Cystic Fibrosis Research News № 5

February 2022

Mimicking the Mucus Barrier for CF Drug Testing

The design of inhaled medicines for CF is challenging because of the thick, sticky mucus often found in CF lungs. This mucus has the tendency to prevent inhaled drugs from fully penetrating into the lungs. Often this permits bacteria to hide from inhaled antibiotics, and certain regions of the lungs go untreated by mucus-thinning medicines, CF modulators, and other helpful compounds.

A team of researchers at the University of Torino in Italy have devised an artificial drug-testing platform that mimics the mucus-dense CF lung environment, and may allow for more effective CF drug design.

The platform combines an artificial membrane with a proprietary “pathological mucus” layer.

The artificial membrane is called PAMPA (the Parallel Artificial Membrane Permeability Assay). It is commonly used to mimic the lung epithelial surface in drug testing experiments. The PAMPA construct consists of two wells (which simulates the lumen of the lung and the interior of lung epithelial cells respectively) divided by a porous membrane made up of synthetic phospholipids that acts as the outer cell membrane.

The ‘pathological mucus’ was designed in the lab to be sticky like CF mucus, and consisted mainly of water, pig mucins (mucins are the main structural component of mucus), and calcium ions, which help to increase the viscosity of the artificial mucus.

Testing the platform was performed with a suite of 45 common CF drugs that were widely variable in terms of chemical structure including the antibiotics tobramycin and aztreonam, and over the counter anti-inflammatory drugs like ibuprofen.

PAMPA was tested alone, and then in combination with the mucus construct. The researchers found that the addition of the mucus made nearly half of the drug compounds less permeable. In other words, the drugs’ rate of movement (in centimeters per second) from the “lung lumen” compartment to the “cell interior” compartment was slower - meaning that in the body, the drugs would have a harder time reaching their physiological targets - whether that be lung epithelial cells or bacterial pathogens - if they make it to their targets at all.

For context, the researchers consider a rate of movement above 4 x 10-6 cm/sec to be ‘highly mobile’ (the number is so small because we are talking about tiny chemicals with sizes on the order of nanometers). Before the mucus construct was added, a little less than half of the tested drugs were highly mobile. After it was added, only about ⅕ of the drugs beat the 4 x 10-6 cm/sec threshold.

This finding may not be all that surprising, as an additional mucus barrier would be expected to slow the movement of drugs through the lungs. But the finding does have important implications. Traditional drug-testing models that do not have this mucus barrier may not reflect the true nature of the CF lung environment, and may be prone to overestimate drug mobility. The drug testing platform introduced in this study, however, would be able to give a more accurate picture of a drugs’ ability to penetrate CF mucus.

Featured Article: Butnarasu C, Caron G, Pacheco DP, Petrini P, Visentin S. Cystic Fibrosis Mucus Model to Design More Efficient Drug Therapies. Mol Pharm.2021;10.1021/acs.molpharmaceut.1c00644. doi:10.1021/acs.molpharmaceut.1c00644.

Barriers to CF Modulator Treatment Go Beyond Biology

When gauging the effectiveness of a drug, we’re often drawn to incredible stories of individual recovery: dramatic improvements in lung function or the end of constant hospitalizations. This is one crucial dimension of medical progress, and the stories of positive patient outcomes on a new drug are a testament to the ceaseless efforts of physicians, lab researchers, and drug developers. But in the push for development and approval of a new drug, there is another dimension of care that must be considered: it is not just how effective, but how broadly accessible a new therapy is that counts.

This is a challenge that those working in the CF community have taken to heart. It is well established that certain pockets of the CF community – nationally and internationally – have not yet been able to benefit from the new modulator drugs. With this in mind, A team of researchers from three universities – UC San Francisco, University of Alabama at Birmingham, and Virginia Commonwealth University have constructed a road map towards broadening access to CF modulators for all CF patients by writing a detailed review to outline disparities in drug accessibility.

To address these disparities, the authors demonstrate, will require moving forward on multiple fronts. On one level, disparities in access to modulator therapy arise due to differences in population genetics. Consider the most common CFTR mutation, Delta-F508. The mutation is most prevalent in Caucasian patients with CF – around 90% of patients possess it and therefore are eligible for treatment with Trikafta, the most effective modulator therapy to date. However, only 70% of the black population, and 75% of the Hispanic population are eligible for any form of modulator therapy.

Researchers have already started working to bridge this gap in several ways. First, ongoing n-of-1 trials which assess the effectiveness of existing modulator therapies on patients with rare mutations are helping to get some additional patients approved for drug treatment. Second, the development of new drugs that target the root genetic cause of CF may help patients with more severe mutations that aren’t amenable to modulator therapy.

But as the review points out, even these steps are not likely to equalize access to highly effective drugs entirely. Differences in economic security between racial / ethnic groups in the US, more specific differences in levels of insurance coverage, and distrust of the medical system at large due to a history of unethical treatment for African Americans and other minority groups also contribute to the disparities in care. To ensure that all patients benefit to the same degree, measures will need to be taken that go beyond biology to address the social factors that impact health outcomes.

Outside the US, disparities are even more pronounced. Only 11 countries aside from the EU have actually approved at least one CFTR modulator for patient use (this includes the US, Canada, Australia, Brazil, Russia, Israel, and a number of non-EU countries in Europe - but no countries in Africa, and minimal coverage in Asia and South America). Furthermore, modulator drugs are costly to produce and expensive to acquire. In a country like the US or Canada with relatively strong networks of public and private insurance, many patients have access to affordable coverage. In countries where insurance infrastructure is lacking, this is much less likely to be the case.

With an understanding of the factors that limit access to CF modulators and other life-saving CF therapies, the promise of a new life that has touched the lives of many with CF already can be extended to all patients no matter their geographical location or socioeconomic circumstances.

Featured Article: McGarry ME, Gibb ER, Oates GR, Schechter MS. Left Behind: The Potential Impact of CFTR Modulators on Racial and Ethnic Disparities in Cystic Fibrosis. Paediatric Respiratory Reviews, 2021. ISSN 1526-0542.

Vertex and AbbVie Race to Make New Modulator Therapies

Over the past decade, Vertex has essentially established the market for CF modulator therapy – with four separate single and combination therapies approved (Ivacftor, Orkambi, Symdeko, and Trikafta) and even more modulator drugs currently in clinical trials. But Vertex is no longer the only company developing CF modulators. Recently AbbVie has now entered phase II clinical trials to bring its own triple combo therapy to market.

AbbVie is entering a market that is expected to grow to $20 billion dollars by 2026. Much of this growth is driven by expansion of regulatory approval. As patients become eligible for Trikafta in more places outside of the US and the EU, the number of patients who may be treated with Trikafta (or a successful competitor drug, like the triple combination therapy that AbbVie is developing), will grow immensely.

How do the drug development pipelines of AbbVie and Vertex stack up? AbbVie’s ongoing phase II clinical trial is assessing the safety and efficacy of its galicaftor/navocaftor/ABBV-119 treatment. Like Vertex’s Trikafta, AbbVie’s triple combo contains two CFTR correctors – galicaftor and ABBV-119 – which help shuttle CFTR to the cell membrane, and one CFTR potentiator – navocaftor – helps re-fold the protein to a more functional conformation once it has reached the cell surface. Phase II trials for the AbbVie triple combo therapy began in Fall 2021, and are expected to be completed by Fall of 2022.

While AbbVie is advancing towards market launch, and has other modulators in development, Vertex has certainly not rested easy after the approval of Trikafta in the Fall of 2019. Since then, it has seen the subsequent approval of Kaftrio – same drug, different branding – by the European Medicines Agency in the Summer of 2020, and has pushed to expand the age range of patients who have access to Trikafta / Kaftrio. Furthermore, Vertex also has more modulators in development. A new Vertex triple combo therapy is already in phase III trials, and includes one corrector carried over from Trikafta (tezacaftor), a chemically modified form of ivacaftor (Trikafta’s potentiator) that is built to be more stable in the body, and a brand new corrector VX-121. This study, which started in Fall 2021, is expected to be completed by late 2023 / early 2024. Vertex is also investigating new forms of therapy, in partnership with several gene therapy companies (CRISPR Therapeutics, Exonics), and forays into mRNA drugs – which stand to benefit CF patients as well as patients with other diseases.

But don’t expect Vertex - or AbbVie for that matter - to avoid further contest in this market for CFTR-correcting therapies for long. The CF Foundation (CFF), which has helped fund the development of Vertex modulators, is also providing support to other intrepid companies. For example, the CFF is partially funding the mRNA therapy under development by Arcturus Therapeutics (which would carry a copy of the CFTR gene into the body to be translated by cells in the lungs). The CFF is also supporting a therapy from Icagen, Inc. for patients with nonsense mutations who are not currently treatable with CFTR modulators. Both drugs are currently in pre-clinical trials.

And that’s not all. The CF foundation is supporting a whole suite of CF therapeutics in various stages of development - not just new modulators and other therapies that treat the root cause of CF, but new anti-inflammatory medications, antibiotic regimens, and mucociliary clearance drugs too. The whole pipeline is quite astounding when you consider that prior to 2012 no patient had access to any form of modulator therapy whatsoever. Now, the CFTR modulator drugs and other up-and-coming therapies may soon push all CF patients regardless of mutation status towards normal lung function.

No matter how the contest between Vertex and AbbVie shakes out, people with CF stand to benefit from new and improved medicines. And it’s not just CF modulators – other companies aside from Vertex and AbbVie are consistently working to develop pancreatic enzyme replacement therapy (Chiesi, Nestle Health Science, AbbVie), mucolytic drugs (Chiesi. Genentech), inhaled antibiotics (Gilead, Viatris, Chiesi), and other treatments to help people with CF live and breathe a bit easier.

Featured Five CF Stories

It’s impossible to list all of the amazing research that is on-going for CF. Below is a quick list of a few fascinating articles that seem to show significant promise.

Better Delivery of Bacteria-Killing Phages: New drug delivery approach allows for better treatment of Pseudomonas aeruginosa and Staphylococcus aureus lung infections. The researchers involved have combined phage therapy – a promising new treatment regimen involving bacteria-killing viruses – with biodegradable, porous microparticles to deliver the phages to the CF lung more effectively. (Advanced Healthcare Materials).

CF Pregnancy Rates are on the Rise!: A cross-sectional study of pregnancy-related hospitalizations from 2006 to 2017 has found that pregnancies in women with CF have been increasing, and the average age of pregnancy is increasing too (the percentage of women with CF over the age of 25 has crept up from 58.1% to 75.8% over the study period). This is yet another happy sign that CF health outcomes are improving and that people with CF are getting to enjoy fuller lives. (American Journal of Obstetrics & Gynecology).

Diagnostic Trends and Treatment Options for CF Bone Disease: This recent review surveys the landscape of CF bone disease, an increasingly common complication for CF patients as lung disease has become more treatable and life expectancy is on the rise. The review discusses the suite of new treatments in development: from monoclonal antibody therapy to anabolic therapy,and contemplates how CFTR modulators may lead to improvements in bone health for people with CF. (American Journal of Obstetrics & Gynecology).

Achromobacter: Monitoring an Emerging CF Pathogen of Concern: More news on the clinical effects of infection with Achromobacter species, a CF pathogen that is rising in prevalence. The researchers conducting this study have found, in a retrospective analysis of health outcomes in Achromobacter-infected CF patients vs. non-infected controls, that Achromobacter infection is indeed associated with more rapid lung function decline and more frequent hospitalization. (Pediatric Pulmonology).

Drug Screen Identifies Nearly 200 New Drug Candidates for Alternative Chloride Therapy: New study opens the door to many new drug candidates for alternative chloride channel therapy. This study screened over one thousand siRNAs (small RNA molecules that interfere with mRNA translation into protein) and found 179 that enhance the trafficking of chloride channel TMEM16A to the cell membrane. As roughly 10-20% of CF patients, are not yet eligible for highly effective modulator therapy, activating other chloride channels aside from CFTR is a very promising treatment alternative. (Journal of Molecular Biology).

Clinical Trial Watch

The latest news on CF drug development and clinical trials.

Madrid, Spain. Recruiting: People with CF have long been counseled to make exercise a part of their daily routine. In this new clinical trial, researchers aim to gauge the effectiveness of a remotely supervised exercise program. The central focus of the exercise program will be strength training, and the researchers seek to determine the effects of the program on a wide range of clinical outcomes, including lung function, muscle strength, body composition, inflammatory marker production, and general quality of life. (Universidad Europea de Madrid).

Seattle, Washington.Recruiting: For late-stage CF lung disease, lung transplantation is often the best option for extending life. Some patients, in fact, have lived for decades after a lung transplant. Unfortunately, however, many patients die without undergoing a transplant, and an estimated 25-40% choose to decline the procedure rather than join the transplant list. This trial will test the effectiveness of a program for patients with severe CF including zoom interviews, survey assessments, and access to an Internet website with educational resources about lung transplantation. If successful, the counseling program will be rolled out with the outcome of reducing the number of people with CF who decline transplants in focus. (University of Washington).

USA, 28 sites. Recruiting: The new Vertex triple-combo therapy has entered phase III clinical trials. The combination of VX-121 (a new CFTR corrector), tezacaftor (one of the correctors present in Trikafta / Kaftrio), and a chemically modified form of ivacaftor (one that is more stable in the body over a longer period of time), is being tested to see if it can build on the clinical benefits provided by the approved drug Trikafta / Kaftrio. The primary clinical endpoint here is FEV1 (lung function), but the trial will also observe sweat chloride levels as a measure of CFTR function. (Vertex Pharmaceuticals).

Richmond, Virginia. Soon Recruiting: CFTR mutations come in a number of different varieties. The mutations that an individual patient possesses can affect whether or not they are eligible for CF modulator therapy, and determine the severity of their CF symptoms. A new clinical trial, expected to begin in the early months of 2022, will soon enroll patients to see how CFTR mutation impacts patients’ exercise capacity. Participants will be instructed to wear a Fitbit Tracker to keep track of mileage run on a weekly basis over 10 weeks, with the primary endpoint for the study being increase in mileage ran over the 10-week span. Study results may inform guidance for exercise on an individual-patient basis. (Virginia Commonwealth University, CF Foundation).

Funding News

Recent funding for CF researchers or companies.

SalioGen Therapeutics Closes $115 Million Series B Financing: The Cambridge, Massachusetts company SalioGen is developing a novel form of gene therapy which depends on an enzyme called Saliogase to insert new, functional pieces of DNA into the genome that can make up for mutant CFTR. Among the investors included the Cystic Fibrosis Foundation. (SalioGen Therapeutics).

CFF Awards nearly $10 million in January 2022: The Cystic Fibrosis Foundation made several key awards in January 2022. CFF has awarded up to $5 million to BiomX Inc, which is entering phase 2 clinical trials to test the efficacy of its drug candidate BX004. BX004 is a phage therapy that targets the common CF pathogen Pseudomonas aeruginosa. CFF also awarded up to $4.7 million to EnBiotix Inc. to study the potential use of inhaled colistin as an additional option to treat Pseudomonas infections in people with CF who are not responding to current treatments. EnBiotix recently merged with Polyphor to form Spexis AG. (Cystic Fibrosis Foundation).

Kaftrio Approved for Children Ages 6 and Up in European Union, UK: In the UK and across the European Union, Kaftrio (the European brand name equivalent of Trikafta) is now available for children as young as 6 years old. Extension of drug approval to this younger age range has happened already in the US, New Zealand, and Switzerland. And in Canada, the extended age will soon be up for consideration as well. (Vertex).

SpliSense gets orphan drug status for SPL84-23-1: Jerusalem-based SpliSense announced that the FDA and EMA have both granted orphan drug status to SPL84-23-1, an antisense oligonucleotide (ASO) targeting the CFTR 3849 mutation.. Orphan drug designation is reserved for drugs that serve patient populations with life-threatening and currently untreatable conditions. Achieving orphan drug status can mean more regulatory support, an accelerated drug review process, and ultimately, quicker access for patients to drug therapy if it proves effective. (SpliSense).

A Call to Action

Cystic fibrosis (CF) research is very much dependent on the strength of the CF community. It’s not simply an effort carried out by scientists in white lab coats - although there are many of them, and their work has enormous impact. Advances in research also depend on the technicians and engineers who operate the laboratory equipment that enables drug discovery, and the industrial machinery that allows drug development. Research depends on both business and marketing professionals, those who make biopharma companies viable and promote clinical trials. Successful research further depends on clinical trial coordinators, who carry out studies and work tirelessly to recruit and support patients throughout the complicated trial process. Particularly for rare diseases like cystic fibrosis, research depends on the work of foundations and patient advocates, which includes in the United States organizations such as the CF Foundation, Emily’s Entourage, CFRI, and the Boomer Esiason Foundation, as well as countless other across the globe, and hundreds of committed clinicians and researchers. Most importantly, research depends on people with CF and their devoted families and friends.

There can be no progress in CF research without patients willing to participate in clinical trials: not only to test new drugs, but also to provide, quite literally, their flesh and blood. It is with the help of patient samples that scientists can understand the damage that CF inflicts upon the human body, and also how drugs developed by the research community can remedy these damages.

This newsletter aims to pull all of these threads together; allowing the CF community to more fully appreciate how well the aims of its many members are aligned (and it extends an invitation to all readers not yet a part of the CF community, to embrace the cause and take up the task of pushing CF research forward). There’s something here for everyone - those interested in the clinical side of CF care, or in drug development, or the technical work performed in CF-centered laboratories. The newsletter also has as its objective to showcase new clinical trials; an opportunity for patients and clinicians to take part. Wherever and whoever you are in the world, you too may push CF research forward - either by direct participation, or simply by reading and sharing this newsletter with others.