New Therapies in Development for Idiopathic Pulmonary Fibrosis (IPF) Address Existing Challenges With Diagnosis and Management

What Is Idiopathic Pulmonary Fibrosis?

Idiopathic pulmonary fibrosis (IPF) is a spontaneously occurring, progressive, interstitial lung disease characterized by chronic scarring (fibrosis) of the lungs.^1-6 As IPF progresses, scarring causes the lungs to become stiff and decreases their ability to expand and contract, which leads to progressive lung function decline.^1-3 The primary symptoms of IPF are nonspecific and include progressively worsening shortness of breath (dyspnea) and a persistent wet or dry cough.^1-3,5,6 Other observed symptoms that result from diminished lung function include fatigue, weakness, weight loss, chest tightness, and reduced quality of life.^1-3,5,6 The pathogenesis of IPF involves complex mechanisms, including age-related factors, immune dysregulation, and genetic risk. However, despite ongoing research, the exact cause of IPF remains unknown.^3,7

Burden of Disease

IPF affects ~3 million people worldwide and presents a significant burden to patients, caregivers, and the healthcare system.^2,4 The annual incidence in patients aged 65 years and older is nearly 16 times greater than the incidence in adults younger than age 65.4 Patients with IPF have several comorbidities, such as chronic obstructive fibrosis disease (COPD), cardiovascular disease, pulmonary hypertension, lung cancer, and obstructive sleep apnea.^1,5 Most patients are also current or former smokers.⁵ IPF is also associated with a high mortality rate.^1,3,6 The median survival following diagnosis ranges from 3 to 5 years.^4,8 Comorbidities add to the functional consequences of IPF and are also frequently associated with higher mortality rates.9 While most patients with IPF exhibit a slow decline in lung function over time (slowly progressive disease), some patients experience acute worsening of symptoms (exacerbations) that can occur at any time and are associated with a 50% mortality rate (rapidly progressive disease).^4,5,10

Patient Evaluation and Diagnosis

Prompt diagnosis of IPF is essential because early intervention offers the best chance of slowing lung function decline.⁶ Although there is no cure for IPF, early diagnosis facilitating early intervention can significantly preserve quality of life and prolong life expectancy.⁶ However, diagnosis is associated with several complex challenges, including the nonspecific nature and late presentation of symptoms, the delayed presentation of patients to their healthcare provider, and the necessity of biopsy for diagnosis, which is invasive and may be risky in some patients.^3,6,10,11 As a result, the diagnosis of IPF often occurs when the disease has already caused significant, irreversible damage.¹² Furthermore, a delay between the onset of symptoms and initial evaluation is associated with shortened survival, and patients who waited longer than 4 years for a diagnosis had elevated rates of several comorbidities.⁴ Thus, efforts to facilitate early recognition and diagnosis of IPF are critical.²

Disease Management and Treatment

Even once it is properly diagnosed, the management of IPF also poses significant challenges.^3,5,13,14 First, the need to manage multiple comorbidities in patients with IPF increases direct medical costs and healthcare resource utilization.¹⁵ Second, a limited number of treatment options are available, and most are associated with unsatisfactory efficacy, high prices, and adverse events.^13,14,16,17 For instance, the only guideline-recommended therapies are nintedanib, a tyrosine kinase inhibitor, and pirfenidone, an antifibrotic drug with pleiotropic effects.^5,16 However, these are conditional (weak) recommendations based on clinical trial evidence of slowed, rather than halted, disease progression over a relatively short (1-year) treatment period.^5,16,18 In addition, these treatments are expensive compared to alternative management strategies, costing more than $110,000 per year.¹⁹ Third, the use of some therapeutics (eg, glucocorticoids, immunosuppressive agents) is discouraged due to their lack of efficacy, and, in some cases, harmful effects.^3,5,16 Fourth, while lung transplantation may be an option in end-stage IPF, the eligibility criteria for transplantation are strict, and the procedure may not be suitable for many of the older patients who make up most of the patient population with IPF.²⁰ Given the complex mechanisms contributing to IPF pathogenesis and its heterogenic clinical presentation and progression, a precision medicine approach will likely be required to achieve true disease control.^1,2

Looking Ahead

There is an urgent need for new therapies for IPF that may be used alone or in combination with existing antifibrotics.^7,12,21 While specific causes of IPF that might serve as therapeutic targets have remained elusive because of the heterogeneity of IPF presentation and progression, several pathways implicated in IPF pathogenesis are being evaluated as potential therapeutic targets.¹⁸ These include interventions targeting fibrogenesis, remodeling, chemotaxis, epithelial injury, autophagy, and the unfolded protein response, among others.^1,3,12,21 Several novel therapeutics have reached phase 3 clinical development, including a monoclonal antibody targeting connective tissue growth factor, recombinant pentraxin 2 (serum amyloid P), and a small molecule inhibitor of phosphodiesterase 4B.^7,18,22,23 While patient outcomes in clinical trials of phosphodiesterase 4 inhibitors have been promising, further research into the efficacy and safety of these molecules in larger patient populations and for longer treatment periods is needed.^18,23,24 Additionally, advancements in gene expression analysis and the identification of potential diagnostic biomarkers through machine learning algorithms offer new avenues for personalized treatment strategies.^6,14 In sum, despite existing challenges with IPF diagnosis and treatment, the promise of novel therapeutic approaches offers new hope to individuals affected by this devastating disease.¹³

References:

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