Aspirin research heralds new dawn for Vioxx?

The Biosystems Informatics Institute (Bii), set up by the UK government, is combining biophysics research with traditional pharmacology to examine how non-steroidal anti-inflammatory drugs (NSAID) exert their effects across the whole body.

The charity has focused on aspirin but hopes to use that knowledge to create new NSAID combination therapies with fewer side-effects, possibly even using Merck & Co.'s withdrawn drug Vioxx (rofecoxib).

NSAIDs are a widely used class of drugs that reduce pain, fever and inflammation.

Annual sales are estimated to be around $18bn (€12.8bn) for pain treatment alone, according to Bii.

However, their use is limited due to the prevalence of side-effects such as ulcer perforation, upper gastrointestinal bleeding and even heart attacks.

At its height, Vioxx generated sales of around $2.5bn per year before it was withdrawn from the market following safety concerns in September 2004.

Ian Humphrey-Smith, CEO of Bii explained to DrugResearcher.com that the question he asked himself was simply: "How do you build better, safer drugs?"

The answer he came to was to use a systems biology approach to drug development, where the effect of a drug on whole organs and organisms is considered, rather than just its interaction with a single protein target.

Although much more complicated than traditional drug design, it is an approach increasingly adopted within the industry because in addition to efficacy, it can predict - and thus avoid - potential safety issue much more easily.

The approach is implemented in both developing new drugs and repositioning old failures, either in a new indication, dose or combination.

"We have worked to combine aspirin with other NSAIDs to have a combination therapy that doesn't punch holes in your gut and doesn't punch holes in your heart."

According to Humphrey-Smith, the research is based around the concept of combination therapies and chronotherapies that take into account timing, delivery, dosing of treatment.

"And all of this in a single tablet that gives multiple outcomes but based on knowingly understanding the effect of drug on target, which I believe is a first in the pharmaceutical industry," he said.

Results from biophysics research teams in Newcastle, UK and Moscow, Russia, have been cross-validated by 150 different lab studies from around the world.

Humphrey-Smith said that the knowledge gained could be used to predict the different effects of NSAIDS in vitro , in animals and in humans.

Pfizer is currently conducting a $100m (€76m) clinical trial, which aims to examine the safety of its drug, Celebrex (celecoxib), with respect to other NSAIDs. Using the four-year study as an example, Humphrey-Smith said: "During that trial some patients will be put at risk from side-effects.

We believe we are in a position to predict the outcomes of that study now."

He went on to explain that his research team are also gearing up to validate the mechanisms of action they have discovered.

One way they are doing this is by studying the organ specific response of the drugs using technology from Zeptosens - a division of Bayer, which specialises in protein microarrays.

"We're very excited about the technology: we can follow 16 to 20 enzymes in key near target pathways, in 10 to 15 organs, at 10 time-points, in 10 animals and 4 doses of drug - that's around 120,000 biochemical assays."

He added: "By finding the mechanism and then validating it, we're turning the biomarker business on its head."

Bii is now preparing to create a spinout company, which will be launched later in the year, to exploit the research.

Humphrey-Smith revealed that as well as creating combination therapies based on generic NSAIDs, the new company would also look at in-licensing compounds and possibly even creating its own proprietary drugs.

"We can improve on the way NSAIDs are brought to market and the size of that market is enormous," Humphrey-Smith said.