Idiopathic Pulmonary Fibrosis
Novel and Emerging Interventions
While the availability of high-resolution CT scans and addition of anti-fibrotic drugs to the medication arsenal have changed the landscape of IPF diagnosis and management, they have had little impact on survival (Tzilas 2017). Therefore, the search for more effective treatments is ongoing.
Bronchoscopic lung cryobiopsy is emerging as a possible alternative to surgical lung biopsy for diagnosis of interstitial fibrosis. In this technique, a tissue sample is retrieved during an incision-free procedure called bronchoscopy. The tissue sample is generally larger than in a conventional surgical lung biopsy, which increases the likelihood of finding the tissue features indicative of IPF (Scelfo 2017). Bronchoscopic lung cryobiopsy was found to be as useful as surgical biopsy for reaching a confident diagnosis of IPF in uncertain cases (Tomassetti 2016).
The identification of reliable biomarkers could prove valuable in making an early diagnosis, assessing severity, predicting prognosis, and monitoring progression and response to therapy in those with IPF (Drakopanagiotakis 2018). Matrix metalloproteinase-7 is the most widely studied IPF biomarker to date. Elevated blood levels of this enzyme have been helpful in distinguishing patients with IPF from some, but not all, other lung diseases that cause fibrosis (Tzilas 2017).
Mitochondrial DNA and the composition of the respiratory microbiome could provide clues regarding diagnosis and prognosis (Drakopanagiotakis 2018). It has further been proposed that genetic biomarkers as well as markers of oxidative stress have potential value in guiding therapeutic choices (Fois 2018). These and other types of biomarkers are current topics of research.
Mesenchymal stem cells. Mesenchymal stem cells are a type of stem cell with the capacity to produce a variety of cell types. They occur in many body tissues, such as bone marrow, adipose tissue, umbilical cord blood, or placental tissues. They have been shown to induce anti-inflammatory signaling, promote tissue regeneration and repair, and rescue dysfunctional cells by transferring functional mitochondria (Wecht 2016; Li, Yue 2017).
Mesenchymal stem cells are attracted to the sites of tissue injury; in IPF, mesenchymal stem cells travel to the injured airway lining where they may participate in repair activities (Wecht 2016; Li, Yue 2017). Studies in mice suggest the potential usefulness of mesenchymal stem cell therapy in IPF treatment (Li, Han 2017). In a rat model, injection of adipose-derived mesenchymal stem cells led to remission of silica-induced pulmonary fibrosis (Chen 2018). In a case report, intravenous infusions of mesenchymal stem cells led, a year later, to reduced need for oxygen therapy in an individual with emphysema and IPF (Zhang, Yin 2017). The safety of intravenous mesenchymal stem cells in IPF patients has been shown in phase I trials, paving the way for future clinical research (Chambers 2014; Glassberg 2017).
Senolytics. Senolytic compounds trigger the breakdown of senescent cells—aged and dysfunctional cells that have lost their sensitivity to cell-death signals. In this way, they have the potential to reverse one of the root causes of age-related tissue change and restore healthy tissue function (Kirkland 2017). Senolytics are of special interest in IPF because of the condition's close relationship with aging and cell senescence.
Both fibroblasts and cells from the alveolar lining from subjects with IPF show high levels of markers of senescence. Senescence in these two cell types and impaired signaling are important parts of the fibrotic process (Schafer 2017; Kuwano 2016; Yanai 2015). In addition, molecules secreted by senescent cells up-regulate inflammation, cause direct cellular damage, disrupt repair mechanisms involving stem cells, and even induce senescence in other cells, leading to widespread pulmonary dysfunction (Kirkland 2017).
Dasatinib (Sprycel), a chemotherapy drug and inhibitor of enzymes in the tyrosine kinase family, and quercetin, a flavonoid that is widely distributed in the plant world, were among the first agents to be identified as having senolytic potential (Zhu 2015). Treatment with the combination of dasatinib plus quercetin reduced markers of senescence and improved pulmonary function and physical health in an animal model of IPF (Lehmann 2017; Schafer 2017). The first clinical trial using dasatinib plus quercetin to target senescent cells in people with IPF was published in early 2019 (Justice 2019). In this open-label pilot trial, 14 participants over age 50 who had stable IPF were given dasatinib and quercetin intermittently for three weeks. They received oral dosages of 100 mg of dasatinib plus 1,250 mg of quercetin daily for three consecutive days per week for three consecutive weeks (for a total of nine days of treatment and 12 days of non-treatment in the 21-day period). Functional measures including distance walked in six minutes, gait speed during a four-minute walk, and the time it took participants to stand from sitting in a chair significantly improved. Changes in some markers of cellular senescence correlated with the improvements in physical function. Adverse events were primarily mild to moderate. This trial provides a basis for larger randomized controlled trials of senolytics in IPF and other senescence-related diseases.
Pentoxifylline. Pentoxifylline is a xanthine derivative and a drug that has been used for decades to improve vascular health. It has immunomodulatory and anti-fibrotic properties (Lopera 2015; McCarty 2016). It is also a suppressor of inflammation by several mechanisms, including the inhibition of TNF-alpha and IL-6, and one study reported that it resembles anti-inflammatory corticosteroids (Li, Tan 2016; Whitehouse 2004; Garcia 2015). Numerous preclinical studies, several of which are summarized here, have shown that pentoxifylline ameliorates fibrosis due to various diseases (Wen 2017). Nevertheless, pentoxifylline has not been studied extensively in people with IPF, so it is not clear whether the anti-fibrotic benefits of pentoxifylline observed in preclinical models and studies of fibrosis in patients due to other diseases will translate to meaningful benefits for IPF patients. Clinical trials of pentoxifylline on people with IPF are needed.
In a study on 43 patients with radiation-induced fibrosis of the skin and underlying tissues who had radiation therapy for head, neck, or breast cancers, oral pentoxifylline (800 mg/day) and vitamin E (1,000 IU/day) led to regression in the surface area of the lesions and a decrease in a score used to measure the extent of injuries (Delanian 1999). A phase II clinical trial, which enrolled 29 patients with radiation-induced fibrosis in the skin and underlying tissues, showed that pentoxifylline and vitamin E treatment for 3 months led to a 43% average decrease in the surface area of the lesions. A subgroup of patients treated for 6 months exhibited a 72% average lesion surface area regression. In this study, the response at 3 months was better in older patients (Haddad 2005).
Pentoxifylline and vitamin E were found to reduce fibrosis associated with breast cancer (which usually develops in the skin and underlying tissues) in patients undergoing radiotherapy (Kaidar-Person 2018). In a study on fluid that accumulated outside the lungs collected from patients with various non-cancerous diseases (such as congestive heart failure or tuberculosis), pentoxifylline inhibited the proliferation of fibroblasts and synthesis of collagen, and the authors concluded that it may offer a new approach to treat pulmonary fibrosis (Entzian, Schlaak 1997). A meta-analysis examined three randomized controlled trials that used pentoxifylline for oral submucous fibrosis, a condition characterized by fibrosis in the lining of the oral cavity. Both short- and long-term administration of pentoxifylline improved signs and symptoms, including maximal mouth opening, and the efficacy increased with time (Liu, Chen 2017).
Various animal and laboratory studies have observed anti-fibrotic effects of pentoxifylline:
- In a laboratory model of schistosoma infection, a disease that causes liver fibrosis, pentoxifylline inhibited activation of cells involved in liver fibrosis (Li, Hua 2016).
- In a laboratory model of radiation-induced fibrosis, pentoxifylline decreased collagen deposition in irradiated fibroblasts (Kumar 2018).
- In a mouse model of a fungal disease that affects the lungs, early administration of pentoxifylline helped control disease progression by decreasing lung inflammation and collagen deposition in the lung (Lopera 2015).
- The combination of pentoxifylline and alpha-tocopherol significantly reduced collagen deposition in rats with radiation-induced heart muscle fibrosis (Boerma 2008).
- In a rat model of pulmonary fibrosis, oral pentoxifylline (at a dose equivalent to about 1,200 mg/day for an adult human) and intraperitoneal dl-alpha-tocopheryl acetate reduced fibrosis scores after 12 weeks, and the combination was better than either administered alone (Bese 2007).
- In a rat model of radiation-induced lung fibrosis, pentoxifylline showed anti-fibrotic effects, possibly by modulating the expression of proteins involved in signaling pathways (Lee 2017).
- In another study that examined a rat model of radiation-induced lung injury, the combination of vitamin E and pentoxifylline administered orally (into the animal feed) prevented lung fibrosis (Kaya 2014).
- In a rat model of bleomycin-induced fibrosing alveolitis, pentoxifylline reduced the amount of proliferating cells in the lungs and the formation of reactive oxygen species (Entzian, Gerlach 1997).
Antibodies against connective tissue growth factor. Connective tissue growth factor promotes fibrosis in several situations, including radiation injury to the lung. A laboratory study on irradiated mice showed that pamrevlumab, an antibody against connective tissue growth factor, ameliorated radiation-induced lung injury and prolonged survival when compared with non-irradiated animals (Sternlicht 2018). In a study on a mouse model of radiation-induced lung fibrosis, this antibody prevented or reversed lung remodeling, improved lung function, and led to beneficial molecular changes (Bickelhaupt 2017). In a randomized, double-blind, placebo-controlled phase II clinical trial, IPF patients receiving pamrevlumab showed significantly less decline in lung function at 48 weeks compared to a control group (Eduard Gorina 2017).
Leukotriene antagonists. Leukotrienes, a group of inflammatory mediators, are increased locally in IPF, and are one of the more recent targets considered for anti-fibrotic therapies. (Castelino 2012; Gharaee-Kermani 2007; Failla 2006). In a mouse model of lung fibrotic injury, the inhibition of leukotrienes reduced fluid collection in the lungs and decreased inflammation and collagen deposition (Failla 2006). In another study on mice, a molecule that blocks the leukotriene B4 receptor prevented lung fibrosis induced by a toxic compound by decreasing inflammation and changing signaling through several signaling molecules (Izumo 2009). A randomized, placebo-controlled, phase II clinical trial is currently examining the use of a molecule that blocks a leukotriene receptor for its safety and efficacy in IPF patients (Aryal 2018).
Lysophosphatidic acid (LPA) pathway inhibitors. Lysophosphatidic acid (LPA) is small lipid molecule involved in various cellular functions, including the recruitment of fibroblasts. Increased levels of LPA and autotaxin, the enzyme that makes this molecule, were found in the lungs of patients with IPF. Therefore, inhibiting the autotaxin-LPA axis emerges as an attractive therapeutic strategy (Chu 2015; Aryal 2018). Several phase II clinical trials have generated positive results and showed that inhibitors of this pathway could help lung function in patients with IPF (Aryal 2018).
mTOR inhibitors/Rapamycin. Mammalian target of rapamycin, or mTOR, is an enzyme with an important and complex role in regulating key cellular activities affecting cellular metabolism, function, growth, proliferation, survival, and senescence. Excessive mTOR signaling has been linked to age-related immune dysfunction and cancer development, and has recently been implicated in fibrotic diseases, including IPF (Lawrence 2018). Fibroblasts from IPF-affected lungs demonstrate increased mTOR signaling, which may accelerate fibrosis in part by increasing proliferation and activity of fibroblasts, decreasing their sensitivity to normal down-regulating signals, and inactivating cell-death pathways (Lawrence 2018; Nho 2014; Patel 2012).
In early research using animal and laboratory models of pulmonary fibrosis, mTOR-inhibiting agents such as rapamycin have demonstrated anti-fibrotic effects (Shao 2015; Chang 2014; Patel 2012; Jin 2014). A single case report describes marked improvement in an individual with IPF treated with rapamycin (Buschhausen 2005). A clinical trial of the mTOR inhibitor GSK2126458 (Omipalisib) in IPF patients is currently underway. GSK2126458 is an anti-cancer drug that disables both mTOR and another related enzyme (Mercer 2016). However, in a randomized controlled trial in 89 subjects with IPF, treatment with the mTOR inhibitor everolimus (Afinitor) led to more rapid disease progression and a lower chance of survival after three years (Malouf 2011). In an ongoing double-blind, placebo-controlled, phase II clinical trial, rapamycin is being evaluated for its ability to decrease the number of circulating fibrocytes (Aryal 2018). Further research on outcomes associated with mTOR inhibition in IPF is urgently needed.
Proton pump inhibitors, or PPIs, block acid production in the stomach and are used to treat gastroesophageal reflux, a condition that may be more prevalent than it appears in those with IPF. In a study that looked at esophageal acidity in subjects with IPF, high acid levels were detected in 87% of cases, but fewer than half reported experiencing reflux symptoms (Raghu 2006). In an observational study, IPF patients using antacids for gastroesophageal reflux (mainly PPIs) had slower disease progression, fewer episodes of acute worsening, and longer survival time (Lee 2011). Other observational studies examining the relationship between PPI use and IPF survival time have had mixed findings (Lee 2016; Kreuter 2016).
Antacid use has been recommended in patients with IPF and co-existing gastroesophageal reflux, and in 2015, a conditional recommendation was expanded to include patients without gastroesophageal reflux based on a growing body of supportive research (Raghu 2015). Emerging evidence indicates that PPIs in particular may have positive effects beyond the stomach, such as free radical scavenging, improving the oxidant/antioxidant balance, reducing inflammation, and regulating immune function (Ghebre 2016). The PPI esomeprazole (Nexium) has been reported to improve alveolar cell function and inhibit proliferation and collagen production in lung fibroblasts from individuals with IPF; in addition, esomeprazole reduced lung inflammation and fibrosis in an animal model of IPF (Ghebremariam 2015). These findings highlight the need for future research to identify those most likely to benefit from PPI therapy.
Metformin. Metformin (Glucophage) is a commonly prescribed anti-diabetes medication that has also been shown to reduce oxidative stress, inflammation, and fibrosis (Nesti 2017; Ladeiras-Lopes 2015). Metformin has been found to reduce levels of inflammatory markers in both lung tissue and blood samples, lower oxidative stress, and inhibit lung fibrosis in animal models of IPF (Gamad 2018; Choi 2016; Sato 2016). In one study, metformin reversed established lung fibrosis in mice with an IPF-like condition apparently by activating the enzyme AMPK (Rangarajan 2018). AMPK regulates a number of cellular metabolic pathways, and decreased AMPK activity is associated with a wide range of age-related and fibrosis-linked health problems (Jiang, Li 2017).
Glucagon-like peptide-1. Glucagon-like peptide-1 is a signaling molecule involved in glucose regulation that has also been found to inhibit a key inflammatory protein involved in pulmonary fibrosis. In mice with experimentally induced pulmonary fibrosis, the administration of glucagon-like peptide-1 reduced pulmonary inflammation and fibrosis (Gou 2014; Liu, Gou 2017). In other animal research, the anti-diabetes drug vildagliptin (Galvus), which acts in part by inhibiting the breakdown of glucagon-like peptide-1, prevented fibrotic transformation in pulmonary blood vessel cells (Suzuki 2017). Clinical trials are needed to determine whether these benefits extend to humans with IPF.
Participating in a Clinical Trial
Clinical trials can give patients access to emerging and experimental treatments that are not yet approved or widely available, such as those described in the "Novel and Emerging Interventions" section of this protocol. For patients with IPF, participation in a clinical trial may be the only way to access such treatments. Your medical team can help you evaluate whether available clinical trials may be right for you and your situation.
Clinical trials meant to eventually lead to FDA-approved treatments are conducted in five phases (Institute of Medicine 2012; FDA 2018):
- Phase 0 clinical trials are brief, small, preliminary trials intended to determine whether further clinical development should proceed.
- Phase I clinical trials involve under 100 study subjects, last months to years, and test the safety of a drug.
- About 70% of drugs then proceed to a phase II clinical trial. In this phase, researchers study a drug's effectiveness and continue to examine its safety and side effects, over months to up to two years, in up to a few hundred subjects.
- Roughly one-third of drugs then enter phase III clinical trials which are conducted in hundreds to thousands of participants, and last from one to four years. Phase III trials more fully explore the risks, benefits, and efficacy of new treatments, and provide the most robust safety data of the four phases.
- Phase IV trials are conducted on already-approved treatments and are thus sometimes known as "post-market" studies. This phase continues to collect and refine data on risks, benefits, safety, and efficacy.
Participation in a trial does have risks, including unexpected side effects, and undergoing an experimental treatment may not be effective. Benefits to participants include being among the first to have access to cutting-edge treatments and receiving excellent patient care (NIH 2017). Regardless of the trial outcome, every participant helps researchers improve treatment options for future patients.
Information about clinical trials for pulmonary fibrosis is available through the following resources:
Pulmonary Fibrosis Foundation
CenterWatch Clinical Trial Resource