Phase 1, Open-Label, Non-Randomized, Single-Center, Single-Dose Study to Assess the Pharmacokinetics & Safety of ANT3310 Combined With Meropenem Administered as a Single Intravenous Infusion to Adult Subjects With Renal Function Impairment

This is an open-label, non-randomized, single-center, single i.v. dose Phase 1 trial to evaluate the pharmacokinetics and safety of a combination of ANT3310 and meropenem in participants with different degrees of renal function impairment, including participants with End-Stage Renal Disease (ESRD), compared with matching control participants with normal renal function.

Start Date19 Jul 2024

Sponsor / Collaborator

Antabio SAS

[+1]

NCT05905913 / CompletedPhase 1

Phase 1, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of Single- and Multiple-Ascending Doses of Intravenous ANT3310 Alone and in Combination With Meropenem in Healthy Subjects

The purpose of this study is to evaluate the safety and tolerability of single and multiple intravenous ascending doses of ANT3310, a novel, specific, competitive inhibitor of serine β-lactamases, alone and in combination with meropenem in healthy subjects.

Start Date12 Apr 2023

Sponsor / Collaborator

Antabio SAS

100 Clinical Results associated with ANT-3310

100 Translational Medicine associated with ANT-3310

100 Patents (Medical) associated with ANT-3310

Literatures (Medical) associated with ANT-3310

06 Mar 2024·Antimicrobial Agents and Chemotherapy

Meropenem-ANT3310, a unique β-lactam-β-lactamase inhibitor combination with expanded antibacterial spectrum against Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii

Article

Author: Lozano, Clarisse ; Davies, David ; Sable, Carole ; Achard, Pauline ; Hawser, Stephen ; Castandet, Jérôme ; Bousquet, Justine ; Lemonnier, Marc ; Holden, Kirsty ; Ledoux, Adeline ; Llanos, Agustina ; Toomey, Eleanor ; Everett, Martin ; Morrissey, Ian ; Zalacain, Magdalena ; Leiris, Simon

ABSTRACT ANT3310 is a novel broad-spectrum diazabicyclooctane serine β-lactamase inhibitor being developed in combination with meropenem (MEM) for the treatment of serious infections in hospitalized patients where carbapenem-resistant Gram-negative pathogens are expected. In this study, we evaluated the in vitro antibacterial activity of MEM in the presence of ANT3310 at 8 µg/mL against global clinical isolates that included Acinetobacter baumannii ( n = 905), carbapenem-resistant Enterobacterales (CRE), carrying either oxacillinase (OXA) ( n = 252) or Klebsiella pneumoniae carbapenemase (KPC) ( n = 180) carbapenemases, and Pseudomonas aeruginosa ( n = 502). MEM was poorly active against A. baumannii, as were MEM-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, cefepime-taniborbactam, cefepime-zidebactam, and imipenem-relebactam (MIC 90 values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC 90 value of 4 µg/mL, similar to that observed with sulbactam-durlobactam, a drug developed to specifically treat A. baumannii infections. ANT3310 (8 µg/mL) additionally restored the activity of MEM against OXA- and KPC-producing CREs decreasing MEM MIC 90 values from >32 µg/mL to 0.25 and 0.5 µg/mL, respectively. The combination of 8 µg/mL of both MEM and ANT3310 prevented growth of 97.5% of A. baumannii and 100% of OXA- and KPC-positive CREs, with ~90% of P. aeruginosa isolates also displaying MEM MICs ≤8 µg/mL. Furthermore, MEM-ANT3310 was efficacious in both thigh and lung murine infection models with OXA-23 A. baumannii . This study demonstrates the potent in vitro activity of the MEM-ANT3310 combination against both carbapenem-resistant A. baumannii and Enterobacterales clinical isolates, a key differentiator to other β-lactam/β-lactamase combinations.

24 Dec 2020·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of ANT3310, a Novel Broad-Spectrum Serine β-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii

Q1 · MEDICINE

Article

Author: Pallin, David ; Lozano, Clarisse ; Tassone, Giusy ; Elliot, Richard ; Bousquet, Justine ; Marcoccia, Francesca ; Vasa, Srinivas ; Holden, Kirsty ; Valige, Ravindar ; Leiris, Simon ; Docquier, Jean-Denis ; Pozzi, Cecilia ; Davies, David T. ; Kummari, Bhaskar ; Everett, Martin ; Morrissey, Ian ; Sprynski, Nicolas ; Benvenuti, Manuela ; Pattipati, Ramesh ; Warn, Peter ; Zalacain, Magdalena ; Pothukanuri, Srinivasu ; Llanos, Agustina ; Alibaud, Laethitia ; Mangani, Stefano ; Castandet, Jérôme ; De Piano, Cyntia ; Lemonnier, Marc

The diazabicyclooctanes (DBOs) are a class of serine β-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of β-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of β-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO "critical priority pathogen" producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure-activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.

Antimicrobial Agents and Chemotherapy

Assessment of the activity and mechanisms of resistance to cefiderocol and combinations of β-lactams and the novel β-lactamase inhibitors avibactam, taniborbactam, zidebactam, nacubactam, xeruborbactam, and ANT3310 in emerging double-carbapenemase-producing Enterobacterales

Article

Author: Alonso-García, Isaac ; López-Cerero, Lorena ; Rodríguez-Pallares, Salud ; González-Pinto, Lucía ; Bou, Germán ; Pérez-Vázquez, María ; Pascual, Álvaro ; Arca-Suárez, Jorge ; Vázquez-Ucha, Juan Carlos ; Aracil, Belén ; Oteo-Iglesias, Jesús ; Outeda-García, Michelle ; Beceiro, Alejandro ; Sánchez-Peña, Lucía ; López-Hernández, Inmaculada ; Blanco-Martín, Tania ; Aja-Macaya, Pablo

ABSTRACT We aimed to investigate the activity of and mechanisms of resistance to cefiderocol and innovative β-lactam/β-lactamase inhibitor combinations in a nationwide collection of double-carbapenemase-producing Enterobacterales. In all, 57 clinical isolates co-producing two carbapenemases collected from Spanish hospitals during the period 2017–2022 were analyzed. Minimum inhibitory concentration (MIC) values for ceftazidime, ceftazidime/avibactam, aztreonam, aztreonam/avibactam, aztreonam/nacubactam, cefiderocol, cefepime, cefepime/taniborbactam, cefepime/zidebactam, cefepime/nacubactam, imipenem, imipenem/relebactam, meropenem, meropenem/vaborbactam, meropenem/xeruborbactam, and meropenem/ANT3310 were determined by reference broth microdilution. Genetic drivers of resistance were analyzed by whole-genome sequencing (WGS). The collection covered nine carbapenemase associations: VIM + OXA-48 (21/57), NDM + OXA-48 (11/57), KPC + VIM (10/57), KPC + OXA-48 (6/57), IMP + OXA-48 (3/57), NDM + KPC (2/57), NDM + VIM (2/57), NDM + GES (1/57), and KPC + IMP (1/57). Ceftazidime/avibactam, imipenem/relebactam, and meropenem/vaborbactam were the least active options. Aztreonam/avibactam and aztreonam/nacubactam were active against the whole collection and yielded MIC 50 /MIC 90 values of ≤0.25/0.5 mg/L and 1/2 mg/L, respectively. Cefepime/zidebactam (56/57 susceptible), meropenem/xeruborbactam (56/57 susceptible), cefepime/nacubactam (55/57 susceptible), and cefiderocol (53/57 susceptible) were also highly active, with MIC 50 /MIC 90 values ranging from ≤0.25–2 mg/L to 2–4 mg/L, respectively. Meropenem/ANT3310 (MIC 50 /MIC 90 = 0.5/≥64 mg/L; 47/57 susceptible) and cefepime/taniborbactam (MIC 50 /MIC 90 = 0.5/16 mg/L; 44/57 susceptible) also retained high levels of activity, although they were affected by NDM-type enzymes in combination with porin deficiency. Our findings highlight that cefiderocol and combinations of β-lactams and the novel β-lactamase inhibitors avibactam, nacubactam, taniborbactam, zidebactam, xeruborbactam, and ANT3310 show promising activity against double-carbapenemase-producing Enterobacterales.

News (Medical) associated with ANT-3310

03 Sep 2024

·pipelinereview.com

Antabio Announces Successful Completion of Phase 1 Clinical Study of MEM-ANT3310 for Severe Hospital Infections

LABÈGE, France I September 03, 2024 I Antabio , a private biopharmaceutical company developing novel and highly differentiated antibacterial treatments for critical priority pathogens, with a particular focus on life-threatening respiratory infections, today announced that it has completed the Phase 1 clinical trial for MEM-ANT3310 in healthy volunteers. Antabio’s MEM-ANT3310 is a next generation broad-spectrum antibacterial combination that has been designed to address the growing problem of antimicrobial resistance in severe hospital infections. MEM-ANT3310 combines the well-known carbapenem meropenem (MEM) with ANT3310, a breakthrough serine-beta-lactamase (SBL) inhibitor that provides a unique coverage of priority Gram-negative pathogens including OXA-carbapenem-resistant Acinetobacter baumannii (CRAB), KPC- and OXA- carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa (PA). The Phase 1 clinical trial included 72 healthy volunteers across three parts and evaluated the safety, tolerability, and pharmacokinetic (PK) profile of Single and Multiple Ascending Doses (SAD/MAD) of the intravenous beta-lactamase inhibitor ANT3310, administered alone. The potential mutual PK interaction between ANT3310 and meropenem was investigated, followed by an assessment of the combination MEM-ANT3310 during multiple intravenous dosing. ANT3310 was well-tolerated at all doses with no serious adverse events, dose-limiting toxicities or clinically relevant abnormalities reported. The ANT3310 PK parameters were consistent with those determined from studies in rodent and non-rodent species and dose-dependent increases in exposure were observed. ANT3310 and meropenem demonstrated very compatible PK with no mutual PK interaction. This positive Phase 1 data supports further patient studies of MEM-ANT3310. “With matching PK and good tolerability, MEM-ANT3310 shows great promise to address serious infections whenever multidrug resistance is a concern in hospitalized patients.” said Marc Lemonnier, CEO of Antabio . “With a uniquely broad coverage, we believe MEM-ANT3310 will be very well positioned to meet the urgent medical needs in high-risk patients, especially when multidrug-resistant pathogens or polymicrobial infections are suspected”. Antabio is currently conducting a Phase 1 PK study of MEM-ANT3310 in subjects with impaired renal function and is planning a second PK study to assess the distribution of MEM-ANT3310 in the lung (epithelial lining fluid) in healthy volunteers. About MEM-ANT3310 Carbapenems such as meropenem are the cornerstone of therapies for many life-threatening infections. Resistance to carbapenems is considered a critical priority by the World Health Organisation (WHO) and Centre for Disease Control and Prevention (CDC) because it is a major cause of treatment failure, increased mortality, and huge economic costs. Bacteria resistant to carbapenems produce β-lactamase enzymes that render antibiotics, such as meropenem, ineffective. ANT3310 inhibits a broad range of β-lactamases, including the Klebsiella pneumoniae carbapenemases (KPC) and oxacillin-hydrolysing (OXA) type enzymes found in Carbapenem-Resistant Enterobacterales (CRE) and most importantly Carbapenem-Resistant Acinetobacter baumannii (CRAB). The combination of this potent β-lactamase inhibitor with the antibiotic meropenem (MEM-ANT3310) therefore provides a critical solution for the treatment of serious infections that may be caused by MDR pathogens, such as hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). MEM-ANT3310 has received qualified infectious disease product (QIDP) status from the FDA in 2020 for complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI) and HABP and VABP. About Antabio Antabio is a clinical stage biopharmaceutical company developing novel and highly differentiated antibacterial treatments of drug-resistant infections as defined by the CDC and WHO’s critical priority pathogens, with a particular focus on life-threatening respiratory infections, including carbapenem-resistant nosocomial pneumonia and chronic pulmonary diseases. The company’s lead program, MEM-ANT3310, is being developed for the treatment of hospital-acquired infections such as nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Enterobacterales (CRE). Antabio’s portfolio includes additional innovative preclinical programs addressing areas of highest unmet need in the antibacterial space. SOURCE: Antabio

Phase 1Qualified Infectious Disease Product

25 May 2023

·www.globenewswire.com

Antabio Announces First Subjects Dosed in Phase 1 Clinical Trial of MEM-ANT3310, a Highly Differentiated Antibiotic for Severe Hospital Infections

MEM-ANT3310 has the potential to become the next standard of care for life-threatening infections due to its unique coverage including carbapenem-resistant Enterobacterales and Acinetobacter baumannii Labège, France - May 25, 2023 Antabio SAS, a clinical stage biopharmaceutical company developing novel treatments for severe drug-resistant bacterial infections, announces dosing of the first subjects in its Phase 1 clinical trial of MEM-ANT3310. MEM-ANT3310 is a next generation antibacterial combination that has been designed to make a significant impact on the growing problem of antimicrobial resistance in serious hospital infections. MEM-ANT3310 combines the well-known carbapenem meropenem (MEM) with ANT3310, a breakthrough serine-beta-lactamase (SBL) inhibitor developed by Antabio. This combination has been designed to provide a unique coverage of priority Gram-negative pathogens including OXA-carbapenem-resistant Acinetobacter baumannii (CRAB), KPC- and OXA- carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa (PA). ANT3310 represents an important advance as its innovative structure completely inhibits the enzymes that confer resistance and as a result, restores MEM’s activity against these deadly pathogens. Magdalena Zalacain, Chief Scientific Officer of Antabio said, “MEM-ANT3310 is the culmination of a very creative and focused program aiming to develop a truly differentiated antibiotic active against both CRAB and CRE pathogens. MEM-ANT3310 is a strong addition to the clinical armamentarium to treat severe or life-threatening infections due to Gram-negative pathogens.” The Phase 1 clinical trial is designed to assess the safety, tolerability, and pharmacokinetic (PK) profile of single and multiple ascending doses (SAD/MAD) of intravenous ANT3310 administered alone, followed by an assessment of the combination of ANT3310 with MEM in healthy volunteers. Carole Sable, M.D., Infectious Disease expert and clinical advisor of Antabio commented, “There is a very clear need for safe and effective therapies to treat serious antibiotic-resistant infections in hospitalized patients, including when polymicrobial infections are suspected. Based on the preclinical profile of MEM-ANT3310, I believe it has the potential to provide a valuable broad-spectrum therapeutic option to meet unmet medical needs of this high-risk patient population.” Marc Lemonnier, CEO of Antabio added, “We are thrilled to reach this important milestone with the start of our first in man study for MEM-ANT3310. We see great promise for patients in this novel antibacterial combination addressing the highest WHO priorities for antibiotic resistance while building on a well-established regulatory path towards approval.” Initial funding for the development of MEM-ANT3310 of €5.5 million was received in 2022 from the French government through the “ARPEGE” program. *** About MEM-ANT3310 Carbapenems such as meropenem are the cornerstone of therapies for many life-threatening infections. Resistance to carbapenems is considered a critical priority by the World Health Organization (WHO) and Centre for Disease Control and Prevention (CDC) because it is a major cause of treatment failure, increased mortality, and huge economic costs. Bacteria resistant to carbapenems produce beta-lactamase enzymes that render antibiotics, such as meropenem (MEM), ineffective. Antabio has set out to resolve this major healthcare issue via its lead clinical stage program MEM-ANT3310. Its innovative serine-beta-lactamase inhibitor ANT3310 represents a significant breakthrough as it completely inhibits a broad range of beta-lactamases, including the Klebsiella pneumoniae carbapenemases (KPC) and oxacillin-hydrolyzing (OXA) type enzymes found in Carbapenem-Resistant Enterobacterales (CRE) and Carbapenem-Resistant Acinetobacter baumannii (CRAB), and restores MEM activity against these deadly pathogens. This is critical for the treatment of polymicrobial infections such as those causing hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). ANT3310, in combination with the antibiotic meropenem, has received qualified infectious disease product (QIDP) status from the FDA in 2019 for complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI) and hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). About Antabio Antabio is a clinical stage biopharmaceutical company developing novel and highly differentiated antibacterial treatments of drug-resistant infections as defined by the CDC and WHO’s critical priority pathogens, with a particular focus on life-threatening respiratory infections, including carbapenem-resistant nosocomial pneumonia and chronic pulmonary diseases. The company’s lead program, MEM-ANT3310, is being developed for the treatment of hospital-acquired infections such as nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Enterobacterales (CRE). Antabio’s portfolio includes two further programs: 1) ANT3273, a groundbreaking, novel class, novel mode of action inhalation treatment of Pseudomonas aeruginosa (PA) infections, particularly those affecting patients with chronic pulmonary diseases (such as Bronchiectasis, Cystic Fibrosis and COPD); and 2) ANT2681, a novel and potent metallo beta-lactamase (MBL) inhibitor to be combined with meropenem for the treatment of MBL-producing carbapenem-resistant Enterobacterales (CRE), particularly New Delhi metallo-beta-lactamase (NDM) carrying strains. Antabio has built an international team, including former executives from Novexel, Merck, GSK, and AstraZeneca. The company has an impressive track-record in attracting non-dilutive funding, including multi-million-dollar awards from the Wellcome Trust, CARB-X, and ARPEGE. Media Contacts Antabio Marc Lemonnier, CEOpress@antabio.comMEDiSTRAVA ConsultingSylvie Berrebi, Frazer Hallantabio@medistrava.com

Phase 1Qualified Infectious Disease ProductFast Track

100 Deals associated with ANT-3310

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Indication	Highest Phase	Country/Location	Organization	Date
Renal function impairment with growth failure	Phase 1	DE	Antabio SAS	19 Jul 2024
Intraabdominal Infections	Discovery	FR	Antabio SAS	06 May 2020
Urinary Tract Infections	Discovery	FR	Antabio SAS	29 Apr 2020

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