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IVACAFTOR IN MUTATIONS BEYOND G551D |
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De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014 Dec;13(6):674-680.
Moss RB, Flume PA, Elborn JS, et al; VX11-770-110 (KONDUCT) Study Group. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomized controlled trial. Lancet Respir Med. 2015 Jul;3(7):524-533.
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Initial studies of ivacaftor focused on people with cystic fibrosis (CF) from at least one G551D CFTR mutation; however, ivacaftor also has the potential to improve chloride transport in any defective CFTR that resides at the apical surface of epithelial cells. Therefore, studies were undertaken to investigate the effect of ivacaftor in people with other CFTR mutations.
De Boeck and colleagues evaluated 39 individuals with CF aged ≥ 6 years with non-G551D CFTR gating mutations in the two-part, double-blind crossover and open-label extension KONNECTION study. Patients received eight weeks of either ivacaftor 150 mg twice daily or placebo for eight weeks in a crossover fashion with a four- to eight-week washout period. This was followed by a 16-week open label period, so that some patients received 24 weeks of continuous therapy.
In a model-adjusted absolute mean, the difference in lung function measured by FEV1 between ivacaftor and placebo groups was 10.7% (95% confidence interval 7.3-14.1). There were also improvements in body mass index (BMI), sweat chloride and quality of life as measured by the CFQ-R. During the open label period there was a 13.5% improvement in absolute FEV1 (range -6.9 to 36.5), and a 1.3 kg/m2 (range 0.16 to 2.9), improvement in body mass index. These results were similar to those obtained in individuals with CF due to at least one G551D CFTR mutation.
In the KONDUCT study, Moss and colleagues investigated the effect of ivacaftor 150 mg twice daily in patients with CF from at least one R117H CFTR mutation. This was a 24-week, placebo-controlled, double-blind study that enrolled 69 patients aged ≥ 6 years. The investigators found an improvement in absolute FEV1 of 2.6% in those treated with ivacaftor compared to 0.5% in the placebo group.
An interesting phenomenon was seen in the washout from this study. Prior to patients enrolling in a 12-week open label study, there was a rapid loss of lung function back to baseline following discontinuing ivacaftor; however, lung function improvement was restored during the open label phase with a 5.5% improvement in FEV1.
Ivacaftor did not lead to improvement in lung function in children ages 6 to 11, and ivacaftor therapy seemed to have a more profound effect in adults and those with more severe lung function. This trial highlights the difficulty of studying patients with normal or mildly impaired lung function, as well as a group of patients with significant phenotypic variability, which is the case for those patients with R117H CFTR mutations.
The results of these two studies led to an expansion of the initial Food and Drug Administration indication for ivacaftor to include gating CFTR mutations beyond G551D (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D), as well as patients with CF due to R117H CFTR mutations. These data suggest that these drugs are effective in children age 6 and above and are likely to be beneficial in younger children as well, as was seen in studies of patients with cystic fibrosis CF with G551D CFTR mutations.
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IVACAFTOR TREATMENT IN F508DEL HOMOZYGOUS INDIVIDUALS |
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Wainwright CE, Elborn JS, Ramsey BW, et al; TRAFFIC Study Group; TRANSPORT Study Group. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220-231.
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Approximately half of patients with cystic fibrosis (CF) have two F508 CFTR mutations; therefore, developing a therapy for this group has significant clinical importance. Since ivacaftor therapy alone does not benefit this group of patients, a combination therapy of ivacaftor with lumacaftor (a CFTR corrector that can chaperone defective F508del CFTR protein to the cell surface in combination with ivacaftor) was trialed in two distinct studies — TRAFFIC and TRANSPORT. This paper by Wainwright and colleagues reports on the pooled results.
Overall, 1,108 individuals with CF due to two F508del CFTR mutations participated. Subjects received either lumacaftor 600 mg once daily or 400 mg twice daily in combination with ivacaftor 250 mg twice daily, or placebo for 24 weeks. The baseline FEV1 for these patients aged 12 and older was 61% of predicted. Patients in both dosage cohorts showed a significant improvement in lung function as measured by FEV1, with mean improvement in absolute FEV1 ranging from 2.6 to 4.0%. There was also an improvement in nutritional status as measured by body mass index (BMI), and a marked diminution in the number of exacerbations, falling by 61% in the higher dosage group in the number of patients requiring hospitalization, and by 56% in the people requiring intravenous antibiotics.
While the patients receiving lumacaftor/ivacaftor had an increased incidence of adverse events, including chest tightness or other respiratory symptoms, they also experienced a significant decrease in serious adverse events (primarily pulmonary exacerbations). The dose of ivacaftor in this trial was higher than that typically given to patients receiving ivacaftor alone because of drug interactions, which lead to more rapid degradation of ivacaftor.
The results of this trial led to the approval of lumacaftor/ivacaftor by the Food and Drug Administration in July, 2015. The combination is indicated for children age 12 years and above and adults with CF from two F508del CFTR mutations.
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THERAPY FOR NONSENSE CFTR MUTATIONS |
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Kerem E, Konstan MW, De Boeck K, et al; Cystic Fibrosis Ataluren Study Group. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a Randomized, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med. 2014 Jul;2(7):539-547.
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Ataluren is an experimental drug designed to allow ribosomes to read through premature stop codons in class 1 (aka "nonsense") CFTR mutations. These are mutations that end in the letter X, where a stop has been abnormally inserted into the coding region. Kerem and colleagues describe a phase 3 trial of 238 patients with at least one stop codon CFTR mutation, enrolled at 36 sites in 11 countries. Children aged ≥ 6 years and adults with an FEV1 between 40% and 90% predicted, received ataluren three times daily or a matching placebo for 48 weeks. The relative change in percent predicted FEV1 did not differ significantly between the ataluren and placebo treated subjects at the end of the trial (-2.5% vs -5.5%, respectively). In addition, the frequency of pulmonary exacerbations did not differ between the treated and untreated individuals.
However, post hoc analysis of a subgroup of patients not using chronic inhaled tobramycin did show a difference in FEV1 between the ataluren treated individuals and those receiving placebo. There was a 5.7% difference (95% confidence interval 1.5%-10.1% in relative percent predicted, P = .0082) and fewer exacerbations in the ataluren treated group (1.42 events) compared to 2.18 events in the placebo group (P = .0061). The safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentration associated with acute kidney injury, which occurred in 15% of the people treated with ataluren compared to < 1% of the placebo group.
One explanation for the findings in this trial is that tobramycin, which is an inhaled antibiotic that binds to bacterial ribosomes, interferes with ataluren at a cellular level. This is a plausible explanation for the results and has led to the initiation of a second phase 3 trial studying ataluren in people who are not receiving inhaled tobramycin. This trial has recently completed enrollment and results should be available in the coming year. Ataluren therapy did not have an effect on sweat chloride or nasal potential difference measurements in the patients treated with ataluren or placebo. |
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Ivacaftor is effective in people with cystic fibrosis who have CFTR mutations that lead to defective protein at the epithelial cell surface.
- Ivacaftor provides sustained benefits in people with cystic fibrosis from at least one G551D CFTR mutation.
- Ivacaftor is safe and effective in people with severe lung disease.
- Lumacaftor/ivacaftor is safe and effective in patients with cystic fibrosis from two F508del CFTR mutations.
- Therapies that improve CFTR function are unlikely to reverse existing lung damage, so aggressively continuing current symptomatic therapies to preserve lung function remain critically important.
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IMPORTANT CME/CE INFORMATION |
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accreditation
statements
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Johns Hopkins University School of Medicine and the Institute for Johns Hopkins Nursing. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation
credit
designations
Physicians
Newsletter: The Johns Hopkins University School
of Medicine designates this enduring material
for a maximum of 1.0 AMA PRA Category
1
Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses
Newsletter: This 1 contact hour Educational Activity
is provided by the Institute for Johns
Hopkins Nursing. Each Newsletter carries a maximum of 1 contact hours or a total of 7 contact hours for the seven newsletters in this program.
Respiratory Therapists
For United States: Visit
this page to confirm that your state
will accept the CE Credits gained through
this program.
For Canada: Visit
this page to confirm that your province
will accept the CE Credits gained through
this program.
intended
audience
This activity has been developed for pulmonologists, pediatric pulmonologists, gastroenterologists, pediatricians, infectious disease specialists, respiratory therapists, dieticians, nutritionists, nurses, and physical therapists.
There are no fees or prerequisites for this activity.
launch date
This program launched on December 30, 2015 and is published monthly; activities expire two years from the date of publication.
hardware & software requirements
Pentium 800 processor or greater, Windows 98/NT/2000/XP or Mac OS 9/X, Microsoft Internet Explorer 5.5 or later, Windows Media Player 9.0 or later, 128 MB of RAM Monitor settings: High color at 800 x 600 pixels, Sound card and speakers, Adobe Acrobat Reader.
disclaimer
statement
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is
produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.
Statement of Need
Based on a review of the current literature, including national and regional measures, detailed conversations with expert educators at Johns Hopkins, and a survey of potential program participants, this program will address the following core patient care gaps:
Disease-Modifying Therapies |
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Clinicians need guidance in understanding how new findings describing CFTR-modifying therapies may improve their treatment of patients with cystic fibrosis. |
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Incomplete clinician awareness of genotype/phenotype correlations in non-pulmonary targets of CFTR-modifying therapies may limit their ability to provide optimal patient care. |
Nutrition |
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Clinicians lack effective guidance to increase caloric intake in patients who are nutritionally compromised. |
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Clinicians do not fully understand how to manage the complexities of pancreatic enzyme replacement therapy to achieve optimal results in their patients. |
Pseudomonas Aeruginosa |
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Clinicians have unanswered questions about P. aeruginosa eradication in asymptomatic patients with positive cultures. |
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New data and new choices for selecting initial inhaled anti-pseudomonal agents have created confusion. |
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Conflicting data about pulmonary exacerbations has led to incorrect clinical assumptions and inappropriate treatment regimens. |
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Members of the Planning Committee are required to disclose all relationships regardless of their relevance to the content of the activity. Faculty are required to disclose only those relationships that are relevant to their specific presentation. The following relationships have been reported for this activity:
Dr. Noah Lechtzin, has reported that he has served as principal investigator for Vertex Pharmaceuticals Incorporated. In addition, he has served as a consultant for Hill Rom.
Suzanne Sullivan has received honorarium from Vertex Pharmaceuticals Incorporated.
No other planners have indicated that they have any financial interests or relationships with a commercial entity.
Guest
Author's Disclosures
This activity is supported by educational grants from Chiesi USA,Inc, Gilead Sciences, Inc, and Vertex Pharmaceuticals Incorporated.
SUCCESSFUL COMPLETION
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I understand that while I am attending in this
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I understand that I may direct to the Johns Hopkins Privacy Officer any questions I have about my obligations under this Confidentiality Pledge or under any of the Hopkins policies and procedures and applicable laws and regulations related to confidentiality. The contact information is: Johns Hopkins Privacy Officer, telephone: 410-735-6509, HIPAA@jhmi.edu
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For CME Questions, please contact the CME Office
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(Updated 4/09 and 3/14).
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Continuing Medical Education at the Johns Hopkins University School of Medicine will keep your personal and credit information confidential when you participate in a CME Internet-based program. Your information will never be given to anyone outside the Johns Hopkins University School of Medicine's CME program. CME collects only the information necessary to provide you with the services that you request.
To participate in additional CME activities presented by the Johns Hopkins University School of Medicine Continuing Medical Education Office, please visit www.hopkinscme.edu
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Click on link to download instructions for the post-test and evaluation
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