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*The CF Roundtable does not give medical advice. Any medical opinions represented in these articles are those of the writer and do not represent the views of USACFA, any of our community partners, or any other group or individual. We strongly suggest you consult your doctors regarding any medical references and before altering your medical regimen in any way. USACFA does not endorse any products or procedures. 

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© United States Adult Cystic Fibrosis Association 2019

What is new in Cf...

​The Limits of Antimicrobial Sensitivity Testing in Cystic Fibrosis
The aims of infection management include prophylaxis, treatment of exacerbations, and long-term maintenance treatment with antibiotics to reduce bacterial burden. These complex management plans may benefit significantly from cooperative care with pulmonologists and infectious disease specialists, as the former may provide detailed patient histories and guidance on common CF-related complications and the latter may be better positioned to order and evaluate microbial and antibiotic susceptibility testing (AST), which combined allows for personalized care.
The authors of the study suggest that choice of antibiotic therapy should be based primarily on good clinical response, even where discrepancies with in vitro testing suggest resistance to the current therapy. Because lung infections are common in patients with CF, a patient’s primary pulmonologist can provide individualized information regarding clinical responses to previous treatments with varying antibiotics. This information may then allow an infectious disease specialist better leverage in the decision to advise for or against results from in vitro testing.
Researchers have described a “90-60 rule” where infections with susceptible isolates respond to appropriate therapy 90% of the time, whereas infections with resistant isolates (i.e., inappropriate therapy) still respond in 60% of cases. In other words, susceptibility is a stronger predictor of a successful outcome than resistance is of failure.  In contrast, the lungs of patients with CF are colonized with a polymicrobial microbiota varying across a range of microenvironments. Clinical outcomes are most significantly affected by the presence of Pseudomonas aeruginosa. Other organisms typically identified include Staphylococcus aureus, Burkholderia cepacia complex, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and nontuberculous mycobacteria. Over time, and in response to repeated antibiotic exposures, adaptations of these pathogens occurs.
This history is likely best and most accurately charted by pulmonologists, and thus allows for infectious disease specialists to explore, investigate, and tailor treatments based on any genotypic changes including the gradual selection of resistance-conferring mutations and, in the case of P. aeruginosa, the presence of strains with a hypermutator phenotype resulting from defective DNA repair. Phenotypically, P. aeruginosa characteristically switches to a slow-growing anaerobic pattern and forms biofilms with high levels of inherent antibiotic resistance.
Standard AST, performed on sputum samples and throat swabs from patients with CF, identifies only subpopulations from the community of organisms present. This leads to an underrepresentation of the overall pathogen diversity. Moreover, the recovered isolates may or may not contribute to significant clinical disease. A further issue is the possibility of interactions between different bacterial species influencing susceptibility to antimicrobial killing. For example, an enhanced resistance of P. aeruginosa to tobramycin has been documented in the presence of secreted S. aureus exoproducts. Testing of single bacterial isolates is unable to capture these interactions and may misrepresent in vivo susceptibilities.
Another key reason for discrepancy is the interpretation of in vitro inhibitory concentrations. In the lungs of patients with CF, genotypic and phenotypic diversity in respiratory pathogens limit the utility of standard antibiotic susceptibility testing. Standard testing methods lack the sophistication to capture in vivo interactions between bacteria and poorly characterize the multiple subpopulations. AST-driven selection of antimicrobials risks unnecessarily discarding useful antibiotics and switching to less efficacious and more toxic options with greater drug-drug interactions. Treatment efficacy of pulmonary infections in patients with CF therefore is best evaluated through the lens of the clinical acumen of medical professionals from both the field of pulmonology and infectious disease.
https://tinyurl.com/y2nlmx5g

Hero Dogs Can Sniff Out Cystic Fibrosis Before It Takes Hold
Dogs can sniff out bacteria that is a major of cause of lung damage in people with cystic fibrosis before it takes hold. Research found the animals can detect ultra-low concentrations of pseudomonas. Bio detection dogs have a very high level of accuracy when asked to identify bacteria associated with serious lung infections. The study shows the canines can differentiate between Pa and other CF bacterial pathogens by sniffing bacteria grown in a nutrient liquid.
Compared with existing technologies, dogs may ultimately prove more sensitive or more affordable for screening lower airway infection in CF.
https://tinyurl.com/y3xtsznk

Imaging Method Shows Promise for Evaluation of Cystic Fibrosis
An imaging method is showing promise in the early diagnosis and evaluation of cystic fibrosis. The technique, based on optical coherence tomography, is able to provide high-resolution images of cilia lining the nasal pathways, as well as detailed features of the clearance of mucus. The imaging catheter is about 2 mm in diameter with a resolution of about 1 µm — a 50th of the size of a human hair — and can be used to probe the nasal passages of patients without the need for sedatives. The researchers found that in patients with cystic fibrosis, mucus was dehydrated and contained far more inflammatory cells as compared with control subjects. With micro-OCT they were able to measure the reflective qualities of the mucus, and discovered that patches of the patients cilia and epithelium were gone. The researchers expect that this technique will allow clinicians to diagnose diseases much earlier that affect the airways and will provide a higher level of information in monitoring progression and evaluating the effectiveness of drug therapies for individual patients.
https://tinyurl.com/yynw9g26
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Two CF Mutations Corrected Using CRISPR Gene Editing Tool, Study Says
Using the CRISPR gene editing tool, a team of researchers was able to permanently correct two mutations in the CFTR gene in CF patient-derived cells. The researchers showed that the corrected CFTR gene was functional and working normally in mini-intestines called organoids, which had been derived from CF patients and grown in the lab. The gene editing tool CRISPR-Cas9 — a strategy that allows the correction of genomic defects — is considered one of the most promising approaches to correct the mutations in the CFTR gene. However, current attempts to correct these mutations have been hampered by the ineffective delivery of a normal CFTR gene. In the study, researchers used a more precise CRISPR tool to correct permanently two CFTR gene mutations that block the production of a functional CFTR protein. The researchers called their gene editing tool “SpliceFix,” as it can fix the CFTR gene and restore CFTR protein production.
https://tinyurl.com/yy78pjsy
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https://tinyurl.com/y4st8wos

Cellular Metabolism Defect May Be Cause of CF Bacterial Lung Infections
A defect in cellular metabolism is the root cause for the high incidence of lung infections caused by the bacteria Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In CF the CFTR protein works as a channel that transports molecules, such as chloride and water, in and out of cells. Besides working as a channel, CFTR also interacts with other proteins, helping them to make complexes or reaching specific locations within a cell. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of these proteins. In normal conditions, PTEN interacts with CFTR at the membrane of mitochondria — the cell compartments responsible for producing energy — where it helps regulate mitochondria function. However, in CF patients carrying genetic mutations that affect the structure and function of the CFTR protein, the CFTR-PTEN complex does not work properly. In the study, researchers discovered that the dysfunction of both CFTR and PTEN causes a defect in mitochondria metabolism, leading to the excessive production of reactive oxygen species (ROS) and succinate in cells from the lungs. ROS are toxic byproducts of a cell’s normal metabolism that must be broken down regularly to avoid oxidative stress (cellular damage that occurs as a consequence of high levels of oxidant molecules). For that reason, the buildup of ROS inside cells can be, by itself, a major problem. Succinate, another byproduct of cellular metabolism, is a compound that certain bacteria can use as fuel to survive and multiply. These include Pseudomonas aeruginosa. In the study, investigators found that the excesses of succinate stimulates the growth of P. aeruginosa in the lungs of mice with CF. Moreover, researchers found that when P. aeruginosa bacteria have access to succinate, they produce great amounts of sticky slime, which makes them even more difficult to eliminate. On top of that, these succinate-fed bacteria also are capable of shutting down the host’s immune system, further hampering the body’s ability to fight the infection. However, based on study findings made in mice models and human cells cultured in a lab dish, the researchers believe it may be possible to control lung infections caused by P. aeruginosa by finding a way to restore the function of the CFTR-PTEN complex.
https://tinyurl.com/y63r34j7
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https://tinyurl.com/y35lc6k2

Scientists Find Powerful Potential Weapon to Overcome Antibiotic Resistance
Staphylococcus aureus bacteria are a major cause of serious infections that often persist despite antibiotic treatment, but scientists at the UNC School of Medicine have now discovered a way to make these bacteria much more susceptible to some common antibiotics.
The scientists found that adding molecules called rhamnolipids can make aminoglycoside antibiotics, such as tobramycin, hundreds of times more potent against S. aureus. The rhamnolipids effectively loosen up the outer membranes of S. aureus cells so that aminoglycoside molecules can get into them more easily. Rhamnolipids are small molecules produced by another bacterial species, Pseudomonas aeruginosa, and are thought to be one of P. aeruginosa’s natural weapons against other bacteria in the wild. At high doses they make holes in rival bacteria’s cell membranes. The UNC researchers found that rhamnolipids greatly boost the uptake of tobramycin molecules, even at low doses where they have no independent anti-bacterial effect.
https://tinyurl.com/y5a7vqou

In CF Patients, a Fumigatus Linked to Worse Respiratory Quality of Life
The presence of the fungus Aspergillus fumigatus is linked to lower respiratory-related quality of life in people with cystic fibrosis.  A. fumigatus is known to cause allergic bronchopulmonary aspergillosis — an allergic reaction to the fungus. However, it is not clear how this fungus can affect the health of those with the condition in the absence of this allergic response.
Researchers collected samples of sputum from CF patients and cultured them in the lab to look for the fungus. The team compared patients with and without A. fumigatus to look for differences that might be attributable to the presence of the fungus. The two groups were similar in terms of demographic features such as age, sex, and race, as well as for clinical characteristics such as body mass index and forced expiratory volume.
The latter finding runs contrary to some previous studies that suggested that the presence of the fungus was associated with worse disease severity. Additional research with more participants will likely be needed to clarify whether any such relationship exists.
Further analysis showed that individuals who were positive for A. fumigatus were significantly more likely to take inhaled corticosteroids than those without evidence of the fungus. This association has also been reported in previous studies, although the reason for it is not fully clear and may be an avenue for future investigation.
The fungus-affected group also had significantly lower scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised — a measurement of respiratory-related quality of life, compared with those without the fungus. These data suggest that A. fumigatus isolation may be associated with a perception of overall poorer respiratory health independent of other indicators of illness severity.
https://tinyurl.com/y528y8uf

CF Patients with F508del Mutation Tolerate Eluforsen Well, Study Finds
The experimental treatment eluforsen is safe for adults with cystic fibrosis (CF) caused by a mutation called F508del. The F508 del mutation leads to a small deletion in the protein encoded by the CFTR gene, causing the CFTR protein to function improperly.
Eluforsen (formerly QR-010) is an experimental therapy that aims to correct this deletion by modifying the RNA cells made from the CFTR gene, before the RNA is translated into the final protein product. Preclinical tests suggested that eluforsen could improve CFTR protein function, and similar strategies have been highly effective in other diseases.
The new study reports the safety results of a Phase 1b clinical trial (NCT02532764), which was funded in part by ProQR Therapeutics, the company developing eluforsen. The results showed that eluforsen was safe and well-tolerated in all the CF patients. A few serious adverse events (e.g. lung infections) were reported, but all of them were deemed unrelated to eluforsen treatment. Common mild and moderate side effects included gastrointestinal distress, respiratory symptoms such as coughing and congestion, and infections. In terms of efficacy, the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale (CFQ-R RSS) was used to assess patients’ symptoms, and in the MAD cohort, doses of 12.5 and 25 mg both resulted in significant improvements from baseline compared with the placebo. FEV1 was also assessed. No overall change from baseline or improvement was observed in eluforsen-treated patients compared with the placebo group.
https://tinyurl.com/yxnyw7y9

Study: Eluforsen Improves CFTR Function in Cellular, Animal Models of CF
Eluforsen, an investigational therapy for the treatment of cystic fibrosis (CF), improves the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in cellular and mice models of CF that carry the most common mutation associated with the disorder.
The F508 deletion is the most common mutation associated with the disease, in which the deletion of three nucleotides (the building blocks of DNA) in the gene sequence lead to the elimination of an amino acid called phenylalanine from the CFTR protein sequence at position 508 (p.Phe508del). This leads to incorrect protein folding and premature protein degradation, which prevent CFTR from reaching the cell membrane and performing its function.
Eluforsen (formerly known as QR-010) is designed to correct the F508 deletion by modifying the RNA molecule that cells use as a final template for producing the CFTR protein.
In the study, researchers set out to demonstrate how cells uptake (absorb) eluforsen, and how effective the therapy is in restoring the activity of CFTR in cells and mice models of CF carrying the F508 deletion. Overall, the findings indicate that eluforsen improved CFTR function in cell and animal models of p.Phe508del-CFTR-mediated CF, and supported further development of eluforsen in human clinical trials, where eluforsen has also been shown to improve CFTR activity as measured by Nasal Potential Difference.
https://tinyurl.com/y6hbfcaz

Inhaled Gallium Citrate Gets Orphan Drug Designation for Treating Lung Infection in Cystic Fibrosis
The Food and Drug Administration (FDA) has granted Orphan Drug designation to AR-501 (gallium citrate; Aridis Pharmaceuticals, Inc), an investigational treatment for chronic bacterial lung infections in patients with cystic fibrosis (CF).  AR-501, an inhaled formulation of gallium citrate, is a small molecule anti-infective with broad spectrum activity against Gram-negative and Gram-positive bacteria in vitro, including antibiotic-resistant strains. Gallium works as an iron analogue and is believed to inhibit iron-dependent synthetic and metabolic pathways required for disease progression. The inhaled formulation is being developed as a self-administered weekly treatment.
https://tinyurl.com/y27lejwq

CF: Inhaled Murepavadin Well-tolerated by Lung-infected Mice, Data Show
Murepavadin (POL7080), Polyphor‘s lead investigational antibiotic targeting Gram-negative bacteria, behaved as expected and was well-tolerated when administered to mice harboring a lung infection caused by Pseudomonas aeruginosa. Murepavadin belongs to a new class of antibiotics known as outer membrane protein targeting antibiotics (OMPTAs). These antibiotics have been designed to bind to proteins found on the outer membrane of Gram-negative bacteria which are particularly hard to target and eliminate, as well as multi-resistant strains. Results showed that murepavadin had a linear, dose-dependent effect when administered intratracheally in both plasma and epithelial lining fluid samples. However, exposure of the epithelial lining fluid to the antibiotic was approximately 1,000-times higher than that in plasma. The data also showed that murepavadin displayed a strong activity towards four different strains of P. aeruginosa when administered intratracheally at doses lower than one mg/kg. Preliminary findings also suggested that murepavadin was safe and well-tolerated when administered by inhalation.
https://tinyurl.com/y68otxqc

Inhaled Imipenem/Cilastatin Is Alternative for CF Children’s Lung Infection
The inhaled formulation of broad-spectrum antibiotics such as imipenem/cilastatin is a useful alternative to treat chronic lung bacterial infections in children with cystic fibrosis (CF) because it causes fewer side effects. Imipenem/cilastatin is a broad-spectrum antibiotic commonly used to manage resistant bacteria. However, it causes side effects such as toxicity to the liver and gastrointestinal tract when administered intravenously, which can interfere with its prolonged use. Case reports of adults with and without CF show that an inhaled formulation of imipenem/cilastatin successfully treats bacterial infections — namely Mycobacterium abscessus — and causes fewer side effects because the antibiotic is delivered at the site of infection.
https://tinyurl.com/y6pvlyun

Azithromycin Treatment Outcomes May Differ Based on Antibiotic Type
Patients with cystic fibrosis saw a greater increase in FEV1 when given oral azithromycin in combination with certain IV antibiotics for the treatment of Pseudomonas aeruginosa, as well as an increased overall improvement of FEV1.  According to the study, patients treated with combination azithromycin and IV colistimethate saw a +3% relative FEV1 recovery and a 2% overall improvement. Those treated with combination azithromycin and IV tobramycin for P. aeruginosa experienced a –3% recovery of FEV1 as well as a –2.64% overall improvement. The investigators stated that more research is needed to determine whether azithromycin alters the efficacy of IV antibiotics used in the treatment of P. aeruginosa.
https://tinyurl.com/y26mplsh

Study: Amikacin Liposome Therapy Matches Tobramycin for P. aeruginosa
Amikacin liposome inhalation suspension (ALIS) showed the same efficacy and similar safety profile as tobramycin inhalation solution (TIS) for the treatment of cystic fibrosis (CF) patients with Pseudomonas aeruginosa lung infection. One of the current approaches for treating P. aeruginosa infection is the inhaled antibiotic tobramycin. Tobramycin inhalation solution (TIS) can reduce the levels of bacteria, and therefore improve clinical outcomes. However, inhaled antibiotics have limited efficacy because of poor penetration into the infected areas. Furthermore, some CF patients don’t respond to TIS treatment, or do not tolerate it well. For these patients, alternative antibiotic treatments are necessary to manage P. aeruginosa infections. ALIS, an antibiotic manufactured by Insmed under the name Arikayce, is composed of small spherical sacs of phospholipid molecules (liposome) that contain the antibiotic amikacin. This formulation helps amikacin penetrate thick mucus and deliver higher doses of the antibiotic to the lungs. A Phase 3 clinical trial named CLEAR-108 (NCT01315678) was initiated to compare the effectiveness and safety of ALIS and TIS therapies to manage P. aeruginosa infections in CF patients. The primary outcome of the study was to compare changes in lung function (through measurements of forced expiratory volume in one second, or FEV1) from baseline to day 168. Researchers also looked at secondary endpoints, including changes in respiratory symptoms as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R), and changes in the number of P. aeruginosa bacteria. Efficacy and safety were assessed by regular visits to the clinic, and followed up by telephone calls. Results showed that after 168 days of treatment, ALIS was not inferior to TIS in effects on lung function.  Improvements were consistent across all demographic subgroups regardless of age, sex, or ethnicity. In addition, both treatments also showed clinically meaningful improvements in CFQ-R Respiratory Symptoms scores at the end of cycle 1.  Reductions in the number of P. aeruginosa bacteria in sputum were also similar between the ALIS and TIS treatment groups at the end of the treatment period, compared to baseline. The safety of ALIS and TIS treatments were also similar. Altogether, the results demonstrated that once-daily ALIS treatment for P. aeruginosa infection had similar outcomes to the standard twice-daily treatment with TIS, showing improvements in lung function, and reduction in the number of P. aeruginosa bacteria in sputum, regardless of age, sex, or ethnicity.
https://tinyurl.com/y65rd25b

Kalydeco Restored Pancreatic Function in Boy with CF, Report Suggests
A case report about a 10-year-old boy suggests that Vertex Pharmaceuticals‘ Kalydeco (ivacaftor) can restore the function of the pancreas and the production of pancreatic enzymes in children with cystic fibrosis (CF), leading to a reduction or discontinuation of pancreatic enzyme replacement therapy (PERT).
https://tinyurl.com/y589l4dd

Kalydeco Shows Long-term Efficacy in CF Patients in Real-world Setting
In cystic fibrosis, Kalydeco (ivacaftor) preserved lung function, improved the nutritional status, and reduced hospital visits and chronic bacterial infections in people with cystic fibrosis (CF) when administered for up to five years in a clinical setting, a long-term, real-world, observational study showed. Researchers evaluated the differences in lung function, measured by forced expiratory volume (FEV); nutritional status, measured as body mass index (BMI); number of acute pulmonary episodes (disease exacerbations), measured as the need for intravenous antibiotics; number of hospitalizations; incidence of CF-related diabetes, and presence of chronic infections caused by Pseudomonas aeruginosa bacteria. The U.S. cohort consisted of 635 patients who received Kalydeco for five years, and 1,874 patients who did not receive the treatment. The U.K. cohort included 247 patients who received Kalydeco for four years, and 1,230 patients who did not. None of the patients received a lung transplant during the study. Results showed that Kalydeco preserved lung function. In the U.S. cohort, patients taking Kalydeco had a decrease in FEV of 0.7%, whereas the reduction for those not taking the treatment was 8.3%. In the U.K. cohort, the therapy improved pulmonary function (increase of 4.9% in FEV values), compared to FEV decrease of 4.3% in patients not receiving Kalydeco. Kalydeco was also found to induce a significant increase in BMI in both cohorts, suggesting an improvement in patients’ nutritional status. Patients from both cohorts treated with Kalydeco had fewer exacerbations and hospitalizations during each year of the study, and a lower incidence of CF-related diabetes and chronic bacterial lung infections than patients not taking the treatment. The Kalydeco group also tended to survive longer and need fewer lung transplants, although the difference was not statistically significant.
https://tinyurl.com/y57dcc5j
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https://tinyurl.com/y4yjrs82

Kalydeco Offers Better Quality of Life, Eased CF Symptoms, Patients Say
Cystic fibrosis (CF) patients treated with Kalydeco (ivacaftor) who have the G551D mutation reported better health-related quality of life (HRQoL) and symptom relief than those on standard treatment who carry the F508del mutation in the CFTR gene.
https://tinyurl.com/y2m373lv

Kalydeco’s Safety, Benefits Seen in CF Patients with Severe Lung Disease
Treatment with Kalydeco (ivacaftor) improved lung function, exercise capacity, and sweat chloride concentration in cystic fibrosis (CF) patients with severe lung disease. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in the production of a faulty CFTR protein, a “gate” protein that controls the movement of charged salts, such as chloride, in and out of cells. As a result, the mutations cause the “gate” to be stuck closed.
Kalydeco is an approved treatment that targets the underlying cause of CF in people with specific mutations. The therapy rescues the CFTR protein function by keeping the CFTR gate open longer. However, since clinical trials for Kalydeco often exclude CF patients with severe lung involvement, the therapy’s effects in this patient population required further analysis.
In the study, a team of researchers performed a retrospective observational analysis with severe lung disease who were treated with Kalydeco. Severe lung disease was defined as: a percent predicted forced expiratory volume in one second (ppFEV1) of less than 40% in the six months before the analysis; or being on a lung transplant waiting list, or with a fast worsening trend of lung function. Researchers analyzed clinical data, including measures of lung function, six minute walk distance test (6MWT, which assesses exercise capacity and endurance), weight, height, and a sweat test. Results showed after one year of Kalydeco treatment, the mean ppFEV1 increased from 35.1% to 46.6%, corresponding to an absolute increase in lung function of 11.5%. Patients’ ability to walk also increased significantly, from 535.1 meters (585 yards) to 611.6 meters (686 yards), as measured in the 6MWT after one year of treatment. Pulmonary exacerbations were significantly lessened, dropping by a factor of two, from 57 exacerbations to 28 following a year of Kalydeco treatment. Moreover, 38.5% of the patients were free from exacerbations during the year after starting Kalydeco. Patients’ weight also had a marked increase and the results of the sweat test showed that the sweat chloride concentration decreased significantly. Overall, the findings suggest that treatment with Kalydeco is safe and resulted in clinically and statistically significant and sustained improvements in multiple parameters in patients with CF carrying non‐G551D gating mutations and severe lung disease, pointing out that drugs modulating CFTR can benefit patients with CF with severe lung disease.
https://tinyurl.com/y3vclzjh

Ivacaftor may reduce common infections in patients with CF
Patients with cystic fibrosis who take ivacaftor appear to have fewer respiratory infections over time than those not taking the drug. Ivacaftor (Kalydeco) is prescribed to patients whose CF is caused by a “gating” mutation. This group of mutations, which are responsible for about 4 percent of all CF cases, prevents chloride from moving in and out of cells. By restoring the gate’s function, ivacaftor has been shown to improve lung function and quality of life. Researchers report that ivacaftor may also reduce some of the most common lung infections in patients with CF, including P. aeruginosa. If this is true it may mean that some patients taking ivacaftor can take fewer antibiotics long term and still remain clinically stable. The study found that ivacaftor was associated with a 32 percent reduction in the number of people infected with P. aeruginosa and a 15 percent reduction in Staphylococcus aureus. These reductions resulted from both increased clearance of the infection in those already infected and in reduced acquisition in those not infected. Ivacaftor was also associated with reduced Aspergillus spp. infections. The drug did not appear to reduce Burkholderia cepacia complex infections.
https://tinyurl.com/y3cbefzg

Vertex sinks on reports of deaths of patients taking cystic fibrosis drug
Thirty patients have died after taking a Vertex Pharmaceuticals treatment for cystic fibrosis. The deaths relate to patients who took Symdeko. Reports to the database are commonly submitted by health care professionals and often contain incomplete information about how patients died and what other medicines they were taking. It’s also unclear whether any of the deaths are directly related to Symdeko. Symdeko is the most recent of Vertex’s three approved treatments for cystic fibrosis. The drug, tailored for specific genetic subtypes of the rare disease, is also the backbone of a combination cystic fibrosis therapy now under FDA review.
https://tinyurl.com/y2dc87vs

Vertex Asks FDA to Approve 1st CF Triple Combo - Elexacaftor, Tezacaftor and Kalydeco
Vertex Pharmaceuticals is asking the U.S. Food and Drug Administration to approve a first triple combination therapy —  elexacaftor (VX-445) plus tezacaftor, and ivacaftor (Kalydeco) — to treat cystic fibrosis (CF) patients who cannot use its other disease-modifying treatments or don’t benefit as intended. Triple combinations include “next generation” correctors being developed to treat the estimated 40% of people whose underlying mutations don’t respond or respond well to Kalydeco, Orkambi (lumacaftor/ivacaftor), or Symdeko (tezacaftor/ivacaftor, ivacaftor), the company’s approved CF therapies. Its New Drug Application also includes a request for a priority review, which, if granted, means the FDA would complete its appraisal and announce a decision in eight months rather than the usual 12. Data supporting the application was largely drawn from two Phase 3 clinical trials. Patients given the triple combination therapy in both trials demonstrated significant improvements in lung function. Data also showed improvements in secondary endpoints, including a lower annual rate of pulmonary exacerbations, and reduced levels of chloride in patients’ sweat. The treatment was generally well-tolerated.
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Proteostasis Dosing in Phase 2 Testing of 3 CF Investigational Therapies
The first patient has been dosed in a Phase 2 clinical trial testing Proteostasis Therapeutics‘s combinations of three investigational therapies for cystic fibrosis (CF). The three treatments under investigation are all designed to fix the defective CFTR protein due to mutations in the CFTR gene. The compounds under investigation are PTI-428, which is an amplifier; PTI-801, which is a corrector; and PTI-808, which is a potentiator. The therapies are being tested in double (PTI-808 and PTI-801), and triple (PTI-808, PTI-801, and PTI-428) combinations.
In a previous Phase 1 study (NCT03500263), the triple combination therapy was shown to have an acceptable safety and tolerability profile. It also led to a statistically significant reduction in sweat chloride levels, and improvements in lung function after 14 days of treatment. The new Phase 2 study (NCT03251092) will assess the treatments’ effectiveness in 180 patients treated for 28 days. It also will include individuals with either one copy (heterozygous) or two copies (homozygous) of the F508del mutation in the CFTR gene. Patients will be treated with 600 mg of PTI-801 and 300 mg of PTI-808, with or without 10 mg PTI-428 for the double and triple combinations, or with a placebo. The study’s goals include the treatments’ safety profiles, as well as lung function, and sweat chloride concentration.
https://tinyurl.com/y4zatw8k
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Translate Bio unveils interim results for MRT5005 in cystic fibrosis
Translate Bio, an mRNA therapeutics company, has recently announced the interim results from a first-in-human Phase 1/2 clinical study evaluating multiple and single ascending dosages of MRT5005 in patients with cystic fibrosis. MRT5005 was designed to normalize the function of the CFTR protein, regardless of the genetic mutation the cystic fibrosis patient carries. It does so by delivering mRNA — which provides instructions for producing a functional, or working CFTR protein — directly to cells in the person’s lungs through nebulization. In that mode of administration, medication is delivered in the form of mist to be inhaled directly into the lungs. Efficiently delivering the required mRNA sequence is a vital step to creating functional CFTR protein. Despite substantial advances in the treatment of patients with CF, major unmet needs still remain among patients whose genetic mutations are believed non-amenable to CFTR modulators. The study is divided into two parts. In the first, a single ascending dose (SAD) phase, participants will receive a single administration of MRT5005 at three different doses — 8 mg, 16 mg, or 24 mg. The second part, a multiple ascending dose (MAD) phase, will have patients receive MRT5005 once per week, for five weeks, at different doses.
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Eloxx Pharmaceuticals Announces Open Investigational New Drug Application (IND) for a Phase 2 Clinical Trial of ELX-02 in Cystic Fibrosis Patients with the G542X Mutation in the US and Protocol Endorsement from the Cystic Fibrosis Foundation (CFF)
Eloxx Pharmaceuticals, Inc. a clinical-stage biopharmaceutical company dedicated to the discovery and development of novel therapeutics to treat cystic fibrosis, cystinosis, inherited retinal disorders, and other diseases caused by nonsense mutations limiting production of functional proteins, announced that an IND for ELX-02 in cystic fibrosis is now open in the U.S. and the Phase 2 clinical trial has been endorsed by the CFF. ELX-02 is the only therapy to have demonstrated positive results in organoids derived from cystic fibrosis patients across the majority of nonsense mutations and studies have shown the organoid model to be highly predictive of clinical benefit. ELX-02, is a small molecule drug candidate designed to restore production of full-length functional proteins.
https://tinyurl.com/y6ovrbpt

Orkambi Improves Exercise Tolerance in Adults With Severe CF, Study Shows
Treatment with Orkambi significantly improves exercise tolerance in adult cystic fibrosis patients with severe disease as early as 4 weeks after treatment — as shown by results of the six-minute walk test (6MWT). The findings support the use of exercise tolerance as an important clinical outcome for assessing treatments in CF patients with severe disease.
Treatment with Orkambi for 24 weeks has been shown to result in 30 to 39% fewer pulmonary exacerbations in CF patients ages 12 or older with two copies of the F508del mutation who had less severe disease. These patients still retained moderate lung function, as assessed by a percent predicted forced expiratory volume in one second (ppFEV1) of 40 to 80%. However, whether Orkambi’s efficiency is maintained in adult CF patients carrying two copies of the F508del mutation with more severe disease — with ppFEV1 below 40% — is less clear. The team therefore set out to investigate clinical parameters to find the most sensitive clinical measure capable of detecting change in people with severe CF following treatment with Orkambi. Researchers assessed each patient’s response through spirometry tests, and compared the changes to those seen in exercise capacity tests, including the 6MWT, and other lung function tests. These included the nitrogen multi-breath washout test (MBW), the carbon monoxide gas transfer factor (DLCO), and lung volume changes assessed by plethysmography, a measurement of changes in the body’s volume. The MBW measures the capacity and airflow of the lungs, while the DLCO measures the efficacy of the transfer of oxygen from the air to the blood in pulmonary blood vessels. Spirometry, nitrogen MBW test, and 6MWT were performed on the day participants began Orkambi treatment (baseline), and again after four, 12, 24, and 52 weeks. Plethysmography and DLCO tests were performed at baseline, 24 weeks, and 52 weeks. Results showed that treatment with Orkambi led to significant improvements in patient’s exercise tolerance as seen at 4 weeks. No significant improvement in FEV1 was observed until after week 24, though it was maintained at week 52. Forced vital capacity (FVC), another measure of lung function, also improved after 24 weeks of treatment, with this enhanced capacity being maintained at 52 weeks. No differences were detected in the MBW or DLCO. Overall, the results show that treatment with Orkambi results in a clinically significant improvement in 6MWT that was evident at 4 weeks and maintained at 52 weeks.
https://tinyurl.com/y53ccyss

CF Lung Infection Therapy AR-501 Granted FDA Orphan Drug Status
AR-501, an investigational inhaled formulation of gallium citrate to treat chronic lung infections in patients with cystic fibrosis (CF), has been granted orphan drug status by the U.S. Food and Drug Administration (FDA). The treatment, developed by Aridis Pharmaceuticals, is designed to be given once weekly and is self-administered within minutes, allowing a direct delivery to the lungs. The safety and preliminary efficacy of AR-501 is currently being evaluated in an ongoing Phase 1/2 trial in healthy volunteers and CF patients with chronic lung infections due to Pseudomonas aeruginosa. AR-501, also known as panaecin, is a non-antibiotic, inhalable form of gallium citrate. Gallium is a small molecule identical to iron, and is able to substitute for it in iron-dependent biological processes of bacteria. By starving bacteria of iron, gallium is believed to inhibit multiple bacterial pathways involved in infection and antibiotic resistance. According to Aridis, AR-501 mechanism of action is different from antibiotics, and it can also be effective against antibiotic-resistant bacteria. Laboratory tests have shown that AR-501 has broad anti-bacterial activity against different strains of bacteria, including those resistant to antibiotics. It’s also been shown to improve the efficacy of antibiotics, and has a low resistance profile, which means that few bacteria are resistant to the agent. In addition, data from a Phase 2 clinical trial (NCT02354859) demonstrated that intravenous injections of gallium are safe and can effectively improve the lung function of CF patients who had chronic infections. However, intravenous delivery involves a five-day continuous infusion, which is a demanding regimen. AR-501 is more convenient as it can be self-administered and given once weekly, allowing for a direct delivery of gallium to the lungs, where infectious bacteria reside.
https://tinyurl.com/y2qpkrto

AzurRx Launches Trial Testing MS1819-SD Combined With PERT for CF
AzurRx BioPharma has initiated a Phase 2 clinical trial testing its oral capsule MS1819-SD, combined with standard porcine pancreatic enzyme replacement therapy (PERT), in people with cystic fibrosis (CF) who have exocrine pancreatic insufficiency (EPI). PERT is the standard of care for EPI associated with CF or chronic pancreatitis. It was designed to adequately replace pancreatic enzymes that are missing in people with CF, so that digestion can proceed normally. Specifically, the therapy helps fat to be absorbed properly, thus allowing patients to eat a diet with a normal amount of fat and not experience gastrointestinal symptoms. However, a substantial number of CF patients with EPI can’t attain normal fat absorption with PERT alone. The new Phase 2 clinical trial is designed to assess the safety, tolerability, and efficacy of increasing doses of MS1819-SD combined with an unchanging, standard PERT dosage in people with CF who have severe EPI. MS1819-SD, like PERT, is an enzyme-based therapy. However, MS1819-SD is derived from a species of yeast, Yarrowia lipolytica. AzurRx has made a point of emphasizing that MS1819-SD does not contain any animal products (yeast are fungi). PERT is a pig-derived enzyme. Outcomes of the study will include relieving gastrointestinal symptoms, and increasing the coefficient of fat absorption — the percentage of fat in the diet that the body absorbs.
https://tinyurl.com/y3j6wfdy
AND
https://tinyurl.com/y2zlwdx3

Rifampin for biofilm-related Infections
Staphylococcus aureus is a major human pathogen. The bacterium colonizes both tissue and artificial surfaces in humans causing chronic persistent infections that are difficult to cure. Thus, there is an unmet clinical need to target S aureus in biofilm-related infections.
Specific therapies for biofilm-related infection, are scarce. Rifamycins are a class of antibiotics originally shown to be produced by a Gram-positive bacteria Amycolatopsis rifamycinica in 1957 (designated Streptomyces mediterranei at the time). It has excellent bactericidal activity against susceptible Gram-positive bacteria including S aureus and inhibits bacterial DNA-dependent RNA polymerase independently of bacterial division, resulting in activity against slowly dividing dormant organisms. It is active within acidic environments as well as anaerobic conditions and accumulates within neutrophils1 and osteoblasts. These properties render rifamycins particularly attractive to be used as therapeutics for biofilm-related infections. However, the high risk of emergence of rifamycin-resistant mutants requires the concomitant administration of another antibiotic. Preclinical data from animal models support the use of rifampin, the clinically available derivative of rifamycins, in combination with several antibiotics, such as vancomycin and linezolid.
https://tinyurl.com/y4xursq6

MAC Lung Infections in CF Best Treated When Specific Bacterial Species Known, Study Finds
Pulmonary infection with a specific species of the Mycobacterium avium complex (MAC), called Mycobacterium intracellulare, can be aggressive in people with cystic fibrosis (CF), with a greater loss of lung function evident but a lesser incidence of a secondary lung infection.
This species also responded best to antibiotic treatment, suggesting that identifying MAC isolates to the species level would have bearing on the prognosis and management of these infections in CF patients. MAC is comprised by a group of nontuberculous mycobacteria (NTM) that are responsible for about 70% of pulmonary infections in CF patients. Three main mycobacteria species within the MAC group are known to be responsible for most cases of NTM lung infections: Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera. Laboratories routinely identify the MAC group as a whole, but not each bacterial species individually. Some studies suggest that different strains of NTM bacteria have different degrees of virulence, highlighting a need for specificity. Researchers examined MAC isolates, and found that the most common mycobacteria was M. avium, followed by M. intracellulare and M. chimaera. They also identified a fourth bacteria strain, Mycobacterium timonens. Patient outcomes were found to differ significantly according to the mycobacteria strains a person carried. CF patients with M. intracellulare had more aggressive lung disease and were more likely to have the F508del CFTR mutation. But they also had lower rates of secondary infection with Staphylococcus aureus, the most prevalent bacteria infecting CF airways and one that can be resistant to treatment. MAC infections were divided into three categories: a transient infection identified by a single positive MAC culture, followed by a negative laboratory test; a persistent infection identified by two positive MAC tests; and NTM disease, a chronic and progressive lung disorder, defined by the use of anti-MAC antibiotics. Lung function analysis revealed that all species were associated with poorer lung function before MAC identification, with the biggest decrease found in those with M. intracellulare infection. Interestingly, lung function in CF patients with M. intracellulare infection improved after its MAC identification and treatment, supporting the efficacy of anti-MAC antibiotics against this species. In contrast, lung function in those with M. chimaera continued to decline, while it remained stable in those with M. avium infection. Collectively, these findings demonstrate that bacterial DNA analysis can be used to identify individual mycobacteria species, and such identification may help in patient treatment and outcomes.
https://tinyurl.com/yxm29kvh

Italfarmaco Enters Binding Term Sheet Agreement With Neupharma for an Exclusive Option to Develop and Commercialize Inhaled Teicoplanin
Italfarmaco Group announced that Italfarmaco SpA has entered into a binding agreement with Neupharma for an exclusive option to develop and commercialize inhaled teicoplanin. Intravenously administered teicoplanin remains one of the most efficacious antibiotics used to treat cystic fibrosis patients with Methicillin-Resistant Staphylococcus Aureus (MRSA), although the current administration method is inconvenient and results in considerable side effects as well as limited lung penetration. The novel inhaled formulation of teicoplanin, which would deliver the drug directly into the lungs, has the potential to improve the safety, pharmacokinetic and efficacy profile associated with intravenous teicoplanin. As there is currently no defined standard of care for this chronic lung infection, the agreement will allow Italfarmaco to access a new market as well as provide an improved therapeutic option for cystic fibrosis patients suffering from MRSA.
https://tinyurl.com/y5hpwxzo

Arcturus Therapeutics Receives up to $15 Million Commitment from the Cystic Fibrosis Foundation to Create mRNA Therapies to Treat Cystic Fibrosis Patients
Arcturus Therapeutics, a leading RNA medicines company, announced that the Cystic Fibrosis Foundation (CF Foundation), has increased its commitment to $15 million in conjunction with an amended agreement to advance LUNAR-CF, a novel messenger RNA (mRNA) therapeutic formulated with Arcturus’ LUNAR® delivery technology. The goal of the multi-year program is to create mRNA therapies to treat people with cystic fibrosis (CF), develop methods to deliver RNA components to cells in the lung and file an Investigational New Drug (IND) application for a therapeutic candidate.  LUNAR-CF, Arcturus’ first inhaled mRNA therapeutic targeting the lung, represents a novel approach to treat cystic fibrosis.  LUNAR-CF is based on Arcturus messenger RNA (mRNA) design construct and proprietary manufacturing process. LUNAR-CF also utilizes Arcturus’ propriety lipid library and employs the Company’s LUNAR® delivery platform to safely and effectively deliver CFTR mRNA to the lung.  LUNAR-CF is an mRNA replacement therapy designed to enable CFTR-deficient patients to naturally produce healthy functional CFTR in their own lung cells.  LUNAR technology can deliver mRNA to bronchial epithelial cells and results in expression of CFTR protein in animal models.
https://tinyurl.com/yy4t25d3

Chapel Hill Startup Lands Rights to Drug Offering Hope to Cystic Fibrosis Patients
Path BioAnalytics (PBA) has scored the rights to a new drug therapy offering hope to cystic fibrosis (CF) patients with rare mutations. PBA will use its proprietary technology — an organoid platform using primary cells — to identify subpopulations of patients in which the drug candidate is effective. A small number of individuals with CF — who may not benefit from currently available CFTR modulators — could benefit from cavosonstat. PBA has the technology and infrastructure in place to find these individuals and continue the development of cavosonstat specifically for them in a highly targeted fashion.
https://tinyurl.com/y4w3zva3
AND
https://tinyurl.com/y5un9eqq

CF Study Explores Breath Analysis to Detect P. Aeruginosa Lung Infections
The diagnostic potential of breath analysis to detect serious lung infections in people with cystic fibrosis (CF) will be explored in a new clinical trial, which could lead to faster, more accurate diagnoses, and potentially improve the quality of life and prolong the life of these patients. Researchers will collect 288 breath samples from CF patients, 3 and older, from five hospitals across the U.S. The chemicals present in each sample will be analyzed, and compared with the pattern of molecules produced by P. aeruginosa. This will allow the researchers to determine specific molecular profiles that can accurately distinguish which patients have lung infections caused by these specific bacteria or other strains. Previous work showed that different strains of bacteria produce different volatile molecules. Detection of these molecules and how abundant they are can be used to build molecular profiles that are specific for each bacteria strain in both early and chronic infections.
https://tinyurl.com/y2g8t95k

CF Patients Using Nebulizer While Lying on Sides Can Show Better Lung Deposition, Study Finds
People using a nebulizer while lying on their side showed no significant loss in a treatment’s overall deposition in the lungs. Alternating sides instead of sitting upright may better deposit a medicine’s active compounds throughout the lungs, especially across its upper portions.
As many patients prefer the comfort and convenience of nebulized treatment while lying on their side, allowing treatment in this position could improve adherence without affecting efficacy. Effectiveness of inhaled therapies depends, to a great extent, on how they are distributed within the lungs. Sitting during nebulization is often advised, as deposition of inhaled compounds is influenced by airflow patterns. However, this strategy may favor depositing medication across the lower portions of the lungs (basal deposition), with insufficient deposition across the upper portions (apical deposition).To overcome this limitation and improve the homogeneity of drug deposition in the lungs, experts have proposed having patients alternate between right and left side lying during nebulization.
https://tinyurl.com/y3ettdcl

CF Patients Set for Colonoscopy Need Modified and More Rigorous Cleansing Procedure, Study Says
Colorectal cancer (CRC) is common among cystic fibrosis (CF) patients, especially among those who underwent lung transplant. The standard screening procedure for CRC is a colonoscopy, which looks for abnormalities in the rectum and large intestine. The diagnostic accuracy, speed, and completeness of colonoscopy depend highly on the quality of the bowel cleansing preparation. Colonoscopy has been proposed as the diagnostic modality of choice in patients with CF, [however] optimal CRC screening has not been established in patients with CF. The modified CF bowel preparation protocol starts 14 days prior to a colonoscopy with daily use of an iso-osmotic laxative. The standard bowel protocol does not include this laxative. Then, eight days prior to the screening, CF patients start a low-fiber diet (compared to four days pre-screening in the standard protocol); three days prior to the colonoscopy, colonic purging commences combined with a clear-fluid diet. Overall, the modified CF bowel preparation is longer in duration with up to 10 L of colonic lavage over 3–4 days, compared to standard institutional bowel preparation (3–4 L colonic lavage 1–2 days prior to procedure).
Results showed that a higher percentage of CF patients (50.0%) who underwent the modified procedure achieved “excellent/good” scores in GI visualization. The detection rates of adenomatous polyps (colon polyps) during the colonoscopy were higher among CF patients using the modified cleansing procedure.
https://tinyurl.com/y6lop49w

Human Pancreas-on-a-Chip Helps Identify Cause of Cystic Fibrosis Complication
Scientists created a human pancreas on a chip that allowed them to identify the possible cause of a frequent and deadly complication of cystic fibrosis (CF) called CF-Related Diabetes (CFRD). As people with CF get older, they become increasingly at risk for CFRD. Making matters worse is that until now there hasn’t been an effective way to study CFRD in the lab to look for better treatments. This technology closely resembles the human pancreas and potentially may help find therapeutic measures to manage glucose imbalance in people with CF. The in vitro chip technology can be used to study CFRD and glucose imbalance in specific individuals with the condition, creating the potential for diagnosing different disease manifestations on a highly personalized basis. The chip can help assay variability in the glucose measures of different people, determine correlation of glucose levels with the CFTR mutation type, and test small-molecule interventions. When the researchers tested pancreas-on-a-chip by disrupting CFTR gene expression, it impaired cell-to cell communication, fluid exchange and negatively affected endocrine function. This caused an insulin deficiency and recreated the CFRD disease process similar to that observed in the pancreas of a person. Researchers said that this confirmed that the CFTR gene has a direct role in regulating insulin secretion and causing diabetes in people with CF. The research team will now use the devices in a pilot study to test FDA-approved drugs that modulate CFTR gene expression. The goal will be to determine how well different CFTR drugs can slow or reverse lab-simulated CFRD.
https://tinyurl.com/yyedxlua
AND
https://tinyurl.com/y5stq5hb

Little-Used Drug Combination May Extend the Lives of Lung Transplant Patients
Lung transplantation can prolong the lives of patients with end-stage lung disease, but the median survival rate after lung transplant is less than six years. To see what might help lung transplant recipients live longer, researchers developed a novel epidemiological analysis of lung transplant data in the United States focused on regimens that prevent the body’s immune system from attacking the transplanted lung. The study has identified a drug combination that appears to significantly extend patient survival. To prevent chronic rejection, the most common cause of death after a lung transplant, patients must take immunosuppressive drugs for the rest of their lives. Immunosuppression, in turn, may predispose patients to infections and cancers, the second- and third-leading causes of post-lung transplant death. The researchers categorized patients by their immunosuppression regimen and compared survival rates. They singled out an immunosuppressive drug called sirolimus, in a class of drugs called cell cycle inhibitors, based on a few small, long-term studies that found dramatically improved survival, reduced incidence of chronic rejection, and improved lung function in lung transplant patients who took sirolimus. The database study compared sirolimus outcomes with the most commonly used cell cycle inhibitor mycophenolate mofetil (MMF). According to this study, sirolimus appears to offer a survival advantage of almost two years over MMF. The survival improvement with sirolimus was driven by fewer deaths from the top three causes: chronic rejection, infections, and cancer. Another immunosuppressive medication, tacrolimus, is currently used in the vast majority of lung transplant recipients and was common to all patients in the study. Sirolimus plus tacrolimus was associated with a better median survival than MMF plus tacrolimus (8.9 years vs 7.1 years). One downside for sirolimus, though, is that it interferes with wound healing, a potentially life-threatening complication if the drug is administered in the initial days and weeks following transplant surgery. For this reason, prophylactic sirolimus maintenance therapy is typically not started until three to 12 months after surgery. The study also considered induction therapy, an optional addition to maintenance therapy used in over half of transplant centers in the U.S. In induction therapy, patients are given a high dose of immunosuppression at the time of transplantation for a short duration — three to 14 days, with drugs such as basiliximab, daclizumab, alemtuzumab, or antithymocyte globulin. The group that came out with the highest survival of all combinations was given sirolimus plus tacrolimus for maintenance therapy without induction therapy. These patients lived over three years longer on average than patients receiving MMF maintenance with induction therapy.
https://tinyurl.com/y3odn9dg s

Laura is 71 and has CF. She is former director and President of USACFA. She and her husband, Lew, live in Northville, MI.

 

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