Breakthrough Clinical Results
Avalyn Pharma showcased positive clinical data for its lead programs, AP01 (inhaled pirfenidone) and AP02 (inhaled nintedanib), at the American Thoracic Society (ATS) International Conference 2025. Phase 1 trials of AP02 demonstrated favorable safety and tolerability in healthy volunteers and IPF patients, with significantly lower systemic exposure and improved lung exposure compared to oral nintedanib. Long-term data from the ATLAS open-label extension trial of AP01 showed continued antifibrotic effects and favorable safety for up to 4.5 years. Avalyn also presented results from deep learning-based analyses of HRCT scans, exploring novel imaging biomarkers to validate treatment efficacy. These results support the advancement of AP02 into Phase 2 trials and the ongoing Phase 2b trial of AP01.
Key Highlights
- Phase 1 trials of AP02 (inhaled nintedanib) showed improved lung exposure and lower systemic exposure compared to oral nintedanib.
- Long-term data for AP01 (inhaled pirfenidone) demonstrated continued antifibrotic effects and favorable safety for up to 4.5 years.
- Deep learning analyses of HRCT scans validated treatment efficacy and explored novel imaging biomarkers.
- AP02 is advancing to Phase 2 clinical trials in IPF.
Incidence and Prevalence
Idiopathic Pulmonary Fibrosis (IPF), the most common form of pulmonary fibrosis, exhibits varying incidence and prevalence globally due to differences in study methodologies, diagnostic criteria, and populations studied. Here's a summary of the latest estimates based on available data, categorized by geographic region:
Global Estimates (IPF):
- A 2022 study estimated the adjusted incidence and prevalence of IPF to be in the range of 0.09-1.30 and 0.33-4.51 per 10,000 persons, respectively. This study highlighted the variability in reported figures and emphasized the need for standardized methodologies in future research. According to these prevalence estimates, IPF remains a rare disease.
- A 2023 meta-analysis of 17 studies found that the incidence of ILD (including IPF) ranged from 1 to 31.5 per 100,000 person-years, and prevalence ranged from 6.3 to 71 per 100,000 people. This analysis highlighted the heterogeneity of ILD subtypes and the need for standardized reporting.
- A 2018 meta-analysis estimated a conservative incidence range of 3-9 cases per 100,000 per year for Europe and North America. Incidence was lower in East Asia and South America.
Regional Estimates (IPF):
- Asia-Pacific: Adjusted incidence estimates ranged from 0.35 to 1.30 per 10,000, and adjusted prevalence estimates ranged from 0.57 to 4.51 per 10,000. South Korea had the highest reported figures.
- Europe: Adjusted incidence estimates ranged from 0.09 to 0.49 per 10,000, and adjusted prevalence estimates ranged from 0.33 to 2.51 per 10,000.
- North America: Adjusted incidence estimates ranged from 0.75 to 0.93 per 10,000, and adjusted prevalence estimates ranged from 2.40 to 2.98 per 10,000.
- England (specifically): A 2018 study estimated that the best-case incidence of IPF rose throughout the study period, with an estimated 8000-9000 new cases per year in England in 2018. This is higher than previously reported estimates (5000-6000).
Other Important Considerations:
- Non-IPF Fibrotic ILD with Progressive Phenotype: A 2021 study estimated the prevalence of non-IPF fibrotic ILD with a progressive phenotype to range from 12.14 to 29.05 per 10,000 in Medicare Advantage enrollees and 0.89 to 2.36 per 10,000 in commercial enrollees. Prevalence increased with age.
- Occupational Burden: A 2018 meta-analysis reported a population attributable fraction of 16% for occupational factors in IPF causation. Specific exposures included organic dusts, metal dust, wood dust, and silica/minerals. Asbestos exposure is also linked to usual interstitial pneumonia, the histological pattern seen in IPF.
- Post-COVID-19 Pulmonary Fibrosis (PCPF): A 2021 meta-analysis estimated the prevalence of PCPF at 44.9% among COVID-19 survivors. However, the long-term implications and true prevalence of this condition are still being investigated.
It's important to note that these figures represent estimates based on available data, and the true burden of pulmonary fibrosis may vary. Ongoing research and standardized methodologies are crucial for refining these estimates and improving our understanding of this complex disease.
Emerging Mechanism of Action
Pulmonary Fibrosis (PF) is a devastating lung disease marked by progressive scarring of lung tissue. While the exact mechanisms driving PF remain incompletely understood, research over the past three years continues to illuminate key molecular pathways and cellular interactions involved in its pathogenesis. This understanding is crucial for developing effective therapies. Here's a summary of emerging mechanisms of action (MoAs) in PF:
1. Epithelial Injury and Aberrant Repair: Repetitive injury to the alveolar epithelium is considered a central driver of PF. This injury triggers an aberrant wound healing response characterized by dysregulated epithelial cell activation and incomplete repair. This, in turn, leads to the release of profibrotic mediators that activate fibroblasts and promote excessive extracellular matrix (ECM) deposition.
2. Fibroblast Activation and Differentiation: Fibroblasts are key effector cells in PF. Their activation and differentiation into myofibroblasts, the primary collagen-producing cells, are driven by various signaling pathways. Transforming growth factor-β (TGF-β) remains a central mediator of fibroblast activation, but other factors, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and connective tissue growth factor (CTGF), also play crucial roles. Targeting these pathways with inhibitors or neutralizing antibodies is a major focus of therapeutic development.
3. Immune Dysregulation: Immune cells, particularly macrophages, play a complex role in PF pathogenesis. Macrophages can be polarized into different phenotypes, with some promoting fibrosis (M2 macrophages) and others potentially contributing to resolution (M1 macrophages). The balance between these phenotypes and their interactions with other immune cells, such as T cells, influences the fibrotic process. Modulating macrophage polarization or targeting specific immune cell populations may offer therapeutic opportunities.
4. Metabolic Reprogramming and Mitochondrial Dysfunction: Metabolic alterations and mitochondrial dysfunction are increasingly recognized as important contributors to PF. These changes can affect various cell types, including epithelial cells and fibroblasts, leading to increased oxidative stress, impaired energy production, and altered cellular behavior. Targeting metabolic pathways or improving mitochondrial function may offer new therapeutic avenues.
5. Cellular Senescence: Cellular senescence, a state of irreversible cell cycle arrest, is implicated in PF pathogenesis. Senescent cells can secrete profibrotic factors and contribute to the chronic inflammatory microenvironment. Eliminating senescent cells or blocking their secretions may offer therapeutic benefits.
6. Genetic and Epigenetic Factors: Genetic mutations and epigenetic modifications can influence susceptibility to PF and disease progression. Mutations in genes related to telomere maintenance, surfactant production, and other cellular processes have been linked to familial PF. Epigenetic changes can alter gene expression and contribute to the fibrotic phenotype. Understanding these genetic and epigenetic factors may lead to personalized therapeutic approaches.
7. Environmental Factors: Environmental exposures, such as cigarette smoke, asbestos, and silica, are known risk factors for PF. These exposures can induce epithelial injury, inflammation, and oxidative stress, contributing to the fibrotic process. Minimizing exposure to these harmful agents is crucial for prevention.
Emerging Therapeutic Targets and Approaches: Based on these MoAs, several novel therapeutic targets and approaches are being investigated. These include:
- Tyrosine kinase inhibitors (TKIs): Nintedanib, a TKI targeting multiple receptors involved in fibrosis, is already approved for IPF and other progressive fibrosing ILDs.
- Anti-CTGF antibodies: Pamrevlumab, an antibody targeting CTGF, has shown promising results in clinical trials.
- Anti-IL11 antibodies: IL-11 is a cytokine that promotes fibroblast activation, and neutralizing antibodies are being developed.
- Senolytics: These agents selectively eliminate senescent cells and are being investigated for various age-related diseases, including PF.
- Metabolic modulators: Drugs targeting metabolic pathways or mitochondrial function are being explored.
- Antioxidants: These agents may help to reduce oxidative stress and inflammation.
The development of effective therapies for PF requires a multi-pronged approach targeting multiple pathways and cell types. Ongoing research continues to refine our understanding of these complex mechanisms and identify promising new therapeutic targets.
Study Design Parameters
Several clinical trials have investigated treatments for idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), employing various study designs and endpoints. Here's a summary:
CAPACITY Programme (NCT00287729, NCT00287716): * Design: Two concurrent, randomized, double-blind, placebo-controlled trials. * Sample Size: Study 004: 435 patients (2:1:2 ratio for pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, and placebo). Study 006: 344 patients (1:1 ratio for pirfenidone 2403 mg/day and placebo). * Intervention: Pirfenidone at different doses or placebo for at least 72 weeks. * Primary Endpoint: Change in percentage predicted forced vital capacity (FVC) at week 72.
INPULSIS Trials (NCT01335464, NCT01335477): * Design: Two replicate, randomized, double-blind, placebo-controlled trials. * Sample Size: 1066 patients (3:2 ratio for nintedanib and placebo). * Intervention: Nintedanib 150 mg twice daily or placebo for 52 weeks. * Primary Endpoint: Annual rate of decline in FVC. * Key Secondary Endpoints: Time to first acute exacerbation, change in St. George's Respiratory Questionnaire total score.
ISABELA Trials (NCT03711162, NCT03733444): * Design: Two identically designed, phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter studies. * Sample Size: Planned 750 subjects per study (1:1:1 ratio for GLPG1690 600 mg, GLPG1690 200 mg, and placebo). * Intervention: GLPG1690 at different doses or placebo once daily, in addition to standard of care, for at least 52 weeks. * Primary Endpoint: Rate of decline of FVC over 52 weeks. * Key Secondary Endpoints: Week 52 composite endpoint of disease progression or all-cause mortality, time to first respiratory-related hospitalization, change in St. George's Respiratory Questionnaire total score.
TETON Programme (NCT04708782, NCT05255991): * Design: Two replicate, 52-week, randomized, double-blind, placebo-controlled, phase 3 studies. * Sample Size: 396 subjects per study. * Intervention: Inhaled treprostinil or placebo. * Primary Endpoint: Change in absolute FVC at week 52. * Secondary Endpoints: Time to clinical worsening, time to first acute exacerbation of IPF, overall survival, change in % predicted FVC, change in King's Brief Interstitial Lung Disease Questionnaire.
BI 1015550 Trial (NCT04419506): * Design: Phase 2, double-blind, placebo-controlled trial. * Sample Size: 147 patients (2:1 ratio for BI 1015550 and placebo). * Intervention: BI 1015550 18 mg twice daily or placebo. * Primary Endpoint: Change in FVC at 12 weeks.
FIBRONEER-ILD Trial (NCT05321082): * Design: Phase III, double-blind, placebo-controlled trial. * Sample Size: Not specified. * Intervention: BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks. * Primary Endpoint: Absolute change from baseline in FVC (mL) at week 52. * Key Secondary Endpoint: Time to first acute ILD exacerbation, hospitalisation for respiratory cause, or death.
Pamrevlumab Trial (NCT03955146): * Design: Phase 3 randomized clinical trial. * Sample Size: 356 patients. * Intervention: Pamrevlumab (30 mg/kg intravenously every 3 weeks) or placebo for 48 weeks. * Primary Outcome: Absolute change in FVC from baseline to week 48.
Ziritaxestat Trials (NCT03711162, NCT03733444): * Design: Two identical phase 3, randomized clinical trials (ISABELA 1 and 2). * Sample Size: 1306 patients (525 in ISABELA 1, 781 in ISABELA 2). * Intervention: Ziritaxestat (600 mg or 200 mg) or placebo once daily in addition to standard of care. * Primary Outcome: Annual rate of decline for FVC at week 52.
These trials highlight the use of FVC decline as a primary or key endpoint in many IPF/PPF studies. Other important endpoints include mortality, time to clinical worsening or exacerbation, and patient-reported outcomes like quality of life and symptom scores.