Disrupting interactions sends Progen's stocks sky-high

While a share price going astronomical is great news for this Brisbane-based company and for its investors, the real winners stand to be millions of cancer sufferers worldwide for whom the drug on trial may offer a second chance.

Progen's focus is small molecule-based therapeutics that disrupt carbohydrate-protein interactions involved in cancer. Its lead product is PI-88, a heparin sulphate mimic with anti-angiogenic and anti-metastatic properties.

On December 13 last year, Progen sent the share market flurrying with promising interim results from a Phase II trial of PI-88 in post-surgery liver cancer. The drug increased disease-free survival or time to tumour recurrence by 76 per cent in a Taiwanese cohort. The company is now eagerly awaiting the final results on completion of the trial, and planning is well underway for Phase III.

Sarah Meibusch, Progen's VP for business development, says PI-88 works by inhibiting two processes essential to the growth and spread of tumours - angiogenesis and metastasis. The drug is a structural mimic of heparan sulphate (HS), an important part of the extracellular matrix involved in a range of biological activities, including development and cancer. PI-88 blocks the breakdown of HS by heparanase, an enzyme preferentially found in tumour cells to disrupt the tissue matrix and allow escape.

By stopping this, PI-88 should prevent both new tumour growth (via angiogenesis) and the development of metastases. In addition to its action on heparanase, PI-88 binds several pro-angiogenic growth factors such as VEGF and stimulates the release of another potent angiogenic stimulator. It is this multi-target action that makes PI-88 a potentially powerful anti-cancer agent.

History

Progen's history differs from many biotechnology companies in Australia that start as spin-outs of universities and research institutes. Progen began life as a manufacturing company, when a group of business founders bought the QClone manufacturing facility in an industrial suburb of Brisbane in 1989. During the 90s, the company focused on servicing the Australian life science industry, making reagents for laboratory use and acting as distributors for other companies such as Eppendorf.

The metamorphosis to the current Progen Industries started in 1992 when they began sponsoring research with Professor Chris Parish at the Australian National University. His research centred on the role of the polysaccharide heparan sulphate (HS) in a variety of disease processes including cancer. It was that research that really formed the foundation of Progen's success with development of the PI-88 compound.

Following successful pre-clinical, animal-stage development, Progen eventually licensed the entire IP portfolio in the late 90s and moved the research in-house to its facility in Brisbane. In 2001, it set up its own drug discovery team to work on the next generation of products.

At that stage, Progen was still doing everything - manufacturing reagents, distributing products, drug discovery and trying to set up clinical trails. It was time to focus, and in 2003, Progen sold off the life sciences division to focus on clinical development - in particular, getting the lead product to market as fast as possible.

The company retained its manufacturing division, with the bulk of the product being PI-88 for clinical trials.

The current CEO of Progen Industries is Justus Homburg, who took the helm just 12 months ago and is the driving force behind registering PI-88 for liver cancer. "He has motivated the entire company towards this goal," Meibusch says. Homburg is well equipped for the task, having spent about 12 years with Monsanto pharmaceuticals, working with the Celebrex team in a successful race to launch their product ahead of Vioxx (Merck).

Meibusch was also keen to credit Lewis Lee, who steered the company from 2002 to 2006. Lee focused Progen's activities on clinical development and was instrumental in establishing the drug discovery team and all the trial work for PI-88.

According to Meibusch, he was an extremely successful operational manager and fiscally wise CEO, "driving the company through all those years of capital raising and establishing the PI-88 trials without data coming through to drive the share price," she says.

Clinical trials

Progen has established an in-house clinical development team specifically to run its clinical trials in centres all over Australia, Europe, the US and in some other places such as Taiwan. This team monitors all centres and writes the protocols. PI-88 is currently being tested in four Phase II trials for melanoma (five centres in Australia and three in the US); non-small cell lung cancer (13 centres in the US - just concluding); prostate cancer (10 centres in Australia); and post-surgery liver cancer (Taiwan centre).

The Taiwanese trial involves 172 patients and is being conducted by Progen together with its Taiwan-based strategic partner Medigen Biotechnology. Patients who had their liver cancers resected were given PI-88 post-surgery - the aim is to reduce recurrence rates and to prolong the disease-free period.

Primary liver cancer usually recurs in about 50 per cent of cases within 12-15 months, and not much is available to help patients at that stage. Most of the patients in this trial have hepatitis infections, which is the most common cause of liver cancer in Asia. So, although liver cancer is a small market in the US and Europe, it is a huge and growing market in Asia, where it accounts for most cancer deaths.

The post-resection liver cancer model is also a good indication from the perspective of how the product works, Meibusch says. "We think it is a good chance of success at this stage - mechanistically PI-88 will work best if you can get the disease as early is possible and the resected cancer model is a unique way of doing this.

"The data from the Phase II trials, released in December, provided the impetus to move forward with this indication into Phase III trials planned to start in the second half of this year. It improved our profile internationally and helped us to set up the next stage - a huge randomised population in the resected liver model."

This trial will involve many centres in Asia, Europe, the US and Australia. Progen is one of only a few companies in Australia going into Phase III development, and with such a significant indication, the product has huge potential in many other indications as well.

The future

Another of Progen's potential drugs is a cytotoxic small molecule, PI-166. This compound was licensed in 2002 from the University of NSW and is currently in dose-finding Phase Ib trials in Australia for advanced liver cancer following promising pre-clinical studies. Progen also has several next-generation products in pre-clinical models and of course many more in the pipeline.

As for PI-88, the planned Phase III trial will take about three to four years, with the duration really dependent on how well the drug works. If successful, Meibusch estimates about six months to file the required paperwork with the FDA in the US, and then it is ready for market.