Article source: Chinese Journal of Tuberculosis and Respiratory, 2020, 43 (03): 256-262
DOI: 0.3760/cma.j.issn.1001-0939.2020.03.025
Author: Li Yihua Ye Qiao
Unit: Beijing Chaoyang Hospital Affiliated to Capital Medical University Clinical Diagnosis and Treatment and Research Center for Interstitial Lung Diseases
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease with poor prognosis. At present, the anti-pulmonary fibrosis drugs pirfenidone and nidanib have been approved for marketing, which can partially delay the decline in lung function in patients with IPF. With the understanding of the mechanism of pulmonary fibrosis, the research and development of anti-pulmonary fibrosis drugs for different parts and targets has accelerated, showing a trend of diversification. This article reviews the progress of clinical trials of new IPF anti-pulmonary fibrosis drugs.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive pulmonary fibrosis disease, manifested as exertional dyspnea and decreased lung function. Its chest imaging or pathological characteristics are common interstitial pneumonia (UIP). The progress of the disease seriously affects the patient's quality of life, resulting in respiratory failure and death [1,2,3,4]. The prognosis of IPF was poor, and the median survival after diagnosis of untreated patients was 3 to 5 years [1]. The research and development of anti-pulmonary fibrosis drugs for chronic fibrotic lung diseases represented by IPF is based on the understanding of the mechanism of pulmonary fibrosis. Currently, pirfenidone and nidanib have been approved for marketing, and their effectiveness and safety have been confirmed in randomized controlled trials (RCTh) and real-world studies. The research and development of anti-pulmonary fibrosis drugs at different sites and targets has accelerated, showing a trend of diversification (Table 1). This article mainly explains the progress of clinical trials of IPF therapeutic drugs.
. IPF pathogenesis and drug targets
Under the interaction of susceptible genes and environmental factors, smoking, chronic micro-inhalation, occupational exposure, viral infection, mechanical stretching and environmental pollution, resulting in the aging and repeated damage of alveolar epithelial cells, thereby abnormally activated and secreting pro-inflammatory and pro-fibrotic media, including fibroblast growth factor (FGF), connective tissue growth factor (CTGF), chemokines, etc.; at the same time, immune cells such as macrophages can secrete platelet-derived factors (PDGF), metalloproteinases (MMPs), etc., participating in inflammatory response and repair. The above substances promote the proliferation and transformation of fibroblasts into myofibroblasts through various pathways of lung mesenchymal cells, peripheral cells of lung mesenchymal cells, circulating fibroblasts, epithelial mesenchymal transformation and endothelial mesenchymal transformation. Myofibroblasts are the main effector cells of IPF. They can secrete a large amount of extracellular matrix (ECM) through various pathways such as tyrosine kinase, serine-threonine kinase, G protein coupling, etc., and abnormally aggregate to form scar tissue, resulting in lung structure remodeling and loss of function [3, 9, 10, 11].
IPF therapeutic targets include avoiding environmental risk factors, reducing the aging and damage of alveolar epithelial cells, reducing their secretion of proinflammatory and profibrotic media; reducing the inflammatory response and reducing the secretion of cytokines by immune cells; inhibiting the conversion of fibroblasts into myofibroblasts, reducing ECM production and deposition, slowing down and even preventing the occurrence of pulmonary fibrosis, and delaying the decline of lung function [11, 12, 13, 14, 15]. In addition to single drugs, combined treatment of different drugs at multiple targets is also a possible therapeutic strategy for [16].
0.3760/cma.j.issn.1001-0939.2020.03.0252. Drugs acting on fibroblasts
1. Pamrevlumab (FG-3019):
FG-3019 is a human CTGF monoclonal antibody. CTGF is a secretory cell matrix protein that regulates multiple signaling pathways , which can mediate the differentiation of epithelial cells, stellate cells and fibroblasts, induce myofibroblast formation, promote ECM deposition, and lead to tissue remodeling and fibrosis [17]. In the pulmonary fibrosis model of radiation-induced mice, mice received a dose of 20Gy radiation, and were given FG-3019 intervention for 8 weeks 2 days before radiation and 2, 20 and 112 days after radiation, respectively.The results showed that FG-3019 had the effect of preventing, alleviating or reversing lung structure remodeling in mice. The effect of improving lung function and prolonging survival was in different time points. Among them, 70% of the mice in the intervention group survived [18] at 20 days after radiation.
An open-minded, multicenter Phase IIa trial (FGCL-3019-049) in the United States to evaluate the safety and effectiveness of IPF treatment with different doses of FG-3019 was conducted. The study was selected for 89 IPF patients, divided into low-dose group (15 mg/kg, intravenous, 1/3 weeks, lasting 45 weeks) and high-dose group (30 mg/kg, intravenous, 1/3 weeks, lasting 45 weeks). The patients with low-dose group had a %-45%-85% estimated value, and the carbon monoxide dispersion (DLCO) accounted for %-30% predicted value, and the disease progression, lung function worsening or dyspnea worsening 3 to 12 months before the trial; FVC accounted for %-55% predicted value, and the disease progressed within 18 months before the trial; high-resolution CT (HRCT) showed evidence of interstitial pulmonary fibrosis, that is, parenchymal fibrosis (grid shadow) and 25% cellular shadow in the entire lung. The effectiveness endpoints include pulmonary function, high-resolution CT and quality of life assessment; the safety endpoints are adverse events (acute aggravation) and severe adverse events (severe acute aggravation) [19]. The results showed that FG-3019 could delay the decline of lung function. At 48 weeks, the FVC changes in the two groups were -0.15 and -0.13 L, FVC accounts for % change in the expected value of -3.00% and -2.25%, and DLCO accounts for % change in the expected value of -4.50% and -5.61%. Quantitative HRCT showed that the two groups of grid shadows accompanied by lung structure changes, ground glass shadows, honeycomb shadows, and total lung volumes were significantly improved compared with baseline [19]. A total of 24 cases (27%) of the study experienced 38 SAEs, of which 13 were withdrawn from the trial, with pneumonia, IPF worsening, and respiratory failure the most common. There was no significant difference in the incidence and common types of AE and SAE in the two groups [19]. Studies have shown that FG-3019 is safe and effective in treating IPF, and its limitation is the lack of a control group.
PRAISE was double-blind, stage II RCT, and 103 IPF patients with FVC accounted for 55% of the estimated value were randomly assigned to the pamrevlumab group (50 cases, 30 mg/kg, intravenous injection, once every 3 weeks, a total of 48 weeks) and the placebo group (53 cases) [20]. The primary endpoint was the % change in FVC as expected at week 48, and the other endpoints were disease progression (the decrease of FVC as expected at week 48 or death by week 24 and 48, and quantitative HRCT for pulmonary fibrosis. The results showed that the decrease in FVC in the pamrevlumab group (-2.9%) decreased significantly (-2.9%) than the placebo group (-7.2%) at 48 weeks; the proportion of patients with pamrevlumab group (10.0%) was significantly lower than that in the placebo group (31.4%); the change in the pulmonary fibrosis volume of pamrevlumab and placebo groups at 48 weeks was 75.4 and 151.5 ml, respectively, and the treatment difference was -76.2 ml, and this difference was observed at 24 weeks, indicating that pamrevlumab can delay the progression of pulmonary fibrosis; in addition, the St. George's respiratory questionnaire (SGRQ) score in the FG-3019 group was significantly lower than that in the placebo group. The research results show that pamrevlumab treats IPF safely and effectively and can improve patients' quality of life.
2. PBI-4050:
PBI-4050, that is, 3-pentylphenylacetic acid sodium salt, is a newly synthesized small molecule medium-chain fatty acid analog, which has agonistic and antagonistic effects on the G protein-coupled receptors GPR40 and GPR84, respectively. PBI-4050 binds to GPR40 and/or GPR84, which inhibits the conversion of fibroblasts into myofibroblasts, inhibits ECM deposition, and reduces the expression of pro-inflammatory mediators (monocyte chemotaxis proteins-1, IL-8 and IL-6) and pro-fibrosis mediators (CTGF and IL-6) [21].
A single-group design, multi-center phase II trial of PBI-4050 in the treatment of IPF was studied, and 41 IPF patients were included in [22]. Nine of them received PBI-4050 monotherapy (800 mg/d, oral), while the remaining 16 were treated with PBI-4050 combined with pirfenidone or PBI-4050 combined with nidanib for 20 weeks, including 6 follow-up [22]. The primary endpoint was the number of patients with treatment-related laboratory outliers and (or) acute exacerbations at 4 months, and the secondary endpoints included changes in lung function, imaging and biomarkers at 3 months from baseline. The results showed that the pharmacokinetic characteristics of PBI-4050 were similar in the PBI-4050 group and the PBI-4050 combined with nidanib group, but were reduced in the PBI-4050 combined with pirfenidone group, suggesting that the two drugs may have an interaction.In the PBI-4050 group and PBI-4050 combined with nidanib group, the absolute value of FVC may account for % of the expected value at week 12, and the FVC account for % of the expected value in the PBI-4050 combined with pirfenidone group significantly decreased (P0.024), and the drug tolerance of the three groups of patients was good [22]. PBI-4050 single agent or combined with nidanib is expected to become a new treatment plan for anti-pulmonary fibrosis.
3. Autotoxin inhibitor (GLPG1690):
Extracellular lysophosphatidylcholine (LPC) is decomposed under the action of hydrolase autotoxin (ATX), which produces lysophosphatidic acid (LPA). LPA binds to GPR, affecting cell migration and proliferation [23]. ATX is a member of the phosphodiesterase family and is the main pathway for LPA [23]. The increased levels of LPA in lung tissue, bronchial alveolar lavage fluid and exhaled breath in patients with IPF suggest that the LPC-ATX-LPA pathway may become the therapeutic target of IPF [24,25]. GLPG1690 is an ATX inhibitor.
A multi-center, parallel design phase IIa RCT for the safety, tolerance, and pharmacokinetics characteristics of GLPG1690 for the treatment of IPF, was launched from 2016 to 2017. IPF patients were divided into the trial group (GLPG1690, 600 mg/d) and the control group for 12 weeks, and were evaluated and followed up after weeks 1, 2, 4, 8, 12 and 2 weeks of last treatment. Patients were evaluated for HRCT within 1 year before enrollment, with FVC accounting for %≥50% of the estimated value and DLCO accounting for %≥30% of the expected value. The main endpoints were acute exacerbations, abnormal laboratory indicators, abnormal vital signs, abnormal electrocardiogram and changes in LPA plasma concentration. The secondary endpoints were changes in lung function, quality of life assessment, etc. The results showed that the proportion of patients with acute exacerbation in the two groups was 67% and 65%, which were mild to moderate. There was no significant change in laboratory indicators, vital signs, electrocardiogram and SGRQ scores compared with baseline. The LPA plasma concentration in the experimental group decreased at weeks 4 and 12, and the baseline level was restored during follow-up. The FVC change values in the two groups in 12 weeks were 25 and -70 ml, and the FVC decline slowed down and even reversed. GLPG1690 is the first ATX inhibitor to undergo IPF treatment of RCT, representing a potential anti-pulmonary fibrosis drug species.
A double-blind, multi-center, parallel-designed phase III RCT (ISABELA) studied the safety and effectiveness of different doses of GLPG1690 combined with standard treatment of IPF, conducted [26] in November 2018. 750 IPF patients were assigned to the high-dose group (GLPG1690, 600 mg/d), low-dose group (GLPG1690, 200 mg/d) and control group at 1:1:1 for 52 weeks. Patients diagnosed IPF for the first 5 years of the first 5 years of the time of the first 1 year of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time The primary endpoint was the FVC decline rate at 52 weeks, the secondary endpoint was the compound endpoint of disease progression (defined as a decrease of ≥ 10% of FVC in the expected value) or all-cause death, the time for the first time of respiratory disease-related hospitalization, and the change in SGRQ score from baseline, etc. The study is still in progress.
4. LPA1 receptor inhibitor (BMS-986020):
BMS-986020 is a specific LPA1 receptor inhibitor. LPA1 receptor mediates fibroblast aggregation and endothelial cell dysfunction. After bleomycin-induced pulmonary fibrosis, the apoptosis of alveolar epithelial cells, vascular leakage and fibroblast levels of [27] were reduced.
A double-blind, multicenter, and phase II RCT that studied the safety and effectiveness of BMS-986020 in the treatment of IPF was conducted in 2013. 143 IPF patients were assigned to the high-dose group (48 cases, BMS-986020, 1 200 mg/d), low-dose group (48 cases, BMS-986020, 600 mg/d) and control group (47 cases), and continued treatment for 26 weeks. The patient was between 40 and 90 years old and was diagnosed with IPF for the first time within the first six years. After inhaling bronchodilator, FVC accounted for 45% to 90%, and DLCO accounted for 30% to 80%. The main study endpoint was the FVC change rate at 26 weeks, and the secondary study endpoint was the geometric mean ratio of pulmonary fibrosis quantitative score (QLF) at 26 weeks, 6 min walking test, shortness of breath questionnaire change (SOBQ), etc.The results showed that the FVC changes in the low-dose group, high-dose group and control group at 26 weeks were -0.076, -0.05, and -0.136 L (the difference between the latter two groups was statistically significant, P=0.049), the QLF GMR changes in the three groups were 1.14, 1.09, and 1.11, and the 6-min walking test changes were -14.2, 6.1, and 10.3 m, and the SOBQ changes were 3.8, -1.7, and 3.9, respectively, the mortality rates were 4.17%, 4.17%, and 2.13%, and the incidence of acute exacerbation was 18.75%, 33.33%, and 25.53%. Studies have shown that BMS-986020 600 mg bid significantly delays the rate of FVC decline, but dose-related elevations in liver enzymes may occur.
5. Sintozumab (GS-6624):
lysyl oxidase-like protein 2 (LOXL2) is an enzyme that catalyzes collagen cross-linking and plays a role in the onset of pulmonary fibrosis [29,30]. Compared with normal tissues, LOXL2 expression increased in tumor and fibrotic tissues [31]. In the bleomycin-induced pulmonary fibrosis model, murine LOXL2 monoclonal antibody can effectively prevent and reverse pulmonary fibrosis [29], and it is speculated that human LOXL2 monoclonal antibody (GS-6624) may have similar anti-pulmonary fibrosis effects.
A phase I trial of GS-6624 in the treatment of IPF safety, tolerance, pharmacokinetics and pharmacodynamics (AB0024-201) was conducted in 2010 for 113 days. The study included two parts A and B. Part A was a sequential dose escalation and double-blind RCT. 18 patients were selected, while Part B was a randomized, double-dose (GS-6624, 125 or 200 mg, intravenous injection for 1 h) open trial, and 30 patients were selected. The main research endpoints were the safety, tolerance and pharmacocologic characteristics of GS-6624, and the secondary research endpoints were the formation of GS-6624 antibodies and the impact on FVC, DLCO, and SGRQ. The results of this study have not been published.
ATLAS is a phase II trial studying the safety and tolerability of GS-6624 in subjects in AB0024-201. The study was conducted in the United States in 2012, and a total of 34 patients were included. According to the original trial dose, patients with intravenous GS-6624 200 g/L or subcutaneous injection of 125 g/L per (7±2) day were excluded. The main study endpoints were the proportion of patients with acute exacerbation within 30 days to 165 weeks after the last drug treatment, treatment-related biochemical and hematological abnormalities. The secondary study endpoints were 72 weeks and 144 weeks FVC accounted for % of the expected value, DLCO accounted for % of the expected value, etc. The results showed that 33 patients experienced acute exacerbations, of which 35.3% were severe and 3 patients died; at 72 and 144 weeks, FVC accounted for % of the expected value and 12.04% respectively, and DLCO accounted for % of the expected value and decreased by 7.41% and 22.08% respectively.
RAINIER is a double-blind multicenter phase II RCT[32] for the treatment of IPF. The study selected 544 IPF patients and were assigned to the treatment group (GS-6624, 125 mg, intradermal injection, 1/week) and control group at 1:1. The patient's walking distance of 6 min is ≥50 m, and SpO2 ≥89% when he was resting at sea level without oxygen, which can tolerate lung diffusion function examination. The primary endpoint was progression-free survival (PFS), the important secondary endpoints were all-cause mortality, FVC accounted for % of the estimated value, and the other secondary endpoints were 6 min walking distance and SGRQ. Treatment time is determined by clinical events. Interim analysis was performed after 120 and 200 progression-free survival events occurred in the trial. During the second interim analysis, the trial was terminated due to the preset treatment ineffectiveness criteria. The results showed that the % change of PFS and FVC in the two groups accounted for 12.6 and 15.4 months, -11.7% and -7.1%, respectively, with no statistical difference, and no statistical difference in other secondary endpoints. The incidence of AE and SAE in the two groups was similar, with common cough, upper respiratory tract infection, dyspnea and IPF worsening. RAINIER was negative, and GS-6624 did not show anti-fibrotic advantages over placebo.
6. CC-90001:
The second generation Jun N-terminal kinase (JNK) signaling pathway is the downstream signal transduction pathway of TGF-β1. Its abnormal expression can affect the activity of TGF-β1 and change the IPF process [33]. CC-90001 is a JNK inhibitor.
An open, multi-center, multi-dose interlaced and phase Ib clinical trial that evaluates the safety, tolerance, pharmacokinetics and pharmacodynamics of CC-90001 in the treatment of pulmonary fibrosis was conducted in the United States and Australia in 2015.
Article source: Chinese Journal of Tuberculosis and Respiratory, 2020, 43 (03): 256-262
DOI:
Author: Li Yihua Ye Qiao
Unit: Beijing Chaoyang Hospital Affiliated to Capital Medical University Clinical Diagnosis and Treatment and Research Center for Interstitial Lung Diseases
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease with poor prognosis. At present, the anti-pulmonary fibrosis drugs pirfenidone and nidanib have been approved for marketing, which can partially delay the decline in lung function in patients with IPF. With the understanding of the mechanism of pulmonary fibrosis, the research and development of anti-pulmonary fibrosis drugs for different parts and targets has accelerated, showing a trend of diversification. This article reviews the progress of clinical trials of new IPF anti-pulmonary fibrosis drugs.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive pulmonary fibrosis disease, manifested as exertional dyspnea and decreased lung function. Its chest imaging or pathological characteristics are common interstitial pneumonia (UIP). The progress of the disease seriously affects the patient's quality of life, resulting in respiratory failure and death [1,2,3,4]. The prognosis of IPF was poor, and the median survival after diagnosis of untreated patients was 3 to 5 years [1]. The research and development of anti-pulmonary fibrosis drugs for chronic fibrotic lung diseases represented by IPF is based on the understanding of the mechanism of pulmonary fibrosis. Currently, pirfenidone and nidanib have been approved for marketing, and their effectiveness and safety have been confirmed in randomized controlled trials (RCTh) and real-world studies. The research and development of anti-pulmonary fibrosis drugs at different sites and targets has accelerated, showing a trend of diversification (Table 1). This article mainly explains the progress of clinical trials of IPF therapeutic drugs.
. IPF pathogenesis and drug targets
Under the interaction of susceptible genes and environmental factors, smoking, chronic micro-inhalation, occupational exposure, viral infection, mechanical stretching and environmental pollution, resulting in the aging and repeated damage of alveolar epithelial cells, thereby abnormally activated and secreting pro-inflammatory and pro-fibrotic media, including fibroblast growth factor (FGF), connective tissue growth factor (CTGF), chemokines, etc.; at the same time, immune cells such as macrophages can secrete platelet-derived factors (PDGF), metalloproteinases (MMPs), etc., participating in inflammatory response and repair. The above substances promote the proliferation and transformation of fibroblasts into myofibroblasts through various pathways of lung mesenchymal cells, peripheral cells of lung mesenchymal cells, circulating fibroblasts, epithelial mesenchymal transformation and endothelial mesenchymal transformation. Myofibroblasts are the main effector cells of IPF. They can secrete a large amount of extracellular matrix (ECM) through various pathways such as tyrosine kinase, serine-threonine kinase, G protein coupling, etc., and abnormally aggregate to form scar tissue, resulting in lung structure remodeling and loss of function [3, 9, 10, 11].
IPF therapeutic targets include avoiding environmental risk factors, reducing the aging and damage of alveolar epithelial cells, reducing their secretion of proinflammatory and profibrotic media; reducing the inflammatory response and reducing the secretion of cytokines by immune cells; inhibiting the conversion of fibroblasts into myofibroblasts, reducing ECM production and deposition, slowing down and even preventing the occurrence of pulmonary fibrosis, and delaying the decline of lung function [11, 12, 13, 14, 15]. In addition to single drugs, combined treatment of different drugs at multiple targets is also a possible therapeutic strategy for [16].
2. Drugs acting on fibroblasts
1. Pamrevlumab (FG-3019):
FG-3019 is a human CTGF monoclonal antibody. CTGF is a secretory cell matrix protein that regulates multiple signaling pathways , which can mediate the differentiation of epithelial cells, stellate cells and fibroblasts, induce myofibroblast formation, promote ECM deposition, and lead to tissue remodeling and fibrosis [17]. In the pulmonary fibrosis model of radiation-induced mice, mice received a dose of 20Gy radiation, and were given FG-3019 intervention for 8 weeks 2 days before radiation and 2, 20 and 112 days after radiation, respectively.The results showed that FG-3019 had the effect of preventing, alleviating or reversing lung structure remodeling in mice. The effect of improving lung function and prolonging survival was in different time points. Among them, 70% of the mice in the intervention group survived [18] at 20 days after radiation.
An open-minded, multicenter Phase IIa trial (FGCL-3019-049) in the United States to evaluate the safety and effectiveness of IPF treatment with different doses of FG-3019 was conducted. The study was selected for 89 IPF patients, divided into low-dose group (15 mg/kg, intravenous, 1/3 weeks, lasting 45 weeks) and high-dose group (30 mg/kg, intravenous, 1/3 weeks, lasting 45 weeks). The patients with low-dose group had a %-45%-85% estimated value, and the carbon monoxide dispersion (DLCO) accounted for %-30% predicted value, and the disease progression, lung function worsening or dyspnea worsening 3 to 12 months before the trial; FVC accounted for %-55% predicted value, and the disease progressed within 18 months before the trial; high-resolution CT (HRCT) showed evidence of interstitial pulmonary fibrosis, that is, parenchymal fibrosis (grid shadow) and 25% cellular shadow in the entire lung. The effectiveness endpoints include pulmonary function, high-resolution CT and quality of life assessment; the safety endpoints are adverse events (acute aggravation) and severe adverse events (severe acute aggravation) [19]. The results showed that FG-3019 could delay the decline of lung function. At 48 weeks, the FVC changes in the two groups were -0.15 and -0.13 L, FVC accounts for % change in the expected value of -3.00% and -2.25%, and DLCO accounts for % change in the expected value of -4.50% and -5.61%. Quantitative HRCT showed that the two groups of grid shadows accompanied by lung structure changes, ground glass shadows, honeycomb shadows, and total lung volumes were significantly improved compared with baseline [19]. A total of 24 cases (27%) of the study experienced 38 SAEs, of which 13 were withdrawn from the trial, with pneumonia, IPF worsening, and respiratory failure the most common. There was no significant difference in the incidence and common types of AE and SAE in the two groups [19]. Studies have shown that FG-3019 is safe and effective in treating IPF, and its limitation is the lack of a control group.
PRAISE was double-blind, stage II RCT, and 103 IPF patients with FVC accounted for 55% of the estimated value were randomly assigned to the pamrevlumab group (50 cases, 30 mg/kg, intravenous injection, once every 3 weeks, a total of 48 weeks) and the placebo group (53 cases) [20]. The primary endpoint was the % change in FVC as expected at week 48, and the other endpoints were disease progression (the decrease of FVC as expected at week 48 or death by week 24 and 48, and quantitative HRCT for pulmonary fibrosis. The results showed that the decrease in FVC in the pamrevlumab group (-2.9%) decreased significantly (-2.9%) than the placebo group (-7.2%) at 48 weeks; the proportion of patients with pamrevlumab group (10.0%) was significantly lower than that in the placebo group (31.4%); the change in the pulmonary fibrosis volume of pamrevlumab and placebo groups at 48 weeks was 75.4 and 151.5 ml, respectively, and the treatment difference was -76.2 ml, and this difference was observed at 24 weeks, indicating that pamrevlumab can delay the progression of pulmonary fibrosis; in addition, the St. George's respiratory questionnaire (SGRQ) score in the FG-3019 group was significantly lower than that in the placebo group. The research results show that pamrevlumab treats IPF safely and effectively and can improve patients' quality of life.
2. PBI-4050:
PBI-4050, that is, 3-pentylphenylacetic acid sodium salt, is a newly synthesized small molecule medium-chain fatty acid analog, which has agonistic and antagonistic effects on the G protein-coupled receptors GPR40 and GPR84, respectively. PBI-4050 binds to GPR40 and/or GPR84, which inhibits the conversion of fibroblasts into myofibroblasts, inhibits ECM deposition, and reduces the expression of pro-inflammatory mediators (monocyte chemotaxis proteins-1, IL-8 and IL-6) and pro-fibrosis mediators (CTGF and IL-6) [21].
A single-group design, multi-center phase II trial of PBI-4050 in the treatment of IPF was studied, and 41 IPF patients were included in [22]. Nine of them received PBI-4050 monotherapy (800 mg/d, oral), while the remaining 16 were treated with PBI-4050 combined with pirfenidone or PBI-4050 combined with nidanib for 20 weeks, including 6 follow-up [22]. The primary endpoint was the number of patients with treatment-related laboratory outliers and (or) acute exacerbations at 4 months, and the secondary endpoints included changes in lung function, imaging and biomarkers at 3 months from baseline. The results showed that the pharmacokinetic characteristics of PBI-4050 were similar in the PBI-4050 group and the PBI-4050 combined with nidanib group, but were reduced in the PBI-4050 combined with pirfenidone group, suggesting that the two drugs may have an interaction.In the PBI-4050 group and PBI-4050 combined with nidanib group, the absolute value of FVC may account for % of the expected value at week 12, and the FVC account for % of the expected value in the PBI-4050 combined with pirfenidone group significantly decreased (P0.024), and the drug tolerance of the three groups of patients was good [22]. PBI-4050 single agent or combined with nidanib is expected to become a new treatment plan for anti-pulmonary fibrosis.
3. Autotoxin inhibitor (GLPG1690):
Extracellular lysophosphatidylcholine (LPC) is decomposed under the action of hydrolase autotoxin (ATX), which produces lysophosphatidic acid (LPA). LPA binds to GPR, affecting cell migration and proliferation [23]. ATX is a member of the phosphodiesterase family and is the main pathway for LPA [23]. The increased levels of LPA in lung tissue, bronchial alveolar lavage fluid and exhaled breath in patients with IPF suggest that the LPC-ATX-LPA pathway may become the therapeutic target of IPF [24,25]. GLPG1690 is an ATX inhibitor.
A multi-center, parallel design phase IIa RCT for the safety, tolerance, and pharmacokinetics characteristics of GLPG1690 for the treatment of IPF, was launched from 2016 to 2017. IPF patients were divided into the trial group (GLPG1690, 600 mg/d) and the control group for 12 weeks, and were evaluated and followed up after weeks 1, 2, 4, 8, 12 and 2 weeks of last treatment. Patients were evaluated for HRCT within 1 year before enrollment, with FVC accounting for %≥50% of the estimated value and DLCO accounting for %≥30% of the expected value. The main endpoints were acute exacerbations, abnormal laboratory indicators, abnormal vital signs, abnormal electrocardiogram and changes in LPA plasma concentration. The secondary endpoints were changes in lung function, quality of life assessment, etc. The results showed that the proportion of patients with acute exacerbation in the two groups was 67% and 65%, which were mild to moderate. There was no significant change in laboratory indicators, vital signs, electrocardiogram and SGRQ scores compared with baseline. The LPA plasma concentration in the experimental group decreased at weeks 4 and 12, and the baseline level was restored during follow-up. The FVC change values in the two groups in 12 weeks were 25 and -70 ml, and the FVC decline slowed down and even reversed. GLPG1690 is the first ATX inhibitor to undergo IPF treatment of RCT, representing a potential anti-pulmonary fibrosis drug species.
A double-blind, multi-center, parallel-designed phase III RCT (ISABELA) studied the safety and effectiveness of different doses of GLPG1690 combined with standard treatment of IPF, conducted [26] in November 2018. 750 IPF patients were assigned to the high-dose group (GLPG1690, 600 mg/d), low-dose group (GLPG1690, 200 mg/d) and control group at 1:1:1 for 52 weeks. Patients diagnosed IPF for the first 5 years of the first 5 years of the time of the first 1 year of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time of the time The primary endpoint was the FVC decline rate at 52 weeks, the secondary endpoint was the compound endpoint of disease progression (defined as a decrease of ≥ 10% of FVC in the expected value) or all-cause death, the time for the first time of respiratory disease-related hospitalization, and the change in SGRQ score from baseline, etc. The study is still in progress.
4. LPA1 receptor inhibitor (BMS-986020):
BMS-986020 is a specific LPA1 receptor inhibitor. LPA1 receptor mediates fibroblast aggregation and endothelial cell dysfunction. After bleomycin-induced pulmonary fibrosis, the apoptosis of alveolar epithelial cells, vascular leakage and fibroblast levels of [27] were reduced.
A double-blind, multicenter, and phase II RCT that studied the safety and effectiveness of BMS-986020 in the treatment of IPF was conducted in 2013. 143 IPF patients were assigned to the high-dose group (48 cases, BMS-986020, 1 200 mg/d), low-dose group (48 cases, BMS-986020, 600 mg/d) and control group (47 cases), and continued treatment for 26 weeks. The patient was between 40 and 90 years old and was diagnosed with IPF for the first time within the first six years. After inhaling bronchodilator, FVC accounted for 45% to 90%, and DLCO accounted for 30% to 80%. The main study endpoint was the FVC change rate at 26 weeks, and the secondary study endpoint was the geometric mean ratio of pulmonary fibrosis quantitative score (QLF) at 26 weeks, 6 min walking test, shortness of breath questionnaire change (SOBQ), etc.The results showed that the FVC changes in the low-dose group, high-dose group and control group at 26 weeks were -0.076, -0.05, and -0.136 L (the difference between the latter two groups was statistically significant, P=0.049), the QLF GMR changes in the three groups were 1.14, 1.09, and 1.11, and the 6-min walking test changes were -14.2, 6.1, and 10.3 m, and the SOBQ changes were 3.8, -1.7, and 3.9, respectively, the mortality rates were 4.17%, 4.17%, and 2.13%, and the incidence of acute exacerbation was 18.75%, 33.33%, and 25.53%. Studies have shown that BMS-986020 600 mg bid significantly delays the rate of FVC decline, but dose-related elevations in liver enzymes may occur.
5. Sintozumab (GS-6624):
lysyl oxidase-like protein 2 (LOXL2) is an enzyme that catalyzes collagen cross-linking and plays a role in the onset of pulmonary fibrosis [29,30]. Compared with normal tissues, LOXL2 expression increased in tumor and fibrotic tissues [31]. In the bleomycin-induced pulmonary fibrosis model, murine LOXL2 monoclonal antibody can effectively prevent and reverse pulmonary fibrosis [29], and it is speculated that human LOXL2 monoclonal antibody (GS-6624) may have similar anti-pulmonary fibrosis effects.
A phase I trial of GS-6624 in the treatment of IPF safety, tolerance, pharmacokinetics and pharmacodynamics (AB0024-201) was conducted in 2010 for 113 days. The study included two parts A and B. Part A was a sequential dose escalation and double-blind RCT. 18 patients were selected, while Part B was a randomized, double-dose (GS-6624, 125 or 200 mg, intravenous injection for 1 h) open trial, and 30 patients were selected. The main research endpoints were the safety, tolerance and pharmacocologic characteristics of GS-6624, and the secondary research endpoints were the formation of GS-6624 antibodies and the impact on FVC, DLCO, and SGRQ. The results of this study have not been published.
ATLAS is a phase II trial studying the safety and tolerability of GS-6624 in subjects in AB0024-201. The study was conducted in the United States in 2012, and a total of 34 patients were included. According to the original trial dose, patients with intravenous GS-6624 200 g/L or subcutaneous injection of 125 g/L per (7±2) day were excluded. The main study endpoints were the proportion of patients with acute exacerbation within 30 days to 165 weeks after the last drug treatment, treatment-related biochemical and hematological abnormalities. The secondary study endpoints were 72 weeks and 144 weeks FVC accounted for % of the expected value, DLCO accounted for % of the expected value, etc. The results showed that 33 patients experienced acute exacerbations, of which 35.3% were severe and 3 patients died; at 72 and 144 weeks, FVC accounted for % of the expected value and 12.04% respectively, and DLCO accounted for % of the expected value and decreased by 7.41% and 22.08% respectively.
RAINIER is a double-blind multicenter phase II RCT[32] for the treatment of IPF. The study selected 544 IPF patients and were assigned to the treatment group (GS-6624, 125 mg, intradermal injection, 1/week) and control group at 1:1. The patient's walking distance of 6 min is ≥50 m, and SpO2 ≥89% when he was resting at sea level without oxygen, which can tolerate lung diffusion function examination. The primary endpoint was progression-free survival (PFS), the important secondary endpoints were all-cause mortality, FVC accounted for % of the estimated value, and the other secondary endpoints were 6 min walking distance and SGRQ. Treatment time is determined by clinical events. Interim analysis was performed after 120 and 200 progression-free survival events occurred in the trial. During the second interim analysis, the trial was terminated due to the preset treatment ineffectiveness criteria. The results showed that the % change of PFS and FVC in the two groups accounted for 12.6 and 15.4 months, -11.7% and -7.1%, respectively, with no statistical difference, and no statistical difference in other secondary endpoints. The incidence of AE and SAE in the two groups was similar, with common cough, upper respiratory tract infection, dyspnea and IPF worsening. RAINIER was negative, and GS-6624 did not show anti-fibrotic advantages over placebo.
6. CC-90001:
The second generation Jun N-terminal kinase (JNK) signaling pathway is the downstream signal transduction pathway of TGF-β1. Its abnormal expression can affect the activity of TGF-β1 and change the IPF process [33]. CC-90001 is a JNK inhibitor.
An open, multi-center, multi-dose interlaced and phase Ib clinical trial that evaluates the safety, tolerance, pharmacokinetics and pharmacodynamics of CC-90001 in the treatment of pulmonary fibrosis was conducted in the United States and Australia in 2015.18 patients with PF were admitted to the low-dose group (CC-90001, 100 mg/d) and high-dose group (CC-90001, 200 mg/d) at 1:1. When at least 3 patients in the low-dose group completed the shortest 2-week treatment and reached the dose escalation standard after evaluation, 6 patients in the same group were admitted to the high-dose group to start treatment; 1 of 3 cases met the dose escalation standard, and 3 of the remaining 6 cases started low-dose treatment; ≥2 of the remaining 6 cases met the dose escalation standard, and the treatment of high-dose CC-90001 was no longer carried out, and the patients used received treatment for 12 weeks. In addition, patients in the high-dose group were admitted to the low-dose group when they met the criterion for dose escalation. ≥2 cases had this condition, and the trial was repeated or stopped. The selected patients were ≥18 years old, and were diagnosed with pulmonary fibrosis by HRCT, and their liver function was normal and they signed an informed consent form. They were evaluated during the screening period, within 12 weeks of treatment and at 4 weeks of follow-up. The main study endpoint was the number of patients with acute exacerbation at 16 weeks, laboratory evaluation, electrocardiogram, etc., and the secondary study endpoint was the plasma concentration and pharmacologic characteristics of CC-90001 at 16 weeks. The results of this study have not been reported yet.
A study on the safety, pharmacokinetic characteristics, and quality of life assessment of two doses of CC-90001 were double-blind, multicenter Phase II RCT in 2017. A total of 135 IPF patients were included, and they were divided into the low-dose group (200 mg, 1/d, oral), high-dose group (400 mg, 1/d, oral) and placebo group at 1:1:1. After receiving 24 weeks of treatment, the patients entered the treatment prolonged stage. At week 24, the placebo group was divided into the low-dose group and the high-dose group at 1:1, and continued treatment for 80 weeks, totaling 104 weeks. The patient's FVC accounts for 45% to 95%, DLCO accounts for 25% to 90%, and the walking distance of 6 min is ≥150 m. The main study endpoint was the change of FVC as a percentage of the expected value at 24 weeks, and the secondary study endpoint was the change of FVC, the progress of the disease, the SGRQ score, and the 6 min walking distance at 104 weeks, the Borg score. The results of the study have not been reported yet.
7. KD025:
Rho/Rho-associated protein kinase (ROCK) signaling pathway can increase the level of myosin light chain phosphorylation and increase the act-myosin contraction force to promote cells to migrate in ECM. Rho/ROCK signaling can also activate TGF-β1 and CTGF, playing a role in IPF pathogenesis [34]. KD025 is a selective ROCK2 inhibitor.
A randomized, multi-center, open-label phase II clinical trial of KD025 in the treatment of IPF safety and tolerance was conducted in 2016. The study included 76 IPF patients and were assigned to the treatment group (KD025, 400 mg, 1/d, oral) and the control group (optimal supportive treatment, treatment plan developed by the physician) for 24 weeks. The patient diagnosed IPF within the first 5 years of enrollment, with FVC accounting for %≥50%, DLCO accounting for %≥30%, and resting percutaneous blood oxygen saturation (SpO2) ≥88%. The main study endpoints were the FVC change value and the number of patients with AE at 24 weeks. The study is still underway.
. Recombinant human pentraxin-2 (PRM-151):3. Drugs acting on immune cells
PRM-151, also known as serum amyloid P, can inhibit the differentiation of monocytes into pro-inflammatory, pro-fibrotic macrophages and fibroblasts, reduce the secretion of pro-inflammatory cytokines and leukocyte aggregation, and bind with apoptotic cells to accelerate their clearance of [36,37].
A double-blind, multicenter phase Ib RCT of PRM-151 dose-escalation treatment IPF safety, tolerance, and pharmacokinetic characteristics was conducted in 2011 by [37]. A total of 21 IPF patients were included in the study, and they were randomly divided into 3 groups, with the drug doses of 1, 5, and 10 mg/kg, respectively. Two patients were randomly selected for placebo treatment in each group, and finally 8, 7 and 6 cases were included in the 3 groups, respectively. The patient received PRM-151 or placebo intravenous injection on days 1, 3, 5, 8 and 15, and was observed until 57 days, and received pulmonary function tests, 6 min walking distance, SGRQ, and biomarker evaluation [37]. The main research endpoints are drug safety and tolerance, and the secondary research endpoints include peak drug plasma concentration and changes in lung function from baseline. Patients had FVC accounting for % of the estimated value ≥ 45%, DLCO accounting for 35%~80%, resting SpO2≥ 88%, and cyclophosphamide, steroids, immunosuppressants or any test drug were excluded within 35 days before the trial. The results showed that the peak plasma concentrations of PRM-151 in the three groups were 2, 5 and 8 times at baseline, and no infusion reaction, dose-limiting toxicity or SAE were observed, and no PRM-151 antibody was detected.The lung function of patients with intravenous PRM-151 was better than that of the placebo group. On the 57th day of follow-up, the two groups had FVC and FVC accounted for % of the expected value, and DLCO accounted for % of the expected value and baseline changes of (0.064±0.142)L and (−0.063±0.116)L, (2.4±4.0)% and (−1.5±3.3)%, (−1.8±4.9)% and (−2.3±2.1)%, respectively, with no statistical difference between [37]. The level of vascular endothelial growth factor (VEGF) increased with time in the placebo group, and the VEGF level in the PRM-151 treatment group was stable in [37]. The research results show that PRM-151 has good tolerance, effectiveness and pharmacokinetic characteristics in the treatment of IPF, and quantitative HRCT is required to evaluate prospective RCT for patients with lung tissue structure and lung function changes after PRM-151 treatment.
Then, a multicenter phase II RCT[38] was studied in the effect of PRM-151 on FVC treatment. A total of 117 patients were included in the study, with FVC accounting for 50% to 90%, FEV1/FVC0.70, DLCO accounting for 25% to 90%, and walking distance of 6 min ≥ 150 m. They were divided into the trial group (77 cases, 10 mg/kg, 1 time/4 weeks) and the placebo group (39 cases). The primary endpoint was the least squares mean change of FVC as a percentage of the expected value at 28 weeks; the secondary endpoint was lung volume, quantitative HRCT to evaluate lung tissue structure and 6 min walking distance changes. The results showed that the experimental group could significantly slow down the FVC share of % and the walking distance decrease of 6 min (-2.5% and -4.8%, P=0.001; -0.5 and -31.8 m, P0.001), and there was no statistically significant difference in other results [38]. The most common adverse reactions are cough, fatigue and nasopharyngitis [38]. The research results show that PRM-151 can significantly slow down the decline of lung function in IPF patients within 28 weeks, and it is necessary to expand the sample size and continue to conduct RCT to evaluate its efficacy and safety.
. Mammalian target rapamycin protein (mTOR) inhibitor:
fibroblasts are precursor cells derived from circulating bone marrow. They can partially become myofibroblasts in the lungs and promote lung fibrosis. This process relies on the binding of chemokine CXCL12 and fibroblast surface receptor CXCR4. The expression of CXCL12 and CXCR4 can be inhibited by mTOR-specific inhibitor sirolimus [39]. In the bleomycin-induced pulmonary fibrosis model in mice, sirolimus reduced the number of fibroblasts expressing CXCR4 in peripheral blood and lungs, and reduced the degree of pulmonary fibrosis [40].
GSK2126458 is an mTOR inhibitor. A double-blind, dose-escalating phase I RCT was conducted in 2013 to study its safety, tolerability and pharmacokinetic characteristics [41]. A total of 17 patients were included in the study and divided into 4 cohorts. Each cohort was divided into the trial group and the control group at 3:1. The doses of GSK2126458 were given to each cohort of 0.25, 1, 2, and 2 mg, 2 times/d, for 7 to 10 days. The patient was clearly diagnosed with IPF, with FVC accounting for %40% of the estimated value, DLCO accounting for %30% of the expected value, alanine aminotransferase 2 times upper limit of normal value (ULN), alkaline phosphatase and bilirubin ≤1.5 times ULN. The main study endpoints were the area under the blood drug concentration-time curve (AUC) and pharmacokinetic characteristics at baseline and early, mid- and late stages of treatment in each cohort. The secondary study endpoints were lung function assessment and drug safety and tolerance [41]. The study used pharmacokinetic models and 18 fluoro-deoxyglucose-positron emission computed tomography (18F-FDG-PET/CT) results. The results show that GSK2126458 has a dose-dependent and exposure-dependent inhibitory effect on mTOR, and can also reduce glucose signal abnormalities in the IPF pulmonary fibrosis region [41]. The results support further evaluation of the mTOR pathway as a target for new IPF therapy.
A double-blind, placebo-controlled trial was launched in 2015 and is expected to be completed in 2019. The selected patients were clearly diagnosed with IPF and were randomly assigned to the sirolimus group and the placebo group. The main study endpoints were the concentration of fibroblasts expressing CXCR4 in peripheral blood at 22 weeks and the proportion of patients with AE. The trial is still underway.
Lebrikizumab is a human IL-13 monoclonal antibody. Alveolar epithelial cells, mesenchymal cells and inflammatory cells can release cytokines, including GF, IL, IFN, TNF and chemokine [42]. IL-13 can promote fibroblast proliferation and ECM formation, promote the release of TGF-β, PDGF, CTGF, and synthesis of collagen and fibronectin, and play an important role in the onset of IPF [42,43].
double-blind, multi-center, parallel-designed phase II RCT for the effectiveness and safety of Lebrikizumab monotherapy or combined with pirfenidone for the treatment of IPF, and was launched from 2013 to 2017. The study included cohorts A and B, and each cohort was divided into experimental group and control group. The A cohort trial group was given Lebrikizumab (250 mg, intradermal injection, 1/4 week, for 52 weeks), and then extended treatment for 52 weeks during the open label period for a total of 104 weeks; the control group was given placebo for 52 weeks, and then Lebrikizumab for 52 weeks during the open label period for a total of 104 weeks. The B cohort trial group was given pirfenidone combined with Lebrikizumab for a total of 52 weeks, with a pirfenidone dose of 2403 mg/d or the maximum tolerated dose of oral drugs, with a Lebrikizumab dose of cohort A; the control group received pirfenidone and placebo for a total of 52 weeks. The 4 groups included 76, 78, 177 and 174 cases, with a total of 505 IPF patients with stable baseline lung function, FVC accounts for %≥40%, DLCO accounts for %25%~90%, and a walking distance of 6 min ≥100 m. Patients in cohort A did not receive IPF treatment 4 weeks before grouping and placebo treatment, and patients in cohort B had pirfenidone MTD ≤2 403 mg/d. The main study endpoint was the decline rate of FVC in the expected value at 52 weeks, and the secondary study endpoints included the walking distance of 6 min at 52 weeks and the annual decline rate of DLCO, and the proportion of patients with a decrease of ≥10% of the expected value within 122 weeks or deaths due to any cause. The results showed that FVC accounted for % reduction in the expected value at 52 weeks between the two groups in the A cohort (-6.18% and -5.20%, P=0.45), the annual decline in walking distance of 6 min (-44.65% and -22.72%, P=0.31), the annual decline in the DLCO (-4.78% and -4.24%, P=0.60), and the proportion of patients with FVC accounted for ≥10% of the expected value or deaths due to any cause (34.2% and 27.6%, P=0.42). The study results of the two groups in the B cohort were similar, with no statistical difference (-6.04% and -5.54%, P=0.55; -25.56% and -46.98%, P=0.20; -5.75% and -5.57%, P=0.60; 30.3% and 26.6%, P=0.42). The results of the study show that Lebrikizumab monotherapy or combined with pirfenidone cannot delay the progression of IPF lung function or reduce all-cause mortality.
. Rituximab:
B cell abnormalities in serum and lung tissues of IPF patients, plasma B cell stimulation factor concentration is significantly higher than that of normal control group, and the 1-year survival rate of IPF patients with higher B cell stimulation factor concentration is lower [44], considering that B cells may be related to IPF incidence and prognosis. A randomized, multi-center, parallel-design Phase II clinical trial on the effectiveness of CD20B cell monoclonal antibody rituximab in December 2018, 58 patients were included, aged 50 to 85 years old, and all of them were clearly diagnosed with IPF. Patients were divided into the trial group (rituximab, 1 mg, 2 intravenous injections, 14 days between injections) and control group and followed up for 9 months. The main study endpoint was human epidermoid cell-2 antibody titer, and the secondary study endpoints were changes in the concentration of anti-heat shock protein 70 antibody, FVC accounted for % of the expected value, and the incidence of acute exacerbation. The study is still underway.
4. Drugs acting on alveolar epithelial cells
1. Human integrin αvβ6 monoclonal antibody [STX-100 (BG00011)]:
integrin is a transmembrane receptor formed by non-covalent pairing of α and β subunits. It is expressed on the surface of myofibroblasts, participates in the signaling pathway between cells and ECM, controls TGF-β activation and release, and plays an important role in the pathogenesis of IPF [45].
A double-blind, parallel design phase IIa RCT that evaluates the safety and tolerance of BG00011 in the treatment of IPF was carried out in the United States. The study included 41 IPF patients and were divided into the trial group (BG00011, intradermal injection, once a week, 8 consecutive weeks, with a gradual increase in dose) and the control group [46]. Patients account for %≥50% of the estimated value, DLCO accounts for %≥30%, without oxygen inhalation or oxygen flow at rest ≤2 L/min, and residual gas (RV) accounts for %≤50%. The main study endpoint was the proportion of patients with acute exacerbation at 16 weeks, and the secondary study endpoint was the changes in biomarkers in peripheral blood and BALF at 16 weeks, whether BG00011 antibodies were produced, and drug plasma peak concentration, etc. The results showed that the pSMAD2 level in the TGF-β conduction pathway in the test group was suppressed by 70%. PSMAD2 can be significantly inhibited when BG00011≥0.3 mg/kg, and maximum inhibition can be achieved at 1 mg/kg. The incidence of acute exacerbation in the experimental group and the control group was 87% and 70%, respectively.
Another double-blind phase II b RCT was launched in 2018. The study is expected to include 290 IPF patients and are divided into the trial group (BG00011, intradermal injection, 56 mg/week, lasting 52 weeks) and the control group [47]. Patients DLCO accounted for 30% to 79%, FVC accounted for ≥50%, and the dose must be constant within 8 weeks before grouping. The main study endpoint was the FVC decline rate at 52 weeks, and the secondary study endpoint was the FVC decline rate of % expected value, the time of disease progression and the first AE. The study is still underway.
2. Tipelukast (MN-001):
arachidonic acid metabolite leukotrienes (LTs), is one of the regulators of pulmonary fibrosis, [48]. Generated by alveolar epithelial cells in patients with IPF, the LTB4 level in patients with lung tissues significantly increased [49], suggesting that it may be a potential therapeutic target for IPF.
A double-blind, parallel-design phase II RCT that evaluates the safety and tolerance of LTB4 inhibitor MN-001 in the treatment of IPF was conducted in 2016. 15 IPF patients were included in the study and were divided into the trial group (MN-001, oral, 750 mg, 2 times/d, for 26 weeks) and the control group. After all, all patients entered the open-label extension (MN-001, oral, 750 mg, 2 times/d, for 26 weeks) to evaluate the efficacy of the drug. The selected IPF patients are between 21 and 80 years old, with moderate to severe disease manifestations, and GAP index II to Ⅲ stages. The drug dosage is stable within 3 months before enrollment. The main study endpoint was the FVC change at 26 weeks, and the secondary study endpoint was the number of acute exacerbations in each patient at the first, third and six months, the rate of walking distance decline at 6 min, the change of dyspnea score at 26 weeks, etc. The study is still underway.
. Summary of the study of the pathogenesis of pulmonary fibrosis has provided a new target for the treatment of chronic progressive fibrotic interstitial lung diseases represented by IPF, and has promoted the development of new drugs [50]. Paying attention to the interconnection between multiple signaling pathways involved in disease progression and adopting combined treatment of multiple drugs for different sites and different targets may be the direction of anti-pulmonary fibrosis treatment in the future.
References (omitted)
The lung function of patients with intravenous PRM-151 was better than that of the placebo group. On the 57th day of follow-up, the two groups had FVC and FVC accounted for % of the expected value, and DLCO accounted for % of the expected value and baseline changes of (0.064±0.142)L and (−0.063±0.116)L, (2.4±4.0)% and (−1.5±3.3)%, (−1.8±4.9)% and (−2.3±2.1)%, respectively, with no statistical difference between [37]. The level of vascular endothelial growth factor (VEGF) increased with time in the placebo group, and the VEGF level in the PRM-151 treatment group was stable in [37]. The research results show that PRM-151 has good tolerance, effectiveness and pharmacokinetic characteristics in the treatment of IPF, and quantitative HRCT is required to evaluate prospective RCT for patients with lung tissue structure and lung function changes after PRM-151 treatment.Then, a multicenter phase II RCT[38] was studied in the effect of PRM-151 on FVC treatment. A total of 117 patients were included in the study, with FVC accounting for 50% to 90%, FEV1/FVC0.70, DLCO accounting for 25% to 90%, and walking distance of 6 min ≥ 150 m. They were divided into the trial group (77 cases, 10 mg/kg, 1 time/4 weeks) and the placebo group (39 cases). The primary endpoint was the least squares mean change of FVC as a percentage of the expected value at 28 weeks; the secondary endpoint was lung volume, quantitative HRCT to evaluate lung tissue structure and 6 min walking distance changes. The results showed that the experimental group could significantly slow down the FVC share of % and the walking distance decrease of 6 min (-2.5% and -4.8%, P=0.001; -0.5 and -31.8 m, P0.001), and there was no statistically significant difference in other results [38]. The most common adverse reactions are cough, fatigue and nasopharyngitis [38]. The research results show that PRM-151 can significantly slow down the decline of lung function in IPF patients within 28 weeks, and it is necessary to expand the sample size and continue to conduct RCT to evaluate its efficacy and safety.
. Mammalian target rapamycin protein (mTOR) inhibitor:
fibroblasts are precursor cells derived from circulating bone marrow. They can partially become myofibroblasts in the lungs and promote lung fibrosis. This process relies on the binding of chemokine CXCL12 and fibroblast surface receptor CXCR4. The expression of CXCL12 and CXCR4 can be inhibited by mTOR-specific inhibitor sirolimus [39]. In the bleomycin-induced pulmonary fibrosis model in mice, sirolimus reduced the number of fibroblasts expressing CXCR4 in peripheral blood and lungs, and reduced the degree of pulmonary fibrosis [40].
GSK2126458 is an mTOR inhibitor. A double-blind, dose-escalating phase I RCT was conducted in 2013 to study its safety, tolerability and pharmacokinetic characteristics [41]. A total of 17 patients were included in the study and divided into 4 cohorts. Each cohort was divided into the trial group and the control group at 3:1. The doses of GSK2126458 were given to each cohort of 0.25, 1, 2, and 2 mg, 2 times/d, for 7 to 10 days. The patient was clearly diagnosed with IPF, with FVC accounting for %40% of the estimated value, DLCO accounting for %30% of the expected value, alanine aminotransferase 2 times upper limit of normal value (ULN), alkaline phosphatase and bilirubin ≤1.5 times ULN. The main study endpoints were the area under the blood drug concentration-time curve (AUC) and pharmacokinetic characteristics at baseline and early, mid- and late stages of treatment in each cohort. The secondary study endpoints were lung function assessment and drug safety and tolerance [41]. The study used pharmacokinetic models and 18 fluoro-deoxyglucose-positron emission computed tomography (18F-FDG-PET/CT) results. The results show that GSK2126458 has a dose-dependent and exposure-dependent inhibitory effect on mTOR, and can also reduce glucose signal abnormalities in the IPF pulmonary fibrosis region [41]. The results support further evaluation of the mTOR pathway as a target for new IPF therapy.
A double-blind, placebo-controlled trial was launched in 2015 and is expected to be completed in 2019. The selected patients were clearly diagnosed with IPF and were randomly assigned to the sirolimus group and the placebo group. The main study endpoints were the concentration of fibroblasts expressing CXCR4 in peripheral blood at 22 weeks and the proportion of patients with AE. The trial is still underway.
Lebrikizumab is a human IL-13 monoclonal antibody. Alveolar epithelial cells, mesenchymal cells and inflammatory cells can release cytokines, including GF, IL, IFN, TNF and chemokine [42]. IL-13 can promote fibroblast proliferation and ECM formation, promote the release of TGF-β, PDGF, CTGF, and synthesis of collagen and fibronectin, and play an important role in the onset of IPF [42,43].
double-blind, multi-center, parallel-designed phase II RCT for the effectiveness and safety of Lebrikizumab monotherapy or combined with pirfenidone for the treatment of IPF, and was launched from 2013 to 2017. The study included cohorts A and B, and each cohort was divided into experimental group and control group. The A cohort trial group was given Lebrikizumab (250 mg, intradermal injection, 1/4 week, for 52 weeks), and then extended treatment for 52 weeks during the open label period for a total of 104 weeks; the control group was given placebo for 52 weeks, and then Lebrikizumab for 52 weeks during the open label period for a total of 104 weeks. The B cohort trial group was given pirfenidone combined with Lebrikizumab for a total of 52 weeks, with a pirfenidone dose of 2403 mg/d or the maximum tolerated dose of oral drugs, with a Lebrikizumab dose of cohort A; the control group received pirfenidone and placebo for a total of 52 weeks. The 4 groups included 76, 78, 177 and 174 cases, with a total of 505 IPF patients with stable baseline lung function, FVC accounts for %≥40%, DLCO accounts for %25%~90%, and a walking distance of 6 min ≥100 m. Patients in cohort A did not receive IPF treatment 4 weeks before grouping and placebo treatment, and patients in cohort B had pirfenidone MTD ≤2 403 mg/d. The main study endpoint was the decline rate of FVC in the expected value at 52 weeks, and the secondary study endpoints included the walking distance of 6 min at 52 weeks and the annual decline rate of DLCO, and the proportion of patients with a decrease of ≥10% of the expected value within 122 weeks or deaths due to any cause. The results showed that FVC accounted for % reduction in the expected value at 52 weeks between the two groups in the A cohort (-6.18% and -5.20%, P=0.45), the annual decline in walking distance of 6 min (-44.65% and -22.72%, P=0.31), the annual decline in the DLCO (-4.78% and -4.24%, P=0.60), and the proportion of patients with FVC accounted for ≥10% of the expected value or deaths due to any cause (34.2% and 27.6%, P=0.42). The study results of the two groups in the B cohort were similar, with no statistical difference (-6.04% and -5.54%, P=0.55; -25.56% and -46.98%, P=0.20; -5.75% and -5.57%, P=0.60; 30.3% and 26.6%, P=0.42). The results of the study show that Lebrikizumab monotherapy or combined with pirfenidone cannot delay the progression of IPF lung function or reduce all-cause mortality.
. Rituximab:
B cell abnormalities in serum and lung tissues of IPF patients, plasma B cell stimulation factor concentration is significantly higher than that of normal control group, and the 1-year survival rate of IPF patients with higher B cell stimulation factor concentration is lower [44], considering that B cells may be related to IPF incidence and prognosis. A randomized, multi-center, parallel-design Phase II clinical trial on the effectiveness of CD20B cell monoclonal antibody rituximab in December 2018, 58 patients were included, aged 50 to 85 years old, and all of them were clearly diagnosed with IPF. Patients were divided into the trial group (rituximab, 1 mg, 2 intravenous injections, 14 days between injections) and control group and followed up for 9 months. The main study endpoint was human epidermoid cell-2 antibody titer, and the secondary study endpoints were changes in the concentration of anti-heat shock protein 70 antibody, FVC accounted for % of the expected value, and the incidence of acute exacerbation. The study is still underway.
4. Drugs acting on alveolar epithelial cells
1. Human integrin αvβ6 monoclonal antibody [STX-100 (BG00011)]:
integrin is a transmembrane receptor formed by non-covalent pairing of α and β subunits. It is expressed on the surface of myofibroblasts, participates in the signaling pathway between cells and ECM, controls TGF-β activation and release, and plays an important role in the pathogenesis of IPF [45].
A double-blind, parallel design phase IIa RCT that evaluates the safety and tolerance of BG00011 in the treatment of IPF was carried out in the United States. The study included 41 IPF patients and were divided into the trial group (BG00011, intradermal injection, once a week, 8 consecutive weeks, with a gradual increase in dose) and the control group [46]. Patients account for %≥50% of the estimated value, DLCO accounts for %≥30%, without oxygen inhalation or oxygen flow at rest ≤2 L/min, and residual gas (RV) accounts for %≤50%. The main study endpoint was the proportion of patients with acute exacerbation at 16 weeks, and the secondary study endpoint was the changes in biomarkers in peripheral blood and BALF at 16 weeks, whether BG00011 antibodies were produced, and drug plasma peak concentration, etc. The results showed that the pSMAD2 level in the TGF-β conduction pathway in the test group was suppressed by 70%. PSMAD2 can be significantly inhibited when BG00011≥0.3 mg/kg, and maximum inhibition can be achieved at 1 mg/kg. The incidence of acute exacerbation in the experimental group and the control group was 87% and 70%, respectively.
Another double-blind phase II b RCT was launched in 2018. The study is expected to include 290 IPF patients and are divided into the trial group (BG00011, intradermal injection, 56 mg/week, lasting 52 weeks) and the control group [47]. Patients DLCO accounted for 30% to 79%, FVC accounted for ≥50%, and the dose must be constant within 8 weeks before grouping. The main study endpoint was the FVC decline rate at 52 weeks, and the secondary study endpoint was the FVC decline rate of % expected value, the time of disease progression and the first AE. The study is still underway.
2. Tipelukast (MN-001):
arachidonic acid metabolite leukotrienes (LTs), is one of the regulators of pulmonary fibrosis, [48]. Generated by alveolar epithelial cells in patients with IPF, the LTB4 level in patients with lung tissues significantly increased [49], suggesting that it may be a potential therapeutic target for IPF.
A double-blind, parallel-design phase II RCT that evaluates the safety and tolerance of LTB4 inhibitor MN-001 in the treatment of IPF was conducted in 2016. 15 IPF patients were included in the study and were divided into the trial group (MN-001, oral, 750 mg, 2 times/d, for 26 weeks) and the control group. After all, all patients entered the open-label extension (MN-001, oral, 750 mg, 2 times/d, for 26 weeks) to evaluate the efficacy of the drug. The selected IPF patients are between 21 and 80 years old, with moderate to severe disease manifestations, and GAP index II to Ⅲ stages. The drug dosage is stable within 3 months before enrollment. The main study endpoint was the FVC change at 26 weeks, and the secondary study endpoint was the number of acute exacerbations in each patient at the first, third and six months, the rate of walking distance decline at 6 min, the change of dyspnea score at 26 weeks, etc. The study is still underway.
. Summary of the study of the pathogenesis of pulmonary fibrosis has provided a new target for the treatment of chronic progressive fibrotic interstitial lung diseases represented by IPF, and has promoted the development of new drugs [50]. Paying attention to the interconnection between multiple signaling pathways involved in disease progression and adopting combined treatment of multiple drugs for different sites and different targets may be the direction of anti-pulmonary fibrosis treatment in the future.
References (omitted)
