Promising Shionogi Candidate Moves Ahead In Gram-Negative Pneumonia
Executive Summary
Novel Shionogi antibiotic candidate set to move ahead following positive results in Gram-negative pneumonia, where resistance and unmet needs remain critical factors.
Shionogi & Co. Ltd.’s novel siderophore cephalosporin antibiotic cefiderocol has met its primary non-inferiority endpoint in the international Phase III APEKS-NP Phase III trial in nosocomial pneumonia, matching high-dose meropenem in all-cause mortality at 14 days.
The results are significant in that, while there are a number of new antibiotics for carbapenem-resistant infections, there are relatively few candidates able to address all resistant Gram-negative pathogens. These have multiple mechanisms of resistance to drug and can therefore be very difficult to treat, with high morbidity and mortality rates as a result.
The APEKS-NP trial, results from which were presented on 3 October at IDWeek 2019 in Washington, DC, compared cefiderocol 2g intravenously infused over three hours every eight hours with high-dose meropenem 2g IV, a carbapenem, given over a three-hour period every eight hours, for seven to 14 days in a hospital setting. Linezolid was additionally administered for at least five days in both arms to provide coverage for methicillin-resistant Staphylococcus aureus and for Gram-positive bacteria in the cefiderocol group.
The Shionogi drug showed all-cause mortality in the modified intent-to-treat population at day 14 of 12.4%, versus 11.6% for meropenem (difference: 0.8, 95% CI: –6.6; 8.2).
Cefiderocol also met key secondary endpoints including clinical outcome at test of cure (TOC), which was 64.8% versus 66.7% for meropenem (difference: –2.0, 95% CI: –12.5; 8.5), while microbiological eradication at TOC was 47.6% versus 48% (difference: –1.4, 95% CI: –13.5; 10.7). Day 28 all-cause mortality was 21.0% versus 20.5% (difference: 0.5, 95% CI: –8.7; 9.8).
Additional results showed clinical cure rates were similar between the treatment arms in the modified intent-to-treat population for major target pathogens at TOC. For example, for Klebsiella pneumoniae this was 64.6% for cefiderocol versus 65.9% for meropenem (difference: –1.3, 95% CI: –20.8; 18.1) and for Pseudomonas aeruginosa 66.7% versus 70.8% (difference: –4.2, 95% CI: –30.4; 22.0).
No unexpected safety signals were observed in the study and the incidence of treatment-emergent adverse events was similar between the two arms, at 87.8% for cefiderocol versus 86.0% for meropenem (difference: 1.8, 95% CI: –5.8; 9.5).
The new data “provide meaningful evidence that cefiderocol has the potential to be an effective treatment option for severely ill hospitalized patients with pneumonia,” said Tsutae Nagata, Shionogi’s chief medical officer. “In this trial, nearly 60% of patients were ventilated and approximately 33% experienced treatment failure of prior therapy.”
Prior GSK Alliance
Cefiderocol has also been investigated in the Phase II APEKS-cUTI trial in complicated urinary tract infections, and is seen filling a need for an effective new broad-spectrum agent in an area that big pharma has de-emphasized in recent years. The first approvals of the drug in this and other infection settings are expected in Shionogi’s current fiscal year ending 31 March next year.
Work on cefiderocol (S-649266) first began under a 2010 collaboration with GlaxoSmithKline PLC to develop and commercialize multiple novel cephalosporins for multidrug-resistant bacterial infections, which ended in late 2015. As part of the split, Shionogi continued with the independent development of cefiderocol and GSK with another molecule GSK3342830.
As part of the split, GSK agreed to make certain payments to Shionogi including certain milestones for the UK firm's molecule, while undisclosed royalties will also be payable by each party to the other on net sales of their respective compounds.
Novel Mode Of Action
Cefiderocol has a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens, including multidrug-resistant strains, and has what Shionogi says is a “unique ability” to overcome all three major mechanisms of carbapenem resistance - porin channel alterations, beta-lactamase inactivation, and efflux pump overproduction.
The drug binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, which incorporate this essential nutrient for bacteria. In addition, cefiderocol can enter cells by passive diffusion through porin channels and is stable against all known classes of beta-lactamases, including both the metallo- and serine-beta-lactamases.
The company says these mechanisms allow the drug to achieve higher concentrations in the periplasmic space where it can bind to receptors and inhibit cell wall synthesis in bacterial cells.
Shionogi submitted an NDA in December 2018 for use in complicated urinary tract infections (including pyelonephritis) in the US, where cefiderocol has been designated as a Qualified Infectious Disease Product by the FDA with an action date of 14 November 2019. A marketing authorization application has also been filed with the European Medicines Agency for multidrug-resistant Gram-negative bacterial infections with limited treatment options, which was accepted in March 2019 and has been granted accelerated assessment.
The timings for a supplemental NDA for hospital-acquired/ventilator-assisted nosocomial pneumonia setting - based mainly on the new results from the APEKS-NP trial - are not yet clear.
Medical Need
The increasing occurrence of many Gram-negative resistant bacterial infections, including carbapenem-resistant Enterobacteriaceae and non-fermenting species such as P. aeruginosa, A. baumannii, and S. maltophilia, means there is a critical need for new, effective therapies. The number of Gram-negative pathogens resistant to multiple antibiotics in increasing, making them difficult to treat and resulting in high mortality rates.
Cefiderocol has shown potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii, P. aeruginosa, Enterobacteriaceae and Stenotrophomonas maltophilia.
In the US, at least two million people are infected with antibiotic-resistant bacteria, and at least 23,000 die, each year. In the EU, about 25,000 patients a year die from an infection with a multidrug-resistant bacteria.
The World Health Organization and the US Centers for Disease Control and Prevention several years ago identified carbapenem-resistant strains of Enterobacteriaceae, P. aeruginosa, and A. baumannii as “critical” top priority pathogens for antibiotic R&D.
In Europe, a recently unveiled EU-backed consortium project with 11 members, led by German firm Evotec SE, aims to move forward in parallel three antibiotics for Gram-negative bacteria, with a view to getting one candidate through a Phase I trial by the end of 2024.
The EU has committed just under €13m ($14m) to the GNA NOW program via its Innovative Medicines Initiative (IMI) and Evotec is set to put a similar amount into the project, resulting, once other contributions are included, in a total budget of around €31m. (Also see "Evotec Takes The Lead On EU-Backed Antibiotic R&D Project" - Scrip, 2 Aug, 2019.)
Other Drugs In Development
Informa’s Biomedtracker shows other late-stage molecules in development for Gram-negative infections include Melinta Therapeutics Inc.’s Baxdela (delafloxacin) and Nabriva Therapeutics PLC’s Contepo (fosfomycin), both awaiting US approval, for community-acquired pneumonia and urinary/reproductive tract infections respectively.
Merck & Co. Inc.’s Recarbrio (imipenem, cilastatin and relebactam) was recently approved in the US for the narrow indication for complicated urinary tract infections and complicated intra-abdominal infections, but with labeling safeguards. (Also see "Keeping Track: Recarbrio Approval Highlights Two-Week Roundup" - Pink Sheet, 19 Jul, 2019.)