Dalvabancin - Second-Generation Glycopeptide for Serious Gram-Positive Infections

Originally developed by Vicuron Pharmaceuticals (subsequently acquired by Pfizer), dalbavancin is a novel second-generation glycopeptide indicated for the treatment of serious gram-positive bacterial infections in hospitalised patients.

In December 2004, the company filed an NDA with the US FDA for use of dalbavancin in the treatment of complicated skin and soft tissue infections. The NDA included data on more than 1,850 subjects enrolled in three phase III trials, which evaluated the safety and efficacy of dalbavancin in patients with complicated skin and soft tissue infections.

At the end of 2007, Pfizer received an approvable letter from the FDA for the use of dalvabancin as a treatment for adult patients with complicated skin and soft tissue infections, including those caused by MRSA. The FDA will grant marketing nod upon submission of requisite additional data by Pfizer.

Pfizer has also submitted the European marketing authorisation application (MAA) seeking approval of the European authorities to market dalbavancin in the region. However, the application was withdrawn later in 2008 for conducting additional clinical trials.

Until dalbavancin is approved, Zyvox (linezolid IV/oral) will be the only Pfizer drug that will treat MRSA-caused skin diseases.

Additional phase III clinical trials

Pfizer announced plans to withdraw all dalbavancin marketing applications globally, including the US NDA and the European MAA in September 2008, for conducting additional Phase III clinical trials. The decision was based on the feedback from regulatory authorities and was aimed to support regulatory submissions planned for future.

Advances in glycopeptide antibiotic development

Dalbavancin is a member of the glycopeptide class of antibiotics, to which vancomycin and teicoplanin also belong. They are an important class of antibiotics for the treatment of serious gram-positive infections, including those due to staphylococci and enterococci.

For many years vancomycin was the mainstay of difficult-to-treat infections, such as those due to methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). Recently, evidence has emerged to suggest that some strains of S. aureus are becoming less susceptible to vancomycin, while more strains of enterococci are becoming fully resistant.

Dalbavancin has been specifically developed as an improved alternative to vancomycin, with potentially enhanced in vitro potency, including bactericidal activity, against gram-positive pathogens such as MRSA and MRSE.

Its enhanced potency and long half-life enable it to be administered intravenously just once per week as opposed to vancomycin, which typically involves multiple daily infusions. This simpler dosing regimen may reduce the need for the continued presence of IV lines in some patients and potential for fewer local and blood stream infections.

Dalbavancin has a favourable pharmacokinetic (PK) profile since the drug is not a substrate, inducer or inhibitor of cytochrome P450 enzymes and there is no need to monitor drug levels.

Evidence for efficacy in pivotal phase III trials

Dalbavancin has shown solid evidence of efficacy in three phase III studies in patients with complicated skin and soft tissue infections and in a phase II study in catheter-related bloodstream infections (CR-BSI), where it proved superior to vancomycin.

In the randomised, open-label phase II clinical trial, 67patients with CR-BSI due to suspected or documented gram-positive pathogens were treated with either two doses of dalbavancin one week apart or vancomycin twice daily for 14 days. Primary endpoint was a composite of clinical and microbiological responses 21 days after the end of treatment.

Based on the primary endpoint, 87% (20/23) of dalbavancin-treated patients responded to therapy compared with 50% (14/28) of those treated twice daily with vancomycin.

In the phase III clinical trials, dalbavancin met the primary and secondary endpoints of non-inferiority in comparison with linezolid, cefazolin or vancomycin; three commonly used standard-of-care antibiotics for complicated skin and soft tissue infections. The vast majority of the patients treated in these studies had infections caused by S. aureus, with more than 400 patients infected with MRSA.

Pfizer acquisition of Vicuron strengthens anti-infectives portfolio

In June 2005 Pfizer and Vicuron announced plans for the companies to merge. The development was aimed at facilitating better marketing of dalbavancin as well as Vicuron's novel antifungal agent anidulafungin, which received FDA approval in 2006.

The merger, which was completed in September 2005, has also broadened Pfizer's portfolio of anti-infective products. Pfizer has a major presence in the anti-infectives market, where it markets antifungal agents, such as fluconazole, and the antibiotics azithromycin and linezolid.

The two companies already have an existing collaboration that has made significant advances in the discovery of potential next-generation oxazolidinones, one of the most significant new classes of antibiotics to emerge in 30 years.

It is hoped that this new generation of orally-active antibiotics will have improved potency and a broader spectrum of activity than existing compounds, such as linezolid.

Marketing commentary

In an era of rising rates of bacterial resistance to commonly used antibiotics, new agents are urgently needed to treat bacterial infections effectively and halt the spread of resistant strains. This need is arguably greatest in the hospital environment where rates of bacterial resistance are highest. MRSA is a particular problem because it displays resistance to most classes of antibiotics.

Although the hospital antibacterial market represents only a third of all antibacterial sales, increasing antibiotic resistance in the hospital environment has increased the demand for more effective antibiotics making it an attractive sector for new antibacterial agents. As a potential successor to vancomycin, dalbavancin appears well placed to succeed, especially when backed by the resources of Pfizer.