Finafloxacin background (phase II cUTI trial & drug characteristics)

Finafloxacin – a novel powerful antibiotic active against Gram-negative pathogens with enhanced activity at low pH
Finafloxacin is a novel member of the fluoroquinolone class of antibiotics. It demonstrates the unique property of its activity being substantially enhanced under acidic conditions, where the activity of many existing antibiotics is severely impaired. Bacterial infections frequently create local, acidic environments yet many marketed antibiotics are most effective at a neutral pH. Finafloxacin provides a unique opportunity to exceed the efficacy of gold standard treatments against a wide range of bacterial infections including a number of resistant Gram-negative pathogens. The compound recently successfully completed a phase 2 trial in patients hospitalized with complicated urinary tract infections (cUTIs), including pyelonephritis. The product is also active against other bacteria, including difficult to treat pathogens where there are currently few treatment options, such as Acinetobacter baumannii.

Phase II trial in cUTIs including pyelonephritis

Trial design
The trial was a double-blind, double-dummy, active-controlled phase 2 study, involving 193 microbiological intent to treat patients ("mITT") hospitalized with complicated urinary tract infections (of whom 70% were diagnosed as suffering from pyelonephritis). Patients were randomized (1:1:1) into three arms and received either 800mg of finafloxacin once per day for five or for 10 days, or 400mg of ciprofloxacin twice per day for 10 days. Each patient's progress was reviewed after three and ten days of treatment and patients returned 17 days after start of therapy for a test of cure ("TOC") evaluation; with a final assessment (End of Study Visit) seven days later. Clinical and microbiological outcomes, safety and other parameters were recorded on all visits. The primary efficacy end point was a patient's Composite Response (i.e. both microbiological eradication and elimination of clinical symptoms) at TOC. Secondary endpoints included microbiological eradication three, 17 and 24 days after the start of treatment.

Finafloxacin was highly active against Gram-negative bacterial pathogens (83% of the causative pathogens in the trial were E. coli) with, in the mITT populations, patients treated for both five and ten days with finafloxacin demonstrating microbiological and clinical cure rates superior to those of ciprofloxacin. At TOC the Composite Response rate amongst the patients that received finafloxacin for five days was 70%; 68% for those that received finafloxacin for 10 days, as compared to only 57% for those patients treated with ciprofloxacin.
Microbiological eradication after three days of treatment with finafloxacin was 89% as compared to 79% with ciprofloxacin. At the End of Study Visit (24 days after initiation of treatment) the comparable figures were 75% for patients who had received finafloxacin for five days vs. 59% in patients who had received ciprofloxacin for 10 days.

Finafloxacin demonstrated a strong safety profile with low rates of, predominantly gastrointestinal, side effects.

Next steps
These data support phase 3 development of finafloxacin for the treatment of serious infections, including those caused by a number of resistant Gram-negative pathogens.

Interested in licensing opportunities or just finding out more?
MerLion welcomes enquiries from potential partners interested in finding out more about finafloxacin.
Interested parties should contact David Dally at +65 6778 5700
E-mail: [email protected]

Superior product characteristics
Finafloxacin's chemical structure is such that at low pH there is a substantially higher take-up and accumulation of the compound in bacterial cells. Once inside the bacterial cell, finafloxacin has a substantially higher binding affinity than any other fluoroquinolones to both fluoroquinolone targets (DNA gyrase and topoisomerase IV).

The hostile conditions prevailing in many sites of infection include low pH (typically pH 5-6 in cUTIs; pH 6-7 in RTIs and pH <5-6 in abscesses), often under anaerobic conditions and with slow cell growth. Whilst the activity of other antibiotics is significantly impaired in an acidic environment, the activity of finafloxacin surpasses that of other fluoroquinolones by up to 64-fold.

Under such conditions, finafloxacin's spectrum includes superior bactericidal activity against a wide range of Gram-negative pathogens, including a number of ESBL producing E coli. mutants, strains with TEM enzyme producers (which cause resistance to penicillins), strains with resistance arising from first and second step mutations and strains with plasmid-mediated mechanisms which are primed for resistance against other fluoroquinolones. Finafloxacin also shows excellent activity against MRSA and MRSE isolates, including strains resistant to other fluoroquinolones.

As well as being active against the whole spectrum of pathogens typically found in cUTIs, finafloxacin is, under actual infection conditions, also very active against pathogens causing intra-abdominal, lung, skin and deep seated chronic infections. Finafloxacin's broad spectrum includes anaerobic and atypical pathogens as well as stationary phase or persistent populations, small colony variants and bacteria growing in biofilms. Finafloxacin is also highly active against difficult to treat intracellular pathogens such as Acinetobacter baumannii 1 which causes wound, bloodstream and respiratory tract infections (often in immunocompromised patients) and Burkholderia pseudomallei.2

The safety and tolerability profile seen in pre-clinical and pervious clinical studies with finafloxacin supports high (800mg) once-daily dosing and no unusual or unexpected adverse events were observed during the recent trial. This, together with an excellent PK profile and bioavailability, results in a high Cmax and sustained drug exposure giving rise to finafloxacin's very rapid and sustained bactericidal effects and a low propensity for development of resistance.

IV and oral formulations of finafloxacin of equivalent bioavailability have been developed. This offers physicians the possibility of treating patients in hospital or at out-patient infusion centres for 1-3 days with the IV regimen, then allowing them to complete their treatment at home, reducing the risk of complications and/or secondary infections. Using finafloxacin in the ambulatory setting avoids putting finafloxacin in direct competition with the novel cephalosporin or monobactam combinations with beta lactamase inhibitors, which are IV only.

1 Acinetobacter baumannii has emerged as one of the most troublesome pathogens for health care institutions globally. Its clinical significance has been propelled by its ability to up-regulate or acquire resistance determinants. A. baumannii is able to survive for prolonged periods throughout a hospital environment, thus potentiating its ability for nosocomial spread. The organism commonly targets the most vulnerable hospitalized patients, those who are critically ill with breaches in skin integrity and airway protection. Hospital-acquired pneumonia is still the most common infection caused by this organism. Infections involving the central nervous system, skin and soft tissue, and bone have emerged. A. baumannii has more recently caused a range of infectious syndromes in injured military personnel.

2 Burkholderia pseudomallei infection can lead to Melioidosis, an illness that affects skin, blood, lungs or muscles and occurs when a person touches or inhales the bacteria which are found in soil and water and common in parts of Southeast Asia and northern Australia. With existing antibiotic treatments, approximately 40% of people who become ill from the infection die, whilst up to 90% die if not treated. Burkholderia pseudomallei is viewed by the Biomedical Advanced Research and Development Authority (BARDA) and other agencies as a serious bioterrorism threat.