The ageing of Cystic Fibrosis patients with new modulators: current gaps and challenges

KEYWORDS:

• Adult Cystic Fibrosis
• CFTR modulators
• aging
• comorbidities
• clinical challenges

1. Introduction

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene (Cystic Fibrosis Transmembrane Conductance Regulator), leading to a reduction in the synthesis and/or function of the CFTR protein. While it has been classically considered a potentially life-threatening condition, recently the CFTR modulators (CFTRm) and in particular the Highly Effective CFTR Modulator Therapy (HEMT), which directly address the protein defect, have brought about a significant shift in the disease’s progression for the majority of patients.

2. From a children’s disease to an adult disease

Until just a few years ago, this condition was predominantly seen as a childhood disease, with a life expectancy not exceeding 18 years and an early mortality rate [1]. Advances in treatment (nutritional support, new antibiotics, respiratory physiotherapy, multidisciplinary care in specialized centers, lung transplant programs, CFTRm, etc.) and early diagnosis (implementation of neonatal screening) have progressively increased the life expectancy of people with CF (pwCF), allowing them to reach adulthood in the majority of cases [2].

According to the latest European Cystic Fibrosis Patient Registry (ECFSPR) data in 2021, 54% (n = 28.986) of pwCF were over 18 years old [3]. A European working group’s data published in 2015 indicated a projected 50% increase in the CF population, with 75% being adults by 2025 [4]. Furthermore, with the increasingly early introduction of CFTRm, these patients may achieve a median survival age of 83 years [5]. However, this projection has some important limitations as, for example, it does not take into account the increase in the proportion of pwCF who will suffer from comorbidities such as cancer or cardiovascular disease as part of the aging of this population. Within this marked increase in life expectancy of pwCF, CFTRm play a very important role, especially the HEMT, however, this only affects modulator-eligible patients whose percentage varies by geographic area.

Because of this demographic shift, the typical profile of a pediatric CF patient has given way to a new one – with increasing age and different medical needs compared to the pediatric group, and with additional concerns in areas such as employment, family, and social aspects [6].

3. CFTRm: a revolution in treatment

In 2011, a pioneering study was conducted in which ivacaftor was administered for the first time in pwCF and at least one copy of G551D with very promising results (improvement in FEV₁ and body mass index, as well as a decrease in sweat chloride). Until then, the available treatments for pwCF were focused on addressing the consequences of the disease and its symptoms. The approval of the first CFTRm (ivacaftor) and subsequently, the other modulators available to date (lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor), has revolutionized the medical care of pwCF by directly targeting the genetic root of the disease (Table 1). The results generated by ivacaftor were established as the standard, leading subsequent modulators to be considered HEMT.

Table 1. Evolution of the approval of CFTR modulators and their indications.

CFTRm^1	FDA first approval^2	EMA first approval^3	Current indications
Ivacaftor (Kalydeco®)	2012	2012	Kalydeco® (EEUU) Age: ≥ 1 month Mutations: at least one of the following 97 mutations (https://www.cff.org/sites/default/files/2022–02/Kalydeco-Approved-Mutations.pdf) [7]
			Kalydeco® (EU and UK) Age: ≥ 4 months Mutations: at least one of the following 10 mutations (R117H, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R)
Lumacaftor/Ivacaftor (Orkambi®)	2015	2015	Orkambi® (EEUU) Age: ≥ 2 years Mutations: homozygous for F508del mutation
			Orkambi® (EU and UK) Age: ≥ 1 year Mutations: homozygous for F508del mutation
Tezacaftor/Ivacaftor (Symdeko® in EEUU^4/Symkevi® in EU^5 and UK^6)	2018	2018	Symdeko® (EEUU) Age: ≥ 6 years Mutations: homozygous for F508del mutation or at least one copy of the F508del mutation and one of the following 154 mutations (https://www.cff.org/sites/default/files/2022–02/Symdeko-Approved-Mutations.pdf) [8]
			Symkevi® (EU and UK) Age: ≥ 6 years Mutations: homozygous for the F508del mutation or at least one copy of the F508del mutation and one of the following 14 mutations (P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, 3849+10kbC→T)
Elexacaftor/Tezacaftor/Ivacaftor (Trikafta® in EEUU^4/Kaftrio® in EU^5 and UK^6)	2019	2020	Trikafta® (EEUU) Age: ≥ 2 years Mutations: at least one copy of the F508del mutation or any of the following 177 mutations (https://www.cff.org/sites/default/files/2022–02/Trikafta-Approved-Mutations.pdf) [9]
			Kaftrio® (EU and UK) Age: ≥ 6 years Mutations: at least one copy of the F508del mutation *The EC^7 has already approved Kaftrio® (November 23, 2023) for the treatment of children aged 2 to 5 years with at least one copy of the F508del mutation. With this authorization, the laboratory can now apply for the inclusion of this new indication in the national health system of each EU country. The eligible patients in Austria, Denmark, Ireland, Norway, Latvia, and Sweden will have access to the expanded indication shortly following regulatory approval by the EC. *In the UK, following MHRA^8 approval on November 15, 2023, and as a result of the agreement between the laboratory and the National Health Service, children ages 2 years and above, have access to this expanded indication for Kaftrio®. In addition, Kaftrio® is also approved for the same 177 mutations as Trikafta®.

^aCFTRm: Cystic Fibrosis Transmembrane Conductance Regulator protein modulator.

^bFDA: Food and Drug Administration (EEUU).

^cEMA: European Medicines Agency (EU).

^dEEUU: United States.

^eEU: European Union.

^fUK: United Kingdom.

^gEC: European Commission.

^hMHRA: Medicines and Healthcare products Regulatory Agency.

These modulators have had a significant impact on lung function, reducing respiratory infections, and improving the quality of life for pwCF. This shift in treatment has translated into increased optimism and hope for patients, their families, and healthcare professionals. However, not all news is positive. The availability and coverage of these HEMT vary in different parts of the world [10]. In developed countries, such as the EEUU (United States) and Europe or UK (United Kingdom), access to these treatments is often more widespread and supported by the approvals from the FDA (Food and Drug Administration), the EMA (European Medicines Agency) and MHRA (Medicines and Healthcare products Regulatory Agency) for the UK. In contrast, in middle and low-income countries (Central and South America, India, the Middle East, and southern Africa), access is more limited due to economic and resource-related issues [10]. Lack of disease awareness, prioritization of endemic diseases, absence of CF registries, lack or limitation of neonatal screening, and limited access to diagnostic tests are the primary challenges in these regions [10]. For these reasons, one of the main objectives today is to raise awareness about the importance of ensuring fair, high quality, and equitable medical care for pwCF worldwide.

4. Comorbidities

With the gradual aging of the pwCF, a phenomenon already underway and set to intensify with the introduction of HEMT, pwCF will increasingly approach the age of the general aging population. This gives rise to emerging problems and associated challenges.

While pulmonary complications contribute significantly to CF morbidity and mortality, CF is a multisystemic disease with many non-pulmonary complications. In addition to the classic CFTR related disease comorbidities (bronchiectasis, rhinosinusitis, nasal polyposis, pancreatic insufficiency, diabetes, infertility/subfertility, etc.), new comorbidities are now added that are not directly related to CFTR but rather to adulthood and the prolonged administration of multiple medications throughout life (intravenous or nebulized antibiotics especially aminoglycosides, non-steroidal anti-inflammatory drugs, etc.) and even to the introduction of HEMT. For example, HEMT enhance malnutrition and could predispose to obesity and other cardiovascular diseases in the future. In the context of these new non-CFTR-related comorbidities, obesity, hypertension, retinopathy, nephropathy, vascular disease, osteoporosis, renal failure, anemia, anxiety, depression, neoplasms, fertility disorders, etc., stand out [11,12].

These new comorbidities manifest at much earlier ages than in the general population and are likely to vary depending on the age of disease diagnosis [13]. Moreover, there is a clear increase in the complexity of both classic and new comorbidities, leading to a parallel shift in treatment objectives.

5. Challenges in the era of HEMT

Up to 10% of pwCF may be intolerant to HEMT, and between 10–25%, depending on the geographical area, may have non-responsive variants to this treatment [14]. The lack of access to HEMT can be attributed in part to specific mutations within a population; however, the socio-economic situation of each country plays a much more significant role. In the not-too-distant future, and over the years, access to HEMT worldwide should become more equitable. This necessitates close collaboration among healthcare professionals, pharmaceutical companies, patients’ associations, and policymakers to ensure more affordable prices regardless of the country of origin.

It is important to note that specific populations, such as pwCF with advanced lung disease (ppFEV1 ≤40%), solid organ transplant recipients, and pregnant or lactating women, are excluded from clinical trials [15–17]. Although studies are starting to emerge in these populations, the role of HEMT in these groups is still being individually evaluated by healthcare professionals, always outside the indications provided by laboratories [18].

On the other hand, upcoming studies should focus on developing more effective HEMT that cover 100% of mutations, allowing for global coverage of all pwCF. Additionally, we must not forget the need for long-term safety studies to closely monitor potential adverse effects and interactions with other medications.

6. Conclusions

The treatment landscape for CF has undergone a significant transformation in recent years, with the increasing introduction of HEMT to a growing number of patients and at an earlier age.

In the era of HEMT, the aging of the CF population is a crucial factor to consider. The aging population will also present increasingly complex comorbidities at much earlier ages than the general population. Accordingly, it is essential, for instance, to adapt programs for cardiovascular disease diagnosis and neoplastic screening from the general population to this patient group. As a result, there will be a growing divergence in diagnostic, monitoring, and treatment objectives between the pediatric and adult CF populations. It is noteworthy that the initiation timing of HEMT can affect the development of CF related complications. Therefore, studies characterizing these new comorbidities, understanding how aging influences disease progression and elucidating the actions of HEMT in this context are necessary.

On the other hand, access to HEMT for all pwCF remains a challenge. A considerable percentage of pwCF are still ineligible due to ineligible mutations, and the high-cost poses accessibility issues in several countries. While advancements in HEMT persist, future research must focus on developing effective therapies for pwCF who currently cannot access these treatments. Examples of such future therapies include organoids and gene therapy that could increase the spectrum of patients eligible for some treatment.

7. Expert opinion

Despite the challenges we still need to face in the treatment of CF, we are experiencing a promising era in addressing the disease. Medical advances and innovative therapies have significantly increased both life expectancy and the quality of life for pwCF. The emergence of new comorbidities secondary to an aging population, largely with the help of HEMT, raises the need for specific screening programmes for pwCF or even their introduction at a much earlier age. While unresolved issues persist, such as the search for a definitive cure, pwCF now have access to more effective treatments than in the past. This ‘splendid era’ represents a deeper understanding of the disease and greater hope for those affected, with the prospect of ongoing advancements on the horizon.

Abbreviations

CF	=	Cystic Fibrosis
CFTR	=	Cystic Fibrosis Transmembrane Conductance Regulator
CFTRm	=	Cystic Fibrosis Transmembrane Conductance Regulator protein modulator
HEMT	=	Highly Effective CFTR Modulator Therapy
ECFSPR	=	European Cystic Fibrosis Patient Registry
pwCF	=	people with Cystic Fibrosis
FDA	=	Food and Drug Administration
EMA	=	European Medicines Agency
MHRA	=	Medicines and Healthcare products Regulatory Agency
EEUU	=	United States
UK	=	United Kingdom
EU	=	European Union
EC	=	European Commission

Declaration of interest

A Felipe Montiel, A Álvarez Fernández and E Polverino have received honoraria from Vertex as speakers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.