Idiopathic pulmonary fibrosis (IPF) of rare diseases in China

Idiopathic Pulmonary Fibrosis (IPF) is a rare, chronic, progressive, and fibrotic interstitial lung disease with unknown etiology and pathogenesis
.
The lesions are mainly confined to the lungs, and are more likely to occur in middle-aged and elderly men.
His lung histopathology and or chest high-resolution CTHRCT are characteristically manifested as Usual Interstitial Pneumonia (UIP)
.
Its clinical features are progressive scarring or fibrosis confined to the interstitial space of the lung, leading to loss of lung function and eventually death
.
Symptoms include dry cough, exertional dyspnea and fatigue
.
In the late stages of the disease, as blood oxygen levels decrease, the skin may appear blue (cyanosis), and the ends of the fingers may become thick or sticky
.
As the disease progresses, signs of pulmonary hypertension and right heart failure will also be observed
.
Although the disease progression is variable, progressive fibrosis (scarring) eventually leads to death, and the median survival time after diagnosis is only 3-5 years
.
Potential serious complications in patients with idiopathic pulmonary fibrosis include pulmonary hypertension (Pulmonary Hypertension), gastroesophageal reflux disease (Gastroesophageal Reflux disease), obstructive sleep apnea (Obstructive Sleep apnea) and coronary artery disease (Coronary Artery Disease)
.
Smoking, dust exposure, certain viral infections (such as cytomegalovirus, Epstein-Barr virus, etc.
), gastroesophageal reflux, etc.
are risk factors for IPF, and certain mutations in the telomerase gene may be related to familial IPF
.
The prevalence of IPF in the general population is 2/100 000~ 29/100 000, and the age of onset is over middle-aged.
It is more common in elderly men who smoke heavily (>20 pack years)
.
On May 11, 2018, five departments including the National Health Commission jointly formulated the "List of the First Batch of Rare Diseases", in which idiopathic pulmonary fibrosis was included
.
The treatment goals of IPF are to relieve symptoms, improve quality of life, slow down or stop disease progression, and improve survival
.
Prednisone, azathioprine, and N-acetylcysteine ​​(NAC) have been used to treat symptoms associated with IPF, but they usually do not significantly increase life expectancy
.
Lung transplantation is an option for some patients and can improve the quality of life and life expectancy
.
Other treatments to relieve symptoms include oxygen therapy and pulmonary rehabilitation
.
1.
Transforming growth factor β1 (TGF-β1) TGF-β family members include TGF-β1, TGF-β2 and TGF-β3, which are involved in inflammation, wound healing, extracellular matrix accumulation, bone formation, tissue development, cell differentiation and tumors progress and so on
.
Transforming growth factor β1 (TGF-β1) is an important factor in driving tissue fibrosis, which can directly activate Smad signal transduction, thereby triggering the overexpression of pro-fibrotic genes
.
Studies have shown that the dysregulation of the TGF-β1/Smad pathway is an important pathogenic mechanism of tissue fibrosis
.
Smad2 and Smad3 are the two main downstream regulators that promote TGF-β1-mediated tissue fibrosis, and Smad7, as a negative feedback regulator of the TGF-β1/Smad pathway, blocks TGF-β1-mediated fibrosis
.
In addition, in recent years, it has been reported that microRNA (miRNA) can regulate the TGF-β1/Smad signaling pathway, thereby affecting the process of tissue fibrosis [1]
.
Representative drug: pirfenidone
.
It was launched in Japan for the first time on October 16, 2008
.
The drug has been approved for marketing in the European Union, China, and the United States for the treatment of idiopathic pulmonary fibrosis
.
2.
Vascular Endothelial Growth Factor (VEGF) VEGF is a type of glycoprotein that specifically acts on vascular endothelial cells.
It exists in the form of homodimers.
It is a pro-angiogenic factor with high biological activity and has a strong epithelial-promoting effect.
Cell proliferation can promote the formation of new blood vessels
.
VEGF increases vascular permeability; endothelial cells proliferate, migrate, and adhere to each other; change the extracellular matrix, build a new blood vessel growth environment, and play an inducing and gene-regulating role in angiogenesis [2-3]
.
There are three main types of VEGF receptors: VEGFR-1, VEGFR-2 and VEGFR-3, all of which are tyrosine kinase receptors
.
VRGFR-1, VEGFR-2 is mainly expressed in vascular endothelial cells, and VEGFR-3 is expressed outside lymphatic endothelial cells
.
3.
Fibroblast growth factor (FGF) FGF is a large family of protein peptides (FGFs) composed of peptides with a wide range of biological activities
.
So far, 24 members of the FGF family have been found
.
FGF-1 (also known as acidic fibroblast growth factor, aFGF) and FGF-2 (also known as basic fibroblast growth factor, bFGF) belong to the FGF family with extensive mitogenic effects
.
It participates in a series of physiological processes: including embryonic development, cell proliferation, tissue repair, tumor growth and infiltration
.
FGF-2 has a broad spectrum of nuclear fission, blood vessel growth and neurotrophic factors [4]
.
The biological activity range of the two structures is the same, and they function by acting on the same cell surface receptor group [5]
.
4.
Platelet-derived growth factor (PDGF) PDGF is a cytokine secreted by a variety of cells.
It acts on tissue cells in an autocrine or paracrine manner and is involved in tissue repair, embryonic development, immunity and many common diseases Play an important role[6]
.
PDGF exerts its biological effects by acting on specific receptors on the cell membrane
.
PDGF was originally found in platelets, and was released from platelet alpha particles in the early stage of injury to initiate and accelerate tissue wound repair
.
The biological activities of PDGF mainly include: (1) Chemotactic activity
.
In the early stage of trauma, it can promote the accumulation of surrounding cells to the trauma site, cooperate with the coagulation of platelets, activate the immune system of the trauma site, and lay the foundation for wound repair
.
(2) Constriction of blood vessels
.
In the initial stage of trauma, it can stimulate the rapid contraction of capillaries at the trauma site, reduce the blood pressure and flow rate of the trauma site, promote blood coagulation, and create conditions for wound repair
.
At the same time, PDGF can induce the division and proliferation of damaged epithelial cells and endothelial cells, promote the formation and regeneration of blood vessels, and provide guarantee for wound repair [7]
.
(3) Schizophrenia
.
PDGF transmits cell signals by activating the PDGF receptor transmembrane protein, and stimulates fibroblasts, glial cells, smooth muscle cells and other cells that are arrested in the G0/G1 phase to enter the division and proliferation cycle [8]
.
(4) Participate in phosphatase activation and prostaglandin metabolism
.
When PDGF interacts with cells with receptors, it can induce the phosphoinositide cycle and the release of arachidonic acid, and promote the production of prostaglandins, PGI2 and PGE2
.
The increase of PGI2 and PGE2 may accelerate bone resorption and increase its vasodilator and antiplatelet activity
.
3.
Anti-IPF drug 01 listed drug (1) Pirfenidone Pirfenidone developed by Intermune is a small molecule oral collagen (Collagen) inhibitor and TGF-β1 inhibitor for idiopathic disease Treatment of pulmonary fibrosis
.
On October 16, 2008, pirfenidone was approved for marketing by the PMDA of Japan's Agency for Pharmaceuticals and Medical Devices
.
On February 27, 2011, pirfenidone was approved by the European Medicines Agency EMA
.
December 25, 2013, pirfenidone China's State Drug Administration approved the NMPA (Zhunzi H20133375, commodity Mingaisirui) on the market, in 2020 the national health insurance B
.
On October 15, 2014, pirfenidone was approved by the US Food and Drug Administration (trade name Esbriet)
.
The results of the New England Journal of Medicine (NEJM) ASCEND study (evaluation to confirm the effectiveness and safety of pirfenidone in the treatment of idiopathic pulmonary fibrosis) showed that after 52 weeks of treatment, pirfenidone can effectively slow down Disease progression in patients with primary pulmonary fibrosis
.
In the pirfenidone group, compared with the placebo group, the predicted value of forced vital capacity (FVC) had an absolute decrease of ≥ 10% or the rate of patient death decreased by 47.
9%, while the FVC did not decrease or the rate of patient death increased relatively 132.
5%
.
At the same time, pirfenidone can reduce the range of 6-minute walk distance reduction and improve the progression-free survival of IPF patients
.
Moreover, the pirfenidone group also showed significant differences in all-cause mortality and idiopathic pulmonary fibrosis-related mortality compared with the placebo group, and the incidence was significantly lower than that of the placebo group
.
Pirfenidone is sold in Europe by Roche Registration Gmbh, Beijing Kantine Pharmaceutical Co.
, Ltd.
is responsible for sales in China, and Genentech is responsible for sales in the United States
.
The percentage growth rate of pirfenidone's global sales from 2015 to 2020 is 19.
60%
.
(2) Nintedanib Nintedanib is a small molecule chemical synthesis drug developed by Boehringer Ingelheim and is a selective antagonist of VEGF, FGF and PDGF receptors
.
In October 2014, the U.
S.
FDA approved the marketing of nintedanib ethanesulfonate for the treatment of idiopathic pulmonary fibrosis
.
On November 21, 2014, nintedanib ethanesulfonate was approved by the European Medicines Agency EMA
.
On July 3, 2015, nintedanib ethanesulfonate was approved for marketing by the PMDA of Japan's Bureau of Medicines and Medical Devices
.
On September 20, 2017, the nintedanib ethanesulfonate soft capsule was approved by the National Medical Products Administration of China NMPA (trade name Vegat), and it will be Class B of the National Medical Insurance in 2020
.
Compared with patients treated with placebo, the annual decline rate of FVC in patients treated with nintedanib was significantly reduced; the risk of disease progression of patients was reduced by 40% compared with placebo; the total score of SGRQ found that Nida Compared with the placebo group, Nimb has worsened more slowly; the number of patients with acute exacerbation of IPF at 52 weeks in the nintedanib group (2.
3%) is less than that in the placebo group (13.
8%), and the overall mortality rate (5.
5%) It was lower than 7.
8% of the placebo group
.
The annual report of Boehringer Ingelheim shows that the sales of nintedanib ethanesulfonate soft capsules in 2019 were US$1.
671 billion, and the sales in 2020 were US$2.
525 billion, an increase of 51.
1%
.
02 Anti-IPF drugs under clinical research Drug data show that there is no drug applied for marketing at present, and only one case of anti-IPF drugs under clinical research has entered the clinical phase III research phase, and there are few anti-IPF drugs in other research phases
.
Pamrevlumab is a fully human monoclonal antibody developed by Fibrogen and is a connective tissue growth factor (CTGF) inhibitor
.
The drug is a class of Chinese biological drugs
.
At present, the highest research and development stage of the drug is clinical phase III, which is used to treat Duchenne muscular dystrophy, pancreatic cancer and idiopathic pulmonary fibrosis
.
November 19, 2020, by Fibrogen Inc
.
Boehringer Ingelheim Pharma Gmbh & Co Kg and Fabojin (China) Medical Technology Development Co.
, Ltd.
conducted a phase III clinical trial in mainland China (a phase 3 evaluation of the effectiveness and safety of Pamrevlumab in the treatment of idiopathic pulmonary fibrosis (IPF) , Randomized, double-blind, placebo-controlled study, CTR20202271) for the treatment of idiopathic pulmonary fibrosis
.
The CDE drug clinical trial registration and information disclosure platform shows that the clinical trial has not yet begun to recruit
.
Among the cytokines involved in pulmonary fibrosis, connective tissue growth factor (CTGF) can stimulate fibroblast proliferation and collagen secretion
.
CTGF is one of the highly conserved immediate early gene CCN family members, which include CTGF (fisp-12), Nov, cyr61, WISP-1, WISP-2 and WISP-3
.
The common structural feature of this family is its high sequence homology and similarity of sequence structure
.
The biological activity of CTGF is mainly manifested in (1) promoting cell proliferation and accelerating DNA synthesis; (2) promoting blood vessel formation; (3) promoting fibroblast proliferation and stimulating the synthesis of extracellular matrix; (4) mediating cell adhesion and stimulating Cell migration; (5) Inducing cell apoptosis
.
The expression level of CTGF is low under physiological conditions, while the expression is significantly higher under pathological conditions
.
Its overexpression is closely related to the occurrence and development of fibrosis or certain proliferative diseases, such as: scleroderma, atherosclerosis, systemic sclerosis and some benign and malignant tumors, as well as major organs such as lung, liver, kidney, pancreas, etc.
Fibrosis, chronic pancreatitis, etc.
[9]
.
Yinfenidone Hydrochloride is a TGF-β1 inhibitor and collagen inhibitor developed by Dongyang Sunshine Pharmaceutical Co.
, Ltd.

.
On August 23, 2016, Guangdong Dongyang Sunshine Pharmaceutical Co.
, Ltd.
submitted an IND application (Chemical Drug Category 1) (CXHL1600161, CXHL1600162) to the China National Medical Products Administration NMPA for the treatment of idiopathic pulmonary fibrosis
.
On July 9, 2018, the US FDA granted its orphan drug designation for the treatment of idiopathic pulmonary fibrosis
.
A Phase II clinical trial of idiopathic pulmonary fibrosis (CTR20210132) will be launched in Mainland China on January 26, 2021
.
IDL-2965 is a small molecule heterocyclic compound developed by Indalo Therapeutics.
Its mechanism of action is ITGAV&ITGB1 inhibitor, ITGAV&ITGB6 antagonist and ITGAV&ITGB3 antagonist
.
At present, the world's highest research and development stage of the drug is clinical phase II, which is used to treat non-alcoholic fatty liver and idiopathic pulmonary fibrosis
.
PLN-74809 is a small molecule drug developed by Pliant Therapeutics.
It is an inhibitor of ITGAV&ITGB1 and an antagonist of ITGAV&ITGB6
.
At present, the highest research and development stage of the drug in the world is clinical phase II, which is used to treat adult respiratory distress syndrome, primary sclerosing cholangitis and idiopathic pulmonary fibrosis
.
BMS-986263 is a biological drug developed by Hokkaido University and Sapporo Medical University.
It is an inhibitor of RNA interference and Colligin
.
At present, the highest research and development stage of the drug is clinical phase II, which is used to treat non-alcoholic fatty liver and idiopathic pulmonary fibrosis
.
Romilkimab is a bispecific antibody and humanized monoclonal antibody developed by Sanofi.
It is an IL13 inhibitor and IL4 inhibitor
.
At present, the highest research and development stage of the drug is clinical phase II, which is used to treat idiopathic pulmonary fibrosis
.
4.
Summary Although the listing of pirfenidone and nintedanib has brought hope to patients with pulmonary fibrosis, and clinically researched anti-IPF drugs have gradually entered the public’s field of vision, the biggest cause of idiopathic pulmonary fibrosis is currently The problem is still missed and misdiagnosed
.
In people with pulmonary fibrosis, the vast majority of patients may not have any symptoms in the early stage of the disease.
As the disease progresses, lung function gradually deteriorates, showing dyspnea and shortness of breath
.
Some elderly patients often ignore the symptoms of dyspnea, thinking that it is physical discomfort caused by aging
.
When the patient has symptoms such as shortness of breath and dyspnea, it is already in the middle and late stages of the disease, and the lung ventilation function has been impaired by at least 50%
.
Therefore, for middle-aged and elderly people, especially those who smoke, repeatedly cough, shortness of breath, people who have been exposed to dust for a long time, and those who have a family history, they should be more vigilant and should go to the hospital for lung function tests on a regular basis
.
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.
Research progress of TGF-β1/Smad signaling pathway in tissue fibrosis[J]
.
International Journal of Pharmaceutical Research
.
2019, 46(10): 738-744
.
[2] The function and application of vascular endothelial growth factor, Advances in Physiological Sciences, 1996, 27(3): 255-257
.
[3] Vascular Endothelial Growth Factor, Harbin Medicine, 2006, 26(5): 73-75
.
[4] The characteristics and molecular functions of fibroblast growth factor, Life Science Research, 2005, 9(4): 10-13
.
[5] Physiological function and application of fibroblast growth factor, Chongqing Medical University, 1996, 21:162-165
.
[6] Progress in cell signal transduction and biological effects of PDGF, Journal of Practical Medicine, 2001, 14(1): 44-46
.
[7] Hoch RV, Soriano P.
Roles of PDGF in animal development[J].
Development, 2003, 130:4679-84.
[8] Bennett NT, Schultz.
Growth factors and wound healing.
Am J Surg, 1993, (166): 74-81.
[9] Gao Yuan, Qin Jun
.
Research progress on the relationship between connective tissue growth factor (CTGF) and pulmonary fibrosis[J]
.
Journal of Clinical Pulmonary Medicine, 2011, 16(4): 601-606.