Shots:

• Simon spoke about the new data on FETROJA (cefiderocol), an antibiotic for the treatment of serious Gram-negative (highly resistant) bacterial infections
• He also talked about Shionogi’s agreement with GARDP & CHAI for the manufacturing and commercialization of cefiderocol in different countries
• The interview summarizes how Shionogi is advancing by developing medicines to treat serious unmet medical needs

Smriti: Can you share the Epidemiology/statistics of AMR cases in the US and globally (epi, diagnosis, deaths, etc.)

Simon Portsmouth: Antimicrobial resistance (AMR) happens when germs like bacteria and fungi develop the ability to defeat the drugs designed to kill them and continue to grow.

AMR is recognized by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) as one of the world’s most urgent public health threats. In 2019, globally, approximately 1.27 million people died as a result of infections caused by resistant pathogens, surpassing deaths from HIV or malaria.

Smriti: Can we talk about FETROJA (cefiderocol) in detail (MoA, RoA, formulation, etc.)

Simon Portsmouth: Fetroja® (cefiderocol) is the first siderophore cephalosporin antibiotic with a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens. 

In addition to entering cells by passive diffusion through porin channels, Fetroja binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, which function to incorporate this essential nutrient for bacteria.

These mechanisms allow Fetroja to achieve high concentrations in the periplasmic space where it can bind to penicillin-binding proteins (PBP) and inhibit cell wall synthesis in the bacterial cells. The drug is bactericidal rather than bacteriostatic.

Carbapenem resistance (CR) in Gram-negative bacteria is due to three main mechanisms: 

• Beta-lactamases which cause enzymatic breakdown of beta-lactams 
• Porin channel deletions (through mutations and decrease in number) through which beta-lactams and other antibiotics diffuse into cells
• Efflux pumps up-regulation which occurs post-exposure and pumps antibiotics out of cells

As a result of its mechanism of cell uptake, Fetroja can overcome these three major mechanisms of CR. 

Smriti: Can we talk about the results based on which Fetroja received FDA approval and which also leads to Fetroja being listed in the WHO Model List of Essential medicines?

• cUTI incl. Pyelonephritis
• HABP/VABP

Simon Portsmouth: The FDA approved Fetroja for the treatment of Complicated Urinary Tract Infections (cUTI) caused by certain Gram-negative pathogens in November 2019 and Hospital-Acquired Bacterial Pneumonia Ventilator-Associated Bacterial Pneumonia (HABP/VABP) caused by certain Gram-negative pathogens in September 2020.

The FDA’s approval of Fetroja for cUTI was based on data from the pivotal APEKS-cUTI study, a multinational, multicenter, double-blind clinical trial that evaluated the efficacy and safety of Fetroja versus imipenem/cilastatin (IPM/CS) in patients with cUTI. Study results showed the response rates for the composite endpoint of microbiological eradication and clinical response at the test of cure (TOC) were significantly higher in the Fetroja arm compared to the IPM/CS arm. In the study, 72.6% (183/252) of patients in the Fetroja arm met the primary endpoint versus 54.6% (65/119) in the IPM/CS arm at TOC. The adjusted difference between the groups was 18.6% (95% CI: 8.2%, 28.9%). Microbiological response rates at the TOC visit was 73.0% (184/252) of patients in the Fetroja arm compared to 56.3% (67/119) in the IPM/CS arm, the treatment difference was 17.3% (95% CI:6.9%, 27.6%). Clinical response rates at the TOC visit were similar between Fetroja and IPM/CS.

This expanded indication of Fetroja for HABP/VABP was based on the results of the Phase III APEKS-NP study, which showed Fetroja met the primary endpoint of non-inferiority compared to high-dose extended-infusion meropenem in all-cause mortality 14 days after initiation of study drug in the treatment of patients with HABP, VABP and healthcare-associated bacterial pneumonia (HCABP).

In 2021, Fetroja was added to the World Health Organization’s (WHO) Model List of Essential Medicines (EML). Inclusion of Fetroja was recommended as a reserved antibiotic for carbapenem-resistant Enterobacterales and carbapenem-resistant Pseudomonas aeruginosa.” Fetroja will also be considered a “reserve” antibiotic in the AWaRe classification.

Smriti: What evidence is Shionogi presenting on Fetroja at IDWeek? 

Simon Portsmouth: This year at IDWeek, Shionogi will present new real-world evidence demonstrating Fetroja’s efficacy against some of the most difficult-to-treat Gram-negative bacterial infections. Key data include 

Findings from PROVE, an ongoing international retrospective study assessing real-world outcomes and safety of Fetroja in hospitalized patients with Gram-negative bacterial infections, which showed that Fetroja achieved clinical cure in 63% (48/76) of patients with Acinetobacter baumannii infections and 63% (76/120) of patients with Pseudomonas aeruginosa infections. Of the Acinetobacter baumannii infections, 96% were resistant to carbapenems (a last-line antibiotic), and 97% of the Pseudomonas aeruginosa infections were carbapenem-resistant. Safety and tolerability data were generally consistent with the safety profile of Fetroja in clinical studies. Of a total cohort of 220 patients treated with Fetroja for either pathogen (A. baumannii or P. aeruginosa), five had adverse drug reactions (ADR), of which two had rashes, one had an increase in liver function test values, and two had diarrhea. One patient who was treated with Fetroja experienced a severe ADR (interstitial nephritis). Fetroja was withdrawn in two patients. For both Acinetobacter baumannii and Pseudomonas aeruginosa infections, 79% of patients were alive and 21% of patients died within 30 days of starting Fetroja (30-day all-cause mortality).

In an analysis of early use experience, including compassionate use where patients had limited treatment options, 80% of patients treated with Fetroja reported clinical cure (74/92) for difficult-to-treat Gram-negative infections (including Pseudomonas aeruginosa and Acinetobacter baumannii). Adverse event (AE) data was reported for 53 patients, of whom 13 (24.5%) reported AEs and 40 (75.5%) did not.

In vitro data from SENTRY – an antimicrobial surveillance program that monitors highly resistant bacteria and antimicrobial resistance patterns globally – that showed of the antibiotic treatments assessed, Fetroja demonstrated in vitro activity against more than 96% of all the tested difficult-to-treat resistant (DTR) Gram-negative pathogens from European countries, Israel and Turkey, and more than 92% of all the tested DTR Gram-negative pathogens from the U.S. (using Clinical and Laboratory Standards Institute [CLSI] susceptibility testing breakpoints). As a reminder, in vitro activity does not necessarily correlate with clinical efficacy.

Smriti: What are the other geographies where Fetroja is being filed to be marketed and what are the timelines?

Simon Portsmouth: In Europe, Fetroja is commercially available in the UK, France, Germany, Italy, Austria? and Sweden, and in the remaining European countries, Fetroja is available through an access program. In the remaining European (EEA) countries, Shionogi is working with national pricing and reimbursement authorities to make Fetroja commercially available. Before commercial availability in these countries, physicians can access Fetroja for eligible patients via an access program administered by our partner Inceptua.

Fetroja is currently under review by PMDA in Japan. 

Additionally, Shionogi is planning to seek approval for Fetroja in other markets with high unmet medical needs. The company recognizes the need to make Fetroja available in low-and-middle-income countries (LMICs) and has taken concerted action to improve access across the world.

Smriti: What is Shionogi doing to educate and promote action related to AMR?

Simon Portsmouth: Shionogi actively participates in various national and international initiatives addressing AMR, as a means of contributing to the global resolution of this public health challenge. This includes participating in educational programs for healthcare professionals to raise awareness of issues around AMR stewardship. 

For example, Shionogi contributed to a Nature Outlook supplement on AMR (‘Antimicrobial Resistance – Preserving the power of life-saving drugs’).The supplement raised awareness about the threat of AMR, highlighted key areas for policy action, and educated readers on advances in efforts to tackle AMR. 

Other initiatives Shionogi has undertaken to address AMR, including

• Signing the Davos Declaration on Antibiotic Resistance in 2016
• Signing the Industry Roadmap for Progress on Combating Antimicrobial Resistance in 2016
• Supporting the founding of the AMR Industry Alliance and retaining a seat on the Board

Supporting the creation and funding of the AMR Action Fund

Smriti: Please tell us more about Shionogi’s agreement with GARDP & CHAI. (its terms, details, coverage, etc)

Simon Portsmouth: Shionogi has a philosophy of “supplying the best possible medicine to protect the health and wellbeing of the patients we serve,” but Shionogi’s global footprint and limited resources mean that it is a challenge to manufacture and deliver products to many parts of the world. Building collaborations with like-minded organizations is one way for Shionogi to deliver on its access goals. In June 2022, Shionogi and the Global Antibiotic Research and Development Partnership (GARDP) announced the execution of a license and technology transfer agreement, with the Clinton Health Access Initiative (CHAI), a collaboration agreement that aims to significantly transform the landscape of access to antibiotics for countries around the world.

The agreements will provide access to cefiderocol in low and middle-income countries (LMIC) and are the first license agreement for an antibiotic to treat serious bacterial infections between a pharmaceutical company and a non-profit organization driven by public health priorities. Under this agreement, GARDP will manufacture and commercialize cefiderocol through sub-licensees in a large range of countries that have delayed access (if any) to newer antibiotics. The licensed territory includes all low-income countries, most lower-middle and upper-middle-income countries, and select high-income countries (135 countries total, almost 70% of countries worldwide). It includes a significant proportion of the world’s population living in areas most affected by antibiotic resistance. 

About cefiderocol 

Cefiderocol for injection is the first and only siderophore cephalosporin antibiotic for the treatment of serious Gram-negative infections. It has a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore. In addition to entering cells by passive diffusion through porin channels, cefiderocol binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, which function to incorporate this essential nutrient for bacteria. These mechanisms allow cefiderocol to achieve high concentrations in the periplasmic space where it can bind to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells. Cefiderocol has also demonstrated in vitro activity against certain bacteria that contain problematic resistant enzymes such ESBLs, AmpC, and serine- and metallo-carbapenemases. Data from multinational surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii complex, P. aeruginosa, Enterobacterales, and S. maltophilia. The clinical significance of the in vitro data is unknown. Cefiderocol has no clinically relevant in vitro activity against most Gram-positive bacteria and anaerobic bacteria.  

U.S. INDICATIONS 

Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. 

Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. 

USAGE 

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. 

IMPORTANT SAFETY INFORMATION 

CONTRAINDICATIONS 

Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja. 

WARNINGS AND PRECAUTIONS 

Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections  

An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.  

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established.  

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. 

Hypersensitivity Reactions 

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja-treated patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.  

Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs. 

Clostridioides difficile-associated Diarrhea (CDAD) 

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Fetroja. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit the overgrowth of C. difficile. 

Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. 

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. 

Seizures and Other Central Nervous System (CNS) Adverse Reactions 

Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins, particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued. 

Development of Drug-Resistant Bacteria  

Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 

ADVERSE REACTIONS 

The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%). 

Click here for Full U.S. Prescribing Information for Fetroja® (cefiderocol). 

Source: Canva

About the Author: 

Simon Portsmouth is the VP, Head of Clinical Development, at Shionogi. He joined Shionogi Inc in Florham park NJ in 2015. His area of interest is in the development of medicines for infectious diseases. Recent development activities include the successful New Drug application for cefiderocol (Fetroja) and baloxavir marboxil (Zofluza), and the clinical development of Ensitrelvir, a 3CL protease inhibitor for SARS-Co-V2. Simon did MBChB (Medicine) and M.D. from the Sheffield University Medical School.

Related Post: Martin Kilsgård, Head of Product at Trialbee, Shares Insights from the Launch of Trialbee Honey™ Analytics at DPHARM 2022