Fighting for a life unlimited with the Cystic Fibrosis Trust – Health Europa

Founded in 1964, the UKs Cystic Fibrosis Trust offers support and resources to patients affected by cystic fibrosis (CF), as well as funding research into treatments and the search for a cure for CF; and ensuring that CF patients can receive appropriate care and therapy. Cystic Fibrosis Trust Director of Research Dr Lucy Allen tells HEQ about the Trusts research strategy and the implications of precision treatment.

The Cystic Fibrosis Trust is the only UK charity dedicated to fighting for a life unlimited for everyone affected by CF. Cystic fibrosis is a genetic condition that affects the lungs, digestive system and other organs. It is caused by a faulty gene that controls the movement of salt and water in and out of cells, causing a buildup of thick, sticky mucus. There are more than 10,500 people living with CF in the UK; and one in 25 of us carries the faulty gene that causes it, usually without knowing. Living with CF means hours of nebulisers, physiotherapy and up to 60 tablets a day, just to stay healthy. Only half of those born with CF today are expected to live past 47 years.

Medication, physiotherapy and general health all must be considered when planning the simplest activity and being unwell can often interfere with work and education but we are fighting to overcome all those hurdles and are achieving great things through our investment in an exciting and dynamic portfolio of research and innovation. The Cystic Fibrosis Trust is the biggest charity funder of research specifically for the benefit of people with CF in the UK. New research is vital for discovering the next transformational breakthrough that will help deliver our vision of a life unlimited for all people affected by CF.

We have also established a groundbreaking Clinical Trials Accelerator Platform (CTAP) a UK-wide initiative bringing together cystic fibrosis (CF) centres, to increase participation and improve access to and delivery of high impact CF clinical trials. CTAP works with the CF community and informs them of relevant clinical trials and how they can take part in them, which is a crucial step in ensuring we get more new CF therapies and technologies to the market.

Much of this work is supported by the UK Cystic Fibrosis Registry: a secure centralised database, sponsored and managed by the Cystic Fibrosis Trust. The Registry records health data on consenting people with cystic fibrosis (CF) in England, Wales, Scotland and Northern Ireland. CF care teams enter data at every specialist centre and clinic across the UK, with over 99% of people with CF consenting to their data being submitted.

We also provide support to CF clinical teams in the NHS and support the continuous improvement of care that is provided across the UK, which is a fundamental role of the Cystic Fibrosis Trust. We also support and attract new talent into the field of CF care. The Trust provides up-to-date information, support and advice that enables even more people with CF to make the right choices for them at all stages of their lives; and our high impact campaigns for change are helping to influence key people in government and industry. Ultimately, we want everyone with CF to be in control of their own lives, and not have their conditions in control of them.

Our five-year research strategy, called putting the person into personalised medicine, was published in 2018. It sets out how our research investments will focus on research to deliver treatment and care that is tailored to everyone with cystic fibrosis (CF).

Cystic fibrosis is caused by mutations in the CFTR gene. Some effective treatments for people with specific mutations, known as precision medicines, have now been developed; and arrangements for access to the latest of these drugs, Kaftrio, are currently under discussion. For the latest updates on these ongoing discussions, please see the Life Saving Drugs area of our website at http://www.cysticfibrosis.org.uk.

These treatments could have a dramatic impact on the lives of people with CF (and have begun doing so already) by improving their life expectancy, reducing the number of lung infections and improving their quality of life. However, the era of precision medicines brings new challenges which the research strategy aims to help solve. The impact of taking these precision medicines will be different for everyone with cystic fibrosis. For example, older people with CF may have more lung damage, or complications such as CF-related diabetes (CFRD). This means that the way that their CF is managed will be unique to them, and treatments will need to reflect this. Were funding research to look at how treatments can be personalised to everyone with cystic fibrosis.

The development of precision medicines for people with CF is a huge leap forwards, but there are several reasons we shouldnt be complacent. More research is needed to determine whether CFTR modulators may be beneficial for more genotypes than they are currently approved for. To address this, we are working hard to assess whether people with other, rarer genotypes may also benefit from these drugs. Studies such as HIT-CF and research within the UK Cystic Fibrosis Innovation Hub will be important to determine this.

There is also room for improvement in the drugs that are licensed: by tweaking the drug design we could improve how they work and reduce the side effects, creating the next generation of precision medicines. To achieve this, we also need to continue lab-based biomedical research to increase our understanding of how the CFTR protein works and how it goes wrong in cystic fibrosis, and novel ways to restore its function.

Its also important to keep the interest of the drug companies involved, working with and supported by CTAP where appropriate, as they may decide to work on easier (and more profitable) disease areas if we dont. Importantly, we are still looking to develop drugs that would work for anyone with CF, whatever their genotype. This would be of particular benefit to people with rare mutations or those for whom the current drugs dont work or cause side effects.

In June of this year, we heard the exciting announcement from the European Medicines Agency (EMA) that they had found the CF drug Kaftrio safe and effective, meaning it can now progress towards being prescribed across Europe. Kaftrio is a triple-combination therapy made up of three different compounds, tezacaftor and ivacaftor (which together make up Symkevi) combined with elexacaftor.

Initially, Kaftrio is licensed for children and adults aged over 12 who have two copies of the F508del mutation, the most common CF causing mutation of the CFTR gene, or one copy of F508del and one copy of a minimal function mutation. The details of which precise genotypes the latter group covers is still to be confirmed. In addition, clinicians will be able to prescribe Kaftrio for certain patients with other rare mutations that are covered by the US Food and Drug Administrations (FDA) licensing decisions. We also expect that following completion of clinical trials, the drug licensing will expand availability to children under 12. Trials are actively being conducted in six- to 11-year-olds and the next step will be to conduct trials in children under six years old.

In clinical trials for Kaftrio, people with two copies of the F508del mutation had a 10% increase in lung function compared to treatment with Symkevi, and people with a single copy of F508del had more than a 14% increase in lung function compared to treatment with the placebo.

In England, NHS England have agreed a deal with the drugs manufacturer Vertex to facilitate access to Kaftrio from the first day the European licence is granted, which is expected to be later this summer or early autumn. Similarly, in Wales, the Health Minister also recently announced that a deal had been agreed for Kaftrio. We are continuing to work with all key stakeholders to ensure access to everyone in the UK who could benefit. In the first instance, that is seeking more information and updates about negotiations and access in Scotland, Northern Ireland, and the crown dependencies of Jersey, Guernsey, and the Isle of Man. We are also working to understand the mutations covered in the NHS England and NHS Wales deals and what flexibility clinicians will have in prescribing Kaftrio for people with rare or other mutations.

We are working with the UK Cystic Fibrosis Medical Association to support plans for rollout to ensure everyone can start Kaftrio as fast as clinically possible and we also support the UK CF Registry, which will continue its valuable work in monitoring the effectiveness of this drug, among many others.

At least three companies, including AbbVie, Proteostasis Therapeutics and Vertex Pharmaceuticals, are developing other potential triple combination therapies. Through our Clinical Trials Accelerator Platform, we are actively working to support the ongoing HIT-CF Europe research project which aims to provide better treatments for people with rare CF mutations who are currently ineligible for Kaftrio.

An important role for the CF Trust is to push the boundaries, demonstrating leadership and innovation to ensure research is excellent, timely and relevant. The ongoing development of our flagship research programmes, which include Strategic Research Centres, the Innovation Hub in CF Lung Health, the CF Syndicate in Antimicrobial Resistance, investments in digital health and CTAP, has enabled us to create a unique platform, placing the Trust in a strong position to facilitate research which addresses some of the key challenges that will confront healthcare over the next decade.

As the general population gets older, they start to become affected by a range of different diseases and conditions. The same will be true for people with cystic fibrosis. We know that people with CF may also be affected by conditions like cancer, diabetes, heart disease and social wellbeing, and perhaps in different ways to those who dont have cystic fibrosis. It is important to explore and better understand these multiple long term conditions, also a current priority for UK government, and to reduce their impact.

Rather than using drugs to correct the function of the CFTR protein, another area of research underway is looking to correct the CFTR gene itself, either by delivering healthy, non-mutated copies of the gene using gene therapy, or by correcting the existing damaged copy of the gene using gene editing. If this cutting-edge research is successful, future gene editing treatments for CF could either do on the job repairs to the cells that line the surface of the lungs, or the CF gene could be edited in cells in the lab and then corrected cells could be delivered back into the lungs. Whilst good progress is being made towards genetic-based treatments it is unlikely this will be available as a standard treatment for people with CF for many years. However, if they do become available, they could make a significant difference to everyone, irrespective of their genetic mutation.

People with CF can have a range of different lung infections, and its important to know which infections are present and how to treat them. Current post-licensing drug studies on the first of the CFTR modulators Ivacaftor showed that while people taking this modulator drug have fewer flare-ups of poor lung health and fewer infections, people are still susceptible to some infection, highlighting the importance of continuing investment in research to treat and understand lung infections in CF.

The earlier the infections are detected, the better chance there is of effectively treating them. Understanding how the bugs (bacteria, viruses and fungi) work can help researchers to identify possible druggable targets Increasingly these bugs are becoming resistant to antimicrobial therapies used to treat infections which means that better understanding and overcoming antimicrobial resistance is a key priority for CF, just as it is for public health globally.

As the lungs get more damaged, for many with CF a lung transplant may become the only treatment option, but there are sadly not enough donor lungs readily available. Researchers are investigating whether a combination of stem cell technology and gene editing could replace damaged lung cells, regenerating the lungs and providing an alternative to lung transplant.

The Cystic Fibrosis Trust supports a balanced portfolio of research, conducted within universities, private companies, hospitals and other healthcare settings around the world. The impact of the COVID-19 pandemic on Trust-funded research studies will vary on an individual study-by-study basis, and any true negative or positive impact is likely to emerge over time. As part of an ongoing dialogue with our grantees, we have put measures in place to try and protect both the research and the researchers we fund from the financial impact of COVID-19. We have encouraged all grantees to make use of the government-initiated financial support schemes where appropriate. We are also receiving regular updates on how or whether the pandemic has affected their ability to complete their research studies in a timely way.

COVID-19 has impacted on every area of life for many around the globe and has caused great deal of anxiety for many people with cystic fibrosis. In fact, many of the CF community will have been shielding to protect themselves from the risk of infection.

At the CF Trust, we are doing all we can to try and support people with CF and their families through this unprecedented time:

The UK Cystic Fibrosis Innovation Hub based at Cambridge University is a groundbreaking strategic partnership between the Cystic Fibrosis Trust and the University of Cambridge. Its aim is to harness multidisciplinary world class research to accelerate progress towards preventing lung damage in CF and subsequent loss of lung function. Its a five-year programme that began in 2018. The CF Trust aims to raise 5 million over the next five years for the Innovation Hub, which the University of Cambridge has already committed to match pound for pound to 5 million. In addition, the Innovation Hub has secured a physical presence for CF research in the new Heart and Lung Research Institute (HLRI) located close to Royal Papworth Hospital.

Increasingly CF bacterial infections are becoming resistant to these antibiotics, known as antimicrobial resistance or AMR, and it can become harder and harder to treat them. There is increasing concern worldwide about AMR; the UK Government has recently appointed the former Chief Medical Officer Dame Sally Davies as its Special Envoy on AMR, to raise its profile in the G7 and G20. Researchers within the Innovation Hub are designing new antibiotics to tackle AMR and to treat these serious CF infections from a first-principles approach. They are applying world-leading and cutting-edge methods to investigate the transmission of infection, and the biology of what makes Pseudomonas aeruginosa and Mycobacterium abscessus, two of the most aggressive bacterial infections in the CF lung, grow and survive.

They are aiming to combine all their approaches to design new, more effective antibiotics to deliver a shorter, more efficient eradication of bacteria and treatments that are harder for bacteria to develop resistance to. As many infections develop AMR, treating infections across the population is a world-wide health concern. Innovations made in tackling AMR in CF will also be applicable to solving AMR for all those with drug-resistant infections.

Dr Lucy AllenDirector of ResearchCystic Fibrosis Trustwww.cysticfibrosis.org.uk

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Fighting for a life unlimited with the Cystic Fibrosis Trust - Health Europa