Progress in CF care in Ireland

Cystic Fibrosis Ireland, Annual Conference, virtual, 29-30 March 2022.

Ms Sarah Tecklenborg, Senior Research and Policy Coordinator, Cystic Fibrosis Ireland (CFI), reports on CFI’s Annual Conference, which was held at the end of March.

The impact of new modulator therapies on the lives of people with cystic fibrosis (CF) and advances in care for people who are not eligible for modulator therapies were among the key issues addressed at Cystic Fibrosis Ireland’s (CFI) 2022 Annual Conference, which took place virtually in March. 

There have been dramatic improvements in CF treatment in recent years, including the development of CF transmembrane conductance regulator (CFTR) modulator therapies and standardised multidisciplinary patient care. Roll-out of the new triple combination CFTR modulator compound, Kaftrio (Vertex pharmaceuticals), started in Ireland in September 2020. 

RECOVER study 

Prof Paul McNally, Consultant in Paediatric Respiratory Medicine and Director of Research and Innovation at Children’s Health Ireland at Crumlin, shared research into the impact of ground-breaking new therapies for people with CF. 

Prof McNally leads the RECOVER study, an ongoing multicentre real-world study in eight centres in Ireland and the UK. Funded by CFI, the CF Foundation (US), and the CF Trust (UK), the study is examining in detail the impact of Kaftrio on the lives and health of people with CF. RECOVER is looking at the impact of Kaftrio as it is prescribed clinically. The project will gather both routine health data and less commonly used clinical endpoints such as the lung clearance index (LCI), chest CT, gastrointestinal symptoms, inflammation, and medication adherence, providing unique insights into the effects of the triple combination drug. 

In the first 12 months of RECOVER, 116 adults and adolescents have been recruited across UK and Irish sites. In line with what was seen in clinical trials, the team have seen significant improvements in sweat chloride, lung function, and nutrition in people with CF taking Kaftrio. 

In people with CF there is a problem in moving chloride across cell membranes, which lead to higher concentrations of salt in sweat. The study has shown that, for participants with two copies of the F508del mutation, more than 40 per cent had a sweat chloride level well within the ‘normal’ range while on Kaftrio. The significance of this genotype advantage for those with two copies of the F508del mutation remains unclear and ongoing work is needed to ascertain whether this leads to long-term improved outcomes for this subgroup. 

The team have also identified significant improvements in outcomes not used in the original clinical trials, including the LCI (a sensitive lung function test) and exhaled nitric oxide (a marker for airway inflammation). 

Three new sub-studies have been established as part of RECOVER: A psychology sub-study, in collaboration with Trinity College Dublin, examining experiences of young people (12-to-17 years) who have started taking Kaftrio; a study examining the impact of Kaftrio on nasal and sinus disease in children with CF aged six-to-11 years in collaboration with the RCSI and St James’s Hospital, Dublin; and, finally, a study with the University of Amsterdam using breath analysis to detect changes in airway metabolism and inflammation with Kaftrio treatment. 

Prof McNally and his team hope to further their work to investigate the duration of beneficial effect from modulator therapies and whether disease can be prevented in children if they begin modulator therapy early enough. 

Experiences of people living with CF 

The voice of people living with CF was central to the conference. Not all people with CF have access to an effective therapy and among those who do, the experience can vary. For some, however, Kaftrio has been life-changing. 

“The last year of my life has been nothing short of a miracle and this is all down to the drug Kaftrio. Prior to December 2020, my life was getting more and more difficult to bear. I had constant chest infections, I couldn’t speak without violently clearing my throat, I had very low energy and regular hospital admissions. It really was becoming increasingly difficult for me to see myself living the life I wanted. 

“In December 2020, with nervous excitement based on stories I had heard from the US, I started Kaftrio. Within a couple of hours it felt like a weight had been lifted off my chest. A week with little to no coughing turned into a month. Fourteen months later I can share with you that not only have I not needed one antibiotic for my chest or my sinuses, I have hardly coughed. I no longer have to plan my life around suspected hospital admissions. I no longer feel I need to sleep several times throughout the day and I no longer have to haggle with my medical team to prescribe me just one more oral antibiotic in a desperate attempt to avoid being locked in the CF isolation room in Christopher’s Ward. Thanks to Kaftrio, these are all things I no longer have to do. But let me tell you what I now can do. 

“I can feel the air enter and exit my entire chest. I can laugh until my sides hurt without ending up in a coughing fit. I have healthier hair and brighter skin. I get up early to meditate and read instead of (doing) my rigorous CF treatments, and most of all I can plan for a bright future, knowing that my body will not let me down. Kaftrio has completely changed my life and I will never take that for granted.” 

Person living with CF 

CF treatment in the modulator era 

As modulator therapies bring improvements in the health, symptom burden and experiences of people living with CF, questions are being asked by clinicians about what CF care now looks like in the era of modulator therapy. Prof Barry Plant, Consultant Respiratory Physician and Director of the Adult CF Centre in Cork University Hospital, discussed inhaled antibiotic therapies and how they may be best used to protect lung health in the era of precision medicine. 

CF is characterised by inflammation of the airway, chronic infections and progressive decline in lung function. Studies have shown that up to 25 per cent of CF exacerbations fail to recover to baseline pulmonary function levels after the exacerbation. Daily treatment regimens for CF include the use of inhaled antibiotics and mucolytics, which have led to significant improvements in respiratory disease and improved patient outcomes. Aerosolised antibiotics offer advantages over systemic therapy, as relatively high levels of the drug are delivered directly to the airways through a variety of delivery systems, including standard nebulisers or dry powder eFlow. 

Patients on the new modulator therapies feel better, produce less sputum, and have fewer exacerbations. Prof Plant discussed his patients’ experiences on Kaftrio, noting that at three months post-initiation of therapy only approximately 10 per cent of patients could provide a sputum sample. This poses problems with monitoring the microbiological status of patients as they cannot provide a sample to confirm whether they do, or do not, have an infection. 

As patients experience fewer exacerbations and produce less sputum, some have been discontinuing their other time-consuming burdensome therapies. A retrospective analysis of patient adherence to inhaled therapies before and after CFTR modulation with ivacaftor in the Cork CF clinic found there was a reduction in the frequency of use of inhaled therapies after starting the modulator. 

In keeping with the increased liberation that Kaftrio has offered to people with CF, a more individualised approach to their inhaled antibiotics may help to optimise their adherence. 

How to reduce the treatment burden associated with CF has been identified as a top research question for the CF community. Daily nebulised treatments, often taking up to two hours a day, are considered burdensome. There are ground-breaking trials underway to find out if people taking Kaftrio can safely start to reduce the number of treatments they have to manage as part of their daily healthcare routine. Two randomised studies, CF STORM (UK) and SIMPLIFY (US), aim to assess if stopping certain daily muco-active nebulisers is safe for people taking Kaftrio. The studies will have patients actively disengage from their daily nebulised muco-active therapies (inhaled hypertonic saline and/or dornase alfa) and assess lung function over time. 

If people with CF choose to give up their nebulised therapies without trials like STORM and SIMPLIFY, there would be no quantified evidence for clinicians to refer to and confidently advise their patients. In the short-term, Prof Plant recommends encouraging patients to continue to use inhaled antibiotics, using personalised approaches to improve adherence where appropriate: “Modulator therapy works, but it probably works even better when used as an add-on to traditional CF therapies.” 

Towards personalised medicine 

Not everyone with CF is eligible for a modulator therapy like Kaftrio. Over 2,000 mutations in the CFTR protein, which causes CF, have been described. Many new drugs are mutation class-specific and are currently only being clinically tested in patients with specific mutations. These are often very common and well-described mutations. As a result, market authorisation and financial reimbursement of these drugs has been limited to specific subsets of people with CF. People with fewer common mutations, however, might also benefit from them. 

Prof Kors van der Ent, Professor in Paediatric Pulmonology and co-ordinator of the European HIT-CF project, provided the meeting with an overview of the HIT-CF study, which aims to develop a path for access to therapies for individual patients who show response to therapy in a lab-based test. The HIT-CF project uses organoids, a tissue model derived from a person’s own cells obtained during a rectal biopsy. These organoids are used to test the efficacy of available therapeutics in a lab setting. Only patients with rare genotypes could participate in the study. Organoids from consenting participants will be stored in a biobank to use in future research and to test the efficacy of any future therapies, including genetic therapies. A follow-up clinical trial, CHOICES, is planned for later this year, which will assess the clinical impact of the therapy in people whose organoids responded highly. The trial aims to validate the organoid model of predicting clinical response to a therapy and this could pave the way for organoid-based personalised medicine in the future.