Vertex Pharmaceuticals announces submission of NDA/MAA filings in US and Europe for amprenavir pro-drug (GW433908)

Vertex Pharmaceuticals Incorporated has announced that GlaxoSmithKline (GSK) has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for marketing approval of GW433908 (also known as 908 or VX-175), an investigational HIV protease inhibitor in development for the treatment of HIV infection.

GSK has simultaneously submitted a Marketing Authorisation Application (MAA) for regulatory approval of 908 in the European Union. The 908 compound was co-discovered by GlaxoSmithKline and Vertex Pharmaceuticals.

The submissions for registration include data from more than 1,100 treatment-naïve and treatment-experienced patients who have participated in Phase III trials to evaluate the safety and efficacy of 908 in comparison with two widely used HIV protease inhibitors. In clinical trials, 908 was dosed as two tablets in both once-daily and twice-daily regimens.

If approved, GSK will market 908 and Vertex will co-promote in the US and key markets in Europe.

Comment

GW433908 is the calcium phosphate ester prodrug of amprenavir, which is much more water soluble than the currently available Agenerase version of amprenavir. This amprenavir prodrug appears to be hydrolyzed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium. This new formulation is a 465-mg tablet, which would allow for a reduction in both the daily pill count and pill size.

Amprenavir itself is a protease inhibitor that is already approved for treatment of HIV infection. There are, however, formulation and pharmacokinetic shortcomings that limit its utility. Despite a relatively long plasma half-life, amprenavir must be given twice daily. Moreover, because of the relatively low solubility of this drug it is coformulated with a number of additives limiting capsules to 150 mg in size. Additionally these capsules are extremely large leading to difficulties in administration. The recommended dosage of amprenavir is 1200 mg (eight capsules) twice daily. The development of a more compact formulation of amprenavir would likely improve dosing convenience and tolerability