Researchers at UOW developed a new chemotherapy, Deflexifol, which overcomes the problems of severe adverse side effects associated with existing treatments. They completed a detailed preclinical program, established a worldwide patent portfolio, and out-licensed the drug to an Australian biotechnology company, FivepHusion, with IP owned by UOW. FivepHusion has now completed a clinical trial, showing that Deflexifol is able to control disease progression whilst reducing toxicity. The research developed a novel drug to improve cancer patient outcomes, led to a successful model of commercialisation with a local drug development company, and built capacity in the region for both clinical trial and pharmaceutical business development.
3. Good health and well-being
9. Industry, innovation and infrastructure
Details of the Impact
Chemotherapy plays a key role in cancer treatment; however, problems persist with severe adverse side effects. In a cornerstone chemotherapy regimen used in millions of patients each year, Leucovorin (LV) is given with 5-Fluorouracil (5-FU) to enhance its clinical activity. However, due to the chemical incompatibility of the two drugs, LV is absent for most of the 5-FU infusion in cancer patients. This results in reduced efficacy, in addition to many adverse events such as vein irritation and catheter blockage, which lead to poorer patient outcomes.
Over 15 years researchers at UOW led biomedical research to design and test novel cancer treatments in pre-clinical models and clinical populations. Researchers fused the cornerstone chemotherapeutic drugs 5-FU and LV, to create a novel compound, Deflexifol, in a team led by UOW academic Prof Marie Ranson together with Prof John Bremner, and renowned oncologist and UOW academic Prof Philip Clingan OAM.
In an open-label Phase Ib/2a clinical trial, Deflexifol shows greatly reduced toxicity compared to the same dose of 5-FU. Disease control was seen in 64% of patients, despite most having failed previous 5-FU regimens. In a relatively short time span, this fundamental biological research, initiated and conducted at the regional level, translated into clinical trials showing improved patient outcomes. Accelerated drug testing and development was made possible through strong relationships with regional and community organisations and donors.
Beyond this, the research was pivotal in increasing translational capacity in the Illawarra region and enabled economic benefit for a local drug development company (FivepHusion Pty Ltd).
Worldwide patents were granted for Deflexifol including the U.S., China, Europe and Australia. Regulatory consultants provided advice to UOW, leading to a pre-Investigational New Drug meeting with the US Food and Drug Administration (FDA) in 2011, who confirmed the suitability of the drug for fast track new drug registration via the 505(b)(2) pathway.
Deflexifol was out-licensed in 2013 to a local drug development company FivepHusion, who secured sufficient investment to complete a Phase 1a/2b trial of the drug. UOW researchers continued to provide advice to FivepHusion during the conduct of this trial. R David Ranson, Chairman of FivepHusion, stated: “I see the out-licensing of this drug by the University to Fivephusion Pty Ltd as a great success overall, and an excellent model for the transfer of future research projects to industry in general. It has enabled a smooth transition of this technology into the private market, whilst still retaining a fair share of any eventual commercial returns for the University.”
Phase II trials are planned to satisfy regulatory requirements for fast track registration of the drug with the US FDA and other regulatory agencies. FivepHusion engaged local pharmaceutical business development consultants Bio-Link Pty Ltd, to assist with seeking funding for this phase 2 trial and subsequent registration and commercialisation of the drug. Bio-Link are presently in discussions with several listed pharmaceutical companies in Australia and overseas about this opportunity.
FivepHusion also presented the drug and clinical trial findings at several international biotech investment conferences and are also advising other UOW researchers on commercialization pathways and requirements. Ranson, FivepHusion stated: “As far as impact goes, this project has cemented clinical trial development and management expertise in Wollongong, as well as pharmaceutical business development and regulatory requirements skills. These are already being used to advise other early stage research projects at the University - guiding commercialisation and fund-raising efforts… I've also been invited to provide guidance to other start-ups by our industry organisation, AusBiotech.”
A strong liaison between the research team and the community led to philanthropic funding from Illawarra Cancer Carers (who donated over $500k towards development/testing of this drug), Tour De Cure, the Robert East Memorial-Kiama Rotary, Wollongong Centrelink and individual donors, which accelerated development and testing of Deflexifol.
The Centre for Oncology Education and Research Translation (CONCERT) was established in 2014 with UOW and IHMRI as Institutional partners and UOW's Prof Ranson as an Executive Member. In this role Prof Ranson is Chair of the T1/T2 Working Research Committee which aims to improve the implementation of early research findings into the clinic.
Through this position, Prof Ranson and CONCERT have been able to build translational research capacity in the local region. For example, the Biomarkers in Gastrointestinal Cancer project evaluated clinical biomarkers in gastrointestinal cancers, to improve treatment approaches that are personalised to the individual patients. Only limited research capacity and operational service provisions for gastric cancer biomarkers existed at Wollongong Hospital before commencing this program in 2014 with CONCERT Translational Cancer Research Centre funding. To ensure adequate patient recruitment, this project opened recruitment in 4 cancer centers across 3 health districts (including Illawarra Shoalhaven Local Health District), strengthening local research links between cancer clinicians in these hospitals.
Through the processes and collaborations described above, there is now a fully developed process for routine patient sample collection and analysis within the Illawarra, with firm research links established to other clinical and academic institutes in NSW. This increased capacity will facilitate ongoing translational projects in cancer research and accelerate knowledge generation among translational cancer researchers and clinicians.
- Cancer patients: Improved treatment outcomes with fewer side effects
- Clinicians/Researchers: Improved translational research capacity and clinical trial practice in the local community and in Australia generally
- Start-up biotech company: Enabled economic benefits for a local start-up company
Approach to Impact
Summary of the approaches to impact
Our strategy focuses on the translation of research for the wider community and improved quality of life. As part of this strategy to translate fundamental research into the clinic, UOW has strategically appointed joint academic/clinical positions to foster translation. We also have an active and efficient legal team that supports researchers with development of patents and intellectual property. Our major research Institute, Illawarra Health and Medical Research Institute, a joint initiative between UOW and ISLHD, further enhances our strategic approach and capacity to translate fundamental research to the clinic, especially to the benefit of local communities. UOW engagement with the local community such as Illawarra Cancer Carers further supports our approach to impact.
Approach to Impact
The UOW mission is to be a global leader in discovery and learning, working to transform people and the world we live in. As part of this mission, one of our strategic goals is to engage with our networks of academic and community partners to ensure that our research contributions are effectively disseminated and have impact at regional as well as global levels. To achieve this our approach is to link academic and clinician researchers around common health and medical issues, so that research findings can be rapidly translated into clinical innovation and practical improvements to health services which will improve the health of communities in the Illawarra region and beyond. As described in Part A this approach allowed for an area of research to be developed locally from basic fundamental research through to drug development, preclinical testing and clinical trials.
UOW has a strong fundamental research program in the biomedical sciences, providing a strong future pipeline of translational opportunities. Fundamental research is supported by Faculty and UOW Grant Programs. The research described in the impact case study was initially supported by UOW Cancer Research Grant (pre-clinical evaluation of innovative formulations of anti-cancer agents). This support for collaborative fundamental research provided foundation data that led to the successful NHMRC Development Grant by this team and subsequent innovation and clinical translation.
Similarly, UOW Research Partnership Grants support our researchers to take their first steps into industry engagement. A study of the effects of fish oil on reducing aggressive behaviour among prison inmates was seeded by a UOW internal grant in 2011 with a single non-university partner (NSW Correctional Services). It has since grown into a successful 2015 NHMRC Partnership Project Grant with three major industry/government partners and $500K partner cash support.
We provide strong intellectual property and legal support that facilitates the transition of innovation into patents. The Innovation and Commercial Research (ICR) unit is responsible for technology transfer activities at UOW. ICR assisted with the IP protection and commercialisation of Deflexifol (then known as Fluorodex). Provisional patent applications covering the Fluorodex formulation was filed in the USA in 2007. The PCT application entered National Phase in September 2009 in six jurisdictions (US, CA, EP, CN, IN, & AU) and UOW paid for the provisional and PCT applications as well as the national phase costs.
We provide support for generating start-up companies. A UOW start-up company (through ICR), Warrapharm Pty Ltd, was created in Feb 2009 to commercialise the fluorodex technology. UOW agreed to grant Warrapharm an exclusive world-wide licence to exploit the technology. Warrapharm wound up in 2011 and UOW out-licensed the drug to FivepHusion P/L who now has an exclusive world-wide licence to exploit the technology.
The Illawarra Health and Medical Research Institute (IHMRI) was established in 2008 and is a joint initiative of UOW and the Illawarra Shoalhaven Local Health District (ISLHD). Reflecting this partnership, IHMRI provides an independent medical research environment to bring academics and clinicians together to solve broadly relevant health problems and foster a research culture in ISLHD, which is traditionally a non-research environment.
Development of relationships between the two organisations (IHMRI/ISLHD) has increased capacity to conduct research such as the clinical trials in the impact case study. IHMRI incorporates both academic and clinical leadership including for each of the three major research themes. This has allowed the development of collaborative partnerships between academic and clinician researchers such as Clinical Psychiatrist Prof Nagesh Pai and academic researchers Profs Xu-Feng Huang and Chao Deng, whose collaborative research showed that betahistine, a drug prescribed for common vestibular disorders such as vertigo, could be combined with the current schizophrenia treatment, olanzapine, to significantly decrease appetite and reduce weight gain by up to 45 per cent in an animal model.
Research grants through the IHMRI Clinician-Led Research Grant Program and the IHMRI Collaborative Clinician: Academic Grant Program further support clinician/academic researcher collaborations, empowering clinician researchers to undertake translational research projects, whilst also building clinician research capacity. For example, IHMRI funded the translation of the above mentioned fundamental research into betahistine to a local clinical trial in the Illawarra with ISLHD psychiatrists, (Pai N, Deng C, Lal S, Malesu R, Mullan J, Huang XF. 2011. The efficacy of betahistine in attenuating olanzapine-induced body weight gain in antipsychotic- naive patients: a placebo-controlled pilot study).
Furthermore, an IHMRI Collaborative Research Grant between Dr Bruce Ashford (cancer surgeon in the Illawarra) and Prof Marie Ranson on “Understanding the molecular and genetic changes that lead to metastasis in cutaneous squamous cell carcinoma (cSCC)” in 2014 has allowed Dr Ashford to lead a translational research project, whilst also enabling Dr Ashford to enrol in a PhD program, under the supervision of Prof Marie Ranson.
Clinical staff embarking on postgraduate degrees fosters translational research and builds clinical research capacity in the Illawarra region, for example, Dr Daniel Brungs, Oncology Staff Specialist, is undertaking a PhD at UOW and is providing on site recruitment and support for Phase II clinical trials for Deflexifol. This approach is further fostered through the Graduate Medical School established at UOW in 2007, which recruited local clinicians (including Prof Clingan) to establish its teaching program, which has flowed on to clinicians collaborating with academic researchers to further support this translational approach.
1. Locke JM, Stutchbury TK, Vine KL, Gamble AB, Clingan PR, Bremner JB, Ranson M. 2009. Development and assessment of novel all-in-one parenteral formulations with integrated anticoagulant properties for the concomitant delivery of 5-fluorouracil and calcium folinate. Anti-Cancer Drugs 20:822-831
2. Stutchbury TK, Vine KL, Locke JM, Chrisp JS, Bremner JB, Clingan PR, Ranson M. 2011. Preclinical evaluation of novel, all-in-one formulations of 5-fluorouracil and folinic acid with reduced toxicity profiles. Anti-Cancer Drugs 22:24-34.
3. Watson CA, Vine KL, Locke JM, Bezos A, Parish CR, Ranson M. 2013. The antiangiogenic properties of sulfated B-cyclodextrins in anticancer formulations incorporating 5-fluorouracil. Anti-Cancer Drugs 24:704-714.
4. Ackland S, Garg M, Ranson M, Jokela R, Reynolds G, De Souza P, Clingan P. 2016. Pharmacokinetics of Deflexifol: A novel formulation of 5-fluorouracil and Leucovorin in a Phase 1 trial. Poster Presentation. Sydney Cancer Conference.
5. Bremner JB, Clingan P, Stutchbury T, Locke JM, Hadi S, Gamble AB, Mbere JM, Ambrus JI. 2008. Patent Number: WO/2008/106721, compositions and methods for delivery of anti-cancer agents.
6. Clingan P, Ackland S, Ranson M, Brungs D, Aghmesheh M, Tafreshi A, Garg M, Parker S, Henderson A, Jokela R, De Souza P. 2017;Deflexifol (a novel formulation of 5FU): Phase 1 dose escalation study of infusional and bolus schedules after failure of standard treatment. Journal of Clinical Oncology 35 (suppl; abstr 2529).
7. Ackland S, Garg M, Ranson M, Jokela R, Brungs D, Aghmesheh M, Tafreshi A, Ranson R, Parker S, De Souza P, Clingan P. 2017. Deflexifol (a novel formulation of 5FU): Pharmacokinetics in a phase 1 trial in comparison to 5FU. Journal of Clinical Oncology 35 (suppl; abstr 2530).
8. Clingan P, Ackland S, Brungs D, De Souza P, Aghmesheh M, Garg M, Ranson R, Parker S, Jokela R, Ranson M. A Phase I trial of infusional and bolus schedules of Deflexifol, a novel 5-fluorouracil and leucovorin formulation, after failure of standard treatment. 2018 Under Review by Cancer Medicine.
9. Ranson RD, 2017 Deflexifol - A new standard for fluoropyrimidine therapies. Presentation at Biotech Showcase, San Francisco.
10. Ranson RD, 2107 Deflexifol - An improved chemotherapy. 2017 Presentation AusBiotech Asian Event Series, Shanghai.