Thursday, February 02, 2006

Replidyne marches on in the development of novel antibiotics for the treatment of drug-resistant skin infections

The market for antibacterials, valued at $24 billion in the seven major markets, faces significant revenue loss in the period 2005-2007 due to major patent expiries (see Commercial Insight: Antibacterials).

Despite the problems faced by companies involved in antibacterials considerable success has been met by those targeting drug resistant infections such as MRSA. This is highlighted by the rapid uptake of products focused on drug-resistant infections, such as Pfizer's Zyvox (linezolid).

One company heavily involved in the development of antibacterials targeted against drug resistant microbes is Replidyne. Only last month (Jan, 2006) Replidyne announced that they had submitted an NDA for Orapem (faropenem medoxomil). Through this submission the company is seeking marketing approval for the use of Orapem against infection caused by multiple pathogens (click here for press release).

In addition to the development of Orapem, Replidyne has an active drug development program directed to inhibitors of bacterial DNA replication and it is the development of one candidate from this program, REP8839, that is the focus of today’s DailyUpdates (Feb 2nd, 2006).

REP8839 has emerged from Replidyne’s methionyl tRNA synthetase program that it in-licensed from GlaxoSmithKline in 2003. The program includes multiple series of advanced leads that utilize a novel mechanism-of-action to inhibit bacterial protein synthesis. REP8839 targets methionyl tRNA synthetase, the enzyme responsible for the synthesis of methionine.

Methionine is unique among amino acids in that it is always the first amino acid to be incorporated into proteins. Thus, inhibitors of methionyl tRNA synthetase interfere with the initiation as well as the elongation phase of protein synthesis. Currently, only one anti-infective agent that inhibits a tRNA synthetase is on the market - mupirocin (Bactroban), an inhibitor of isoleucyl tRNA synthetase.

REP8839 has been selected by Replidyne as a lead methionyl tRNA synthetase inhibitor and is being developed as a new topical antibacterial agent. REP8839 is very active against major skin pathogens. The Antimicrob Agents Chemother paper featured in today’s DailyUpdates highlights this efficacy. Potent antibacterial activity was reported for clinical isolates of Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus epidermidis and other clinically important gram-positive bacteria. All isolates of these bacteria were susceptible to REP8839 including multiple resistant strains.

Bacterial skin and skin structure infections are among the most common infections treated. There are a wide range of different types of infection, each with individual symptoms, epidemiology and etiology. However, the majority requires antibacterial treatment and, as a result, represent potential lucrative targets for novel product development (see Skin Infections - Where In The Antibacterial Lifecycle?). The efficacy of REP8839 against such a broad range of pathogens including resistant strains suggests that this therapeutic candidate should attract considerable success. Drug resistance underpins a high unmet need in the management of skin infections. This should increase the likelihood of compounds novel antibiotics gaining fast-track designation in the US. This has already been demonstrated by Cubist’s Cubicin (daptomycin) and Basilea’s novel cephalosporin, BAL5788. Hopefully REP8839 will follow a similar path as it moves out of preclinical development into the clinic bringing rewards to Replidyne and the patient sooner rather than later.


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