Breakthrough Clinical Results
Sionna Therapeutics announced the presentation of Phase 1 clinical trial data for SION-719 and SION-451, first-in-class NBD1 stabilizers, at the 2025 North American Cystic Fibrosis Conference (NACFC). The Phase 1 trials demonstrated that both drugs were generally well tolerated and exceeded target exposure levels in healthy volunteers. New preclinical data showed that NBD1 stabilizers restored the half-life of F508del-CFTR up to wild-type levels. Sionna is also advancing a Phase 2a proof-of-concept study in CF patients, with read-outs expected in mid-2026.
Key Highlights
- Phase 1 data of SION-719 and SION-451 demonstrated they were generally well tolerated and exceeded desired pharmacokinetic targets.
- New preclinical data show that NBD1 stabilizers restored the half-life of F508del-CFTR up to wild-type levels.
- Sionna has initiated a Phase 2a proof-of-concept study in CF patients.
- Sionna's NBD1 stabilizers have the potential to improve CFTR half-life up to wild-type levels.
Incidence and Prevalence
Latest Global Estimates of Cystic Fibrosis Incidence and Prevalence
Global Incidence Trends
Cystic fibrosis is the most common life-limiting autosomal recessive disease in western countries. The most recent data from 2023 indicates that contemporary CF incidence rates in Canada and the US are lower than previously reported, with substantial regional variation within both countries.
In 2019, the estimated incidence rate for CF was 1:3848 (95% CI: 1:3574, 1:4143) live births in Canada compared to 1:5130 (95% CI: 1:4996, 1:5267) in the US. Since 1995, incidence rates have decreased at a rate of 1.6% per year in both Canada and the US.
Earlier reports indicated that in the United States, CF has been estimated to occur in 1 out of 3500 infants, while some sources cite an incidence of 1:2500. In some European countries, the incidence is reported as 1:1000.
In Italy, the estimated incidence was 1:9,097 living births in 2021 and improved to 1:6,232 in 2022.
Regional Variations
In the Middle East, similar incidences were noted with variations from 1 in 2560 to 1 in 15,876 according to the degree of consanguinity. A study from Lebanon found 5.5%-7% of newborns were carriers of a variant strongly suggestive of pathogenicity, comparable to published literature worldwide. In Saudi Arabia, the eastern and northern provinces have the highest prevalence of CF.
Prevalence Data
In Italy, the prevalence rates were 10.1 and 10.3 per 100,000 residents for 2021 and 2022 respectively. Earlier data showed prevalence of 9.36/100,000 residents in 2019 and 9.79/100,000 residents in 2020.
Ethnic and Racial Disparities
In the United States, Non-Hispanic White CF patients had the highest prevalence of CF (26.30 per 10,000 hospitalizations). The prevalence of inpatient deaths were highest among those identified as NH-Others and NH-Blacks (71.35 and 68.83 per 10,000 CF hospitalizations, respectively).
Based on CFTR mutations alone, 92.4% of non-Hispanic White patients, 69.7% of Black/African American patients, 75.6% of Hispanic patients, and 80.5% of other race patients were eligible for CFTR modulators. For each CFTR modulator, Black/African American patients were least likely to have eligible mutations, and non-Hispanic White patients were most likely.
Underestimated Global Burden
Recent epidemiological studies suggest a higher global prevalence of CF than previously thought. Emerging data reveal higher-than-expected prevalence of cystic fibrosis among non-European populations worldwide including in the Indian subcontinent.
In a study from India, among 120 people with CF, 55 CFTR variants were identified, with F508del being the predominant mutation, yet with a lower allele frequency than reported among European populations (27% versus 70%).
Comprehensive CF data remains extremely scarce among African populations, contributing to a significant information gap within the African healthcare system. The prevalence of CF in North African countries is likely underestimated due to the complexity of the disease and the lack of a timely, proper clinical and genetic investigation.
Key Unmet Needs in Cystic Fibrosis Treatment
Patients with Rare Mutations
Despite the revolutionary impact of CFTR modulators like elexacaftor/tezacaftor/ivacaftor (ETI), several patient populations remain without effective treatment options. More than 2000 mutations have been identified in the CFTR gene, with approximately 240 causing CF. Patients with rare CFTR variants are often not candidates for innovative treatments, creating a significant unmet need.
Key underserved populations include: * Patients with rare mutations not yet eligible for CFTR modulators * Individuals with F508del/unknown genotypes (about 1.3% of Italian CF patients) * Patients whose mutations produce no CFTR protein (more than 10% of CFTR mutations) * Those with mutations in NBD1 domain that respond poorly to modulators
Emotional and Psychological Impact
Patients ineligible for ETI experience intense disappointment and conflicting emotions that significantly impact their well-being. These emotions are linked to diminishing/renewal hope and require specialized support. There is a critical need for integrated care including mental health monitoring programs to help these patients cope with their exclusion from breakthrough therapies.
Research Approaches for Rare Mutations
Current research focuses on developing solutions for these underserved populations through: * Using ex vivo models for preliminary assessment of CFTR modulators in rare cases * Testing drug responses on nasal epithelial cells to predict clinical efficacy * Evaluating the impact of rare mutations on CFTR expression and processing * Understanding why mutations in TMD1 respond better to modulators than those in NBD1
Alternative Treatment Approaches
Several approaches are being developed for patients with ineligible mutations: * Broadening the numbers of mutations eligible for CFTR modulators * Developing mutation-specific or mutation-agnostic therapies * Creating readthrough agents for nonsense mutations * Advancing nucleic acid-based therapies (RNA or DNA-based) * Exploring cell-based therapies
Most of these approaches remain in pre-clinical development or early clinical phases, highlighting the ongoing unmet need.
Continuing Needs Despite Modulators
Even patients receiving CFTR modulator therapy continue to experience unmet needs requiring palliative care to address: * Physical, emotional, and spiritual distress * Communication difficulties with family and friends * Anxiety over illness or treatment * Persistent lack of energy
Additionally, patients with advanced CF lung disease have generally been excluded from initial clinical trials of CFTR modulators, and randomized controlled trial data for this population are lacking. Current transplant referral guidelines have not fully incorporated the status of new CFTR modulator therapies.
Study Design Parameters
Study Design Parameters and Endpoints in Key Cystic Fibrosis Trials
Study Design Parameters
Randomized controlled trials are essential for evaluating new therapies in CF, with placebo-controlled studies commonly used to demonstrate maintenance of lung function and reduced exacerbations. Both cross-over designs and parallel designs are utilized, with cross-over designs maximizing patient participation. A 2022 review of airway clearance techniques included 11 cross-over studies (153 participants) and one parallel study (41 participants).
Sample sizes vary considerably due to CF being an orphan disease. Recent trials range from smaller studies (74 patients in a derivation cohort) to larger ones (a 2024 meta-analysis included 6 studies with 1,127 patients). Trial durations span from single-treatment studies to longer follow-ups, with some measuring outcomes at 12 months (primary endpoint) and 15 months (secondary endpoint).
Blinding is standard in medication trials but impossible in airway clearance studies, leading to unclear risk of performance bias. Studies with less than seven days duration are often excluded from systematic reviews.
Primary Endpoints
Lung function remains a standard clinical efficacy measure, typically assessed through: - Forced expiratory volume in 1 second (FEV1) percent predicted - Absolute change in percentage of predicted FEV1 from baseline - Relative change from baseline in FEV1
Acute pulmonary exacerbations serve as a critical endpoint associated with progressive lung function decline and increased mortality.
Other primary endpoints include: - Sweat chloride concentration changes - Coefficient of fat absorption - Quality of life measured with validated instruments
Secondary Endpoints
Secondary measures frequently include: - Pulmonary exacerbation rates - Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain scores - Body mass index (BMI) and weight - Sweat chloride concentration (when not a primary endpoint) - Rate of events leading to hospitalization or use of intravenous antibiotics - Symptoms and adverse events
Key CFTR Modulator Trials
Ivacaftor trials demonstrated clinically relevant impacts at 24 and 48 weeks, with improvements in relative change from baseline in FEV1 (mean difference 16.90%).
Lumacaftor/ivacaftor studies in young children showed the treatment was generally safe with significant reductions in sweat chloride concentration (-29.1 mmol/L).
Elexacaftor-tezacaftor-ivacaftor (ETI) trials included a phase 3, randomized, double-blind, placebo-controlled trial with 403 patients that showed: - FEV1 improvement of 14.3 points through 24 weeks - 63% lower rate of pulmonary exacerbations - 20.2 points higher respiratory domain score on the CFQ-R - 41.8 mmol/L lower sweat chloride concentration
A recent N1303K variant trial (2024) evaluating ETI showed significant improvements in ppFEV1 (9.5 percentage points increase) despite no significant change in sweat chloride.
The CF research community continues to develop biomarkers and surrogate endpoints while emphasizing the importance of patient-centered outcomes and treatment burden measures.