A sweet pill to swallow
Thanks to pioneering UQ research, people suffering from inflammatory bowel disease and rare blood disorders worldwide could soon benefit from safer and more convenient treatments.
Few of the thousands of people streaming onto UQ’s St Lucia campus each weekday are probably aware they share their campus with a pioneering biotechnology company currently trialling three potentially life-changing drugs.
But tucked away on the edge of campus is one of two places you’ll find Protagonist Therapeutics, the other being in California. The company was spun out from research conducted by Associate Professor Mark Smythe at UQ’s Institute for Molecular Bioscience (IMB), which is also located at the St Lucia campus.
Since the company was established in 2001, Protagonist has been focused on developing new drugs for hard-to treat conditions, including inflammatory bowel disease (IBD) and rare blood disorders.
These include orally stable peptide drugs that, when available, will give patients an alternative to injectable-only drugs.
IBD cases are on the rise in both developed and developing countries, and Australia has one of the highest rates in the world according to a 2013 PwC report.
Treatment options – surgery and injected drugs – are costly and inconvenient. But two new drug candidates developed by Protagonist are designed to be taken orally as a pill, which would offer better healing, safety and convenience, as well as longer-term disease remission.
The first of these showed improved healing of the gut in Phase 2 clinical trials in the last quarter of 2018, while the second has completed Phase 1 and will be entering Phase 2, which will determine its efficacy.
The third Protagonist drug candidate that is currently in Phase 2 trials is an injectable treatment for Beta thalassemia – a rare genetic blood disorder that causes chronic anaemia.
Currently, the only treatment available is regular blood transfusions for life. There’s potential for this drug candidate to be developed into treatments for other rare blood disorders too.
These potential treatments have arisen out of two decades of research that began in Associate Professor Smythe’s laboratory at UQ. As a medicinal chemist, he was struck by the lack of suitable drugs for a range of diseases.
“My inspiration was to solve a problem in the pharmaceutical industry, which was to find drugs for difficult targets,” he says.
“These targets are called ‘protein-protein interactions’ and as the name suggests, they occur when two proteins come into contact with each other.
“These interactions underpin many diseases, for example, inflammatory diseases such as inflammatory bowel disease, which are predominately treated today by antibodies.”
Image credit: Getty Images/Thanit Weerawan
Associate Professor Smythe explains that drugs typically fall into one of two categories: antibodies or small molecules.
“Antibodies can hit these protein-protein interaction targets, but they have to be injected, which means you get high drug concentrations throughout your whole body, and less in your gut or stomach tissue,” he says.
“This is an issue if you’re trying to treat diseases of the gut, such as inflammatory bowel disease, and it is also more of a burden on the patient and the health system.
“Small molecules are taken orally as a pill, which is much more convenient, but they don’t hit the protein-protein interaction targets that underlie inflammatory diseases.”
Associate Professor Smythe realised early on in his research that the ideal drug to treat diseases such as IBD would hit the right target but be available as a pill. But the big question was: what molecules could he use to achieve this goal?
Location played a key role in answering this question.
“UQ's IMB does a lot of work in venoms and Australia is blessed with a lot of venomous animals,” Associate Professor Smythe says.
“Back in the early 2000s, we were finding that some of those toxins worked on these targets.
“The interesting part of this discovery for me, as a medicinal chemist, is that these venoms comprise a class of molecules called constrained peptides, which seemed to combine the best properties of antibodies and small molecules: they could hit the right targets and be developed into oral pills.
"Back in the early 2000s, we thought if nature uses constrained peptides, why aren’t we exploiting them as human drugs?"
Associate Professor Smythe and his team developed stabilising techniques that would allow these peptides to be delivered orally and engineering techniques allowing them to hit the same targets as the injectable drugs.
Apart from the convenience of taking a pill instead of having a treatment injected, constrained peptides also offer the promise of high potency at a low dose, and very specific binding to their target, meaning patients experience fewer adverse side effects.
“IMB is a good, fertile environment for peptide chemistry that combines great infrastructure with leading minds in life sciences,” he says.
“This, along with financial and commercialisation support from UQ, provided an ideal incubator to translate research that will not only help people, but also bring economic benefit.”
Protagonist has raised a total of AU$88 million in private funding since 2001, which has helped build industry relationships and accelerate the technology’s development.
In 2009, Protagonist Therapeutics was established in the United States to access the greater amounts of venture capital available in that market.
As well as its own proprietary drug pipeline in development, Protagonist has secured a number of commercial partnerships, including collaborative research with Massachusetts-based Ironwood Pharmaceuticals and Denmark-based Zealand Pharma A/S, both of which are industry leaders in peptide therapeutics.
In 2016, Protagonist was listed on the NASDAQ for US$90M, and was named ‘Australian Company of the Year’ at the AusBiotech and Johnson & Johnson Innovation Industry Excellence Awards.
In 2017, Protagonist announced a deal with Janssen Pharmaceuticals. This involved a US$50 million upfront payments and US$940 million in milestone payments for the co-development of PTG-200 for inflammatory bowel disease.
While these achievements are impressive, Associate Professor Smythe has never lost sight of the bigger picture.
“The best thing from this research is the benefit to patients. There’s a big need for medicines like these, and that’s the reason you do it: you’re trying to help people live a better life.”
The story so far:
2001: Protagonist Therapeutics Pty Ltd is established as a start-up company out of UQ’s Institute for Molecular Bioscience, with a focus on developing orally stable peptide drugs.
2008: Protagonist is established in the USA.
2011: Protagonist enters into a partnership with Massachusetts-based Ironwood Pharmaceuticals.
2012: Protagonist signs a collaboration agreement with Denmark-based Zealand Pharma A/S .
2016: Protagonist’s lead compound – a novel, orally stable peptide therapeutic for inflammatory bowel diseases – enters Phase 1 clinical trials.
2016: Protagonist Therapeutics Inc. is listed on the NASDAQ stock exchange and raises $US90 million in its initial public offering of 7.5 million shares.
2016: Protagonist Therapeutics Pty Ltd is named Australian Company of the Year at the AusBiotech and Johnson & Johnson Innovation Industry Excellence Awards.
2018: A second drug candidate for IBD developed by Protagonist enters Phase 1 trials.
2019: An injectable treatment for Beta thalassemia enters Phase 1 trials.
Opening video credit: Getty Images/ The Stock Studio
Image credit: Getty Images/Nipitphon Na Chiangmai / EyeEm
Associate Professor Mark Smythe
Associate Professor Mark Smythe, Institute for Molecular Bioscience
Phone: +61 7 334 62977
This article was last updated on 29 March 2019.