National CF conference returns with focus on progress and new challenges

Following a five-year hiatus, the Irish National Clinical Cystic Fibrosis Conference took place
in January to highlight the latest developments in the field

The Irish National Clinical Cystic Fibrosis Conference returned to Limerick on 30 -31 January 2025. Held for the first time in five years, the conference highlighted the recent dramatic changes that have occurred in the cystic fibrosis (CF) landscape. While there has been increasing life expectancy thanks to highly effective therapies, there are also a host of new challenges in relation to CF care.

One in every 2,200 children born in Ireland has CF. Prof Barry Linnane, Paediatric Respiratory Consultant at University Hospital Limerick, provided an overview of 10 years of CF newborn screening in Ireland. The programme, which aims to diagnose children with CF before they present with respiratory symptoms and/or features of fat malabsorption, identified 284 children as having CF between July 2011 and June 2021. The programme measures excellently against international standards with key performance indicators, such as the average age for a sweat test to be conducted (23 days old) and time to call from a CF centre (21 days), falling well below the European Cystic Fibrosis Society guidelines of 32 days. The ultimate aim of medical care should be to prevent decline, not just to slow it. Early initiation of modulator therapy may bring enhanced results and the early detection of CF is critical to this.

Eligibility for CFTR modulator therapies

CF is caused by variants in the cystic fibrosis transmembrane regulator (CFTR) gene. CFTR modulators, which can restore the function of the defective protein in the majority of cases, have become the standard of care. The most recent of these, Kaftrio, has been transformative, both physically and psychologically, for those who can access the therapy.

It is a combination therapy of elexacaftor, tezacaftor, ivacaftor (ETI). ETI was developed initially based on laboratory testing of the most common CFTR variant F508del. Two phase three trials included people with either one or two copies of F508del and led to the licensing of the drug with a highly impressive efficacy signal (including lung function, pulmonary exacerbation rates and quality-of-life assessment) combined with good safety. Initial licenses (FDA 2019 and EMA 2020) provided access to those with at least one copy of F508del.

ETI will not work for all people with CF (pwCF); this is due to the fact that over 2,000 different variants (mutations) have been reported in the CFTR gene. For some of these variants, the mutation gives rise to an absence of the CFTR protein, resulting in no substrate for ETI therapy to work on. The other variants give rise to a protein with abnormal structure or function. Many of these variants are ultra-rare and clinical trials assessing the efficacy of ETI for these rare variants have been impossible to conduct.

Modulator therapies were initially developed and refined through a screening system on Fisher rat thyroid (FRT) cells, which were specifically engineered to express various forms of mutated CFTR. The Food and Drug Administration in the US has twice expanded its licence for ETI use based on data generated from in vitro studies with FRT cells. A further 177 variants were included in 2020 and another 94 in 2024. Perhaps unsurprisingly for such a novel approach, questions were initially raised about the suitability of FRT in predicting drug responsiveness, leading, until now, to a lack of acceptance of such data by the European Medicines Agency (EMA).

Prof Pierre Régis-Burgel, Cochin Hospital and Paris-Cité University, Paris, France, outlined his work on a French compassionate use programme, which expanded access to trials of ETI for those aged six years and older without a F508del variant causing their CF. Participants were given a four-to-six week trial of ETI and their response was determined by a centralised committee based on the evolution of clinical data on lung function and sweat chloride. Promising data was presented showing that to date, of the 650 patients included in the programme, 55 per cent have been responsive to ETI, benefiting 350 patients. The French reimbursement system allows ongoing access for these people.

The French compassionate use programme took brave steps in expanding access to these therapies to all who may benefit from them, giving hope to those with ultra-rare mutations who had been left behind. Real-world reports are unanimous in confirming clinical trial data: The course of the disease improves dramatically on ETI with a rapid, major and sustained improvement in clinical manifestations and lung function, strongly predicted to result in longer survival.

Of note, since the conference, on 28 February 2025, the EMA’s Human Medicines Committee recommended expanding the indication of two medicines – Kaftrio and Kalydeco (ivacaftor) – for the treatment of CF to include their use in combination for patients aged two years and older who have at least one non-class I mutation in the CFTR gene. The extension of this indication paves the way for all patients likely to respond to these modulator therapies to be treated. Up to 97 per cent of people living with CF may now have access to these highly effective therapies if marketing authorisation and reimbursement
are approved.

Update from the National Clinical Programme

Prof Charles Gallagher, National Clinical Lead for Cystic Fibrosis, took attendees through the historical approach to CF care in Ireland prior to 2015, the setting up of the National Clinical Programme that year, and the key changes that have been made between 2015 and 2024.

We were reminded of the most notable and pivotal piece of work regarding CF care which was commissioned in 2003 and carried out by Dr Ronnie Pollock. This independent review of CF services in Ireland led to a publication in 2005 calling for urgent action to correct the dangerously inadequate staffing provision for CF care within the health service. In doing so, it set the foundation for future standards of care.

Prof Gallagher spoke of the core objective and philosophy of the National Clinical Programme. In outlining the key developments, he emphasised the introduction of the CF model of care and its progression towards publication, along with plans to include a complementary model focused on CF and transplant care

The concluding elements of the presentation described the CF landscape today and into the future with a focus on CF and aging, CF-related diabetes and the drugs for non-F508del mutations. As part of his conclusion, Prof Gallagher addressed the need to support ‘team wellbeing’, highlighting it as a core component to future CF care.

Marking his retirement, Prof Gallagher was presented with a Lifetime Achievement Award at the conference. The award acknowledged his dedication and commitment to CF care in Ireland since becoming Director of the St Vincent’s University Hospital adult CF unit in 1997. Overseeing the care of over 480 pwCF, St Vincent’s University Hospital now has one of the largest CF centres in the world. It is staffed by an excellent multidisciplinary team focused on the delivery of the best care for pwCF. In 2012, Prof Gallagher oversaw the development and opening of the new CF unit, which is located in the Nutley wing of the hospital. This state-of-the-art facility, with 34 dedicated single rooms with en-suite bathrooms for pwCF, is one of the most modern and well-equipped CF units in the world. 

More recently, Prof Gallagher was appointed as the first Chair of the HSE National Clinical Programme, which published the first model of care for CF in Ireland, as well as the first model of care for Irish CF lung transplantation. Prof Gallagher’s contribution to St Vincent’s University Hospital, respiratory medicine and cystic fibrosis, nationally and internationally, has been immense. He will be sorely missed by all his colleagues, the CF team, and all the pwCF and their families that he cared for over the years.

Future of CF clinics

In this era of modulator therapies, enhanced multidisciplinary care and improving health for those with CF, the question was asked: Do we still need CF centres? The answer was a robust yes. While the responsibilities of multidisciplinary care have changed, with a shift in focus to the management and prevention of chronic diseases in pwCF, the volume of work remains. There is an increased emphasis on physical fitness and general health and the need to prevent typical comorbidities of ageing in pwCF. Specialists working on the complications of CF – such as liver disease, diabetes, and renal issues – and genetic counsellors for those considering starting a family, all have important roles to play in CF care.

Remote monitoring in the clinic has also gained increased focus. Prof Patrick Flume discussed the important role that telemedicine may play in the future of CF care. Highlighting its benefits and barriers, Prof Flume spoke to the overall accessibility of this approach. Recent research examined this new model of care, incorporating variables such as asynchronous visits versus all-in-one clinics, to provide an evidence-based approach to CF care. From an outcome perspective, while it is still unknown if it is the best model of care, it serves as a template to refine best practice. 

Advances in CF-related diabetes

As people with CF live longer, non-pulmonary complications are becoming increasingly prevalent and burdensome. CF-related diabetes (CFRD) shares characteristics of both type 1 and type 2 diabetes. Dr Melissa Putman, Massachusetts General Hospital and Harvard Medical School, US, highlighted the impact of CFRD on clinical outcomes, evidenced in compromises in nutrition, declining body mass index, reduced pulmonary function and increased CF exacerbations. Long-term diabetes complications were also seen, as well as impacts on mental health and an earlier rate of mortality.

Advances in CFRD screening were outlined, coupled with an overview of some of the current restrictions. While oral glucose tolerance is the recommended test for diabetes, the demands of the test are not ideal, and screening rates remain low.  Dr Putman added that alternative screening tests have limited sensitivity and this can be a challenge.

Current guidelines in the treatment of CFRD were reported on, with insulin being the only recommended treatment for CFRD currently. Highlighting the challenges of managing CFRD, Dr Putman spoke of the burden of diabetes tasks on top of other health priorities for those with CF and the overall impact on quality-of-life. Concluding statements addressed diabetes technology and how it may help to improve glycaemic management and reduce treatment burden.

Sexual and reproductive health

The conference plenary was provided by Prof Jennifer Taylor-Cousar, Professor of Adult and Paediatric Pulmonary Medicine, National Jewish Health, Colorado, US, who discussed evolving issues in sexual and reproductive health for pwCF. Approximately 98 per cent of men with CF are born infertile. Prof Taylor-Cousar highlighted a study carried out with 264 men with CF, which found that 17 per cent were over the age of 20 when they found out about their infertility, reinforcing the importance of conversations from an early age explaining the side-effects of CF from this perspective. 

Prof Taylor-Cousar stated that pregnancy after transplant is and remains highly discouraged and many couples seek surrogacy as a pathway to parenthood. The use of modulators during pregnancy and breastfeeding was addressed. Retrospective studies of women with CF who used modulators during pregnancy and breastfeeding at normal human doses found no alarming safety signals to the foetus. From the perspective of miscarriage or congenital anomalies, the use of CFTR modulators during partner conception and/or pregnancy in men with CF was discussed. The findings presented showed that this has not resulted in a higher-than-expected miscarriage rate or congenital anomalies. 

To conclude, Prof Taylor-Cousar addressed a retrospective study of parenthood in pwCF, which showed that short-term health outcomes were adversely impacted, an effect that was mitigated by modulator use. 

Significant questions remain around best practices in the care of pregnancy and fertility among people with CF. Early discussions with pwCF around the implications of CF on their reproductive lives are encouraged and essential.

Future of infection management in the era of ETI

Prof Pradeep Singh, University of Washington School of Medicine, US, addressed in detail the effect of ETI on CF lung infections and inflammation, expanding the presentation to address why infections might persist after treatment. From the good news perspective, Prof Singh reported that ETI rapidly reduced CF pathogens in sputum.  Gram positive and negative bacteria and fungi were found to respond similarly, consistent with non-specific clearance from the lungs. There was no sign of an infection rebound 3.5 years after ETI. A study of Pseudomonas aeruginosa (Pa) inflammation markers suggests that ETI diminishes other inflammatory mechanisms.

Addressing the perspective of not-so-good news, it was reported that few subjects were found to become repeatedly pathogen negative. If infection remained in one lung region, all sampled regions would test positive, and the lung may continue to deteriorate globally. In persistently infected subjects, sputum pathogen density was found to decrease modestly and then stabilise. In addition, some people in their study became “newly” infected with Pseudomonas, Staphylococcus aureus, and Stenotrophomonas maltophilia after starting ETI, but the fate and consequences of these infections were unknown. Persistently Pa-infected subjects had Pa and inflammation in all sampled segments including those with the mildest disease.

Dr Charles Haworth, Royal Papworth Hospital and University of Cambridge, UK, presented a very informative piece which highlighted that the M avium complex and M abscessus were the most prevalent non-tuberculosis mycobacterial (NTM) infections. While ETI had resulted in clearance of NTM in some patients, it was noted that the clinical relevance of chronic NTM infection in patients on ETIs was often unclear.

As reported in 2023, out of 33,288 pwCF, 10,035 had a mycobacterial culture, with 5 per cent accounting for the M avium complex and 3 per cent M abscessus. In patients that met the diagnostic criteria for NTM pulmonary disease, the initiation of treatment was suggested rather than watchful waiting. Dr Haworth described a modified therapy protocol which can lead to clearance. Two out of three patients with chronic long-term NTM were cleared of the infection with the new protocol. The prolonged use of IV beta-lactams in combination with oral clofazimine plus bedaquiline appears better tolerated and effective than conventional regimens for multidrug resistant mycobacterial infections.

Typical CF infections remain a significant concern in the ETI era and may become more challenging to treat due to difficulties associated with their detection as people treated with ETI produce less sputum for sampling.

The meeting highlighted the profound impact that collaboration and shared knowledge can have on the lives of those affected by CF. 

Over the course of the conference, attendees had the opportunity to engage with leading experts in the field and hear inspiring keynote presentations that highlighted innovative approaches to managing CF now and into the future. The conference addressed the multifaceted challenges faced by pwCF and healthcare providers alike, ensuring a collaborative perspective on the journey of living with CF.