Recently, the application for clinical trial of Class I drug XNW4107 for injection from Suzhou Sinovent Pharmaceuticals Co., Ltd. was accepted.
XNW4107 is a new type of β-lactamase inhibitor. The preclinical trial data show that the drug has strong lethality to gram-negative bacteria, and has the simultaneous effect on acinetobacter baumannii, pseudomonas aeruginosa and enterobacteriaceae. Its bacteriostatic effect is better than that of similar products on the market or in clinical stage. In May 2020, the drug was approved for phase I clinical trial in the United States.
β-lactam antibiotics are the most commonly used antibiotics in clinic. They have advantages of strong fungicidal activity, low toxicity, wide indications and good clinical efficacy, but there is severe drug resistance. The main resistance mechanism of β-lactam antibiotic is the production of β-lactamase by bacteria. It is particularly evident in carbapenem-resistant bacteria such as enterobacteriaceae (CRE), pseudomonas aeruginosa (CRPA), acinetobacter baumannii (CRAB), etc. Their main mechanism of resistance is the production of various carbapenemases. The β-lactamase inhibitor can combine with the enzyme produced by the bacteria and inactivate it, thereby reducing drug resistance and improving the efficacy of antibiotics.
Since the discovery of clavulanic acid, the first β-lactamase inhibitor in 1976, many β-lactamase inhibitors have been approved worldwide, such as tazobactam, sulbactam, avibactam, vaborbactam and relebactam. These β-lactamase inhibitors are often combined with β-lactam antibiotic to make compound preparations.
At present, the domestic compound preparation composed of tazobactam, sulbactam and avibactam has been approved, and the compound preparation MK-7655A composed of relebactam, cilastatin and imipenem from MSD is in phase III clinical trial. Previously, there are many domestic new β-lactamase inhibitors in the development stage, such as Durlobactam (ETX2514) of Entasis and Zai Lab Limited and VNRX-5133 of VenatoRx.
Durlobactam: About Acinetobacter Baumannii
Durlobactam (ETX2514) is a new, broad-spectrum Class A, C, and D β-lactamase inhibitor for intravenous administration from Entasis. Preclinical studies show that the drug restores antibiotic activity of sulbactam by inhibiting β-lactamase, which is common in acinetobacter baumannii. In April 2018, Zai Lab Limited entered into a partnership with Entasis to acquire rights of exclusive development and commercialization in the Asia-Pacific region (including Japan) for the drug.
Entasis is developing SUL-DUR (Sulbactam-Durlobactam, a fixed dose combination) as a new antibiotic for intravenous administration for the treatment of a series of multidrug resistant severe sepsis caused by acinetobacter baumannii. On October 19 this year, Entasis announced a positive result from global phase III registered clinical research on evaluating the efficacy and safety of SUL-DUR in the treatment of carbapenem-resistant acinetobacter baumannii infection. Compared with polymyxin, SUL-DUR can reach a statistical non-inferiority standard and has better safety in the treatment of patients with carbapenem-resistant acinetobacter baumannii.
The study was conducted in 95 clinical centers in 17 countries around the world, with 207 patients enrolled. The study consists of two parts. Part A refers to randomized control part (SUL-DUR vs polymyxin), which is aimed at patients with Hospital-aquire Acinetobacter Bacterial Pneumonia (HABP), Ventilator-Associated Bacterial Pneumonia (VABP), Ventilation Pneumonia (VP) or Bacteremia. Part B is an open label part (SUL-DUR only) of ABC infections that are resistant or failed to treat polymyxin or polymyxin B.
Specific research data are as follows. 1) In part A (n=125): the mortality rate of SUL-DUR was 19.0% (12/63), which reached the main end point of 28-day all-cause mortality (Vs 32.3% that of polymyxin group). Moreover, the difference of clinical cure rate observed in clinical cure evaluation is of statistically significance, which is 61.9% in SUL-DUR group and 40.3% in polymyxin group. 2) In part B, the 28-day all-cause mortality in SUL-DUR group was 17.9% (5/28), which was consistent with the results observed in part A. 3) In terms of safety, SUL-DUR achieved the main safety goal, and the nephrotoxicity was statistically and significantly reduced. Nephrotoxicity was 13.2% (12/91) in the SUL-DUR group compared with 37.6% (32/85) in the polymyxin group, and overall adverse events (AE) in the safe crowd were comparable with treatment groups, with 87.9% (80/91) in the SUL-DUR group compared with 94.2% (81/86) in part A and 89.3% (25/28) in part B in the polymyxin group.
VNRX-5133: About Serine and Metallo-β-lactamase
VNRX-5133 (taniborbactam) is a potential best-in-class cyclic borate compound for injection, which can simultaneously inhibit serine and metallo-β-lactamase. It is the only β-lactamase inhibitor known to block class B carbapenemase in later clinical development. In September 2018, Everest Medicine reached a cooperation with Venatorx to acquire the rights and interests of the drug in the greater China region, South Korea, Singapore and other regions.
In 2019, Everest Medicine and VenatoRx announced the launch of phase III registered clinical trials of this drug combined with the fourth generation cephalosporin cefepime hydrochloride for patients with complicated Urinary Tract Infection (cUTI). In September 2020, Everest Medicine announced that the phase I clinical research of VNRX-5133 combined with cefepime hydrochloride in the treatment of Multi-Drug Resistant bacteria (MDR) infection in China had achieved the main goal -- the combined treatment scheme of cefepime hydrochloride and taniborbactam was safe and well tolerated in healthy Chinese volunteers, and no racial differences were found in its key pharmacokinetic parameters. At present, the drug is in phase III clinical trial in China, and is intended to be used to treat complicated Urinary Tract Infections, including pyelonephritis.
In addition, there are several new β-lactamase inhibitors with an inhibitory effect on B metalloenzyme at abroad, such as zidebactam, WCK-5153, GT-1-GT-055 and so on.
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