexacaftor/tezacaftor/ivacaftor
For people starting elexacaftor/tezacaftor/ivacaftor, weight gain is correlated with both individual BMI at start and lenght of treatment;
The status of ‘BMI responder’ is independently associated with BMI at start, pancreatic insufficiency and previous exposure to earlier CFTR modulators.

The landscape of nutritional outcomes for people with cystic fibrosis (CF) has changed dramatically in recent years [1]. Traditionally, body mass index (BMI) has been considered the main indicator for nutritional status in people with CF. Patients with low BMI showed accelerated decline in FEV1, a higher rate of pulmonary exacerbations and increased mortality [2]. Therefore, international guidelines recommend BMI targets ≥ 22 kg/m2 for adult females and ≥ 23 kg/m2 for adult males [1].

Advances in CF treatment, including aggressive nutritional interventions, have led to increased life expectancy with overweight and obesity progressively emerging as an open issue, especially in adults and high-income countries [3, 4]. The recent advent of highly effective CFTR modulator therapy is supposed to contribute to this trend. Elexacaftor/Tezacaftor/Ivacaftor (ETI) was associated with improved BMI in both clinical trials and real-world studies. In the registrational trials, ETI demonstrated a significant increase in BMI after 24 weeks of treatment (1.04 kg/m2 versus placebo in Phe508del heterozygous and 0.60 kg/m2 versus Tezacaftor/Ivacaftor in Phe508del/Phe508del, respectively) [5, 6].

In a series of real-world observational studies, ETI has been confirmed to be effective in increasing BMI across different patient groups, including those with advanced lung disease [7, 8]. However, this response has appeared to vary significantly, while the factors related to BMI response have not yet been studied.

The aim of this Italian multicenter study was to investigate predictive factors for weight gain and identify a subgroup of individuals subject to enhanced BMI increase among those initiating ETI treatment.

Study design and data collection. This was an observational, prospective, longitudinal multicenter study. Consecutive adults (≥ 18 years) with CF who started treatment with ETI were enrolled during clinical stability at two major CF Centers in Italy (IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan; Ospedale Pediatrico Bambin Gesù, Rome). Data were prospectively collected by two qualified investigators between August 2021 and June 2022. The investigators were provided with a protocol including the following study definitions. The study protocol was approved by local IRBs and all participants provided written informed consent to take part in the study. This project had no funding and relied upon voluntary participation.

Study groups. Two groups of participants were retrospectively identified based on the median increase in BMI (1 kg/m²) after 6 months from the start of ETI. For the purpouse of this manuscript, patients who showed an increase in BMI greater than the median increase in BMI for the whole cohort were termed as ‘responders’. BMI responders included patients with BMI increase ≥ 1.0 kg/m² during the study period; and BMI poor responders included patients with BMI increase < 1.0 kg/m² during the study period.

Study definitions. CF was defined following the last diagnostic criteria [9]. Minimal function mutations (MF) and residual function mutation (RFM) were defined according to the list of mutations included in the registration studies of ETI and tezacaftor/ivacaftor, respectively [5, 10]. BMI classes were defined by WHO as overweight (OW) including patients with BMI ≥ 25.0 kg/m², normal weight (NW) including patients with BMI 18.6–24.9 kg/m², and underweight (UW) including patients with BMI ≤ 18.5 kg/m² [11]. Chronic P. aeruginosa infection was defined by the isolation of P. aeruginosa in sputum culture in more than 50% of samples over the last 12 months with a minimum of three samples [12]. A pulmonary exacerbation was defined according to Fuchs criteria [13]. Referring to comorbidities, pancreatic insufficiency (PI) was defined in patients treated with pancreatic enzymes, while CF-related diabetes (CFRD) was diagnosed according to oral glucose tolerance test.

Statistical analysis. Qualitative and quantitative variables were summarized with frequencies and medians (interquartile ranges, IQR). Differences between groups were assessed with chi-squared for qualitative variables and with Mann-Whitney for non-parametric quantitative variables. Continuous variables were correlated using Pearson’s correlation. Regressions analyses were performed to assess the relationship between BMI responder status with demographic and clinical variables. Odds ratios (OR) were computed with their 95% confidence interval (95% CI). A two-tailed p-value was considered statistically significant when less than 0.05. All statistical computations were performed with IBM SPSS, Statistics for Mac, version 22.0.

Patient cohort characteristics and response to ETI treatment. A total of 93 consecutive patients (median [IQR] age: 38 [33–44] years; 40% female) were included, as reported in Table 1. Among them, 24 (26%) patients were Phe508del homozygous, 51 (55%) were Phe508del/MF and 13 (14%) patients had at least one RFM. A total of 78 (84%) of patients had PI and 33 (35%) had CFRD. Median ppFEV1 for the whole cohort was 52 (39–73). Chronic P. aeruginosa infection affected 59 (63%) patients and the median (IQR) exacerbation frequency was 1 episode (0–1) per year. Median (IQR) BMI before ETI start was 21.2 (19.3–23.5) kg/m², while OW and UW groups included 9 (10%) and 9 (10%) patients, respectively. ETI treatment was generally well tolerated by the study population. No discontinuation of treatment and no dosage adjustment were reported.

Median BMI (IQR) increased from 21.2 (19.3–23.5) kg/m² to 21.8 (19.7–24.1) kg/m² after one month and to 22.3 (20.6–24.6) kg/m² after six month of ETI treatment. Median change in BMI at six months was 1.0 (0.4–1.7) kg/m² and correlated with both BMI before ETI initiation and the lenght (months) of ETI treatment, as reported in Fig. 1 (r -0.392, P < 0.001; and r 0.293, P = 0.006, respectively).

Median BMI changed differently across WHO BMI classes, as showed in Fig. 2. While BMI increase after 6 months of ETI treatment was significant in UW and NW groups (17.8 [17.0-18.4] kg/m² VS. 19.3 [18.7–19.6] kg/m², P = 0.010; and 20.9 [19.7–23.1] kg/m² VS. 22.3 [20.8–24.4] kg/m², P = 0.029, respectively), OW group did not show any significant change (26.5 [25.3–27.3] kg/m² VS. 26.1 [25.5–26.5] kg/m², P = 0.088).

BMI responders after initiation of ETI. Comparison between BMI responders and BMI poor responders is reported in Table 2. When compared with poor responders, BMI responders were more likely to have Phe508del/MF genotype (71% VS. 37%, = <0.001) and younger age at diagnosis (1 [0–4] VS. 5 [0–14] years, P 0.018). From a clinical point of view, this group was more likely to show PI (92% VS. 77%, P = 0.042) and CFRD (49% VS. 21%, P = 0.006) than comparisons. Individuals with previous use of earlier CFTR modulators were more prevalent among BMI responders than comparisons (39% VS. 16%, P = 0.012). No differences between the two groups were reported in terms of gender and age.

Median BMI before ETI initiation was lower among BMI responders than comparisons (20.38 [19.03–22.72] VS. 22.23 [19.31–24.50], P = 0.036). BMI responders were more likely to be UW (19% VS. 2%, P = 0.025), while OW status was significantly more frequent in BMI poor responders (17% VS. 0% P = 0.001). No significant differences were reported in terms of chronic respiratory infection and pulmonary exacerbations between the groups.

Multivariate regression analyses showed a set of factors associated with BMI increase after 6-month ETI treatment in people with CF as independent predictors for BMI responder status, including BMI before ETI initiation (OR 0.75; 95% CI 0.64-0.0.92; P = 0.005), PI (OR 5.08; 95% CI 1.34–19.28; P = 0.017) and the use of earlier CFTR modulators (OR 3.41; 95% CI 1.21–9.57; P = 0.020).

This study demonstrated that: 1) the change of BMI after six months of ETI treatment is heterogeneous across people with CF; 2) the increase in BMI is correlated with both individual BMI at ETI start and lenght of ETI treatment; 3) the status of BMI responder is independently associated with BMI before ETI initiation, pancreatic insufficiency and previous exposure to earlier CFTR modulators.

This study highlights the existing heterogeneity of weight gain across CF adults after 6 months of treatmen with ETI. We investigated what factors might be related to changes in BMI during treatment. We found that greater improvements were observed in the population with lower BMI at enrollment (Fig. 1A). The metabolic effect of ETI through the restoration of CFTR is therefore exerted with different magnitudes in people with CF, with the highest degree of response in patients with underweight and malnutrition secondary to CF. In line with the exposed results, while post-treatment BMI changed significantly in both the UW and NW groups, there was no evidence of weight gain among patients with OW (Fig. 2).

This observation opens to further considerations. First, the fact that OW patients are less susceptible to weight gain is reassuring that ETI might not have the undesirable effect of worsening the cardio-metabolic risk profile in this population. Therefore, ETI treatment should not be considered potentially problematic for patients with OW nor should OW and obesity be evaluated as a disadvantage for a timely initiation of treatment. This is relevant as previous studied showed high prevalence of OW in people with CF across different settings [3, 4].

Second, these data could highlight possible mechanisms of weight gain following CFTR modulators. Weight gain has been hypothesized to be multifactorial and might include decreased energy expenditure at rest, gut inflammation and fat malabsorption [14]. Our data suggest that correction of these mechanisms could achieve a ‘ceiling effect’ in a population with adequate nutritional outcomes. Interestingly, this loss of effect is not observed for pulmonary function with improvements in ppFEV1 in all three BMI classes of this cohort. In addition, the time of exposure to the drug might also play a role in explaining the different degrees of weight gain following ETI (Fig. 1B). However, whether long-term ETI can increase the incidence of OW and obesity among people with CF is a topic of current debate [4, 7].

We also investigated the presence of a group of patients with the highest effect to therapy in terms of BMI increase during the study period. In this regard, we have considered the median increase in BMI in our cohort to be a significant marker of response and in line with what has been previously demonstrated by other authors [7, 15]. The results suggest that low BMI at the start of treatment and pancreatic insufficiency are predictors of metabolic efficacy in ETI-treated patients. Thence, we might postulate that the best candidates for weight gain are those individuals with severe phenotipic expression and pancreatic disease, in which underweight and malabsorption have a significant impact on long-term clinical outcomes and survival.

The use of previous CFTR modulators was another factor that emerged from the multivariate analysis and identified individuals with full clinical expression, corresponding in our cohort to the Phe508del/Phe508del subgroup already exposed to the use of lumacaftor/ivacaftor.

To our knowledge, this is the first study investigating the heterogeneity of drug effects on BMI and which factors are involved in this issue. This approach is the main novelty of our study and might help to further move the clinical research into a deeper analysis of ETI impact on a real-world basis. The multicenter design contributed to make our results more consistent.

We acknowledge that increase in BMI is not a good clinical endpoint to assess response to CFTR modulators for several reasons, including the fact that weight gain is not desiderable for everyone starting ETI and the mechanism of action for weight gain is not well established. We used the term “responder” for the very purpouse if this paper in order to define those individuals who have been showed to be more prone to gain weight during treatment.

However, limitations exist in our study, including the number of participants and geographical differences that might hamper the final analysis. Furthermore, we did not investigate whether the presence of RFM or pancreatic sufficiency acted as a non-response factor for an increase in BMI. The low number of these patients did not allow further investigations nor we could find confirmation of these results in the studies already published. Unfortunately, the phase-3 clinical trial by Barry and colleagues on the role of ETI for Phe508del and RFM genotypes did not report any data about change in BMI in the study population [16].

The responder rate in the entire treated population has yet to be fully understood by the means of multicenter retrospective studies and stratification analyses from national and international registries.

Since the drug's approval, clinical research on ETI and its impact on multisystemic involvement of CF has produced a growing body of evidence from real-world reports, including data on changes in BMI and other metabolic parameters [7, 8, 15]. In particular, this aspect is object of a renewed interest due to the recent thought that nutritional management in CF deserves a profound reconsideration [17].

Our results might help in the identification of a group of patients that are candidates to significant weight increase after ETI start. This approach opens to both clinical and research implications. First, while patients with OW and obesity are considered to be at higher metabolic risk, we must not forget to address the cardiovascular consequences in those, although UW, with rapid and uncontrolled weight gain, which could include a higher prevalence of hyperlipidemia and hypertension and [7, 18].Second, since the increase in BMI can be interpreted as a reflection of improved CFTR function, we identified a population of responders that might deserve a full clinical and biological characterization. Third, this study could help to shift clinical research on CFTR modulators from analyzing efficacy in individual aspects of CF to the investigation of new tools to measure clinical response and its indicators.

Ethics approval and consent to partecipate: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by local Institutional Ethical Committee, followed by the approval of the other local ethical committees (CE Milano Area B, parere n. 594_2016bis).

Consent for publication: All participants provided written informed consent to take part in the study.

Avaibility of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare no conflict of interest in relation to this manuscript.

Funding: Regione Lombardia Cystic Fibrosis Project FSR 2021 COD 18563 CHAPT 13.01.104.8378, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano RC 2022-260-02.

Authors’ contributions: Conceptualization: AG, FM. Data curation and formal analysis: MC, GL, LC. Methodology: AG, FM, AGF, FB. Writing - original draft: AG, GL. Writing - review and editing: AG, MC, FM, SA, FA. All authors read and approved the final manuscript.

Acknowledgments: not applicable.

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Table 1. Clinical characteristics of the study cohort

Variables	All cohort (n=93)
Male gender, n (%)	56 (60)
Median (IQR) age, years	38 (33-43)
Median (IQR) age at CF diagnosis, years	2 (0-11)
Phe508del /Phe508del, n (%)	24 (26)
Phe508del /MF[5], n (%)	45 (48)
Median (IQR) ppFEV1, %	52 (39-73)
ppFEV1 <40, n (%)	25 (27)
ppFEV1 >40 to <70, n (%)	41 (44)
ppFEV1 >70, n (%)	27 (29)
Chronic P. aeruginosa infection, n (%)	59 (64)
Median (IQR) pulmonary exacerbation rate, n	1 (0 – 1)
Median (IQR) BMI at baseline, kg/m2	21.2 (19.3-23.5)
Pancreatic insufficiency, n (%)	78 (85)
CFRD, n (%)	33 (36)
Median (IQR) length of ETI treatment, months	7 (5-13)
Median (IQR) change in ppFEV1 after 6 months, %	15 (7.25-23.75)
Median (IQR) change in BMI after 1 month, kg/m2	0.5 (0.0-1.0)
Median (IQR) change in BMI after 6 month, kg/m2	1.0 (0.4-1.7)

Definitions. MF: minimal function CFTR mutation, RF: residual function CFTR mutation, FEV1: forced expiratory volume in one second, BMI: body mass index, CFRD: cystic fibrosis related diabetes

Table 2. Demographic and clinical characteristics across the two study groups.

Variables	BMI poor responders ΔBMI <1.0 kg/m2 (n= 43)	BMI responders ΔBMI ≥1.0 kg/m2 (n= 49)	P value
Male, n (%)	24 (56)	32 (65)	0.405
Median (IQR) age, years	39 (33-43)	36 (32-42)	0.719
Median (IQR) age at CF diagnosis, years	5 (0 – 14)	1 (0 – 4)	0.018
Phe508del /Phe508del, n (%)	15 (35)	9 (18)	0.059
Phe508del /MF[5], n (%)	16 (37)	35 (71)	<0.001
Phe508del /RF[10], n (%)	8 (19)	5 (10)	0.197
Earlier CFTR modulators, n (%)	8 (19)	17 (35)	0.012
Median (IQR) length of ETI, months	7 (6 – 8)	8 (6 – 22)	0.370
Median (IQR) BMI at ETI start	22.2 (19.3-24.5)	20.4 (19.0-22.7)	0.036
UW at ETI start, n (%)	1 (2)	8 (16)	0.027
OW at ETI start, n (%)	8 (19)	1 (2)	0.008
Pancreatic insufficiency, n (%)	33 (77)	45 (92)	0.042
CF related diabetes, n (%)	9 (21)	24 (49)	0.006
Pre-ETI median (IQR) FEV1, %	49 (35-57)	42 (38-63)	0.241
FEV1 <70% predicted, n (%)	9 (21)	5 (10)	0.068
FEV1 <40% predicted, n (%)	8 (19)	12 (24)	0.450
Chronic P. aeruginosa, n (%)	30 (70)	29 (59)	0.201

Definitions. RFM: residual function mutation, ETI: elexacaftor/tezacaftor/ivacaftor, BMI: body mass index, UW: underweight, NW: normal weight, OW: overweight, FEV1: forced expiratory volume in one second.

Table 3. Multivariate logistic regression analysis of predictive factors of BMI responder status in the study cohort.

Variable	OR (95% CI)	P
BMI at ETI start	0.78 (0.65 – 0.94)	0.010
Use of earlier CFTR modulators	3.47 (1.23 – 9.76)	0.018
Pancreatic insufficiency	5.07 (1.34 – 19.17)	0.017

Definitions. BMI: body mass index, ETI: elexacaftor/tezacaftor/ivacaftor

No competing interests reported.

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Heterogeneity of weight gain after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis

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