Nearly 2 billion people with latent infections, the tuberculosis war has never ceased-an overview of multi-drug-resistant pulmonary tuberculosis drugs

0 1.
Pulmonary tuberculosis Pulmonary tuberculosis (commonly known as "tuberculosis" or "tuberculosis") is an ancient disease.
It is an infection caused by Mycobacterium tuberculosis (M.
tuberculosis) invading the lungs
.
Mycobacterium tuberculosis mainly invades the lungs (80%).
Secondary infections can also occur in other parts such as cervical lymph, meninges, peritoneum, intestines, skin, and bones
.
The disease is mainly spread through the respiratory tract, and the source of infection is the excreted tuberculosis patients
.
Tuberculosis is widely distributed around the world, and it was once an infectious disease that seriously affected human life and health
.
Although the disease has been gradually controlled after centuries of efforts, tuberculosis has become more and more serious in recent years due to the influence of many factors
.
Mycobacterium tuberculosis (M.
tuberculosis), commonly known as tuberculosis (Tubercle Bacillus), is the pathogen that causes tuberculosis
.
In 1882, it was discovered by the German bacteriologist Robert Koch and proved to be the causative bacteria of human tuberculosis
.
The bacteria can invade all organs of the body, but it is the most common cause of tuberculosis
.
Mycobacterium tuberculosis is a type of bacteria that is obligate aerobic and has positive acid-fast staining
.
It has no flagella, has fimbriae, has microcapsules but does not form spores, and its bacterial wall has neither teichoic acid of gram-positive bacteria nor lipopolysaccharide of gram-negative bacteria
.
Multi-drug-resistant tuberculosis (MDR-TB) refers to tuberculosis in which Mycobacterium tuberculosis is resistant to isoniazid and rifampicin at least at the same time
.
The formation of drug-resistant strains is the main cause of failure of multidrug-resistant tuberculosis and chemotherapy.
The more drug resistance, the more failures, and the higher the mortality rate
.
Molecular biology research has found that the emergence of drug resistance is related to the mutation of certain genes on the chromosome of the strain
.
Insufficient treatment stimulated the development of drug resistance in Mycobacterium tuberculosis (ie acquired multi-drug resistance), and then multi-drug-resistant Mycobacterium tuberculosis spread among the population, resulting in infection with multi-drug-resistant Mycobacterium tuberculosis, forming primary Multidrug resistant tuberculosis
.
In addition, certain patient populations, such as AIDS patients, elderly and weak, immunocompromised patients, and secondary immunodeficiency patients (leukemia, aplastic anemia, connective tissue disease, neutropenia, hemolytic anemia, etc.
), long-term use In patients with hormones or other immunosuppressive agents, the above factors promote the progression and deterioration of tuberculosis, easy to spread, not easy to localize, often involving multiple organs and multiple sites, poor response to treatment, and prone to multidrug-resistant tuberculosis [1]
.
PART 0 2.
Epidemiology [2] Tuberculosis is a chronic and slow-onset infectious disease that is prone to occur in young people
.
The disease can occur all year round, and adolescents between 15 and 35 years old are the age at which tuberculosis occurs
.
The incubation period is 4 to 8 weeks
.
On October 14, 2020, the World Health Organization (WHO) released the "Global Tuberculosis Report 2020"
.
According to WHO estimates, the number of people latently infected with tuberculosis in the world is close to 2 billion
.
In 2019, there were approximately 9.
96 million newly diagnosed tuberculosis patients worldwide, which has basically remained at the same level in recent years
.
The global incidence of tuberculosis is 130/100,000, and the burden of tuberculosis varies greatly among countries.
The incidence ranges from less than 5/100,000 to more than 500/100,000 in some countries
.
Adult male patients accounted for 56.
0% of all new-onset patients, and children younger than 15 years old and those with tuberculosis/HIV infection accounted for 12.
0% and 8.
2% of new-onset patients, respectively
.
The 30 countries with a high burden of tuberculosis account for 86% of the global number of new patients.
The estimated number of new tuberculosis patients in China is 833,000 (866,000 in 2018), and the estimated incidence of tuberculosis is 58/100,000 (61 in 2018).
100,000), the estimated tuberculosis incidence rate ranks 28th among 30 countries with a high burden of tuberculosis
.
The global estimated number of HIV-negative tuberculosis deaths in 2019 is approximately 1.
21 million, with a mortality rate of 16 per 100,000
.
Among the 30 countries with a high burden of tuberculosis, the highest number of tuberculosis deaths is India (436,000), the lowest is Lesotho (0.
1 million), and the highest tuberculosis death rate is the Central African Republic (98/100,000)
.
The number of tuberculosis deaths in China is estimated to be 31,000, and the tuberculosis mortality rate is 2.
2 per 100,000.
For the first time, the tuberculosis mortality rate has dropped to the bottom of the 30 high-burden countries
.
Among the newly diagnosed tuberculosis patients worldwide in 2019, about 3.
3% of new patients and 18% of retreated patients were resistant to rifampicin
.
Globally, it is estimated that the number of patients with rifampicin-resistant tuberculosis is about 465,000, of which MDR-TB accounted for about 78%
.
Among the 30 countries with a high burden of multidrug-resistant tuberculosis, India (124,000, 27% of the world) and China (65,000, 14 %) and Russia (39,000, accounting for 8% of the world)
.
Tuberculosis is still one of the top 10 causes of death in the world, and has been the leading cause of death from a single infectious disease since 2007
.
PART 03.
Multi-drug-resistant pulmonary tuberculosis (MDR-TB) global approved drugs based on drug transit data surveys, search for indications "anti-tuberculosis/Mycobacterium tuberculosis infection", it can be found that a total of 31 drugs have been approved for marketing, and there are more 8 compound drugs were approved
.
Among them, the only drugs used for the treatment of multidrug-resistant tuberculosis are Pretomanid, Dramani, bedaquinoline fumarate, and rifabutin.
The specific details are as follows: Some data have a long history and cannot be verified
.
For more details, please refer to Yaodu Data
.
Target pattern of listed drugs for multidrug-resistant tuberculosis (drug crossing data) 01 Pretomanid (PA-824) On August 14, 2019, the US FDA approved the listing of Pretomanid developed by the non-profit organization-Global Tuberculosis Drug Development Alliance (TB Alliance) , Combined with Bedaquiline and Linezolid for the treatment of patients with drug-resistant tuberculosis (TB)
.
Pretomanid kills replicated Mycobacterium tuberculosis by inhibiting mycolic acid biosynthesis, thereby preventing the production of cell walls
.
On July 31, 2020, the drug was approved by the European Medicines Agency EMA for the treatment of multidrug-resistant tuberculosis (trade name Dovprela)
.
On October 31, 2018, Shanghai Foxingtai Pharmaceutical Technology Co.
, Ltd.
and Shanghai Fosun Pharmaceutical Industry Development Co.
, Ltd.
launched a phase I clinical trial (CTR20181897) in mainland China for the treatment of Mycobacterium tuberculosis infection
.
On January 16, 2020, the non-profit drug R&D organization TB Alliance announced that it has granted Shanghai Fosun Pharmaceutical (Group) Co.
, Ltd.
wholly-owned subsidiary Shenyang Hongqi Pharmaceutical Co.
, Ltd.
a license to sell the tuberculosis drug Pretomanid in China [3]
.
The phase III clinical study Nix-TB (NCT02333799) trial included 109 patients with MDR-TB who were XDR-TB, drug intolerant or treatment failure
.
The data showed that 89.
9% of patients who received the BPaL regimen (Pretomanid+bedaquinoline+linezolid) for 6 months achieved good outcomes, and the results were consistent regardless of the type of tuberculosis, HIV infection status, and linezolid medication regimen [4 ]
.
02 Delamanid Delamanid is a mycolic acid synthase inhibitor developed by Otsuka Holdings Co Ltd
.
On April 27, 2014, the drug was approved by the European Medicines Agency EMA for the treatment of multidrug-resistant tuberculosis (trade name Deltyba)
.
On July 4, 2014, the drug was approved by PMDA of Japan's Bureau of Medicines and Medical Devices for the treatment of tuberculosis
.
On March 12, 2018, Delamanib tablets were approved by the National Medical Products Administration of China NMPA.
Under the indication that an effective treatment plan cannot be formed due to drug resistance or tolerance, this product can be used as a part of a combined treatment plan , For the treatment of adult patients with multi-drug resistant tuberculosis (MDR-TB) (trade name Delba)
.
In April 2008, Otsuka initiated a phase II clinical trial (NCT00685360) in MDR-TB patients (n=481) in Japan, China, South Korea, the Philippines, Egypt, Estonia and Latvia
.
Among a total of 481 registered subjects, the sputum culture conversion rate (SCC) increased by 53% after two months of the use of Delramani 100 mg bid combined with the best background treatment
.
The data showed that 45.
4% and 41.
9% of subjects in the 100 and 200 mg bid groups achieved SCC, respectively, while 29.
6% of the subjects in the placebo group achieved SCC
.
At the end of week 5, 24% and 23% of subjects in the 100 and 200 mg bid groups achieved SCC, respectively, compared with 13% in the placebo group
.
03 Bedaquiline Fumarate Bedaquiline Fumarate is an ATP synthase inhibitor developed by Johnson & Johnson
.
On December 28, 2012, the drug was approved by the U.
S.
Food and Drug Administration (trade name Sirturo) for the treatment of Mycobacterium tuberculosis infection
.
On March 5, 2014, the drug was approved by the European Medicines Agency EMA (trade name Sirturo) for the treatment of multidrug-resistant tuberculosis
.
On November 23, 2016, the drug was approved by the China National Medical Products Administration NMPA (trade name Snair) for the treatment of multi-drug-resistant tuberculosis
.
In a placebo-controlled, double-blind, randomized trial in newly diagnosed sputum smear-positive pulmonary tuberculosis drug-resistant patients, all patients were combined with 5 other anti-mycobacterial drugs (e.
g.
, ethionine, kana MDR-TB with pyrazinamide, ofloxacin and cycloserine/terizidone or other alternatives) for 18-24 months or at least 12 months after the first confirmation of negative culture
.
In this trial, compared with the placebo group, the Bedaquinoline treatment group had a shorter sputum culture negative time and an increased sputum culture negative rate at week 24
.
The median time for sputum culture to become negative in the Bedaquinoline treatment group was 83 days, and that of the placebo group was 125 days
.
04 rifabutin (Rifabutin) rifabutin developed by Pfizer is an RNA polymerase inhibitor
.
Rifabutin is a semi-synthetic rifamycin drug with similar structure and activity to rifampicin.
In addition to its anti-gram-negative and positive bacteria, it also has anti-tuberculosis and avium bacillus (M.
avium) activity
.
On December 23, 1992, it was first approved by the US FDA for the treatment of Mycobacterium intracellulare infection, with the trade name "Mycobutin"
.
On February 24, 2014, the FDA approved it for the treatment of multi-drug-resistant tuberculosis under the trade name "Rifabutin"
.
On December 28, 2007, China National Medical Products Administration NMPA approved Sichuan Mingxin Pharmaceutical Co.
, Ltd.
's rifabutin capsules for the treatment of AIDS patients with Mycobacterium avium infection syndrome, pneumonia, and chronic drug-resistant tuberculosis
.
Rifabutin capsules cannot be used for the prevention of avium-intracellular mycobacterium complex infection in patients with active tuberculosis
.
Patients with active tuberculosis taking rifabutin alone may cause tuberculosis to develop resistance to both rifabutin and rifampin
.
05 Other phase II clinical research in the pharmaceutical WX-081 WX-081 was developed by the Chenxin Pharmaceutical Co.
, Ltd.
is an inhibitor of ATP synthase complex
.
This medicine is a class of Chinese chemical medicine
.
At present, the highest research and development stage of the drug is clinical phase II, which is used to treat tuberculosis and multi-drug resistant tuberculosis
.
On April 11, 2017, Chenxin Pharmaceutical Co.
, Ltd.
submitted an IND application to the China National Medical Products Administration NMPA for the treatment of Mycobacterium tuberculosis infection
.
WX-081 Domestic clinical progress (data source: Yaodu data) Pyrifazimine Pyrifazimine is a small molecule drug developed by Peking Union Pharmaceutical Factory and Institute of Materia Medica, Chinese Academy of Medical Sciences.
A class of Chinese chemical medicine
.
At present, the highest research and development stage of the drug is clinical phase II, which is used to treat tuberculosis
.
Pyfazimine domestic clinical progress (data source: Yaodu data) Efesovir Efesovir is a drug for the treatment of Mycobacterium tuberculosis infection developed by The Scientific Center For Anti-Infectious Drugs
.
On September 1, 2015, the drug was approved by Kazakhstan to be marketed for the treatment of Mycobacterium tuberculosis infection
.
On December 1, 2013, the Scientific Center For Anti-Infectious Drugs, Kazakhstan launched a phase III clinical trial (NCT02607449) in Kazakhstan and Kyrgyzstan for the treatment of multi-drug-resistant tuberculosis
.
Tuberculosis vaccine (Archivel Farma) Tuberculosis vaccine (Archivel Farma) is a preventive viral vaccine developed by the Spanish company Archivel Farma
.
At present, the highest research and development stage of the drug is clinical phase II, which is used to prevent tuberculosis, new coronavirus pneumonia and multi-drug resistant tuberculosis
.
On September 1, 2021, Archivel Farma Sl will start a Phase II clinical trial (NCT04919239) in India for the treatment of tuberculosis
.
On March 18, 2020, Archivel Farma Sl conducted a Phase II clinical trial (NCT02711735) in Ukraine for the treatment of multi-drug-resistant tuberculosis
.
PART 04.
Summary The causes of multi-drug-resistant pulmonary tuberculosis (MDR-TB) are multifaceted.
The prevalence and incidence of MDR-TB in different countries or regions are due to differences in the treatment and management of tuberculosis in the past and the patients’ own conditions.
Big difference
.
Countries with high prevalence and incidence of MDR-TB are facing a very severe situation.
The DOTS strategy is the most effective measure to prevent the occurrence of MDR-TB
.
That is, ① the government's commitment to the tuberculosis program; ② use sputum smear microscopy to detect infectious pulmonary tuberculosis patients; ③ provide short-term chemotherapy under correct management; ④ establish a regular anti-tuberculosis drug supply system; ⑤ establish and maintain tuberculosis monitoring and evaluation Supervision system
.
The implementation of the DOTS strategy can find the source of infection in large quantities and directly, help patients strictly follow the doctor's instructions, take medication according to the prescribed course of treatment, deal with adverse drug reactions in a timely manner, reduce treatment costs, increase disease outcome, and effectively reduce the occurrence of MDR-TB
.
Among the four multi-drug resistant pulmonary tuberculosis (MDR-TB) drugs that have been on the market, only bedaquinoline fumarate has a domestic ANDA application (Beijing Fuyuan Pharmaceutical Co.
, Ltd.
, CYHS2000373, 2020-06-02) , Is still in the review and approval stage
.
The basic population in China is relatively large, and the number of patients with tuberculosis and MDR-TB is still at a high burden stage.
The development of more updated drugs for the treatment of tuberculosis and MDR-TB can not only meet the needs of clinical treatment, but also promote enterprises.
Constantly innovate and achieve greater profits
.
References: [1] Shi Yunfang, Zhang Yanxia, ​​Li Hairong
.
Discussion on the etiology of multidrug-resistant tuberculosis [J]
.
Chinese Journal of Experimental and Clinical Infectious Diseases, 2010, 4(3): 348-349.
[2] China Center for Disease Control and Prevention
.
[3] TB Alliance Announces Partnership with Hongqi Pharma to Commercialize New Therapy for Highly Drug-Resistant Forms of TB in China.
https:// -new-therapy-highly-drug-resistant.
[4] Liu Shengsheng, Tang Shenjie
.
Research progress of the new anti-tuberculosis drug Putomani[J]
.
Chinese Medical Journal, 2020, 100 (26): 2071-2074.