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Fosfomycin

Home / pipeline & research / Fosfomycin

CONTEPO’s inhibition of cell wall formation occurs at an early stage in cell wall synthesis, differentiating its mechanism of action from all other injectable antibiotics.

CONTEPO™ (previously referred to as ZTI-01 and ZOLYD) is an investigational, first-in-class epoxide antibiotic with a broad spectrum of bactericidal Gram-negative and Gram-positive activity, including activity against most contemporary MDR strains that threaten hospitalized patients..


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Antibiotics inhibit bacterial replication by inhibiting cell wall synthesis, disrupting cell wall integrity, or interfering with DNA function, folate metabolism, or protein synthesis.

Bacterial protein synthesis involves ribosomal subunits binding to messenger RNA in the peptidyl transferase center, or the PTC, at 3 active sites: the A, P, and E sites. As the first transfer RNA enters the PTC with its amino acid, another transfer RNA migrates adjacent to it. The ribosome then links the amino acid chain.

Pleuromutilins are a new class of systemic antibiotics being studied for human use with a novel mechanism of action that results in disruption of ribosomal protein synthesis. Pleuromutilins bind to the 50-S subunit of the bacterial ribosome at a highly conserved region on the PTC, via multiple interactions. The tricyclic core positions centrally at the PTC pocket close to the A site, whereas the C-14 side chain extends towards the P site, causing steric interference with ribosomal nucleotides, which consequently interact with each other. This results in the closing of the ribosomal binding pocket around the pleuromutilin and tightens binding between the pleuromutilin and the ribosome. In vitro and crystallography work have indicated where antibiotic classes are believed to bind around the PTC, which differs from the binding sites of the pleuromutilins.

The antibacterial spectrum of activity of the pleuromutilins is targeted to Gram-positive, Gram-negative, and atypical pathogens commonly associated with community-acquired respiratory infections, including multi-drug—resistant strains, and skin and skin structure infections caused by Streptococcus and Staphylococcus species, including MRSA. Noteably, the in vitro activity of the pleuromutilins does not include normal flora of the gastrointestinal tract, including B. fragilis, E. coli, and E. faecalis.

Despite decades of pleuromutilin therapeutic use in the treatment of livestock infections, the incidence of pleuromutilin-resistant isolates remains rare. It is believed the pleuromutilins’ novel mechanism of action results in a low propensity for the development of resistance, as in vitro studies have demonstrated a mutation frequency of 10-9 to 10-12 and rare cross-resistance to other antibiotic classes.

Our Research Program

Fosfomycin IV has an extensive history from markets outside the U.S., where it has been utilized for over 45 years in nine indications. CONTEPO utilizes a new dosing approach, developed by Zavante, to optimize the compound’s pharmacokinetics and pharmacodynamics.

The company believes that these attributes, along with the positive clinical experience worldwide, support CONTEPO as a first-line treatment for complicated urinary tract infections (cUTI) suspected to be caused by MDR pathogens. Approximately 25% of cUTIs are caused by MDR bacteria and limited treatment options are available. In addition, non-clinical data have shown that CONTEPO acts synergistically with certain other antibiotics to improve bacterial killing and restore susceptibility to agents otherwise demonstrating resistance.

The CONTEPO development program is initially focused on obtaining regulatory approval for the treatment of cUTI, including acute pyelonephritis, with the pivotal ZEUS™ study (ZTI-01 Efficacy and Safety study). In the ZEUS study, CONTEPO met the primary endpoint of statistical non-inferiority to piperacillin/tazobactam in this patient population. In October 2018, Nabriva Therapeutics submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) to seek marketing approval for CONTEPO™ to treat cUTIs, including acute pyelonephritis. On April 30, 2019,  we received a Complete Response Letter (CRL) from the FDA for the NDA. The CRL requests that Nabriva address issues related to facility inspections and manufacturing deficiencies at one of Nabriva’s contract manufacturers prior to the FDA approving the NDA. In December 2019, Nabriva resubmitted its New Drug Application (NDA) to the FDA for CONTEPO™ (fosfomycin) for injection for the treatment of complicated urinary tract infections (cUTIs), including acute pyelonephritis. Nabriva anticipates a six-month review period by the FDA..

The FDA has granted CONTEPO Qualified Infectious Disease Product (QIDP) and Fast Track designations for:

  • Complicated urinary tract infections (cUTI)
  • Complicated intra-abdominal infections (cIAI)
  • Hospital-acquired bacterial pneumonia (HABP) / Ventilator-associated bacterial pneumonia (VABP)
  • Acute bacterial skin and skin structure infections (ABSSSI)

 

Collaborate With Us

We actively seek collaborators and licensing opportunities focused on the discovery, development, and commercialization of technologies and therapies that address infectious diseases. Contact us to learn more.

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