Cystic Fibrosis Disease Severity Linked to Immune Overreaction to Fungus, Study Reports

By Ana Pena

Disease severity in cystic fibrosis (CF) may be associated with an overreaction of the immune system to the fungus Aspergillus fumigatus, particularly due to a type of white blood cell called a phagocyte — which ingests and kills invading organisms — a study suggests.

U.K. researchers found that phagocytes from CF patients release higher amounts of harmful reactive oxygen species in response to Aspergillus fumigatus, a common cause of lung infection in these patients.

The study, “Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity,” was published in the journal ERC Open Research.

Recent studies have supported the idea that the widespread environmental fungus Aspergillus fumigatus may play a critical role in CF lung disease.

Up to 58% of CF patients are colonized with this fungus, and an estimated 47.7% of adult patients are affected by either allergic reactions or infection caused by the fungus.

Persistent infections with A. fumigatus are also known to be adversely correlated with lung function and hospitalization in CF patients.

Researchers hypothesized that the anti-fungal defense mechanism in CF patients might be altered and have an impact on the progression of lung disease.

To investigate this hypothesis, the team compared the immune response of phagocytes from CF patients with those of healthy individuals used as controls, and tried to correlate them to clinical metrics of disease severity.

For original article please visit CF News Today.

CF Foundation ‘Venture Philanthropy’ Model Crucial to CF Breakthroughs

By Larry Luxner

When the Cystic Fibrosis Foundation (CFF) was established in 1955, most people with cystic fibrosis (CF) didn’t make it to their sixth birthday. Today, the average life expectancy of a CF patient is 47 years.

To date, the U.S. Food and Drug Administration has approved 12 CF therapies. Three of them are CFTR modulators that treat the basic disease-causing defect, benefiting 60 percent of all patients, and more therapies are on the way.

Preston W. Campbell III, the CFF’s president and CEO, directly attributes this dramatic improvement to the foundation’s philosophy of “venture philanthropy.”

“We are now in Phase 3 CFTR trials that, if successful, will mean that as early as next year, more than 90 percent of all individuals with CF will have a highly effective therapy targeting CF’s basic defect,” he said. “More therapies that treat the complications of CF are in the pipeline than ever before.

“It begs the question: how did all of this happen?”

Campbell answered that during his March 26 presentation, “Patient advocates taking a real stand in drug development: How the CFF worked with biotech and pharma to find a cure,” at the 2018 World Orphan Drug Congress USA in Oxon Hill, Maryland.

Back in 1960, the Bethesda, Maryland-based foundation broke ground by establishing a Care Center Network to provide multidisciplinary care. Within five more years, it had formed a patient registry.

With only $400,000 in the bank, it would also commit $11 million to research, Campbell said. “Five years later, in 1985, the basic CF defect was identified, and in 1989, the CFTR gene was discovered. That opened the floodgates,” he added.

Campbell’s predecessor, Robert J. Beall, created the Therapeutics Development Program — now called its Venture Philanthropy Model — in 1998 to entice industry to focus on CF, and specifically on CFTR as a target. Its three components were financial assistance, research tools and scientific advice, and a clinical trials network.

“We would lower the risk for industry to come into the CF space. We also made our research tools and scientific advice freely available, and we also embedded the best scientists in the world in these industry programs,” said Campbell, who took over from Beall as head of the CFF in January 2016. “Finally, in order to make sure clinical trials were safely and efficiently done, we created a clinical trials network that originally had seven centers and now has 89.”

In the beginning, CFF’s investments were typically in the $1.5 million range. Ultimately, the foundation invested more than $100 million in Aurora and its successor, Vertex Pharmaceuticals, whose headquarters are in Boston.

To date, the FDA has approved three Vertex CFTR modulators: Kalydeco (ivacaftor) for patients with the G551D mutation in the CFTR gene (2012); Orkambi (lumacaftor/ivacaftor)for patients who are homozygous for F508del, the most common mutation in the CFTR gene (2015); and Symdeko (tezacaftor/ivacaftor) for homozygous F508del patients as well as others (2018).

“Payments are milestone-based, so we pay for success,” Campbell said. “A scientific advisory committee determines if milestones are met and if the project should continue. Successful programs offer a return on our investment, so if the program is foundering, we shake hands and walk away.”

To continue to full article, please click here.

CF and Menopause—I have questions…

By Georgia Brown

As a woman with Cystic Fibrosis, at 47, I am considered old—but it is a title I relish.  It means I have weathered the CF storm and I look at each birthday as an accomplishment.  But as I enter the next phase of my life, I find I have more questions than answers.

While I don’t fear menopause necessarily, I do fear embarking on this life changing phase without understanding how CF puts its unique twist on it.  And that is why I am glad that I have found the Cystic Fibrosis Reproductive and Sexual Health Collaborative (CFReSHC).  Each month the group meets to discuss issues specific to women with CF.  Then CFReSHC uses the feedback from meeting participants to help shape future CF research.  This is one way, we, as patients, pave the way for improved sexual and reproductive healthcare.  

The next virtual meeting “Hormones Across the Lifespan” will be Thursday, February 22, 2018 from 11 am to 1:00 pm EST.  Dr. Raksha Jain of the University of Texas Southwestern will discuss how hormones affect women with CF from puberty to menopause.  Then, the CF women in attendance, will break into smaller groups to discuss personal stories and identify the top three hormone-related topics that need further research.  The meeting is open to all women with CF in the United States.  For more information on CFReSHC and for login information from your laptop, or mobile device, email CFReSHC at cfreprohealth@gmail.com. Women who attend receive a $25 gift card from Amazon.  

Therapy for Reducing P. Aeruginosa Lung Infections Planned Phase 1 Trial

Arch Biopartners recently completed a good manufacturing practice (GMP) production campaign for AB569, a potential inhalation treatment for antibiotic-resistant bacterial lung infections in people with cystic fibrosis (CF) chronic obstructive pulmonary disease (COPD) and other conditions. The campaign, intended to ensure the quality of the investigative therapy, was directed by Dalton Pharma Services.

AB569 is composed of ethylenediaminetetraacetic acid (EDTA) and sodium nitrite, two compounds approved by the U.S. Food and Drug Administration (FDA) for use in people. AB569 can be administered alone or in combination with other compounds to treat multi-drug resistant bacterial infections that can cause reduced lung function.

Pseudomonas aeruginosa is one of the most common bacterial infections in patients with respiratory diseases, including CF, COPD, and pneumonia.

In preclinical studies, AB569 was shown to be capable of killing drug-resistant bacteria like P. aeruginosa and other common pathogens associated with chronic lung infections.

The company also announced that a Phase 1 clinical trial to investigate the safety and pharmacokinetic profile of AB569, planned to start in January, will be conducted at the Cincinnati Veterans Affairs Medical Center (CVAMC). According to an Arch Biopartners press release, Ralph Panos, chief of medicine at CVAMC, will lead the trial.

Three escalating doses of nebulized AB569 will be used to evaluate tolerance to the treatment in about 25 healthy volunteers. Each will be given a single administration of nebulized AB569  to characterize the pharmacokinetic profile of plasma nitrite and nitrate metabolites, exhaled nitric oxide, and circulating hemoglobin.

Pharmacokinetics studies how a drug is absorbed, distributed and metabolized in, and expelled by, the body.

Should the Phase 1 trial in volunteers be successful, Arch Biopartners plans to move its AB569 program into a Phase 2 trial to test its effectiveness in treating chronic P.aeruginosa infections in COPD patients.

AB569 received orphan drug status by the FDA in November 2015 as a potential treatment of P. aeruginosa lung infections in CF patients. Orphan drug status is given to investigative medicines intended for people with rare diseases to speed their development and testing.

Original article: https://cysticfibrosisnewstoday.com/2017/12/12/arch-biopartners-readies-ab569-potential-treatment-for-cf-copd-lung-infections-for-phase-1-trial/

New Promising Results from Phase 3 of Combination Therapy

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

Study Links PPI Use to Treat Gastroesophageal Reflux with More Frequent Hospitalizations

Doctors should frequently re-evaluate the use of protein pump inhibitors (PPIs) for cystic fibrosis (CF) patients, urges a University of Florida study which warns that long-term PPI use leads to a higher risk of hospitalization for pulmonary exacerbations.

Identifying risk factors associated with pulmonary exacerbations is critical since they cause a decline in pulmonary function and survival rates among CF patients.

PPI use, in particular, is believed to cause community-acquired pneumonia (CAP). Even though most CF patients use PPIs to control gastroesophageal reflux (GER), scientists still don’t fully understand the link between PPIs and pulmonary exacerbations in CF.

In the study, “Proton Pump Inhibitor Use Is Associated With an Increased Frequency of Hospitalization in Patients With Cystic Fibrosis,” which appeared in the journal Gastroenterology Research, researchers investigated that link and the risks it entails.

The study involved 114 adults who had been seen at UF’s Adult Cystic Fibrosis Center in Gainesville, Florida, between January and December 2016. Researchers collected data on PPI use and hospitalization during a one-year follow-up.

Results showed that 59 of the 114 patients (51.7 percent) used PPI for six or more months, and that exactly the same proportion (51.7 percent) had been hospitalized at least once during the one-year follow-up period. Among those who were hospitalized, PPI use was closely linked with the number of hospitalizations for pulmonary exacerbation, though researchers observed no link between frequency of hospitalization and PPI dosage.

No significant difference was found in GER between hospitalized and non-hospitalized patients.

The UF study is limited, in that it’s retrospective and therefore doesn’t establish a cause-effect relationship between PPIs and pulmonary exacerbation. Researchers say there’s still a possibility that GER itself — rather than the subsequent use of PPIs — causes increased pulmonary exacerbations. Yet they point out that the prevalence of GER was similar among hospitalized and non-hospitalized patients, supporting a causative link between PPI and pulmonary exacerbations.

Based on their findings, the UF team suggests that “prescribers of PPI therapy should exercise pharmacovigilance; frequently re-evaluating indications and appropriateness of therapy and in the setting of GER considering alternate management modalities such as anti-reflux surgery where appropriate.”

For original article please visit: https://cysticfibrosisnewstoday.com/2017/12/07/proton-pump-inhibitor-use-is-associated-with-an-increased-frequency-of-hospitalization-in-patients-with-cystic-fibrosis/

Trial to Possibly Treat Nonesense Mutations Begins

Sevion Therapeutics and Eloxx Pharmaceuticals announced that a first healthy subject has been dosed in a Phase 1b clinical trial assessing the safety, tolerability and drug properties of ELX-02 as a potential treatment of several genetic diseases caused by nonsense mutations, including cystic fibrosis (CF).

Continue reading Trial to Possibly Treat Nonesense Mutations Begins

OWN IT: Did Science Find an Answer to the Lack of Organ Donors?

As it turns out the future is now. From National Geographic:

In a remarkable—if likely controversial—feat, scientists announced today that they have created the first successful human-animal hybrids. The project proves that human cells can be introduced into a Continue reading OWN IT: Did Science Find an Answer to the Lack of Organ Donors?

Raising Optimism, Strength, Expectations, & Success (ROSES) Project

We know the current treatment regimen for individuals with CF can be time-consuming and complex. We want to learn how busy individuals are able to fit their treatments into daily routines. What works for you may help us develop effective interventions for others. We are conducting two studies about this: Continue reading Raising Optimism, Strength, Expectations, & Success (ROSES) Project