I took great pleasure recently in seeing scientist Jim Aylward nominated for Queensland’s Senior Australian of the Year. Jim is a great Australian, and the man behind Picato – the topical treatment for sunspots – which is today one of the few home-grown pharmaceuticals on the market in Australia. I’m proud to say that QIMR Berghofer played a key role in its journey from folk remedy to pharmacy.
Like most “overnight success stories” it was decades in the making. I was not in the Institute when the story was unfolding so I have relied on the collective inputs and memories of the main players; Jim, Peter and Andreas whose roles are outlined below. I think it is important to capture the history of such research developments. This one is very significant as it is tells how an Australian team brought a completely new product to the pharmacy…and that has happened only a handful of times to date.
It all started in May 1997 when then-CSIRO Scientist Jim Aylward contacted Peter Parsons in the Melanoma Genomics Laboratory at QIMR Berghofer. Jim came to Peter’s lab with an anonymous test tube containing sap diluted in sterile water to disguise its origin. Peter coined it MPA, Magic Potion Aylward.
Peter said: “So, Jim, you think you’re going to cure cancer with what you have in this test tube? Put your drug against these cells, multidrug resistant malignant melanoma, we’ll ring you, don’t you ring us!”
Jim was adamant that his radium weed project would be a commercial venture from day one, with a clear demarcation between the Inventor (himself) and the “Scientist Skilled in the Art”. At CSIRO, where he was project leader and an inventor of a number of his own patent submissions, he had first-hand experience of a bruising patent battle when academic collaboration had later turned difficult. There was going to be no academic collaboration, rather a contract fee for service. He had been waiting for just the right time to find out if it worked in defined laboratory tests against cancer cells as a first step towards trying to isolate the active principle and deciphering its mode of action – whether it was unique or similar to the other known cancer drugs out there. That time had finally arrived.
For over 20 years, Jim had known that the milky sap from Euphorbia peplus, or radium weed, had credence in his family as an effective treatment of sun-spots that are a common occurrence in Queensland. He suspected the plant sap could thus be the source of a new pharmaceutical in the arsenal to fight cancer. Being a trained medical researcher and biochemist, he also knew that one day he would apply his expertise in purification to try to isolate the active ingredient, the first step to turning an extract into a defined molecular entity, on the way to a potentially new drug. In 1984, he had sought patent advice that made it clear that intellectual property could only be obtained if he purified and identified the active principle from the sap responsible for the anti-cancer activity.
The Parsons laboratory did ring Jim. Mark Hayes, a graduate student called after witnessing the change in cell shape for the first time. Peter’s laboratory was dedicated to the screening of a new class of anticancer compounds called differentiating agents. What Mark had observed, and confirmed later by Peter, was a profound change in the appearance of the melanoma cells similar to that seen with other differentiating agents they had previously tested. The difference was the potency and extent of cell reversion, almost back to the shape and appearance of a healthy melanocyte, the cells from which the melanoma had derived. The dramatic cell reversion with MPA was rare, compared to other differentiation agents tested previously in Peter’s laboratory.
Jim had to continue his journey alone, negotiating lab space with CSIRO and paying for every chemical used. In mid-1997, he started on the first steps towards characterising and eventually purifying the active principle from MPA, by experimenting with solvent extraction. On the basis of this information, he lodged a provisional patent, as sole inventor, encompassing the preliminary findings. He knew that the transfer of knowledge in a laboratory to a product on the market would require significant funding and a business structure to drive it forward. On the basis of his patent, Jim established a company with his CSIRO partner and Jim coined the name Peplin, a play on “peplus” and “pepluane”, a new molecule discovered in E. peplus. But Jim knew the clock was ticking once the provisional patent was lodged. Nothing but a defined molecular entity from the plethora of molecules in the plant sap would be a satisfactory outcome. He had 12 months to find the entity and complete the patent. The race was on.
Jim applied his years of purification experience to narrow the search to a few components. During the day, Jim would isolate enriched fractions by solvent extraction and chromatography, using media and chemicals that he had purchased himself. By night, Jim would visit Peter’s lab at QIMR Berghofer and test the new fractions against spare melanoma cells leftover from the day’s experiments in Peter’s laboratory. Over the next day or two, the cells would be scored blind for shape change under the microscope, mostly performed by Peter. Eventually, Jim finally obtained the structure on his pure fraction, still containing the differentiating activity, in consultation with The University of Queensland magnetic resonance facility. Jim had isolated ingenol angelate. He completed his patent in August 1998, with only hours to spare, and claimed a series of compounds and, in particular, a family of ingenol angelates, including PEP005, ingenol mebutate.
Later in 1998, after MPA had been unmasked to Peter as sap from E. peplus, it was drawn to Jim’s attention by Peter that another researcher at QIMR Berghofer, Professor Adele Green, had 10 years earlier published results of a survey of residents from the Nambour region in Queensland, that found E. peplus was the preferred self-treatment for sunspots, compared to other folklore treatments such as lanolin and aloe vera. But the publication was not passed on to Peter and scientists in the cancer drug discovery group within QIMR Berghofer.
In the meantime, the company, Peplin had negotiated a formal contract with QIMR Berghofer to fund all current work and backdate the contract to the first day that Jim arrived at the Institute. Peplin-funded research at QIMR Berghofer began in earnest. Peter began the search for the mode of action – how did MPA work at the cellular level and test for efficacy in animal models? He obtained QIMR Berghofer Animal Ethics Committee approval to test the sap for its ability to alter the course of melanoma tumour growth when topically applied to tumours implanted under the skin of mice. The results were very promising. Peter also arranged for Jim to meet Dr Jonathan Ramsay from the Queensland Radium Institute, a cancer clinician who saw severe cases of skin cancer in patients in his practice. Peplin contracted Jonathan to perform a pilot Phase II clinical trial, using crude sap supplied by Jim. The aim was to get clinical proof of concept. Dr Ramsay obtained Mater Hospital Ethics Committee approval to test MPA (name changed to PEP001) on a range of skin tumours in patients who had refused or failed conventional therapy, a most unusual, but very successful, trial that lasted several years.
The results gave confidence to all involved in the project and helped Peplin gain further investor support.
Another patent was lodged, this time with QIMR Berghofer scientists as co-inventors, and the next phase of the story unfolded. The QIMR Berghofer researchers found the exact step in the functioning of the cell, protein kinase C, that was targeted by the drug. As Research Director of Peplin, Jim contracted another research group at QIMR Berghofer headed by Andreas Suhrbier, which gave another perspective as to how the purified ingenol angelate (PEP005) may work at the cellular level. Andreas and his team used considerable skills to determine what was happening as the body rejected the cancer cells and in the process showed that PEP005 had a unique mechanism of action. The drug killed cancer cells by a process called necrosis. Most other anti-cancer drugs kill cancer cells by inducing apoptosis. Necrosis also stimulates the body’s immune system, which may help in clearing up any left-over cancer cells, helping to explain the excellent clearance rates seen anecdotally and in the pilot clinical trial. It was what is called a first-in-class drug and that opened the way for new families of drugs to be developed that target the same point in the cell-signalling cascade.
On the basis of his patent, and the convincing data emanating from mouse experiments and the clinical trial, Jim convinced some courageous people to invest in his dream of a new treatment for skin cancers without surgery. Peplin grew rapidly from business angel seed funding, through venture capital funding and in 2000 was listed on the Australian Stock Exchange, with eventually more than 1600 shareholders.
The combined QIMR Berghofer work resulted in eight additional patents and numerous scientific papers all of which consolidated the move of the treatment to mainstream medicine.
Knowledge of the precise consequences on the cell and its environment required that the compound was tested on animals. This was to see if the purified molecule PEP005, isolated from other ingredients in the plant, had any bad side effects on the animals, what concentration should be used, and, importantly, whether its efficacy was retained when it was in a real environment rather than in a laboratory dish. This work helped considerably to set guidelines for the formal toxicology that was to follow as part of Peplin’s development program.
More extensive safety and efficacy tests demanded by regulatory authorities needed to be commissioned by Peplin. This necessitated expertise that was found outside Australia and the work was expensive. Funds were dwindling for the research at QIMR Berghofer. Optimism was being challenged as the project followed the difficult pathway to a new pharmaceutical. Researchers working in the Parsons and Suhrbier laboratories were sometimes restricted to three month contracts at a time when working on the project.
In 2004, Peplin submitted an Investigational New Drug application to the United States Food and Drug Administration, and formal clinical trials commenced to test safety and efficacy. This involved blinded, randomised, placebo controlled trial tests on large numbers of patients with the pure compound in an inactive gel for the treatment of actinic keratoses. When the code was broken, PEP005 was indeed found to be an effective treatment.
In 2008, following a series of presentations by the Peplin team, and augmented by the QIMR Berghofer scientists, Peplin Ltd received a significant injection of funds from American investors. Later, in 2009, the Danish company Leo Pharma A/S acquired all shares in publicly-listed Peplin Ltd and assumed ownership. Leo Pharma rapidly moved PEP005 through the regulatory process and obtained approval for the sale of a prescription drug “Picato”, in all major markets.
There are many unusual aspects to this story. It is very rare for research in Australia and Australian Intellectual Property to result in a new therapeutic compound that is brought to market. It is rare that a start-up company surfs the challenging waves to achieve a high valuation and sale. Products that come from folk remedies seldom result in clinically trialled effective compounds. E. peplus is now being grown for commercial purposes on farms in Queensland. Workers are employed at the JH Aylward Manufacturing Facility at Southport, Queensland to extract and purify the active pharmaceutical ingredient in Picato for world-wide distribution. All told, since the start of sales of Picato, at least 100 local jobs have been created.
Peter Parsons and Andreas Suhrbier still work with their groups to understand more about compounds similar to PEP005. They are defining ever-new pathways to explain the actions of this new class of drug. In all, QIMR Berghofer has 12 research teams working on different aspects of melanoma and skin cancer. The Picato story reinforces our commitment to do “research with consequences”.
Jim Aylward continues to give back to the industry that he helped put on the map, by mentoring small start-ups in the biotech industries. He is proud that his initial patent had, over the years, indirectly brought more than $4 million extra funding to the Parsons and Suhrbier laboratories, which helped to maintain a critical mass of dedicated researchers through difficult funding times.
And for QIMR Berghofer, the legacy of Picato is a range of new commercial endeavours within the Institute, drawing on our decades of experience, and eager to emulate Jim Aylward’s “overnight” success story.
— Frank Gannon, CEO and Director, QIMR Berghofer