Dear Members of Colorado’s Prescription Drug Affordability Board:
On behalf of people living with cystic fibrosis in Colorado, the Cystic Fibrosis Foundation writes to provide comments on the Prescription Drug Affordability Board’s (PDAB) affordability review of elexacaftor/tezacaftor/ivacaftor (ETI/Trikafta®). We appreciate the opportunity to provide this written feedback in addition to participating in the Stakeholder Meetings held on September 27, 2023. We have some concerns about the PDAB’s proposed methodology and potential limitations related to Trikafta, which we describe below. We also provide a compilation of published data on the effects of Trikafta on clinical outcomes and other health care utilization. Additionally, we have included our submitted letter from June of this year that further articulates the value of this transformative therapy.
About cystic fibrosis & the Cystic Fibrosis Foundation
Cystic fibrosis is a life-shortening genetic disease that affects nearly 40,000 children and adults in the United States, including more than 700 in Colorado — nearly 94% of whom have a genotype eligible for Trikafta. CF causes the body to produce thick, sticky mucus that clogs the lungs and digestive system, which can lead to lung damage, life-threatening infections, malnutrition, and other complications. Cystic fibrosis is both serious and progressive; lung damage caused by infection is often irreversible and can have a lasting impact on length and quality of life, resulting in extended hospitalizations, transplant, or premature death. As a complex, multi-system condition, CF requires targeted, specialized treatment and medications. There is no cure and CFTR modulators — Trikafta specifically — represent the most impactful treatment to date.
As the world’s leader in the search for a cure for CF and an organization dedicated to ensuring access to high-quality, specialized CF care, the Cystic Fibrosis Foundation supports the development of CF clinical practice guidelines and accredits more than 130 care centers nationally — including two in Colorado.
Concerns with the PDAB’s affordability review methodology
The Foundation has several concerns regarding the process by which the PDAB plans to review the affordability of drugs. To start, the Board’s definition of “therapeutic alternative” is concerning. During the PDAB’s most recent meeting on September 15th, Board members agreed that their consideration of therapeutic alternatives should include any drugs in the same class indicated to treat the same condition. Under this definition, the three other CFTR modulators currently available to patients (Kalydeco®, Orkambi®, and Symdeko®) would be considered therapeutic alternatives to Trikafta. This framework should not be applied to CFTR modulators for several reasons. First, CFTR modulators are indicated for patients with particular genetic variants (mutations) and are not necessarily interchangeable. In fact, approximately 230 people in Colorado have CFTR genotypes that only qualify for Trikafta and are not eligible for other CFTR modulators. Second, Trikafta is a significantly more efficacious treatment than Orkambi or Symdeko and these therapies should not be considered as equivalent alternatives. In fact, because of the additional benefits of Trikafta, 85% of individuals previously prescribed Orkambi or Symdeko have transitioned to Trikafta as of the end of 2022.
The Foundation is also concerned with the timing of this review and the need to have more data on the long-term, real-world impact of this therapy. The U.S. Food and Drug Administration (FDA) approved Trikafta in October 2019, resulting in almost 2 years less available data compared to other therapies currently under review by the PDAB. The COVID-19 pandemic may also skew the "financial effects of the prescription drug on health, medical, or social services costs,” as many people delayed care during the acute early phase of the pandemic. Additionally, the FDA approved several label expansions for Trikafta since its initial approval — as recently as this year for 2- to 5-year-olds. For these additional, younger age groups, it is too early to understand the long-term implications of Trikafta on longer term health and well-being.
We have also heard from the CF community that patients do not understand the PDAB review process and the Board’s plans to use patient and caregiver input. This is especially important given the sensitive questions being asked about cost burden and affordability. More lay-friendly explanations of this process would help the general population better understand the PDAB’s ongoing work and encourage greater, more meaningful participation in stakeholder engagement opportunities.
Additional data and research
In addition to the evidence we shared in our June letter to the PDAB, we have summarized the following key studies to further inform the Board’s review of Trikafta. The manuscripts are both attached and summarized below.
Cystic Fibrosis Foundation Patient Registry (CFFPR) Data
- Approximately 230 people in Colorado have CFTR genotypes that do not qualify for other approved CFTR modulators.
- The rate of hospitalizations among individuals with CF aged 12 and older (at least one copy of F508del) dropped from 932 hospitalizations per 1,000 person years in 2017 to 301 hospitalizations per 1,000 person-years in 2022. The proportion of people with at least one hospitalization per year dropped from 41% in 2017 to 17% in 2022.
- At the population level, Trikafta has decreased the all-cause mortality rate by more than 50% for people 12 years old and above in 2020 with at least one copy of the F508del variant with no history of transplant. From 2017-2019, the mortality rate was 13.6 deaths per 1,000 person-years. Over the three years since Trikafta has been approved (2020-2022), the mortality rate has dropped to 6.0 per 1,000 person-years.
- At the population level, the rate of first lung transplant among people with at least one copy of F508del (age 12 and older as of 2020) has dropped from 11.8 per 1,000 person-years to 0.9 persons per 1,000 person-years from 2017 to 2022.
Impact of Trikafta on Clinical Outcomes — Registration Studies
- Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial (Heijerman, H.G.M, et al)
- Relevance: Phase 3 clinical trial data of the impacts of ETI on percent predicted FEV1, sweat chloride, and CF Questionnaire-Revised respiratory domain (CFQ-R RD).
- Methodology: Phase 3, multi-center, randomized, double blind, trial of ETI impacts for people with CF with homozygous F508d mutations.
- Key Findings: People with CF on ETI experienced a mean 10 percentage point increase in percent predicted FEV1, a 45 mmol/L decrease in sweat chloride, and a 17.4-point increase in their CFQ-R RD score. ETI was also generally well-tolerated with no discontinuations.
- Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial (Sutharsan, S. et al)
- Relevance: An international study comparing ETI to tezacaftor/ivacaftor, another CFTR modulator therapy.
- Methodology: Phase 3b multicenter, randomized, double-blind, active-controlled, phase 3b trial of 176 people in Australia, Belgium, Germany, and the UK. Participants initially took tezacaftor/ivacaftor and then either continued therapy or changed to ETI. Primary endpoint was change in Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score with secondary endpoints being percent predicted FEV1, sweat chloride, and safety and tolerability.
- Key Findings: The CFQ-R RD score increased by 17.1 points for those in the ETI group compared to a 1.2-point increase in the tezacaftor/ivacaftor group. The percent predicted FEV1 increased by 11.2 percentage points in the ETI group compared to 1 percentage point in the t tezacaftor/ivacaftor group. Mean sweat chloride decreased by 46.2 mmol/L for those on ETI compared to 3.4 mmol/L for those on tezacaftor/ivacaftor. ETI was well tolerated.
- Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (Middleton, P.G. et al)
- Relevance: Phase 3 clinical trial data evaluating the impacts of ETI on lung function, pulmonary exacerbations, sweat chloride levels, and quality of life.
- Methodology: Phase 3, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ETI in over 400 people with CF aged 12 or older who have one copy of the F808del mutation and a minimal function mutation.
- Key Findings: ETI, relative to placebo, had the following statistically significant results: a ~14 point increase in percent predicted FEV1, a 63% reduction in pulmonary exacerbation rate, a ~20-point increase in the respiratory domain score on the Cystic Fibrosis Questionnaire– Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points), and a ~42 mmol/liter decrease in sweat chloride concentration. ETI was generally well tolerated with an acceptable side-effect profile.
- A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele (Zemanick, E. et al)
- Relevance: A phase 3 study assessing the safety and efficacy of ETI in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes.
- Methodology: 24-week, open-label, assessing the safety of ETI in children as well as the impacts on percent predicted FEV1, Cystic Fibrosis Questionnaire-Revised respiratory domain score (CFQ-R RD), lung clearance index2.5, and sweat chloride.
- Key Findings: ETI was generally found to be well tolerated in children aged 6-11. Percent predicted FEV1 increase by a mean of over 10 percentage points. CFQ-R RD score increased by 7 points, lung clearance index decreased by over 1.7 units, and sweat chloride decreased by nearly 70 mmol/L. Body mass index-for-age z-score also increased when compared to pretreatment baselines.
- Phase 3 Open-Label Clinical Trial of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged 2–5 Years with Cystic Fibrosis and at Least One F508del Allele (Goralski, J. et al)
- Relevance: A phase 3 study assessing the safety and efficacy of ETI in children 2 through 5 years of age with at least one F508del mutation.
- Methodology: 24-week, open-label, assessing the safety of ETI in children as well as the impacts on lung clearance index, and sweat chloride.
- Key Findings: ETI was generally found to be well tolerated for children aged 2-5. Lung clearance index decreased by over 0.8 units, and sweat chloride decreased by nearly 60 mmol/L.
Impact of Trikafta on Clinical Outcomes — Post-Approval & Long-term Follow-up Studies
- Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis and at Least One F508del Allele: 144-Week Interim Results from a 192-Week Open-label Extension Study*
- Relevance: Open-label extension study following Phase 3 clinical trials to assess the longer-term safety and efficacy of ETI treatment.
- Methodology: Participants with at least one copy of the F508del mutation who participated in Phase 3 studies of ETI were invited to participate in a 192-week open label observational study to assess longer term safety and health impacts of ETI in people with CF.
- Key Findings: Nearly all (99.2%, n=506) of participants from the phase 3 study chose to participate in the study. Findings from the first 144-weeks of the study were as follows: ETI was generally safe and well-tolerated and no new safety concerns emerged. Statistically significant improvements in percent predicted FEV1 of 14.8% points occurred and was maintained when those participants who had one copy of F508del and were in the placebo group received ETI. Those who received study drug in the phase 3 trial sustained their >14% percent predicted FEV1 improvements. Improvements in BMI, CFQ-R RD and decreased rates of pulmonary exacerbations were also maintained in participants with one or two copies of F508del. (NOTE: This manuscript and its supplement have been accepted for publication in the European Respiratory Journal. The enclosed copies are the accepted versions of the manuscript and subject to minor edits by the publisher prior to print.)
- Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial (Nichols, D. et al)
- Relevance: Post-approval study in the U.S. looking at impacts of ETI after 6 months of therapy use. This study included people who had never taken a CFTR modulator as well as those who were previously on lumacaftor/ivacaftor, tezacaftor/ivacaftor, or ivacaftor.
- Methodology: Prospective, observational study of over 480 people with CF in the U.S. assessing impacts of ETI on percent predicted FEV1, sweat chloride, BMI, and self-reported respiratory symptoms.
- Key Findings: Statistically significant improvements included a 9.7 percentage point increase in FEV1, a 20-point increase in respiratory symptoms, over a 41 mmol/L decrease in sweat chloride and a significant improvement in BMI. Those who had never taken a modulator experienced the greatest improvement; however, there was significant improvement for those who had transitioned from a different modulator therapy.
- Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study (Bower, J. et al)
- Relevance: Real world, longer-term data on key outcomes for people with CF on ETI in the U.S.
- Methodology: 5-year observational study using registry-based data that assessed long-term effects of ETI on over 16,000 people with CF in the United States. This publication shows interim data from the first 2 years of the study.
- Key Findings: Sustained improvements in lung function, reduced frequency of hospitalizations (both all-cause and pulmonary exacerbation-specific), increased BMI, and lower prevalence of positive bacterial cultures. Additionally, there was a 72% lower rate of death and 85% lower rate of lung transplantation relative to the year before ETI was available.
- Effect of elexacaftor/tezacaftor/ivacaftor on annual rate of lung function decline in people with cystic fibrosis (Lee, T. et al)
- Relevance: Real-world data assessing lung function decline and disease progression for people in the U.S. on ETI.
- Methodology: Observational study comparing lung function decline of ETI phase 3 clinical trial participants to a matched cohort from the CF Foundation patient registry who were not on a CFTR modulator therapy.
- Key Findings: Participants treated with ETI had on average no loss of pulmonary function over a 2-year period compared with a 1.92 percentage point annual decline in percent predicted FEV1 in untreated controls.
- Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study (Wiesel, V. et al)
- Relevance: International study on the change in nontuberculous mycobacteria (NTM) bacterial colonization for people taking ETI (a bacteria that impacts ~10% of people with CF in the U.S. per the 2021 CF Foundation Patient Registry).
- Methodology: Retrospective multicenter cohort study of people with CF in Israel evaluating people with CF older than 6 with a positive NTM airway culture in the past two years. NTM and bacterial isolations, pulmonary function tests, and body mass index were analyzed before and after ETI treatment.
- Key Findings: NTM isolations were eradicated following treatment with ETI, and eradication was associated with improved pulmonary function tests.
- Impact of Cystic Fibrosis Transmembrane Conductance Regulator Therapy on Chronic Rhinosinusitis and Health Status: Deep Learning CT Analysis and Patient-reported Outcomes (Beswick, D. et al)
- Relevance: Assess the impact of ETI on sinus disease, a common complication of CF. This study also looks at patient reported outcomes related to productivity.
- Methodology: Single-center, prospective, observational study of 25 people with CF in the U.S. over 6 months. The study specifically looked at percent sinus CT opacification and patient reported outcomes.
- Key Findings: Participants experienced an over 22% mean improvement in their percent sinus CT opacification at follow up, as well as improvement in presenteeism, activity impairment, and productivity loss.
Impact of Trikafta on Clinical Outcomes — Use in Special Populations
- Rapid Improvement after Starting Elexacaftor-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease (Burgel, P.R. et al)
- Relevance: Assesses the impacts of ETI in people with advanced lung disease and those on the lung transplant path.
- Methodology: Prospective observational study of 245 people with CF in France with advanced lung disease (percent predicted FEV1 <40) assessing clinical characteristics before and after ETI initiation.
- Key Findings: After ETI initiation, the mean percent predicted FEV1 increase was over 15 and the mean weight gain was over 4kg. There was also a significant decrease in the number of patients requiring long-term oxygen (50% decrease), noninvasive ventilation (30% decrease), and enteral tube feeding (40% decrease). At the start of the study 16 people with CF were on the transplant waiting list and 37 were undergoing transplant evaluation, ultimately only 2 received transplant and 5 remained on the transplant path.
- Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis (Martin, C. et al)
- Relevance: Assessment of the clinical impacts of ETI on people with CF on the lung transplant path as well as the impacts on treatment burden.
- Methodology: Prospective study in France assessing the safety and effectiveness of ETI for those with advanced lung disease and were lung transplant candidates.
- Key Findings: Of the 65 lung transplant candidates, 61 no longer met the transplantation criteria due to improvements in clinical outcomes. Treatment burden also substantially decreased (86% decrease in intravenous antibiotics, 59% decrease in oxygen therapy, 62% decrease in non-invasive ventilation).
- Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation (Taylor-Cousar, J, et al)
- Relevance: An assessment of the safety of ETI use during pregnancy for pregnant people with CF.
- Methodology: Anonymous retrospective survey distributed to CF care centers in the U.S. to be completed by providers for pregnant people with CF in the United States.
- Key Findings: 45 respondents reported people with CF using ETI during pregnancy with complications experienced by 2 mothers and 3 infants (2 of which were born to mothers with poorly controlled diabetes). Data provides promising data on the safety of ETI during pregnancy. Importantly, 5 of 6 mothers who discontinued ETI during pregnancy (based on relatively unknown potential risks to the fetus) experienced rapid clinical deterioration and therefore needed to restart therapy.
Impact on Utilization of Other Healthcare Services
- Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials (Mayer-Hamblett, N. et al)
- Relevance: Assessment of the effects of discontinuing nebulized hypertonic saline or dornase alpha (two common maintenance medications for people with CF) for people with CF on ETI.
- Methodology: Multi-center open label, randomized controlled study at 80 clinics in the U.S. Participants were assigned to discontinue one of the two therapies and assessed to determine whether discontinuing was non-inferior to continuing.
- Key Findings: People with CF on ETI with relatively preserved lung function were able to discontinue treatment without any clinically meaningful differences.
- Cost analyses of potential savings based on SIMPLIFY study data (Gold, L. & Kessler, L.)*
- Relevance: Cost analysis of potential savings based on SIMPLIFY data, a study evaluating the effects and safety of stopping inhaled hypertonic saline or dornase alfa (Pulmozyme®) in teens and adults with CF who are also taking ETI. (*NOTE: This manuscript is currently under peer review with the Journal of Managed Care and Clinical Pharmacy and has been submitted through the PDAB’s secure portal.)
- Use of cystic fibrosis inhaled medication before and after elexacaftor/tezacaftor/ivacaftor initiation (Manika, K. et al)
- Relevance: Comparison before and after ETI initiation on use of common CF maintenance therapies in the U.S.
- Methodology: Multi-center retrospective study evaluating maintenance medication use in 71 people with CF taking ETI.
- Key Findings: The medication possession ratio for dornase alpha, colistin, tobramycin, and aztreonam significantly decreased after ETI initiation, suggesting that the use of ETI decreases the use of standard inhaled medications for people with CF.
- The Rapid Reduction of Infection-Related Visits and Antibiotic Use Among People with Cystic Fibrosis After Starting Elexacaftor-Tezacaftor-Ivacaftor (Miller, A. et al)
- Relevance: U.S. study evaluating potential impact of ETI on healthcare utilization (both care visits and antibiotic use).
- Methodology: Retrospective study assessing healthcare visit utilization and antimicrobial prescriptions for over 380 people with CF before and after taking ETI.
- Key Findings: Over a 15-week period, ETI was associated with reduced overall healthcare visit dates, inpatient admissions, infection-related visits, and antibiotic prescriptions.
Projected Future Impact
- Elexacaftor/tezacaftor/ivacaftor projected survival and long-term health outcomes in people with cystic fibrosis homozygous for F508del (Lopez, A. et al)
- Relevance: Simulation of potential impacts of ETI on lifespan compared to those solely taking standard of care therapies.
- Methodology: Person-level microsimulation model estimating the survival and lifetime clinical benefits of ETI treatment versus other CFTR modulator combinations or best supportive care alone in people with CF 12 and older who have two copies of the F508del mutation.
- Key Findings: The median projected survival for people with CF on ETI was 71.6 years. This was an over 23-year increase compared to other CFTR modulators and a 33.5-year increase compared to best supportive care. Treatment with ETI also reduced disease severity, the number of pulmonary exacerbations, and lung transplants. In a scenario analysis, the median projected survival for people with CF initiating ETI between the ages of 12 and 17 years was 82.5 years.
- Projecting the impact of delayed access to elexacaftor/tezacaftor/ivacaftor for people with Cystic Fibrosis (Stanojevic, S. et al)
- Relevance: Simulation of potential impacts of earlier initiation of ETI on lung disease status, pulmonary exacerbations, and deaths in Canada.
- Methodology: A microsimulation transition model was applied to Canadian CF Registry data to forecast lung disease severity, pulmonary exacerbations, deaths, and transplants to 2030 under three scenarios: 1) no availability of ETI, 2) availability in 2021 or 3) availability in 2025.
- Key Findings: Under specific assumptions regarding disease state and treatment effect applied to the Canadian CF population it is projected that by 2030, introduction of ETI in 2021 was expected to reduce the number of individuals with severe lung disease by 60%, increase the number of individuals with mild lung disease by 18%, and reduce the number of pulmonary exacerbations by 19%. Earlier introduction of ETI could reduce deaths by 15% and improve the median age of survival by 9.2 years over a 10-year period. The expected benefits of therapy are cumulative, therefore delayed access to elexacaftor/tezacaftor/ivacaftor will result in preventable health care utilization and deaths.
Impact of Interruption in CFTR Modulator Therapy
- Ivacaftor withdrawal syndrome in cystic fibrosis patients with the G551D mutation (Trimble, A. et al)
- Relevance: Case studies of the negative clinical impacts of gaps in access to CFTR modulators. While this study is evaluating ivacaftor, it is relevant as both ivacaftor and ETI are considered highly effective.
- Methodology: Case series describing three individuals with CF who experienced clinical decline following withdrawal from ivacaftor.
- Key Findings: In each instance, the person with CF experienced rapid deterioration of lung function and an increase in symptoms following cessation of ivacaftor.
Affordability and Access to Care
- Cost burden among the CF population in the United States: A focus on debt, food insecurity, housing and health services (Seyoum, S. et al)
- Relevance: A survey that assesses the impacts of cost burden on CF care and other tradeoffs in the CF population. This survey was fielded prior to ETI’s approval however it is the most recent wide-spread survey to date assessing cost burden in the U.S. A comparable follow-up survey is under development for 2024.
- Methodology: Survey to over 1,850 people with CF in the U.S. in 2019 asking questions about cost, tradeoffs, and social risk factors.
- Key Findings: 64% of respondents faced at least one financial burden: 55% reported debt issues, 26% housing issues, and 33% food insecurity issues. A third reported at least one unmet medical need: 24% faced unmet prescription needs, 12% delayed or shortened a hospitalization, and 10% delayed or skipped a care center visit because of the cost of care.
The Cystic Fibrosis Foundation and the undersigned CF physicians in Colorado appreciate the opportunity to serve as a resource for the PDAB as it explores solutions to improve access to care for Coloradans. As you assess the cost of Trikafta, it is critical to consider the lifesaving impact these therapies have already had for so many and the long-term value we expect these medicines will continue to provide. In addition to these written comments, the Foundation will provide the PDAB with additional data from our patient registry and other research to aid the Board as they consider the affordability of Trikafta.
Thank you for the opportunity to comment on these important issues.