Trial and Error

DRUG INNOVATIONS: An Irish scientist has spent a decade developing sensor technology that could save pharmaceutical companies a fortune in drugs trials

WHEN YOU develop a new pharmaceutical drug the stakes are high. Get it right and not only can you help alleviate suffering, you stand to make a healthy profit too. But get it wrong and you could flush away several years of research and trials, not to mention funding that's counted in millions, if not billions.

Before a candidate drug can get to market, it has to pass a series of tests. Pharma companies usually start with several potential candidates and select the most promising compounds as they move forward through rounds of lab and animal pre-clinical testing. Then it's on to small and eventually larger phases of human clinical trials to ensure the drug is safe and effective at the recommended dose.

But even as the clinical trials get larger and the ultimate goal of regulatory approval looms, it's no guarantee of success. Earlier this year, Dublin-based drug development company AGI Therapeutics reported it was discontinuing development of its lead product Rezular for irritable bowel syndrome due to disappointing results in phase III human trials.

Meanwhile, even those drugs that make it past phase III and go off into the wide world remain under the watchful eye of "post-marketing surveillance" for any signs of adverse effects. Small wonder then that pharma companies pay close attention to innovations that help safeguard the pipeline of drug discovery and validation, and it's an area where Irish initiatives are making a name.

"At the moment the pharmaceutical industry is really in trouble in the sense that a lot of compounds are bombing out in the clinical trial phase," says Prof John Lowry, head of chemistry at NUI Maynooth (NUIM).

"Getting to phase III could cost a billion dollars - that's a huge amount of investment for one molecule, and they really can't afford for chemicals to be dropping out in clinical trial phase. So what they are looking for now is more relevant pre-clinical data that will translate from the pre-clinical to the clinical environment."

Lowry has developed an invention that could make that link in neuroscience - a tiny implantable sensor monitors brain chemicals in real time. Unlike the current method used to test the response of the brain to a candidate drug treatment (sampling brain fluid at different times), Lowry's sensors are placed in situ and convey the relevant information back to the researcher as the animal goes about its business.

Lowry has developed the sensor technology over a decade, working on some "fancy chemistry" on the miniscule electrode surface to measure indicators like oxygen and glucose, and key chemicals for brain function including serotonin and glutamate. Such a view of real-time brain function could help "early attrition" of candidate drug compounds and let researchers know what effects drugs have in the brain.

His initial work sparked interest in pharma companies, including Eli Lilly and Solvay, and demand for the technology has been so high that NUIM has just spun out a company, BlueBox Sensors, to manufacture the devices and target that pre-clinical market.

Streamlining drug discovery is also on the mind of Cellix, a spin-out from Trinity College Dublin that makes "vein on a chip" platforms to mimic bloodvessels in the lab. By pumping samples of cells or blood through the plastic chip's tiny microfluidic channels, researchers can watch how the cells stick and behave, getting a steer on how drug treatments would affect an animal or human system.

The approach replaces more cumbersome equipment currently used to test candidate drugs in the lab, says Vivienne Williams, co-founder and chief executive of Cellix, which launched in 2006 and supplies global pharmaceutical companies including AstraZeneca and Pfizer.

"We would target it at a very late-stage development of drug discovery, so they will have gone through all their high-throughput screening and the battery of tests," she says.

Their drug-screening systems can help select the most promising candidates to go towards clinical trials, says Williams.

"Normally when we are involved in labs they have maybe 20-50 compounds under development and they are trying to pick out of those compounds which ones to put into clinical trials. [With our system] they are seeing differences in adhesion profiles and behaviour of cells under conditions of continuous flow where they haven't spotted those things beforehand in static, well-plate experiments or in animal models."

Not only does picking the right candidate drug to go forward help protect investment in the long run, the Cellix system uses tiny volumes of samples, adds Williams. "You might only need to use a few microlitres instead of a millilitre of a sample to test it - and some of these samples can cost several hundred euro a pop."

But what if everything has gone well in the early stages, only to turn out that when it gets to clinical trials, or even to market, a drug has an undesirable outcome like serious side-effects in sub-groups of patients?

Another area of development is that of "companion diagnostics". "It's a huge new area emerging now," says Prof Brian MacCraith, director of the Biomedical Diagnostics Institute at Dublin City University. "When you start to develop a drug, you develop a diagnostic to go with it," he says. "If you imagine where you have got a drug and let's say there are adverse effects in 10 per cent of the population - so the whole multi-billion development of the drug has to be shelved. But what if there exists a diagnostic test that tells whether a person is suited to this or not?"

The motivation is there for pharmaceutical companies who could use the approach to help guide drugs to market for populations where they will be effective, and to monitor their effects once there, he says.

Researchers at DCU are currently developing companion diagnostics technology, using nanoparticles that can detect and image molecules or other biomarkers within living systems, adds MacCraith. "It's an area we are very excited about."

Bio pharm Growth area

IN ANY business, inefficiency means money wasted. That's why a new initiative in Ireland is targeting the production of "biopharmaceuticals" - protein-, gene- or cell- based drugs.

Growing the cells to make large quantities of such drugs is currently wildly inefficient, and the three-year BioPAT programme is bringing together multinational drug development companies, indigenous Irish businesses and academic expertise to whip it into shape.

"The focus of the project is really on next-generation efficiencies in biopharma production," says Dr Keith O'Neill, director of life sciences and food commercialisation at Enterprise Ireland, which is funding the €2.3 million initiative. "A report recently quoted rates of between 30 and 40 per cent inefficiency for biopharma manufacturing - that pushes up the cost of healthcare and this contributes to the extremely high cost of biopharmaceutical medicines. And when you look at the ICT sector, which has production efficiencies in the high 90s, there's huge room for improvement."

The research programme brings together 15 companies and several academic institutions to develop sophisticated tools to monitor the large-scale production processes and make them more efficient, including ways of safely extracting and testing samples of cells from bioreactors, says O'Neill.

So why is Ireland investing in this now? "The timing is perfect. There is such huge pressure on the healthcare system, there's a constant drive to increase efficiencies and reduce costs and at a time globally when industry is struggling to find new ways to adapt to a difficult market, Ireland has chosen to take the bull by the horns and invest in the next generation of technologies to secure biopharma companies that are already here and to partner them with indigenous companies that are here to drive the manufacturing processes," says O'Neill.

"No one company is incentivised to go off and develop these things themselves. It's too much of a regulatory risk. . . So we will develop a platform in a collaboration between the multinationals, the Irish indigenous companies and the academic ability and develop a platform they can all build on, it moves the whole sphere up a notch."