The tuberculosis war never stopped: an overview of multidrug-resistant tuberculosis drugs

PART 0 1.
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 (M.
tuberculosis), commonly known as tuberculosis (Tubercle Bacillus), is the pathogen that causes tuberculosis
.

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
.

PART0 2.
Epidemiology [2]

Tuberculosis is a chronic and slow-onset infectious disease that young people are prone to
.

According to WHO estimates, the number of people latently infected with tuberculosis in the world is close to 2 billion
.

Among the newly diagnosed tuberculosis patients worldwide in 2019, about 3.
3% of new patients and 18% of retreated patients were resistant to rifampicin
.

PART0 3.
Multi-drug-resistant tuberculosis (MDR-TB) globally approved drugs

According to the data survey of Yaodu, searching for the indication "Anti-tuberculosis/Mycobacterium tuberculosis infection", it can be found that a total of 31 drugs have been approved for marketing, and another 8 compound drugs have been approved
.

Because part of the data has a long history, it cannot be verified
.

Target pattern of listed drugs for multi-drug resistant tuberculosis (Yaodu 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), to be used in combination with Bedaquiline and Linezolid for resistance Drug treatment of patients with 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

De mani by Otsuka Holdings Co Ltd R & D is a mycolic acid synthase inhibitors
.
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
.

03Bedaquiline Fumarate

Betaquinoline 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 is an RNA polymerase inhibitor developed by Pfizer Pharmaceuticals
.
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 clinical Phase II drugs under development

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

Pyfazimine is a small molecule drug developed by Peking Union Pharmaceutical Factory and Institute of Materia Medica, Chinese Academy of Medical Sciences.
The drug is a class of Sinochem
.
At present, the highest research and development stage of the drug is clinical phase II, which is used to treat tuberculosis
.

Domestic clinical progress of Pyfazimine (Data source: Yaodu Data)

Efesovir

Efesovir is a drug developed by The Scientific Center For Anti-Infectious Drugs to treat Mycobacterium tuberculosis infection
.
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
.

PART0 4.
Summary

The etiology of multi-drug-resistant tuberculosis (MDR-TB) is multifaceted.
The prevalence and incidence of MDR-TB in different countries or regions are quite different due to differences in the treatment and management of tuberculosis in the past and the patient’s own conditions.

.
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 Centers 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.