Finafloxacin

Finafloxacin is a novel member of the fluoroquinolone class of antibiotics with a new pH activated profile offering therapeutic potential for severe and difficult to treat bacterial infections:

Enhanced and powerful activity under infection relevant conditions (low pH, low oxygen tension)
Activity against bacterial biofilms and persisters
Broad spectrum with enhanced activity against resistant strains and a very low potential to select for resistance at low pH
Excellent safety and tolerability in humans permit high doses
Potential new treatment for cUTI, cSSSI, RTI and other serious infections with the option of intravenous to oral step down

HOW CAN FINAFLOXACIN OFFER IMPROVED EFFICACY WITHOUT COMPROMISING SAFETY?

Finafloxacin is a novel fluoroquinolone that is differentiated from its predecessors because it is fine tuned to exhibit enhanced and powerful antibacterial activity under infection relevant conditions. This unique balance has origins in the discovery process. Fluoroquinolones have traditionally been selected on the basis of outright potency under laboratory or test tube conditions. The selection criteria for finafloxacin were very different and focused upon safety (avoiding class related and toxicity effects) and activity in a very stringent infection model.
After testing several hundred quinolones in vivo, finafloxacin was the chosen candidate molecule and subsequent preclinical work not only confirmed that this was a leader in terms of safety, but also exhibited a number of unique properties, not shared with other fluoroquinolones. This profile is expected to translate into a greater therapeutic potential in severe and difficult to treat infections.

This focus on safety and activity under infection relevant conditions helped to select a molecule with unique properties, best suited to work in an infectious environment.

AT A GLANCE – FINAFLOXACIN EXHIBITS AN ANTIBACTERIAL AND SAFETY PROFILE SURPASSING THOSE OF ITS PREDECESSORS

	Ciprofloxacin	Levofloxacin	Moxifloxacin	Later FQs^a	Finafloxacin
Gram positive activity	(+)	+	+	+	+
Gram negative activity	+	+	(+)	+	+
Anaerobic pathogens activity	-	-	+	+	+
Biofilm and persister cells	-	-	(+)	(+)	+
pH activation	-	-	-	(+)	+
Free from Qt effects	+	+	-	-	+
Half life for once daily dosing	-	(+)	+	(+)	+
Free from serious toxicities ^b	+	+	(+)	-	+

- ; not applicable, (+) ; generally applicable, + ; fully applicable

Covers new generation fluoroquinolones including trovafloxacin, grepafloxacin, gatifloxacin, clinafloxacin, gemifloxacin and sparfloxacin.
Toxicities including hepatotoxcicity, cardiotoxicity, phototoxicity, hyperglycemia and rash

WHAT MAKES FINAFLOXACIN UNIQUE?

Some of the characteristics of finafloxacin which set it aside from other members of the fluoroquinolone class can be summarised as follows:

pH activation and activity under infection relevant conditions. The activity of finafloxacin increases at pH values below neutral. This considerable gain in potency is expected to surpass other FQs (by 4 - 32-fold) in tissues and body fluids acidified by the infection or associated inflammation processes. Greater potency also results in faster bacterial killing and slower resistance development.
Infection relevant physiology. Finafloxacin is also more active than other marketed fluoroquinolones against the growth / physiological forms of bacteria which cause the most serious and recurrent infections; namely biofilms, slowly growing cultures and persister subpopulations.
Widest spectrum. Finafloxacin exhibits an all inclusive spectrum of activity that covers Gram positive, Gram negative, anaerobic and atypical pathogens.
Superior activity in vivo. Finafloxacin was more effective than the classical fluoroquinolones: ciprofloxacin, levofloxacin and moxifloxacin over a range of sepsis, cSSSI, RTI, UTI and IAI infection models; demonstrating the principal of activity under infection relevant conditions vs. test tube potency.
Safety. Finafloxacin has an outstanding safety profile compared to other fluoroquinolones. Data from preclinical studies, regulatory toxicity studies and four human clinical trials (total 160 patients) support this.

Thus, finafloxacin improves on the safety profile of its early predecessors with an excellent therapeutic outlook, delivered by its enhanced ability to kill bacteria under infection relevant conditions.

IN WHICH INDICATIONS IS FINAFLOXACIN EXPECTED TO BE MOST USEFUL?

Finafloxacin appears to be especially suitable for the treatment of serious bacterial infections associated with (i) acidic foci found in many infection sites (e.g. urine, abscesses, macrophages, and stomach mucosa) (ii) deep seated or chronic infections where inflammation creates an acidic environment (iii) reduced oxygen availability due to infection site or inflammation (iv) infections where these conditions promote persisters and biofilm growth.

The following indications comprise the environmental conditions favourable to finafloxacin and involve a broad range of susceptible Gram positive and/or Gram negative pathogens, including anaerobes, and require antibiotics with an excellent safety/tolerability profile. The following indications would be most appropriate for further clinical investigation of intravenous finafloxacin:

Complicated skin and skin structure infection
Complicated urinary tract infection
Hospital / healthcare acquired, ventilator associated and hospitalised community acquired pneumonia
Complicated intra-abdominal infection
Cystic fibrosis infections
COPD, treatment of moderate to severe exacerbations

FURTHER CLINICAL DEVELOPMENT
Finafloxacin has progressed through early and mid-stage clinical development in an oral formulation which has proven safety, good pharmacokinetics (supportive of once daily dosing) and efficacy in two indications (UTI and H. pylori). An intravenous formulation has now been developed and will be tested in humans in Q4 2010. This will provide the opportunity for finafloxacin to be tested against the most serious bacterial infections, with the option of iv. to oral step down therapy.

It is suggested that the initial indication selected for development is either cUTI, cSSSI or hospitalised CAP and that integrated Phase II/III trials are initiated in early 2011 thus enabling NDA filing as early as 2013. Clinical investigation of a second indication could be initiated during this study period plus additional clinical studies of pharmacokinetics / pharmacodynamics in specialised patient groups, tissue penetration and metabolism and investigative interventional studies in further indications. Further clinical options for oral therapy include: uUTI, H. pylori eradication and additional RTI indications.