BACKGROUND:Elexacaftor/tezacaftor/ivacaftor (ETI) has dramatically changed the landscape of cystic fibrosis (CF) care, including in those who require lung transplantation. The objectives of the study were to describe the cohort demographics and outcomes of primary lung transplant recipients before and after the availability of ETI. METHODS:This is a descriptive study of lung transplants performed at the Toronto Lung Transplant Program for CF during two time periods: 2019 (pre-ETI era) and 2021-2023 (post-ETI era). All subjects were referred from the Adult CF program at St. Michael's Hospital, Toronto. Data were obtained from chart review and the Toronto Lung Transplant database. The Kaplan-Meier method was used to estimate survival probability at 1 year post-transplant. RESULTS:There were 22 lung transplants performed in 2019 (19 [86.4%] primary and 3 [13.6%] re-transplants) compared to 11 lung transplants (8 [72.7%] primary and 3 [27.3%] re-transplants) in the post-ETI era. In primary transplant recipients, median age was 29.4 years (Range 18.6-67.6 years) in 2019 compared to 30.0 years (Range 19.1-64.0 years) in 2021-2023. In the post-ETI era, none of the individuals had a deltaF508 variant, compared to 84% in 2019. One-year survival probability was lower in the post-ETI era (62.5% vs. 84.2%, respectively). CONCLUSION:Lung transplant recipients in the post-ETI era were more complex with high-risk characteristics and had worse post-transplant outcomes. This study highlights the importance of further investigation to better understand the impact of ETI on transplant referral patterns, recipient characteristics, and post-transplant outcomes in the CF population.

Objectives: We assessed the impact of ELX/TEZ/IVA treatment on cough frequency and physical activity using wearable devices in people with CF. Methods: VX20-445-126 (NCT04969224) was a Phase 3b, open-label, hybrid, decentralized study of ELX/TEZ/IVA in CFTR modulator-naïve people with CF aged ≥12 years heterozygous for F508del and a minimal function mutation. A wrist-worn actigraphy sensor (worn continuously during the study period) and an ambulatory cough-monitoring device (worn once/week for 24 continuous hours) were used for monitoring. Primary endpoint was percent reduction from baseline in cough frequency/day to the average of Week 8 through Week 12. Secondary endpoint was absolute change from baseline in total step count/day to the average of Week 8 through Week 12. Results: Eighty-one participants enrolled and received ≥1 dose of ELX/TEZ/IVA (mean [SD] age 25.7 [9.6] years; ppFEV1 67.8 [14.3]). Two participants discontinued treatment due to adverse events (AEs). Mean cough frequency/day was reduced by 91.7% (95% CI: 89.2, 93.6), from 241.3 coughs/day at baseline to 20.3 coughs/day at the average of Week 8 through Week 12. Cough frequency/day was reduced by 80.6% at Week 2. Mean step count increased by 638 steps/day (95% CI: 298, 977), from 5,279 (SD: 2,132) steps/day at baseline to 5,907 (SD: 1,909) steps/day at the average of Week 8 through Week 12. Time above sedentary, time in moderate to vigorous physical activity, and total activity improved. Most AEs were consistent with common manifestations of CF. Conclusion: In participants with CF receiving ELX/TEZ/IVA, mean cough frequency/day decreased rapidly and by 91.7% to 20.3 coughs/day, which is similar to cough frequency in healthy people without CF. Activity level, as measured by steps/day, increased in a clinically important manner compared to baseline. These results show ELX/TEZ/IVA has a clinically meaningful impact on cough frequency and activity levels in people with CF.

performed.This quality improvement project aims to evaluate the impact of changes in the Pennsylvania CF NBS algorithm on referral for sweat testing and time to diagnosis.Methods: We conducted an institutional review board-exempt review of Pennsylvania NBS results between 2019 and 2023.Deidentified CF NBS data were provided by the Department of Health.We analyzed data from three epochs: October 10, 2019, to March 10, 2020 (before the COVID-19 pandemic), 2021 to 2022 (during the pandemic), and 2022 to 2023 (after the NBS algorithm changed).We collected data on number of infants screened, number of referrals, time to diagnosis, diagnostic outcomes, and patient race and ethnicity.Results: The number of infants with high IRT was similar during all three periods (Table 1).The number of referrals was similar between the first two periods but decreased by 91% from 2022 to 2023, after inclusion of NGS in the CF NBS algorithm.Despite the decrease in referrals, the number of CF diagnoses in 2021 to 2022 was similar to that in 2022 to 2023.Time to diagnosis was similar from 2019 to 2022, but decreased to less than 30 days between 2022 and 2023.Conclusions: The number of infants screened and with high IRT was stable in Pennsylvania during the periods assessed, but fewer infants required referral for diagnostic testing after inclusion of NGS, even though the number of CF diagnoses remained similar to that before the change.Time to diagnosis decreased after addition of NGS despite a slight increase in time to completion of NBS.A more accurate and precise screening tool may expedite access to treatment while minimizing costs and burden on families associated with sweat testing.Analysis is ongoing to track the number of infants referred for sweat testing and their diagnostic outcomes, including those in racial and ethnic minority groups, since the change in the NBS algorithm.Additional NBS data reviewed over the upcoming year will be incorporated into the final analysis.

Objectives: We assessed the impact of ELX/TEZ/IVA treatment on glucose tolerance in people with CF and either impaired glucose tolerance (IGT) or CF-related diabetes (CFRD) over a 48-week period. Methods: VX19-445-117 (NCT04599465) was a Phase 3b, single-arm, open-label study of ELX/TEZ/IVA in people with CF aged ≥12 years heterozygous for F508del and a minimal function mutation and who had abnormal glucose tolerance as determined by oral glucose tolerance testing (OGTT), with either IGT or CFRD at screening. Primary endpoint was change in 2-hour OGTT blood glucose levels from baseline to the average of Week 36 and Week 48. Secondary endpoints were proportion of participants with improved dysglycemia categorization at Week 48 (defined as change from CFRD at baseline to IGT or normal glucose tolerance or change from IGT at baseline to normal glucose tolerance), and safety and tolerability. Results: Sixty-nine participants enrolled and received ≥1 dose of ELX/TEZ/IVA (mean [SD] age 25.1 [9.5] years; BMI 20.54 [2.60]; 2-hour OGTT blood glucose 217.6 [73.1] mg/dL); 29 participants had IGT and 40 had CFRD at screening. Three participants discontinued treatment (commercial drug availability [n = 2]; physician decision [n = 1]). Mean change from baseline in 2-hour OGTT blood glucose at the average of Week 36 and Week 48 was –35.0 mg/dL (95% CI: –49.2, –20.7; P < 0.0001). Overall, 37.7% of participants (95% CI: 24.8, 52.1) had improved dysglycemia categorization at Week 48; 35.5% of participants had normal glucose tolerance at Week 48 compared to 13.0% at baseline. Safety and tolerability were generally consistent with established safety profile of ELX/TEZ/IVA. Conclusion: In this largest trial to date of a CFTR modulator in people with CF and abnormal glucose metabolism, ELX/TEZ/IVA treatment led to clinically meaningful benefits in blood glucose regulation with statistically significant within-group decreases in blood glucose levels and improved dysglycemia categorization.

2021 vs. 48.2% of people with CF) and older (average age 31.9)than people with CF (average age 23.8).As expected, the CFRDO group had better pulmonary and nutritional outcomes than the CF group.Genotyping has been reported for most people with CFRDO, although 49 people have unknown CFTR variants in both alleles.Of those for whom genotyping was reported, the most common combination was F508del/R117H (n = 40).Overall, 32% of people with CFRDO had one F508del variant.Average sweat chloride value (highest reported) in people with CFRDO was 44.5 mmol/L (vs.94.4 mmol/L in people with CF).57% had a sweat value between 30 mmol/L and 60 mmol/L and 14% had a sweat value greater than 60 mmol/L.The most common reasons for diagnosing individuals with CFRDO were non-diagnostic sweat test (65%), fewer than two CF diseasecausing mutations (51%), and pancreatitis (7%) (not mutually exclusive values).Bronchiectasis, chronic sinusitis, and asthma were relatively common free-text entries for other reasons for CFRDO diagnosis.Significantly more people with CFRDO (43.5%) than with CF (29.3%) had asthma.People with CFRDO were also more likely to be diagnosed with pancreatitis and nontuberculous mycobacteria than those diagnosed with CF. 23% of the CFRDO group were reported to be taking pancreatic enzymes and 9.6% had a sputum culture with Pseudomonas aeruginosa (Table 1).Table 1.Characteristics of people with CF and CFRDO in the CFFPR.Conclusions: People with CFRDO are a growing group in the CFFPR, with a wide range of clinical features.As with CRMS/CFSPID, periodic reassessment of people with CFDRO may result in a change in diagnosis.Some of the individuals in this cohort may have been misdiagnosed.A CF diagnosis for such individuals would mean that they could benefit from a broader range of therapies and interventions available to people with CF.

Background: Despite early diagnosis through newborn screening, 75% to 90% of children with CF (CwCF) experience at least one pulmonary exacerbation (PEx) in the first 3 years of life.Diagnosing PEx in CwCF is challenging because of the frequency of respiratory viral infections in this age group and limited data on clinical features associated with the diagnosis of PEx in this age group.The goal of this study was to identify clinical features associated with diagnosis of PEx in CwCF.Methods: We reviewed the medical records of CwCF followed at the Children's Hospital of Philadelphia born between 2007 and 2019.We defined PEx as treatment with oral or intravenous antibiotics.We generated data for a comparison cohort of CwCF born between 2013 and 2019 (when electronic medical records were available) who presented with respiratory symptoms but were not diagnosed with PEx.In both cohorts, all phone encounters and clinic visits were reviewed for each patient in the first 3 years of life.We performed mixed-effects logistic regression controlling for patient age at encounter to calculate odds ratios for clinical features associated with PEx diagnosis.This project was reviewed and approved by our local institutional review board before data collection and analysis.Results: 155 patients were included in our analysis, of which 151 (97%) had at least one PEx in the first 3 years of life.The mean number of PEx per patient was 7.95 ± 6.73 range 1-36); 55% of patients had six or more PEx in the first 3 years of life.Antibiotics were prescribed via phone encounters in 66% of cases; during a CF clinic visit in 19%; and during inpatient admissions, emergency department visits, primary care provide visits, and urgent care visits in 15%.78 patients were available for our comparison analysis.Demographic and clinical features associated with PEx diagnosis are shown in Table 1.Race, ethnicity, and insurance status were not significantly associated with PEx diagnosis.Treatment with medications for gastroesophageal reflux disease (GERD) and dornase alfa were associated with greater likelihood of PEx diagnosis, but a history Pseudomonas infection and hypertonic saline therapy were not significantly associated with PEx.The odds of PEx diagnosis were significantly greater with symptom duration of longer than 3 days, nasal or chest congestion, signs of lower respiratory tract disease, and symptoms of systemic illness.Presence of nocturnal or wet cough markedly increased the likelihood of PEx, but rhinorrhea, fever, and sore throat were not significantly associated with PEx.

Background: Cystic Fibrosis Foundation (CFF) guidelines for pancreatic enzyme dosing recommend that lipase units not exceed 2,500 units of lipase/kg per meal.This is approximately 7,500 units of lipase/kg per day, not counting snacks [1].According to CFF guidelines, excessive doses are unlikely to increase growth or decrease gastrointestinal complaints.A pancreatic enzyme dose of more than 6,000 units of lipase/kg per meal has been associated with fibrosing colonopathy.We sought to compare BMI percentiles in children who were on more or less than 7,500 units of lipase/ kg per day to determine if there was a significant difference in BMI percentile between the groups.Methods: A retrospective chart review was done on all pancreaticinsufficient people with CF younger than 20 in the pediatric CF clinic.Information was collected on the last documented BMI percentile and units of lipase/kg per day for 2022.We compared the BMI of patients who were on more than 7,500 units of lipase/kg per day with the BMI of patients who were on less than 7,500 units of lipase/kg per day.Means and standard deviations were used to describe BMI percentile and units of lipase/kg per day of enzyme administration; the Student t-test was used to determine if there was a significant difference between the groups.p < 0.05 was used to indicate significance.Results: Thirteen children from a pediatric CF center were included.Mean BMI percentile was 61 ± 29%, and mean units of lipase/kg per day of enzyme administration 7,449 ± 2,378 units.BMI percentile in children taking more than 7,500 units of lipase/kg per day (57.9 ± 34.6%) was not statistically significantly different from that of those taking less than 7,500 units of lipase/kg per day (64.5 ± 22.1%) ( p = 0.694).Conclusions: BMI percentiles of children receiving low-and high-dose pancreatic enzyme supplements were not statistically significantly different.Therefore, high-dose enzyme supplements (more than the average recommended in CFF guidelines), with the potential for adverse effects, may not be needed for every patient.Other factors such as malabsorptive features, gastrointestinal symptoms, individualized pancreatic enzyme supplement dose for optimum growth, and potential risk of adverse effects with the high-dose pancreatic enzyme should be considered for each patient.

Methods: APPLAUD was a double-blind, placebo-controlled study in adults with CF, randomized (1:1) to LAU-7b or placebo for six consecutive treatment cycles of 21 days separated by 7-day drug-free periods.Eligible subjects had a percentage predicted forced expiratory volume in 1 second (FEV 1 pp) between 40% and 100% at screening and had had at least one pulmonary exacerbation (PEx) in the prior year.The study drug was administered orally once daily, in addition to standard of care.The primary efficacy endpoint was absolute change from baseline in FEV 1 pp at 24 weeks.Secondary endpoints included parameters related to PEx, quality of life, and systemic inflammatory and lipidomic biomarkers.Results: One hundred sixty-six subjects from 40 sites in the United States, Canada, and Australia were randomized.Preliminary results showed that absolute change in FEV 1 pp at 24 weeks was 0.8 points in favor of LAU-7b (-0.8 FEV 1 pp change from baseline in the LAU-7b arm, n = 83, versus -1.6 FEV 1 pp in the placebo arm, n = 83; p = 0.43).Planned stratification factor analysis showed that subjects with FEV 1 pp of 70% or greater at baseline responded better, resulting in a treatment difference of 3.0 points in FEV 1 pp at 24 weeks favoring LAU-7b (-0.9 FEV 1 pp change from baseline in the LAU-7b arm, n = 29, versus -3.9 FEV 1 pp in the placebo arm, n = 27; p = 0.06).Although the number of subjects was small, similar positive trends were noted in subjects already treated with CFTR modulators, including elexacaftor/tezacaftor/ivacaftor.PEx incidence and number of days of intravenous antibiotics were lower in the LAU-7b than the placebo arm.The safety profile of LAU-7b treatment was consistent with the safety profile observed in previous clinical studies with fenretinide.Serious adverse events and their severity and relationship distribution were similar between the two treatment arms, with no unexpected serious adverse reaction or deaths reported.Conclusions: Compared to placebo, LAU-7b treatment reduced loss of lung function by 50% at 24 weeks in the overall subject population and by 77% in the subgroup of subjects with mild lung disease (FEV 1 pp≥70%), suggesting a potential beneficial effect on the loss of lung function over 24 weeks.LAU-7b was well tolerated and had a favorable safety profile, similar to previously obtained data.The final efficacy data, including inflammation biomarker analyses, will be presented at the North American Cystic Fibrosis Conference.

Background/Rationale: Lung transplant (LTx) candidates with cystic fibrosis (CF) have ventilatory and musculoskeletal limitations contributing to reduced functional capacity.CF LTx candidates participate in prerehabilitation to improve their physical fitness, but perspective training response of CF related clinical factors has not been described.The aims of the study were to: 1) Characterize the muscle training volume response and six-minute walk distance (6MWD) in CF LTx candidates[D1] with rehabilitation 2) Evaluate the determinants of pre-LTx 6MWD at baseline and with rehabilitation.We hypothesized that CF LTx candidates will have significant improvements in aerobic and muscle training volumes despite severe ventilatory limitations.Methods: Singlecenter retrospective cohort study of CF LTx candidates with available pre-transplant exercise data between January 2010-May 2018.LTx candidates participated in supervised center-based rehabilitation 3 times/week until transplantation.Demographics, CF-related characteristics, and aerobic and muscle training volumes were abstracted from chart review.Paired t-tests were used to evaluate the change in 6MWD (start of program, 6 weeks, and every three-months) and weekly treadmill and muscle training volumes (lbs*repetitions*sets).Multivariable regression was used to evaluate the contribution of clinical co-variates on 6MWD pre-transplant.Results: 86 CF LTx candidates (age 32±10 years, 49% males, BMI:19.6±2.8 kg/m 2 ;FEV1: 23±5%, and listing 6MWD of 421±89 meters) were evaluated.At listing, 88% required supplemental oxygen for exercise, 72% had ≥ 3 respiratory exacerbations in the prior year, and 37% were using non-invasive ventilatory (NIV) support at home.Median time on the transplant list was 87 days IQR .With rehabilitation, there was a significant increase in treadmill speed of 0.6 mph (n=74, 95% CI(0.1-1.1),p=0.02) and in both the biceps lbs*repetitions] and the quadriceps training volumes [n=71, 18.8, 95% CI(10.6-27.0)lbs*repetitions, p< 0.0001].The 6MWD did not change pre-transplant [n=42, 1.2 m, 95%CI (-17.5 to 19.9), p=0.90].Oxygen use [High (≥ 4L/min):Low O 2 : -84 95%CI (-143 to -25) meters and Low:No O 2 -43 (-84 to -3) meters, p=0.01] and home NIV support (-57 95%CI (-96 to -19) meters, p=0.004) were associated with lower baseline 6MWD, whereas age, sex, BMI, FEV1, and respiratory exacerbation frequency were not significant.No clinical characteristics were associated with change in 6MWD pre-transplant.Conclusion: CF LTx candidates demonstrated an increase in their exercise training volumes and had preservation of their exercise capacity with rehabilitation.Oxygen use and NIV support were important determinants of lower baseline exercise capacity, whereas 6MWD stability was independent of any identified clinical factors