Challenges in the use of highly effective modulator treatment for cystic fibrosis

Abstract

The last decade has seen development of oral, small molecule therapies that address the basic cystic fibrosis transmembrane conductance regulator (CFTR) protein defect. Highly effective modulator treatment (HEMT) that is efficacious for a large majority of people living with cystic fibrosis (CF) promises to change the landscape of this chronic life-limiting disease. Some people living with CF have a CFTR genotype that renders them eligible for HEMT, but also have comorbidities that excluded them from the original Phase III clinical trials that led to US Food and Drug Administration approval. The purpose of this review is to address the use of HEMT in challenging situations, including initiation for those with advanced CF lung disease, and use after solid organ transplant, during pregnancy, and for individuals with CFTR-related disorders without a definitive diagnosis of CF.

Introduction

Oral cystic fibrosis transmembrane conductance regulator (CFTR) protein modulator treatment has revolutionized the management of cystic fibrosis (CF). The first approved CFTR modulator was ivacaftor (IVA) for treatment of the approximately 4% of individuals with CF with the Gly551Asp (G551D) mutation.(1) The substantial improvements conferred by IVA in CFTR function (as measured by change in sweat chloride concentration) and pulmonary function (as measured by change in percent predicted forced expiratory volume in one second, ppFEV₁) established the benchmark for highly effective modulator treatment (HEMT). Improvement in ppFEV₁ and sweat chloride concentration with the use of elexacaftor/tezacaftor/ivacaftor (ETI) for individuals with CF with at least one copy of Phe508del (F508del) is comparable to, or better than, gains observed for those treated with IVA (Figure 1).(2, 3) Additional benefits of HEMT include decreased frequency of pulmonary exacerbations, and improved nutritional status (as measured by body mass index (BMI)) and respiratory health-related quality of life.(1–3) The development of HEMT that is efficacious for a large majority of people living with CF promises to change the landscape of this chronic life-limiting disease.

Figure 1: CFTR modulator treatment for patients with cystic fibrosis and effect on lung function and sweat chloride concentration.

Abbreviations: CFTR = cystic fibrosis transmembrane conductance regulator; IVA = ivacaftor; FEV₁ = forced expiratory volume in one second; ETI = elexacaftor/tezacaftor/ivacaftor; Res function=residual function (mutation allows some CFTR function and/or is responsive to CFTR modulators in vitro); Min function=minimal function (mutation produces no CFTR protein and/or does not respond to CFTR modulators in vitro)

Changes in the graph for ETI use in patients with CF with mutations for which there were approved therapies in the U.S. (F508del/F508del and F508del/res function) reflect total predicted change compared to placebo. For example, the ETI bar for those homozygous for F508del reflects the addition of the effect of tezacaftor/ivacaftor versus placebo of 4% in the phase III(45) plus the effect of the addition of elexacaftor in those already on tezacafator/ivacaftor of 10% in the phase III trial(3).

In December 2020, the US Food and Drug Administration (FDA) approved ETI for people living with CF, age 12 years and older, with at least one copy of an additional 177 rare CFTR mutations.(4) The effectiveness of ETI for these additional mutations is unclear, so comments on HEMT below refer primarily to individuals with a F508del mutation, not to all individuals who are eligible for ETI.

Some people living with CF have a CFTR genotype that is eligible for HEMT, but also have comorbidities that would have excluded them from the original Phase III clinical trials that led to FDA approval (Table 1).(1–3) The risk to benefit ratio in these unstudied or understudied populations is unclear and few published studies exist to support the role of ETI in these patients. Given the remarkable effects of HEMT seen in clinical trials and in clinical practice, expanding access to other individuals who have the potential to benefit is a priority for the CF community. The purpose of this review is to address the use of HEMT in challenging situations, including initiation for those with advanced CF lung disease, and use after solid organ transplantation, during pregnancy, and for individuals with CFTR-related disorders without a clear diagnosis of CF. While the focus of the review is on the clinical risks and benefits of HEMT, issues of cost and access to HEMT are also briefly addressed.

Table 1.

Major exclusion criteria of common conditions in people with cystic fibrosis for the elexacaftor/tezacaftor/ivacaftor trials.(2, 3)

■ppFEV1 <40

■Clinically significant cirrhosis with or without portal hypertension

■Solid organ or hematological transplantation

■Pregnant or nursing females

■Lung infection with Burkholderia cenocepacia, B. dolosa, and Mycobacterium abscessus

■Single copy of F508del without a second identified CFTR mutation

ppFEV₁ = percent predicted forced expiratory volume in one second; CFTR = cystic fibrosis transmembrane conductance regulator

Advanced CF lung disease: initiation of HEMT

As in the case of most Phase III trials of CFTR modulators in people with CF, individuals with advanced CF lung disease were excluded from the Phase III clinical trials that led to FDA approval of ETI (Table 1).(1–3, 5) Previous experience with the use of IVA in people with advanced CF lung disease suggested more modest clinical benefits in lung function, BMI and exacerbation reduction than were seen in the pivotal trials with a similar safety profile.(5) This experience provides some reassurance for use of ETI in those with advanced CF lung disease. Furthermore, a small number of individuals whose ppFEV₁ fell to <40% of predicted between enrollment and randomization were included in the Phase III studies of HEMT, and these people had similar benefit in lung function compared to the overall cohort during the clinical trials.(2, 5)

Although no randomized trials have been conducted that have intentionally included those with advanced disease, in a single-center open-label cohort study conducted by investigators in Ireland, ppFEV₁, BMI, and pulmonary exacerbation frequency improved dramatically among patients with ppFEV₁ <40% who were treated with ETI, from a mean ppFEV₁ of 27% to 36%.(6) Additionally, in a multicenter retrospective cohort study, Bermingham et al reported that in 64 patients with baseline ppFEV₁ <40%, there was an average increase in ppFEV₁ of 8.2% (compared to approximately 14% in the Phase III trials) with an improvement in BMI of 0.65 kg/m².(7) Early clinical experience suggests varied outcomes for people with advanced CF lung disease treated with ETI, with most experiencing an improvement in BMI, exacerbation frequency and cough, but variable effects on lung function. From the available clinical trial data for ETI, adverse event rates were similar for individuals with ppFEV₁ <40% compared to those with higher lung function.(2, 5) Collective anecdotal experience suggests that some individuals with advanced CF lung disease have severe cough and copious sputum production in the first few days after initiation, suggesting that counseling on early symptom changes is prudent. However, experience to date does not suggest that hospitalization of those with advanced disease is warranted solely for the purpose of initiating ETI. Further studies of ETI for those with advanced CF lung disease are warranted, but initiation of ETI appears to be safe and effective for most patients who are otherwise good candidates for treatment.

An evaluation of data from the US and United Kingdom (UK) registries demonstrated that IVA use was associated with decreased risk of death and need for lung transplant in those treated CF populations.(8) However, it is important to recognize that HEMT does not “cure” CF, and consideration of lung transplant for people with advanced CF lung disease on HEMT is an essential component of comprehensive CF care. When individuals with advanced CF lung disease meet lung transplant referral criteria despite HEMT use, it is appropriate to refer them to a lung transplant program for evaluation. The decision to list for lung transplant will be more complex in the HEMT era, as we lack data about long-term outcomes for a large population treated with HEMT. Early experience has demonstrated that a significant number of persons with CF who were listed for lung transplant improved sufficiently to be removed from the transplant waiting list. Transplant teams are encouraged to consider each patient’s clinical and physiological trajectory, in addition to relevant markers of disease severity (such as oxygen requirement, exacerbation frequency, and presence of hypercapnia and pulmonary hypertension), when determining the timing of listing for lung transplant or when deciding about removal from the transplant waitlist. Also, frank discussion regarding the unknown risks and benefits of ETI post-transplant should occur prior to transplant.

Solid organ transplant: To continue or initiate HEMT

Non-lung solid organ transplant

Individuals with CF who have undergone non-lung solid organ transplant, most often isolated liver transplant, continue to have CF lung disease and treatment with HEMT is indicated to improve pulmonary outcomes, including ppFEV₁ and pulmonary exacerbation frequency. Initiation of ETI in transplant recipients requires consultation with the transplant team. There may be complications in the graft that could prohibit use of HEMT for some period of time following transplant. The risk for liver toxicity due to ETI, especially in the setting of liver transplant, is an important consideration and warrants increased monitoring for elevation of transaminases. Because organ transplant recipients require multiple medications for immunosuppression, attention to drug-drug interactions is critical. Interactions of ETI with cytochrome P450 enzymes leads to induction or inhibition of multiple medications, including azole antifungal agents (e.g. fluconazole, posaconazole), calcineurin inhibitors (e.g. tacrolimus, cyclosporine), mTOR inhibitors (e.g. sirolimus, everolimus), and others that may be used in the transplant setting.(4) Dose reductions of ETI and/or the transplant medication may be necessary, and consultation with the transplant team and a pharmacist is recommended.(4) There are currently no clinical standards for assessing adequate ETI levels at baseline nor in the setting of dose reduction to correct for drug-drug interactions.

Lung transplant

Lung transplant recipients no longer have CF lung disease. FDA approval of HEMT was based on significant improvement in the primary endpoint of ppFEV₁ in the pivotal Phase III trials.(1–3) Therefore, lung transplant recipients with CF will not derive the primary benefit of this treatment. HEMT, including ETI, has effects on important non-pulmonary manifestations of CF, including nutritional outcomes (e.g. BMI)(1–3), sinus disease (9–11), and the severity of CF-related abnormalities in glucose metabolism (12–14). IVA may influence antibiotic responsiveness of Pseudomonas aeruginosa, an important CF pathogen. (15)

For lung transplant recipients with CF, extra-pulmonary manifestations of CF may contribute to development of chronic lung allograft dysfunction (CLAD)(16), otherwise known as “chronic rejection.” CLAD is the largest barrier to long-term survival after lung transplant (16, 17) and reducing the risk of CLAD could drastically impact lung transplant recipient longevity. There are multiple known risk factors for CLAD. Acute cellular rejection is the biggest risk factor for CLAD (18, 19), and antibody mediated rejection (20) is increasingly recognized as a risk factor.(16) Non-immune causes of epithelial injury and subsequent CLAD include: acute infections, specifically with viruses (21, 22); gastroesophageal reflux disease, where a growing body of literature shows an association with CLAD, and anti-reflux surgery may improve ppFEV₁ or prevent progression of CLAD (23, 24); chronic sinus disease and chronic airway infection (18). Airway inflammation likely plays an important role in the development of CLAD, and multiple inflammatory markers have been associated with airway injury in the lung allograft [IL-6, IL-8, TGF-β, IL-17, PMNs](25–27).

Chronic sinus disease is thought to be a risk factor for colonization of the lung allograft with P. aeruginosa and methicillin-resistant Staphylococcus aureus.(28, 29) P. aeruginosa colonization in the lung allograft has been linked to increased risk for development of donor specific HLA antibodies, antibody mediated rejection, and CLAD.(18, 30) Surgical treatment of sinus disease has been associated with decreased risk of pulmonary infections in lung transplant recipients with CF.(31) There have been conflicting results in small studies of sinus surgery for CF chronic rhinosinusitis and effect on lung transplant outcomes.(32–34) One study showed that for patients in whom sinus pathogens were eradicated, there was an improvement in 5-year survival and reduced rates of CLAD.(34) A separate study showed that IVA enhances fluoroquinolone activity against P. aeruginosa.(15) For individuals with refractory symptomatic sinus disease, colonization with P. aeruginosa, and/or difficult to manage chronic rhinosinusitis, use of HEMT after lung transplant has the potential for benefit, but requires further study.

Malnutrition is commonly present for lung transplant recipients with CF.(35, 36) While survival after lung transplant may be worse for malnourished CF recipients compared to CF recipients with normal weight,(36) there are no data about targeted treatment, such as HEMT, to improve BMI after transplant. From clinical experience, CF recipients tend to gain weight after lung transplant due to a combination of corticosteroids, reduced caloric needs, and decreased pulmonary symptoms. Whether HEMT will prove to be beneficial for individuals who struggle with refractory malnutrition after lung transplant is unknown, however, a trial of HEMT may be reasonable for some individuals with refractory malnutrition.

CF lung transplant recipients are at an increased risk of gastrointestinal malignancies (37) and post-transplant lymphoproliferative disorder (PTLD)(38). There is evidence that CFTR protein acts as a tumor suppressor (39) and CFTR dysfunction could play a role in CF recipients’ risk for malignancy after lung transplant. Determining whether HEMT might prevent malignancy will require long-term observation of individuals on treatment for years after lung transplant.

Just as in non-lung solid organ transplant, there are risks associated with the use of HEMT after lung transplant. The potential for drug-drug interactions (4), side effects, and toxicity from HEMT adds additional complexity for a patient population with potentially tenuous clinical status. Further, it is not clear whether the lung transplant population will derive meaningful benefit beyond what can be achieved with traditional therapies for sinus disease or malnutrition. In truth, we are still learning about the many systemic implications of HEMT in the PROMISE (NCT04038047), RECOVER (NCT04602468), and other ongoing clinical studies (NCT04056702). HEMT should be studied in a randomized controlled trial to determine benefits and harms in the lung transplant population.

Pregnancy: To stop or continue HEMT

As women with CF live longer and healthier lives, an increased number are contemplating pregnancy (40, 41); consequently, the number of pregnancies in women with CF is increasing (42). In order to protect the unborn fetus from known or unknown impacts of new therapeutics, pregnancy is an exclusion criterion for most Phase III studies. Pregnancy was an exclusion for enrollment in the studies that led to approval of ETI, as well as for all of the previously approved CFTR modulators (Table 1).(1–3, 43–45) Animal studies, case reports and an international survey have suggested no major harm from use of CFTR modulators during all or part of pregnancy; however, human data are relatively limited.(46–53) Thus, when a woman with CF using CFTR modulators presents to discuss the potential of pregnancy or presents with pregnancy, the risks and benefits must be weighed. There are several considerations, including 1) the benefits to the mother (particularly improved lung function and weight and decreased pulmonary exacerbations) 2) the risk to the mother of stopping (decreased lung function and weight, inability to gain adequate weight, increased pulmonary exacerbations, and in rare cases, death) (54, 55) and 3) the unknown risk to the developing fetus of continuation of the drug (4, 56) (Figure 2).

Figure 2. Risks of continuation or discontinuation of highly effective modulator treatment (HEMT) during pregnancy.

The unknown risk to the fetus includes the potential risk of the development of cataracts based on demonstration of cataract formation in juvenile rats who were administered ivacaftor.(56)

Consider the following scenarios:

1. In spite of counseling about the possibility of increased fertility in women with CF using CFTR modulators (46–48), a G₀P₀ 35 year-old married woman with CF who is heterozygous for F508del and Gly542X (G542X) whose baseline ppFEV₁ is 65% postinitiation of ETI presents to CF clinic with a positive home pregnancy test 3 months after beginning ETI. Prior to beginning ETI, her baseline ppFEV₁ was 50% and she was experiencing approximately 3–4 pulmonary exacerbations per year, including at least 1 that required intravenous antibiotics. She and her husband are planning to continue the pregnancy, and she would like an opinion about whether to continue or stop ETI therapy during pregnancy.

2. A 25-year-old woman is referred to CF clinic with a new diagnosis of CF. She had originally presented to the obstetrics clinic for her first evaluation during which she underwent genetic screening which revealed that she was heterozygous for F508del and 3120 +1G>A. The husband is also determined to be a F508del carrier. The woman and her husband elect to forego amniocentesis because they plan to continue with the pregnancy regardless of the testing outcome. She and her husband would like to know if there are any therapies she can start to ensure her optimal health during her pregnancy that are also safe for her baby.

When considering the risk to the unborn child, sponsors for each new therapy that is being considered by the FDA for approval must evaluate the impact of the therapy in an animal reproduction model.(57) Although none of the approved CFTR modulators were tested in combination in animal reproduction models, IVA, lumacaftor, tezacaftor and elexacaftor were tested in such models individually.(4, 56, 58, 59) Data from animal testing indicated that each drug was transferred across the placenta, but led to no genotoxicity at any tested dose. Further, there was no impact on fetal organogenesis or survival when normal human doses were administered. These data in animals are reassuring. The limited data in women with CF who continued CFTR modulators during pregnancy were reviewed by a task force of the European Respiratory Society/Thoracic Society of Australia and New Zealand. The reproduction and pregnancy in women with airways diseases management task force deemed the approved CFTR modulators as “probably safe” during pregnancy.(60)

When counseling women with CF regarding the risks and benefits of continuing CFTR modulators during pregnancy, care teams must also consider the risk to the mother of discontinuation of CFTR modulator therapy. It is clear from Phase II studies of CFTR modulators that the rapid gains from CFTR modulators are quickly lost following CFTR modulator cessation.(55) Furthermore, Trimble et al. reported the occurrence of “ivacaftor withdrawal syndrome” following abrupt discontinuation of IVA after long-term use; two people experienced rapid and severe decline in lung function and one person died.(54) Finally, in a report of 61 women with CF who continued CFTR modulators during all or part of pregnancy, 9 women experienced clinical decline after cessation of modulator therapy that led to re-initiation of therapy.(53) Severe and/or rapid loss of lung function or other health decline in the mother may also pose a risk to the fetus (Figure 2), thus these risks of modulator discontinuation must be taken into account.

In the reports of women with CF who continued modulators during pregnancy to date (46–53), none have born children with CF. Currently, IVA is approved down to 4 months of age in the US.(56) Based on the data from trials of CFTR modulators in young children, it is clear that some aspects of the complications of CFTR dysfunction, such as pancreatic insufficiency, are completely or partially reversible with early administration.(61–63) These data have sparked interest in whether even earlier administration, at the time of diagnosis, or in utero in a pregnant woman with CF known to be carrying a child with CF would prevent complications in CF.

To evaluate the impact of IVA in utero on CF outcomes in the fetus, Sun and colleagues administered IVA (VX770) to pregnant ferrets generated to be homozygous for G551D, or heterozygous for G551D and a CFTR knock out mutation.(64) In IVA-treated animals homozygous for G551D, investigators demonstrated rescue of multiple downstream consequences of CFTR dysfunction including pancreatic dysfunction and absence of the vas deferens and epididymis in the kits. Furthermore, even in treated pregnant ferrets heterozygous for G551D and a knockout mutation, in utero administration of IVA led to reduction in the incidence of meconium ileus and pancreatic dysfunction in the kits. Thus, it is possible that treatment of a pregnant woman with CF known to be carrying a child with CF could markedly improve outcomes for her child. While treatment of a pregnant woman with CF who is carrying a child with CF might seem an obvious choice to some because of the clear potential benefits to both mother and child, the discussion of treating a mother who is an asymptomatic CF carrier who is discovered to be carrying a child with CF will be more challenging. Treating a mother who is an asymptomatic carrier would offer her no known benefit in the setting of only one abnormal CFTR allele. Furthermore, the costs for a medication not covered by insurance because of lack of indication for the pregnant woman would likely be prohibitive.

The data demonstrating rescue of pancreatic function in pregnant animal models of CF not only have potential implications for mothers with CF whose unborn infant is known to have CF, but also for newborn screening programs. Newborn screening (NBS) programs are now common both in and out of the US. The testing used for newborn screening varies widely. For example, in some states immunoreactive trypsinogen (IRT), a measure of pancreatic function, is used as the initial test. In other states, genetic testing for F508del alone, or for a limited number of mutations, is utilized. Finally, some states use a combination of IRT and genetic testing. Based on data from the CF ferret model, an infant born to a mother with CF treated with HEMT throughout pregnancy might be partially or completely pancreatic sufficient. In such a case, it is highly likely that a NBS test solely relying on IRT for diagnosis would produce a false negative result. Therefore, it will be critical to perform CFTR genotyping for infants born to these mothers in states that rely on IRT for NBS.

People with CFTR-related disorders: a role for HEMT?

Mutations in the CFTR gene that produce lower levels of CFTR function are associated with worsened CF phenotypes. In the US, there are more than 10 million CF carriers, people with only one mutation in CFTR, and they are routinely counseled that they are not at an increased risk of disease. CF carriers may, however, have a form of CFTR haploinsufficiency (the normal CFTR allele produces functioning CFTR protein but the total amount of CFTR protein does not reach a sufficient level of function to allow for a normal phenotype). In a study by Miller et al., investigators aimed to determine whether CF carriers had increased risk for CF-related conditions.(65) The investigators identified a CF carrier cohort and a CF cohort via ICD-9/ICD-10 codes in a large commercial claims research database. They generated age- and sex-matched cohorts at a 5:1 ratio for comparison. The investigators estimated the odds of individuals being diagnosed with a CF-related condition relative to people in their matched cohort using conditional logistic regression. CF carriers had an increased risk for nearly all 59 tested CF-related conditions, across multiple organ systems, when compared to matched controls. The relative log odds ratios across the 59 conditions were correlated between CF carriers and subjects with CF. As the relative odds of a given condition increased among subjects with CF compared to their matched controls, so did the corresponding relative odds for carriers. Multiple sensitivity analyses showed robust results demonstrating increased relative risk for CF carriers compared to matched controls. The authors stressed that the absolute risk for a majority of the CF-related conditions in CF carriers remains low. CF carriers are at increased risk for most conditions that commonly occur in people with CF, such as sinusitis, bronchiectasis and pancreatitis, amongst others which may have implications for screening, prevention, and/or treatment of those conditions.

Variants of uncertain clinical significance or variants of varying clinical consequence pose a similar challenge for clinicians considering treatment for CF-related conditions or a CF phenotype. When an individual with potential CFTR-related haploinsufficiency and a CF phenotype has normal sweat chloride testing and/or only one mutation identified by whole genome sequencing, the use of HEMT has biological plausibility for potential clinical benefit to the individual. Given the high cost of CFTR modulators, it will be cost prohibitive to treat CF carriers, or individuals who do not meet diagnostic criteria for CF, who have CF-related conditions unless there are robust clinical trial data to support the practice, which in turn could lead to insurance coverage of the medications.

Conclusions

While there are anecdotal clinical experiences with the use of ETI in unstudied or understudied populations, there are little to no data published to determine the role of HEMT in most of the challenging situations described herein. Given the potential for tremendous benefit with the use of HEMT in people with native CF lung disease (e.g. advanced CF lung disease, pregnant women with CF, non-lung solid organ transplant recipients), the potential benefits of initiation/continuation of HEMT warrant shared decision making between patients and providers. For populations in which the pulmonary benefit of HEMT may not be experienced (e.g. lung transplant recipients, CF carriers, those without a clear diagnosis of CF), caution is advised until there are data to support the clinical use of these treatments. HEMT is rapidly transforming the severity of many CF manifestations, and the careful consideration of this therapy for populations with the most favorable risk to benefit ratio is critical.

Highlights:

• Highly effective modulator treatment (HEMT) may be indicated in complex settings

• People with native CF lung disease are likely to benefit from initiation of HEMT

• Benefits and harms of HEMT after lung transplant are uncertain and should be studied

• In pregnancy, maternal risks and benefits weigh against uncertain risks to the fetus

• Cost of HEMT may limit access despite biologic plausibility of clinical benefit