Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.09.019
Suzanne Kroes , Marlou C. Bierlaagh , Juliet W. Lefferts , Alessandra Boni , Danya Muilwijk , Carla Viscomi , Natascha D.A. Keijzer-Nieuwenhuijze , Luca Cristiani , Paul J. Niemöller , Tibo F. Verburg , Renato Cutrera , Alessandro G. Fiocchi , Vincenzina Lucidi , Cornelis K. van der Ent , Jeffrey M. Beekman , Federico Alghisi , Fabiana Ciciriello
Cystic fibrosis is a life-shortening genetic disease caused by pathological variants of the cystic fibrosis transmembrane conductance regulator gene. The CFTR modulator therapy elexacaftor, tezacaftor and ivacaftor (ETI) rescues CFTR protein function and has made a significant impact on the lives of many people with CF. In Europe, ETI is currently available for people with CF who have at least one F508del mutation whilst the effect of ETI on rare CFTR variants remains unknown, albeit that many of such variants may be restored through ETI. Italy has a high prevalence of rare CFTR variants compared to the rest of Europe, potentially leading to significant undertreatment of people with rare CFTR variants. In this study, we used patient-derived intestinal organoids to identify individuals harboring rare CFTR variants who might benefit from ETI modulator therapy. Two CFTR-dependent readouts (steady-state lumen area and forskolin-induced swelling) in intestinal organoids were characterized to assess CFTR function rescue upon ETI incubation. Functional restoration by CFTR modulators was compared to wild type CFTR function, ETI-treated organoids harboring genotypes currently eligible for ETI therapy (F508del/class I) and organoids harboring non-responsive genotypes. Our data showed in vitro response to ETI within or beyond the range of CFTR function associated with F508del-ETI in 19 out of 28 organoids. This suggest that a large percentage of people with rare CFTR variants without access to ETI may benefit from this treatment.
囊性纤维化是由囊性纤维化跨膜传导调节基因的病理变异引起的一种缩短寿命的遗传病。CFTR调节剂疗法elexacaftor、tezacaftor和ivacaftor（ETI）可以挽救CFTR蛋白的功能，对许多CF患者的生活产生了重大影响。在欧洲，ETI 目前可用于至少有一个 F508del 突变的 CF 患者，而 ETI 对罕见 CFTR 变异的影响仍不得而知，尽管许多此类变异可能通过 ETI 得到恢复。与欧洲其他国家相比，意大利罕见 CFTR 变异的发病率较高，这可能导致对罕见 CFTR 变异患者的治疗严重不足。在这项研究中，我们利用源自患者的肠器官组织来识别可能从 ETI 调节剂治疗中获益的携带罕见 CFTR 变异的个体。我们对肠道器官组织中两种依赖于CFTR的读数（稳态管腔面积和福斯可林诱导的肿胀）进行了鉴定，以评估ETI培养后CFTR功能的恢复情况。将 CFTR 调节剂的功能恢复与野生型 CFTR 功能、目前符合 ETI 治疗条件的基因型（F508del/I 类）ETI 处理过的器官组织以及无响应基因型的器官组织进行了比较。我们的数据显示，28 个器官组织中有 19 个对 ETI 的体外反应在与 F508del-ETI 相关的 CFTR 功能范围之内或之外。这表明，很大一部分无法获得 ETI 的罕见 CFTR 变体患者可能会从这种治疗中获益。
{"title":"Elexacaftor/tezacaftor/ivacaftor efficacy in intestinal organoids with rare CFTR variants in comparison to CFTR-F508del and CFTR-wild type controls","authors":"Suzanne Kroes , Marlou C. Bierlaagh , Juliet W. Lefferts , Alessandra Boni , Danya Muilwijk , Carla Viscomi , Natascha D.A. Keijzer-Nieuwenhuijze , Luca Cristiani , Paul J. Niemöller , Tibo F. Verburg , Renato Cutrera , Alessandro G. Fiocchi , Vincenzina Lucidi , Cornelis K. van der Ent , Jeffrey M. Beekman , Federico Alghisi , Fabiana Ciciriello","doi":"10.1016/j.jcf.2024.09.019","DOIUrl":"10.1016/j.jcf.2024.09.019","url":null,"abstract":"<div><div>Cystic fibrosis is a life-shortening genetic disease caused by pathological variants of the <em>cystic fibrosis transmembrane conductance regulator</em> gene. The CFTR modulator therapy elexacaftor, tezacaftor and ivacaftor (ETI) rescues CFTR protein function and has made a significant impact on the lives of many people with CF. In Europe, ETI is currently available for people with CF who have at least one F508del mutation whilst the effect of ETI on rare <em>CFTR</em> variants remains unknown, albeit that many of such variants may be restored through ETI. Italy has a high prevalence of rare <em>CFTR</em> variants compared to the rest of Europe, potentially leading to significant undertreatment of people with rare <em>CFTR</em> variants. In this study, we used patient-derived intestinal organoids to identify individuals harboring rare <em>CFTR</em> variants who might benefit from ETI modulator therapy. Two CFTR-dependent readouts (steady-state lumen area and forskolin-induced swelling) in intestinal organoids were characterized to assess CFTR function rescue upon ETI incubation. Functional restoration by CFTR modulators was compared to wild type CFTR function, ETI-treated organoids harboring genotypes currently eligible for ETI therapy (F508del/class I) and organoids harboring non-responsive genotypes. Our data showed in vitro response to ETI within or beyond the range of <em>CFTR</em> function associated with F508del-ETI in 19 out of 28 organoids. This suggest that a large percentage of people with rare <em>CFTR</em> variants without access to ETI may benefit from this treatment.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 175-182"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.12.008
Marina Litvin MD
{"title":"Metabolic syndrome in the post-ETI era","authors":"Marina Litvin MD","doi":"10.1016/j.jcf.2024.12.008","DOIUrl":"10.1016/j.jcf.2024.12.008","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 8-9"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.07.008
Minh Nguyen , Pat MacDiarmid , April Tanzler , Renée Dagenais , Carolina Bevanda , Bradley S. Quon
The mental health effects of elexacaftor/tezacaftor/ivacaftor (ETI) on adults with CF are still uncertain with mixed findings from published studies. To systematically investigate the impact of ETI on symptoms of anxiety and depression in adults with CF, Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire (PHQ-9) scores were evaluated at baseline, 6 months, and 12 months post-ETI. Overall, GAD-7 and PHQ-9 scores improved at 6 months post-ETI, with a greater proportion of individuals experiencing a clinically significant improvement (vs. worsening) of their symptoms, which was sustained at 12 months. Factors influencing mental health outcomes included pre-existing psychiatric diagnoses and psychiatric medication use. In conclusion, although there was overall improvement in anxiety and depression symptoms post-ETI, approximately 10 % of individuals experienced clinically significant worsening.
Elexacaftor/tezacaftor/ivacaftor（ETI）对成年 CF 患者的心理健康影响尚不确定，已发表的研究结果也不尽相同。为了系统研究 ETI 对成年 CF 患者焦虑和抑郁症状的影响，我们在 ETI 后的基线、6 个月和 12 个月评估了广泛性焦虑症-7（GAD-7）和患者健康问卷（PHQ-9）得分。总体而言，ETI 后 6 个月的 GAD-7 和 PHQ-9 分数有所改善，更多的人的症状有了临床意义上的显著改善（相对于恶化），而且这种改善在 12 个月后仍能保持。影响心理健康结果的因素包括既往的精神病诊断和精神病药物的使用。总之，尽管 ETI 治疗后焦虑和抑郁症状总体上有所改善，但仍有约 10% 的人的症状出现了临床意义上的明显恶化。
{"title":"Assessing the impact of elexacaftor/tezacaftor/ivacaftor on anxiety & depression symptom scores in adults with Cystic Fibrosis","authors":"Minh Nguyen , Pat MacDiarmid , April Tanzler , Renée Dagenais , Carolina Bevanda , Bradley S. Quon","doi":"10.1016/j.jcf.2024.07.008","DOIUrl":"10.1016/j.jcf.2024.07.008","url":null,"abstract":"<div><div>The mental health effects of elexacaftor/tezacaftor/ivacaftor (ETI) on adults with CF are still uncertain with mixed findings from published studies. To systematically investigate the impact of ETI on symptoms of anxiety and depression in adults with CF, Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire (PHQ-9) scores were evaluated at baseline, 6 months, and 12 months post-ETI. Overall, GAD-7 and PHQ-9 scores improved at 6 months post-ETI, with a greater proportion of individuals experiencing a clinically significant improvement (vs. worsening) of their symptoms, which was sustained at 12 months. Factors influencing mental health outcomes included pre-existing psychiatric diagnoses and psychiatric medication use. In conclusion, although there was overall improvement in anxiety and depression symptoms post-ETI, approximately 10 % of individuals experienced clinically significant worsening.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 26-29"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Antisense Oligonucleotides (ASOs) are small synthetic nucleic acid molecules able to bind specific sequences within target Ribonucleic Acid (RNA) molecules. SPL84 is an ASO drug developed for treatment of cystic fibrosis (CF) patients carrying the 3849 + 10 kb C->T Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) splicing mutation. The 3849 + 10 kb C->T variant leads to inclusion of cryptic exon harboring stop codon leading to the production of truncated non-functional CFTR proteins. in vitro, SPL84 treatment results in splicing modulation, which leads to an increase of correctly spliced CFTR RNA and higher levels of functional CFTR proteins.
Methods
SPL84 was tested in a blinded, placebo-controlled phase 1 study in thirty two (32) healthy volunteers (HVs), each received a single dose of either SPL84 or placebo by inhalation. A total of 8 participants were randomized to each of the 4 escalating cohorts in a 3:1 ratio (active: placebo). Safety and tolerability were evaluated by monitoring adverse events (AEs), vital signs, physical exam findings, spirometry, electrocardiograms (ECG), and analyses of safety laboratories. Blood samples were obtained periodically over 24 h for measurement of systemic exposure.
Results
There were no significant changes from baseline in vital signs, clinical laboratory values, ECG, physical examination, or pulmonary function. There were no Serious Adverse Events (SAEs) in the study, and there were no significant adverse events. The systemic exposure to SPL84 was low and tended to be dose dependent. The exposure, expressed in terms of area under the curve to infinity (AUCinf), at the no observed adverse effect level (NOAEL) in 9-week toxicological mice study was 7.51 µg/ml*hrs, which is ∼20 times higher than the exposure at the 160 mg dose (444 ng/ml*hrs).
Conclusions
SPL84 was safe and well-tolerated when administered as a single inhaled dose to HVs at doses up to 160 mg, with minimal systemic exposure. There were no safety issues observed, no SAEs, no significant related AEs, and, importantly, no significant effect on pulmonary function. The successful completion of the study enabled the initiation of multi-dosing of CF patients in a phase 2 clinical study.
{"title":"A phase I study assessing the safety and tolerability of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C->T","authors":"Yoseph Caraco , Maor Wanounou , Simcha Blotnick , Lital Friedman , Asaf Cohen , Gili Hart , Eitan Kerem","doi":"10.1016/j.jcf.2024.10.004","DOIUrl":"10.1016/j.jcf.2024.10.004","url":null,"abstract":"<div><h3>Background</h3><div>Antisense Oligonucleotides (ASOs) are small synthetic nucleic acid molecules able to bind specific sequences within target Ribonucleic Acid (RNA) molecules. SPL84 is an ASO drug developed for treatment of cystic fibrosis (CF) patients carrying the 3849 + 10 kb C->T Cystic Fibrosis Transmembrane Conductance Regulator (<em>CFTR</em>) splicing mutation. The 3849 + 10 kb C->T variant leads to inclusion of cryptic exon harboring stop codon leading to the production of truncated non-functional <em>CFTR</em> proteins. <em>in vitro</em>, SPL84 treatment results in splicing modulation, which leads to an increase of correctly spliced <em>CFTR</em> RNA and higher levels of functional <em>CFTR</em> proteins.</div></div><div><h3>Methods</h3><div>SPL84 was tested in a blinded, placebo-controlled phase 1 study in thirty two (32) healthy volunteers (HVs), each received a single dose of either SPL84 or placebo by inhalation. A total of 8 participants were randomized to each of the 4 escalating cohorts in a 3:1 ratio (active: placebo). Safety and tolerability were evaluated by monitoring adverse events (AEs), vital signs, physical exam findings, spirometry, electrocardiograms (ECG), and analyses of safety laboratories. Blood samples were obtained periodically over 24 h for measurement of systemic exposure.</div></div><div><h3>Results</h3><div>There were no significant changes from baseline in vital signs, clinical laboratory values, ECG, physical examination, or pulmonary function. There were no Serious Adverse Events (SAEs) in the study, and there were no significant adverse events. The systemic exposure to SPL84 was low and tended to be dose dependent. The exposure, expressed in terms of area under the curve to infinity (AUC<sub>inf</sub>), at the no observed adverse effect level (NOAEL) in 9-week toxicological mice study was 7.51 µg/ml*hrs, which is ∼20 times higher than the exposure at the 160 mg dose (444 ng/ml*hrs).</div></div><div><h3>Conclusions</h3><div>SPL84 was safe and well-tolerated when administered as a single inhaled dose to HVs at doses up to 160 mg, with minimal systemic exposure. There were no safety issues observed, no SAEs, no significant related AEs, and, importantly, no significant effect on pulmonary function. The successful completion of the study enabled the initiation of multi-dosing of CF patients in a phase 2 clinical study.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 66-71"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.10.008
Margaret Michicich, Zachary Traylor, Caitlan McCoy, Dana M. Valerio, Alma Wilson, Molly Schneider, Sakeena Davis, Amanda Barabas, Rachel J. Mann, David F. LePage, Weihong Jiang, Mitchell L. Drumm, Thomas J. Kelley, Ronald A. Conlon, Craig A. Hodges
Background
People with cystic fibrosis carrying two nonsense alleles lack CFTR-specific treatment. Growing evidence supports the hypothesis that nonsense mutation identity affects therapeutic response, calling for mutation-specific CF models. We describe a novel W1282X mouse model and compare it to an existing G542X mouse.
Methods
The W1282X mouse was created using CRISPR/Cas9 to edit mouse Cftr. In this model, Cftr transcription was assessed using qRT-PCR and CFTR function was measured in the airway by nasal potential difference and in the intestine by short circuit current. Growth, survival, and intestinal motility were examined as well. Correction of W1282X CFTR was assessed pharmacologically and by gene-editing using a forskolin-induced swelling (FIS) assay in small intestine-derived organoids.
Results
Homozygous W1282X mice demonstrate decreased Cftr mRNA, little to no CFTR function, and reduced survival, growth, and intestinal motility. W1282X organoids treated with various combinations of pharmacologic correctors display a significantly different amount of CFTR function than that of organoids from G542X mice. Successful gene editing of W1282X to wildtype sequence in intestinal organoids was achieved leading to restoration of CFTR function.
Conclusions
The W1282X mouse model recapitulates common human manifestations of CF similar to other CFTR null mice. Despite the similarities between the congenic W1282X and G542X models, they differ meaningfully in their response to identical pharmacological treatments. This heterogeneity highlights the importance of studying therapeutics across genotypes.
{"title":"A W1282X cystic fibrosis mouse allows the study of pharmacological and gene-editing therapeutics to restore CFTR function","authors":"Margaret Michicich, Zachary Traylor, Caitlan McCoy, Dana M. Valerio, Alma Wilson, Molly Schneider, Sakeena Davis, Amanda Barabas, Rachel J. Mann, David F. LePage, Weihong Jiang, Mitchell L. Drumm, Thomas J. Kelley, Ronald A. Conlon, Craig A. Hodges","doi":"10.1016/j.jcf.2024.10.008","DOIUrl":"10.1016/j.jcf.2024.10.008","url":null,"abstract":"<div><h3>Background</h3><div>People with cystic fibrosis carrying two nonsense alleles lack CFTR-specific treatment. Growing evidence supports the hypothesis that nonsense mutation identity affects therapeutic response, calling for mutation-specific CF models. We describe a novel <em>W1282X</em> mouse model and compare it to an existing <em>G542X</em> mouse.</div></div><div><h3>Methods</h3><div>The <em>W1282X</em> mouse was created using CRISPR/Cas9 to edit mouse <em>Cftr</em>. In this model, <em>Cftr</em> transcription was assessed using qRT-PCR and CFTR function was measured in the airway by nasal potential difference and in the intestine by short circuit current. Growth, survival, and intestinal motility were examined as well. Correction of <em>W1282X</em> CFTR was assessed pharmacologically and by gene-editing using a forskolin-induced swelling (FIS) assay in small intestine-derived organoids.</div></div><div><h3>Results</h3><div>Homozygous <em>W1282X</em> mice demonstrate decreased <em>Cftr</em> mRNA, little to no CFTR function, and reduced survival, growth, and intestinal motility. <em>W1282X</em> organoids treated with various combinations of pharmacologic correctors display a significantly different amount of CFTR function than that of organoids from <em>G542X</em> mice. Successful gene editing of <em>W1282X</em> to wildtype sequence in intestinal organoids was achieved leading to restoration of CFTR function.</div></div><div><h3>Conclusions</h3><div>The <em>W1282X</em> mouse model recapitulates common human manifestations of CF similar to other CFTR null mice. Despite the similarities between the congenic <em>W1282X</em> and <em>G542X</em> models, they differ meaningfully in their response to identical pharmacological treatments. This heterogeneity highlights the importance of studying therapeutics across genotypes.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 164-174"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.10.012
Charles R. Esther Jr , Melanie Rua , Haoqian Chen , Elizabeth Cromwell , Soko Setoguchi
Background
The Cystic Fibrosis Foundation Patient Registry (CFFPR) provides valuable clinical and demographic data but includes limited information on health services and medications provided outside of CF Care Centers. Linking CFFPR to claims databases such as national Medicaid data could address these data gaps.
Methods
Linkage algorithms based on state of residence, gender, and date of birth were utilized to match individuals with CF diagnostic codes in national Medicaid databases (2016) to individuals in the CFFPR (2015–2016). Subsets of individuals with partial social security numbers or residing in the state of North Carolina were utilized to validate the accuracy of linkages and perform exploratory analyses on care utilization and costs.
Results
Of the 32,152 individuals in CFFPR, 10,616 were uniquely linked to national Medicaid databases. The 372 linked individuals within the NC extract had 8.0 ± 7.6 visits to outpatient providers, substantially higher than the 4.2 ± 2.4 CF Care Center outpatient visits documented within CFFPR. Similarly, linked individuals had 2.1 ± 1.7 oral antibiotic prescriptions within CMS pharmacy databases versus 0.5 ± 1.9 oral antibiotic prescriptions in CFFPR. Total pharmacy costs for the linked individuals in NC were $16.4 million, with pancrealipase (19 %), dornase alfa (24 %), and CFTR modulators (29 %) the largest expenditures. Total non-pharmacy costs were $7.5 million, with inpatient hospitalization representing 53 % of costs.
Conclusion
Linkage of data from Medicaid and CFFPR can produce valid comprehensive data on low-income people with CF and provide opportunities to examine utilization/adherence or comparative effectiveness and safety of medications as well as conduct economic analyses in the low-income CF population.
{"title":"Process and validity of linking cystic fibrosis patient registry with national Medicaid databases","authors":"Charles R. Esther Jr , Melanie Rua , Haoqian Chen , Elizabeth Cromwell , Soko Setoguchi","doi":"10.1016/j.jcf.2024.10.012","DOIUrl":"10.1016/j.jcf.2024.10.012","url":null,"abstract":"<div><h3>Background</h3><div>The Cystic Fibrosis Foundation Patient Registry (CFFPR) provides valuable clinical and demographic data but includes limited information on health services and medications provided outside of CF Care Centers. Linking CFFPR to claims databases such as national Medicaid data could address these data gaps.</div></div><div><h3>Methods</h3><div>Linkage algorithms based on state of residence, gender, and date of birth were utilized to match individuals with CF diagnostic codes in national Medicaid databases (2016) to individuals in the CFFPR (2015–2016). Subsets of individuals with partial social security numbers or residing in the state of North Carolina were utilized to validate the accuracy of linkages and perform exploratory analyses on care utilization and costs.</div></div><div><h3>Results</h3><div>Of the 32,152 individuals in CFFPR, 10,616 were uniquely linked to national Medicaid databases. The 372 linked individuals within the NC extract had 8.0 ± 7.6 visits to outpatient providers, substantially higher than the 4.2 ± 2.4 CF Care Center outpatient visits documented within CFFPR. Similarly, linked individuals had 2.1 ± 1.7 oral antibiotic prescriptions within CMS pharmacy databases versus 0.5 ± 1.9 oral antibiotic prescriptions in CFFPR. Total pharmacy costs for the linked individuals in NC were $16.4 million, with pancrealipase (19 %), dornase alfa (24 %), and CFTR modulators (29 %) the largest expenditures. Total non-pharmacy costs were $7.5 million, with inpatient hospitalization representing 53 % of costs.</div></div><div><h3>Conclusion</h3><div>Linkage of data from Medicaid and CFFPR can produce valid comprehensive data on low-income people with CF and provide opportunities to examine utilization/adherence or comparative effectiveness and safety of medications as well as conduct economic analyses in the low-income CF population.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 118-124"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.07.004
Michael W. Konstan , Deepika Polineni , James F. Chmiel , Lara Bilodeau , Peter G. Middleton , Elias Matouk , Jean-Marie Houle , Radu Pislariu , Patrick Colin , Irenej Kianicka , Diane Potvin , Danuta Radzioch , Tom Kotsimbos , Jonathan B. Zuckerman , Samya Z. Nasr , Theodore G. Liou , Larry C. Lands , study Investigators
Background
Lung inflammation is associated with tissue damage in cystic fibrosis (CF). LAU-7b, a novel oral drug candidate, was shown to control inflammation and stabilize CFTR protein in the epithelial membrane during inflammatory stress in preclinical models of CF.
Methods
A double-blind, randomized, placebo-controlled Phase 2 study was conducted to evaluate efficacy and safety of LAU-7b in adults with CF. LAU-7b or placebo was administered over 24 weeks as six 21-day treatment cycles each separated by 7 days. The primary efficacy endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) at 24 weeks.
Results
A total of 166 subjects received at least one dose of study drug (Intent-To-Treat population, ITT), of which 122 received ≥5 treatment cycles (Per-Protocol population, PP). Both treatment arms showed a mean lung function loss at 24 weeks of 1.18 ppFEV1 points with LAU-7b and 1.95 ppFEV1 with placebo, a 0.77 ppFEV1 (40 s) difference, p=0.345, and a 0.95 ppFEV1 (49 %) difference in the same direction in PP population, p=0.263. Primary analysis of mean ppFEV1 through 24 weeks showed differences of 1.01 and 1.23 ppFEV1, in the ITT (65 % less loss, p=0.067) and PP populations (78 % less loss, reaching statistical significance p=0.049), respectively. LAU-7b had an acceptable safety profile.
Conclusion
Although the study did not meet its primary efficacy endpoint in the ITT population, LAU-7b was generally well tolerated and showed evidence of preservation of lung function to support further development.
{"title":"Efficacy and safety of LAU-7b in a Phase 2 trial in adults with cystic fibrosis","authors":"Michael W. Konstan , Deepika Polineni , James F. Chmiel , Lara Bilodeau , Peter G. Middleton , Elias Matouk , Jean-Marie Houle , Radu Pislariu , Patrick Colin , Irenej Kianicka , Diane Potvin , Danuta Radzioch , Tom Kotsimbos , Jonathan B. Zuckerman , Samya Z. Nasr , Theodore G. Liou , Larry C. Lands , study Investigators","doi":"10.1016/j.jcf.2024.07.004","DOIUrl":"10.1016/j.jcf.2024.07.004","url":null,"abstract":"<div><h3>Background</h3><div>Lung inflammation is associated with tissue damage in cystic fibrosis (CF). LAU-7b, a novel oral drug candidate, was shown to control inflammation and stabilize CFTR protein in the epithelial membrane during inflammatory stress in preclinical models of CF.</div></div><div><h3>Methods</h3><div>A double-blind, randomized, placebo-controlled Phase 2 study was conducted to evaluate efficacy and safety of LAU-7b in adults with CF. LAU-7b or placebo was administered over 24 weeks as six 21-day treatment cycles each separated by 7 days. The primary efficacy endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV<sub>1</sub>) at 24 weeks.</div></div><div><h3>Results</h3><div>A total of 166 subjects received at least one dose of study drug (Intent-To-Treat population, ITT), of which 122 received ≥5 treatment cycles (Per-Protocol population, PP). Both treatment arms showed a mean lung function loss at 24 weeks of 1.18 ppFEV<sub>1</sub> points with LAU-7b and 1.95 ppFEV<sub>1</sub> with placebo, a 0.77 ppFEV<sub>1</sub> (40 s) difference, p=0.345, and a 0.95 ppFEV<sub>1</sub> (49 %) difference in the same direction in PP population, p=0.263. Primary analysis of mean ppFEV<sub>1</sub> through 24 weeks showed differences of 1.01 and 1.23 ppFEV<sub>1</sub>, in the ITT (65 % less loss, p=0.067) and PP populations (78 % less loss, reaching statistical significance p=0.049), respectively. LAU-7b had an acceptable safety profile.</div></div><div><h3>Conclusion</h3><div>Although the study did not meet its primary efficacy endpoint in the ITT population, LAU-7b was generally well tolerated and showed evidence of preservation of lung function to support further development.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 83-90"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.09.020
Inès Nidegger , Julie Macey , Marine Ferey , Allison Singier , Marie Tournier , Justine Perino , Francesco Salvo
Background
A highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database.
Methods
First, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) "Suicide/Self-injury" and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect.
Results
Four cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt.
Conclusions
ETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation.
{"title":"Suicidal behaviour and CFTR modulators: A case series and WHO database disproportionality analysis","authors":"Inès Nidegger , Julie Macey , Marine Ferey , Allison Singier , Marie Tournier , Justine Perino , Francesco Salvo","doi":"10.1016/j.jcf.2024.09.020","DOIUrl":"10.1016/j.jcf.2024.09.020","url":null,"abstract":"<div><h3>Background</h3><div>A highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database.</div></div><div><h3>Methods</h3><div>First, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) \"Suicide/Self-injury\" and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect.</div></div><div><h3>Results</h3><div>Four cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt.</div></div><div><h3>Conclusions</h3><div>ETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 33-39"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jcf.2024.06.002
Henry Danahay , Clive McCarthy , Thomas Schofield , Roy Fox , Holly Charlton , Sarah Lilley , Juan Sabater , Matthias Salathe , Nathalie Baumlin , Stephen P Collingwood , Martin Gosling
Background
Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed?
Methods
Dose-responses with the failed ENaC blockers (VX-371, BI 1265162, AZD5634, QBW276) together with ETD001 (a novel long acting inhaled ENaC blocker) were established in a sheep model of MCC and were used to predict clinically relevant doses that would provide a long-lasting enhancement of MCC in pwCF. In each case, dose predictions were compared with the selected clinical dose.
Results
Each of the failed candidates enhanced MCC in the sheep model. Translating these dose-response data to human equivalent doses, predicted that substantially larger doses of each candidate, than were evaluated in clinical studies, would likely have been required to achieve a prolonged enhancement of MCC in pwCF. In contrast, ETD001 displayed a long duration of action (≥16 h) at a dose level that was well tolerated in Phase 1 clinical studies.
Conclusions
These data support that the ENaC blocker hypothesis is yet to be appropriately tested in pwCF. ETD001 has a profile that enables dosing at a level sufficient to provide a long duration of action in a Phase 2 clinical study in pwCF scheduled for 2024.
{"title":"ETD001: A novel inhaled ENaC blocker with an extended duration of action in vivo","authors":"Henry Danahay , Clive McCarthy , Thomas Schofield , Roy Fox , Holly Charlton , Sarah Lilley , Juan Sabater , Matthias Salathe , Nathalie Baumlin , Stephen P Collingwood , Martin Gosling","doi":"10.1016/j.jcf.2024.06.002","DOIUrl":"10.1016/j.jcf.2024.06.002","url":null,"abstract":"<div><h3>Background</h3><div>Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed?</div></div><div><h3>Methods</h3><div>Dose-responses with the failed ENaC blockers (VX-371, BI 1265162, AZD5634, QBW276) together with ETD001 (a novel long acting inhaled ENaC blocker) were established in a sheep model of MCC and were used to predict clinically relevant doses that would provide a long-lasting enhancement of MCC in pwCF. In each case, dose predictions were compared with the selected clinical dose.</div></div><div><h3>Results</h3><div>Each of the failed candidates enhanced MCC in the sheep model. Translating these dose-response data to human equivalent doses, predicted that substantially larger doses of each candidate, than were evaluated in clinical studies, would likely have been required to achieve a prolonged enhancement of MCC in pwCF. In contrast, ETD001 displayed a long duration of action (≥16 h) at a dose level that was well tolerated in Phase 1 clinical studies.</div></div><div><h3>Conclusions</h3><div>These data support that the ENaC blocker hypothesis is yet to be appropriately tested in pwCF. ETD001 has a profile that enables dosing at a level sufficient to provide a long duration of action in a Phase 2 clinical study in pwCF scheduled for 2024.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 72-78"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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