|Limitations of Current Gram-Negative Therapies
Traditionally, Gram-negative infections have been treated with antibiotics, particularly beta-lactams, including penicillins, cephalosporins and carbapenems, and quinolones, including flouroquinolones. However, the effectiveness of existing antibiotics has been declining due to increasingly prevalent drug resistance. Bacteria develop resistance to drugs through genetic mutations or by acquiring genes from other bacteria that have become resistant. For example, in a recent survey of resistance rates of Gram-negative bacteria to current therapies in the United States, the resistance of E. coli to fluoroquinolones has been dramatically increasing. For example, resistance of E. coli to ciprofloxacin increased from 4% in 1999 to 30% in 2008 and resistance of E. coli to levofloxacin increased from 10% in 2003 to 30% in 2008. Over the same period, resistance of another Gram-negative bacteria, Klebsiella pneumoniae, to third generation
cephalosporins, such as ceftriaxone and ceftazidime, increased from virtually no resistance to 15%. The same survey also showed that by 2008, 17%-19% of Pseudomonas aeruginosa were resistant to fluoroquinolones, 10%-70% were resistant to third generation cephalosporins and 7%-15% were resistant to carbapenems, such as meropenem and imipenem. Therefore, there is an ongoing need for novel antibiotics to combat the widespread proliferation of antibiotic resistance, particularly for Gram-negative bacteria. Additionally, currently marketed products have side effect profiles that can include nausea, diarrhea, vomiting, rash, insomnia, and potential liver toxicity. Also, currently approved antibiotics specifically targeting infections caused by Gram-negative bacteria are only available in either IV or oral formulations, but not both, so patients cannot continue on the same antibiotic therapy they received in the hospital once they are discharged.
In November 2009, we initiated a Phase 1 dose-escalating clinical study for AN3365, to
evaluate the safety, tolerability and pharmacokinetics of AN3365 in healthy volunteers. The
randomized, double-blind, placebo-controlled, dose-escalation study enrolled 72 subjects.
Participants in this study received AN3365 in single or multiple doses for treatment durations
of up to 14 days and included doses that achieve blood levels that are approximately four times
the expected efficacious blood levels based on our preclinical studies. In June 2010, we reported
Phase 1 results showing that AN3365 appeared to be safe and well- tolerated.
Following the completion of the Phase 1 trial, GSK exercised its option to obtain an exclusive
license to develop and commercialize AN3365 and assumed responsibility for further
development of the product candidate and any resulting commercialization.
In June 2011, GSK initiated two separate Phase 2b trials of AN3365 in complicated urinary
tract infections (cUTI) and complicated intra-abdominal infections (cIAI).
In February 2012, GSK halted the clinical trials of GSK ‘052 due to the identification of
microbiological findings of resistance in a small number of patients in the Phase 2b trial for
the treatment of cUTIs. From February through October 2012, GSK conducted additional pre-
clinical research and, after assessing various options, elected to discontinue further development
of GSK ‘052 and return all rights to GSK ‘052 to Anacor. Future development plans are currently under review.