For people with cystic fibrosis, getting “back” into shape is a common occurrence. Because of the nature of the disease, patients often experience set backs in both their health and fitness routines. But, exercise is an important and essential part of remaining compliant with treatments and medications in order to live a longer, healthier life with CF. Continue reading CYSTIC FIBROSIS WIND SPRINT 68: CIRCUIT TRAINING 3
Findings from a phase 3 trial evaluating the efficacy and safety of tezacaftor in combination with ivacaftor in patients with cystic fibrosis (CF) who were homozygous for the Phe508del mutation were published in the New England Journal of Medicine.
The Phe508del mutation has been known to result in greatly reduced conductance regulator (CFTR) protein activity and a loss of chloride secretion, which can lead to impaction of mucus in the airways, gastrointestinal tract, and exocrine organs, with the potential for severe clinical consequences including gradual loss of lung function, nutritional deficits, pulmonary exacerbations, and respiratory failure. It is the most prevalent CFTR mutation worldwide, and affects approximately 46% of American CF patients.
Previous data has shown Ivacaftor’s association with a rate of progressive decline in lung function that is lower than that in untreated patients. In a phase 2 clinical trial involving patients who were homozygous for the Phe508del mutation or heterozygous for the Phe508del and G551D mutations, when combined with the investigational CFTR corrector tezacaftor, it has exhibited enhanced CFTR function and improved lung function.
In August, just one month removed from Vertex’s announcement of positive datafrom Phase 1 and Phase 2 studies, Rare Disease Report covered the acceptance of applications for the use of the tezacaftor/ivacaftor combination treatment in this patient population by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).
The phase 3 trial enrolled a total of 510 patients 12 years and older with CF who were homozygous for the Phe508del CFTR mutation at 91 sites in the U.S., Canada, and Europe from January 30, 2015 to January 20, 2017. Patients were randomly assigned to be administered either tezacaftor and ivacaftor (administered as a fixed-dose combination tablet containing 100 mg of tezacaftor and 150 mg of ivacaftor in the morning and a tablet containing 150 mg of ivacaftor in the evening) combination therapy or placebo for 24 weeks.
In total, 475 patients completed the full 24 weeks of the trial, with 93.6% (n=235) in the tezacaftor-ivacaftor group and 93% (n=240) in the placebo group. While no significant difference in the body mass index (BMI) was experienced between the groups at week 24, the use of the combination therapy led to a significantly greater absolute change from baseline in the predicted forced expiratory volume in 1 second (FEV1) than placebo. Despite advances in standard-of-care therapy, patients with CF continue to lose lung function at a rate of an estimated 1% to 3% per year. This trial exhibited a significant effect of the combination therapy compared to the placebo, as the mean absolute change from baseline in FEV1 through week 24 was 3.4 percentage points in the former, compared to 0.6 in the latter.
The most common adverse events (AEs) among the enrolled patients included infective pulmonary exacerbation, cough, headache, nasopharyngitis, increased sputum production, pyrecia, hemoptysis, oropharyngeal pain, and fatigue. The incidence of AEs was similar in both the group for combination therapy and the placebo group, however, those treated with lumacaftor-ivacaftor in the phase 3 did not experience an increased incidence of respiratory events (33 patients [13.1%] vs. 41 patients [15.9%]).
This improved safety profile of the tezacaftor-ivacaftor combination supports its use in a broad range of patients with CF, and, if approved, the therapy will be the third of Vertex’s drugs approved for CF patients, and the second intended specifically to treat patients with F508del mutations (Orkami [lumacaftor/ivacaftor]).
For original article please visit: http://www.raredr.com/news/phase-3-combination-therapy-cystic-fibrosis?t=physicians
For the published study please visit: http://www.nejm.org/doi/full/10.1056/NEJMoa1709846?query=genetics#t=articleDiscussion
Researchers hypothesize that the newly-discovered mutations help re-hydrate the airways, discouraging bacterial build-up in the lungs.
Despite a narrow average lifespan, there is a big range in how severely cystic fibrosis (CF) affects the lungs and other organs depending on an individual’s specific genetic variation, and even in how long patients sharing the same, most common genetic mutation are able to survive with CF.
This led researchers at Boston Children’s Hospital to wonder if other genetic mutations could be protective against CF’s effects. Recent findings published in the American Journal of Respiratory Cell and Molecular Biology suggest that may be the case.
“There are some patients at one end of extreme severity who need a lung transplant very early in life, then others whose clinical presentation seems to stabilize so that they can live into the fifth and sixth decades of life,” says Pankaj Agrawal, MBBS, MMSc, principal investigator and medical director of The Manton Center’s Gene Discovery Core at Boston Children’s, who was the co-first author on the study.
To find out why, Agrawal and researchers at Boston Children’s — including Ruobing Wang, MD, a pulmonologist, and Craig Gerard, MD, PhD, chief of the Division of Respiratory Diseases — conducted the first-ever longitudinal analysis of genetic modifiers related to CF.
They combed through a population of nearly 600 CF patients registered at the Boston Children’s Cystic Fibrosis Center and found five individuals who stood out because of their advanced age — in their 50s or 60s — and relatively normal lung function.
“Given the large size of our center’s patient population, we were able to find a number of individuals at this rare ‘extreme,'” says Wang, who was co-first author on the paper.
A new hypothesis for mitigating cystic fibrosis
To discover the genetic variants, the researchers collected blood from these patients and performed whole exome sequencing on their DNA, analyzing the “coding” section of the genome that is responsible for most disease-related mutations.
Sequencing the genes of these five Boston Children’s patients — a cohort known as “long-term non-progressors” — the researchers found a set of rare and never-before-discovered genetic variants that might help explain their longevity and stable lung function.
The gene variants are related to so-called epithelial sodium channels (ENaCs), semi-permeable cellular pathways responsible for reabsorbing sodium in the kidney, colon, lung and sweat glands.
“Our hypothesis is that these ENaC mutations help to rehydrate the airways of CF patients, making it less likely for detrimental bacteria to take up residence in the lungs,” says Wang.
The discovery brings ENaCs into the limelight as a potential new therapeutic target.
“For example, if we could target ENaCs with a small molecule or an antibody-based drug, we might be able to incur a protective effect against CF’s progression,” says Agrawal, who is also a physician in the Boston Children’s Division of Newborn Medicine.
Based on their findings, the team is now doing further studies to analyze the genetics of patients at the other end of the CF spectrum — those with extremely severe clinical presentation of symptoms at a young age.
Boston Children’s Hospital. “Some people with cystic fibrosis might live longer because of genetic mutations: Researchers hypothesize that the newly-discovered mutations help re-hydrate the airways, discouraging bacterial build-up in the lungs.” ScienceDaily. ScienceDaily, 25 October 2017. <https://www.sciencedaily.com/releases/2017/10/171025150620.htm>.
Please join us for a FREE private film screening of
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Tuesday, May 9, 2017
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Reception followed by screening and Q & A with Jerry Cahill and the film’s Continue reading Please Join Us for a Free Private Screening of Up for Air at CUMC
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Galapagos doses first patient with novel CF corrector GLPG2222
Galapagos NV (Euronext & NASDAQ: GLPG) announces dosing of the first patient with cystic fibrosis (CF) Class III (F508del and a gating mutation like G551D) with novel CF corrector GLPG2222 as an add-on to Kalydeco® in a Phase 2a study. Galapagos further announced the opening of an Investigational New Drug (IND) file with the US Food & Drug Administration for GLPG2222, triggering a $10 million milestone payment.
Continue reading Phase 2a CF corrector study
Translarna’s Turn In Cystic Fibrosis And Brodalumab’s Approval Tardiness
Welcome to your weekly digest of approaching regulatory and clinical readouts. PTC Therapeutics (NASDAQ:PTC) is awaiting data in the first quarter with its transcription modulator Translarna in nonsense Continue reading Hopeful new clinical trails for nonsense mutations
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Corbus Pharmaceuticals Holdings, Inc. (NASDAQ: CRBP) completed its Phase 2 study evaluating JBT-101 (“Resunab”) for the treatment of cystic fibrosis. JBT-101, the Company’s novel synthetic oral endocannabinoid-mimetic drug, is designed Continue reading Corbus Pharma Completes Phase 2 CF Study
By Piper Beatty Welsh
The holidays are a time for miracles. We see it everywhere we turn, whether in the birth of a newborn baby, or the oil that lit the Temple light, or just in the warmth of family and friends or the gleam in a child’s eye. The holidays are a season of gathering; a season of celebration, generosity, and forgiveness; and a Continue reading ‘Tis The Season
Galapagos NV (Euronext & NASDAQ: GLPG) announced today the first dosing in its Phase 2 exploratory program of GLPG1837 in patients with cystic fibrosis (CF).
GLPG1837 is a candidate CFTR potentiator drug in clinical development for the treatment of Class III mutations in cystic fibrosis. The SAPHIRA Phase 2 Continue reading Galapagos starts SAPHIRA Phase 2 study with GLPG1837 in cystic fibrosis patients