Novoxel seeks to pre-empt MRSA
drug concerns
Novoxel has presented data showing
its Methicillin Resistant Staphylococcus Aureus (MRSA) drug NXL101 to be
bactericidal in vitro against what it believes to be the potentially
problematic future strains of MRSA. In addition to allaying drug resistance
fears, the data suggests NXL101 should be tested for two specific types of
MRSA: community associated MRSA and fluoroquinolone-resistant MRSA.
It is becoming apparent that the type of antibiotic resistance that
Staphylococcus aureus develops in the community environment is subtly, but
importantly different from that of the hospital environment (infections picked
up while a patient is in the hospital). If these differences continue to grow,
community acquired MRSA could require quite different treatment from
hospital-acquired MRSA.
It can be difficult to find the most effective treatment for MRSA at the best
of times, as these organisms are typically resistant to several other
antibiotic agents, including aminoglycosides, chloramphenicol, clindamycin,
the macrolides, and flouroquinolones. Accordingly, this leaves physicians with
very few choices, and on the whole, up until now, that has meant resorting to
vancomycin. However, there is increasing evidence that this reliance could be
cut short as resistance reduces MRSA susceptibility to vancomycin too.
Novoxel is currently developing a novel topoisomerase inhibitor, NXL101, for
gram positive infections, including Staphylococcus aureus. The drug entered
phase I trials in late 2006. However, because of some structural similarities
between NXL101 and the fluoroquinolone classes, it is natural to consider that
MRSA may also be resistant to NXL101.
The studies presented at the European Congress of Clinical Microbiology and
Infectious Diseases in Munich, or ECCMID, were largely designed to allay such
fears, and demonstrate that the candidate has the potential to be a valuable
addition to the armory of products that can be used against MRSA. The drug is
suggested to have particular potential against the growing risk of community
acquired MRSA that does not respond to the treatments used to treat hospital
acquired MRSA.
To demonstrate this potential, the candidate was tested in vitro, in parallel
with a number of other compounds including azithromycin, clindamycin and
levofloxacin against 48 recent EU isolates representative of community
acquired resistance in S. aureus. Just under 80% of the strains showed
resistance against fluoroquinolone levofloxacin, versus 55.6% in azithromycin,
and 24.1% in clindamycin. NXL101, meanwhile, showed favorable minimum
inhibitory concentrations (MIC – or the concentration of antibiotic needed at
which the test bacteria population neither grows nor decreases) against its
comparators, but also activity against strains resistant to the other
compounds.
Data was also presented showing that the compound may offer an alternative
treatment option in the case of fluoroquinolone resistance. This resistance
usually occurs in one of two ways: Either through an efflux pump (or a pump in
the bacterial cell wall which the bacteria uses to get rid of unwanted
chemical compounds), or through specific genetic mutations that interfere with
the drugs’ ability to disrupt the bacterial DNA. These latter mutations
usually occur in the topoisomerase IV gene.
It would appear that NXL101 can overcome both of these mechanisms of
resistance, which could allay some fears regarding the potential of cross
resistance based on NXL101’s shared quinolone ring - the structure which
largely defines drugs from the fluoroquinolone class. Demonstrating superior
activity against strains resistant to moxifloxacin, NXL101 showed MICs
superior across all strains tested. Furthermore, a Novoxel representative
stated that separate lab-work could mean that a lab-created mutant resistant
to NXL101 had resistance mechanism that was very distinct from that of the
fluoroquinolones (in other words, if Staphylococcal resistance to NXL101 was
to occur, it would be in a very different way to that found in fluoroquinolone
resistance), and that it had appeared exceptionally difficult to generate both
fluoroquinolone resistance and NXL101 resistance in the same organism.
The spokesman further stated that this could imply that the genetic mutation
to both forms of resistance could be fatal in S. aureus, which would be a
distinct advantage in promoting the compound as a novel drug separate from the
disadvantages of currently marketed compounds.
Indeed, both of these presentations appeared to be designed to pre-empt
specific concerns about NXL101’s viability as a commercial entity, or
clinically valuable product. Furthermore, the two in vitro analyses appear to
be an early attempt by Novoxel to differentiate it’s product from the concerns
regarding the fluoroquinolone class.
NXL101 could well be a valuable addition to the pipeline of products being
developed specifically to target MRSA, of which there are many. However,
Novoxel will be highly aware that many of these will launch well before its
candidate, namely Televancin (Astellas), Ceftaroline (Forest), Ceftopbiprole (Basilea),
Iclaprim (Arpida) amongst others.
As such, Novoxel’s strategy of pointing out a niche for which NXL101 could
have substantial advantages is an intuitive one. What the company will need,
however, is to bolster this in vitro data with good clinical trial data, and
quantify the impact of Community-Acquired MRSA. To do this, it will need to
demonstrate the level of treatment failures in community acquired MRSA cases,
and show that they are significant by comparison to hospital acquired cases.
Then, it will need to demonstrate NXL101’s ability to improve treatment
outcomes against its competitors. This will increase the cost of clinical
trials for Novoxel (and any of its partners, current or prospective), given
the time taken to recruit enough potential candidates for trial will be longer
than for either general gram-positive infections, or MRSA infections.
Therefore, the company is likely to initially trial the drug for a broader
indication (including community acquired MRSA), and leave the analysis of
community acquired MRSA as a secondary, rather than primary objective.
In summary, therefore, Novoxel has taken good initial steps to allay concerns
that its product may be flawed due to its structural similarity to products
for which resistance is becoming an issue. It has also laid the groundwork for
a concerted campaign to identify a niche within a highly competitive
marketplace, and position its product in a readily defendable position.
However, Novoxel will have to follow up this information with significantly
more detailed data, both regarding the impact of the niche it is targeting
(community acquired MRSA resistance), and the drug’s utility for this purpose
in the real world.
Related research:
Stakeholder Opinions: Nosocomial Infections - The need for new gram-negative
drugs
Commercial Insight: Antibacterials - Growth in resistance rates drives niche
indications
