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Researchers at the LKS Faculty of Medicine of the University of Hong Kong (HKUMed) have invented an oral formulation of arsenic trioxide (Oral-ATO; ARSENOL®) for the treatment of acute promyelocytic leukaemia (APL), a blood cancer with a high fatality rate. The invention and use of oral-ATO is of historic importance for medicine in Hong Kong. It is the first-ever prescription medication wholly invented and manufactured in Hong Kong, and also the first to obtain USA, European and Japanese patents. After over two decades of dedicated work, the HKU research team successfully translated this Hong Kong invention into clinical practice by incorporating oral-ATO into the treatment plan of APL patients. Extensive clinical studies of oral-ATO have demonstrated its high efficacy and safety in curing APL patients, with an overall survival (OS) rate exceeding 97%, along with a significant reduction in side-effects and treatment burden.

A Hong Kong invention of historic importance – Excellent results of oral-ATO for APL
For more than two decades, the HKUMed research team performed extensive studies on oral-ATO for APL. In a 15-year prospective follow-up study of over 400 patients with relapsed APL, oral-ATO-based treatment resulted in a 100% molecular remission rate and a five-year OS rate of 80%. These outcomes were achieved without bone marrow transplantation, a highly toxic treatment which is still used in many parts of the world that do not have access to oral-ATO.

The HKUMed research team then moved oral-ATO to the maintenance treatment of APL patients in first complete remission, resulting in a 90% five-year leukaemia-free survival (LFS) rate and a 97% OS rate. The next step was the incorporation of oral-ATO into frontline treatment of newly diagnosed APL patients, achieving 100% LFS and OS at five years. Following these studies, the HKUMed research team developed a treatment plan comprising timely treatment initiation, necessary supportive care and the frontline use of oral-ATO. This approach has reduced the incidence of early deaths related to APL complications, which in the past had a fatality rate of up to 20–30%.

The HKUMed research team is currently testing frontline treatment in Hong Kong with an entirely oral regimen comprising oral-ATO, all-trans retinoic acid (ATRA) and ascorbic acid (AAA) for APL in a risk-adapted manner.

Oral-ATO as the new standard of care in APL
According to Dr Harinder Gill, Clinical Associate Professor in the Department of Medicine, School of Clinical Medicine of HKUMed, the study’s lead investigator, the entirely oral regimen ‘AAA’ is highly effective and safe and can be administered in an outpatient setting for all risk categories of APL patients. It can minimise chemotherapy in patients at all risk levels – not just in lower-risk patients – as well as in both children and adults.

Recognition by the US FDA and the EMA
As part of the first steps in placing oral-ATO in the international arena of medicine, oral-ATO obtained orphan drug designation (ODD) from US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), as well as an investigational new drug designation (IND) from the US FDA. Oral-ATO is the first prescription anti-cancer drug invented in Hong Kong to obtain key FDA and EMA designations, which are pivotal requisites for global studies of oral-ATO.

The APL Asian Consortium
The APL Asian Consortium, led by HKUMed, brings together researchers from Hong Kong, Malaysia, Singapore and Taiwan to focus on APL research and treatment. Their first retrospective analysis demonstrated the superiority of the frontline ‘AAA’ regimen to more conventional regimens that include chemotherapy. The APL Asian Consortium is currently a platform for promoting the use of oral-ATO in these regions. The multicentre study of frontline ‘AAA’ in Asia is supported by Hong Kong’s Innovation and Technology Fund (ITF).

Globalisation of oral-ATO
Greater Bay Area (GBA) and Asia
The HKUMed researchers have teamed up with researchers in the GBA (through HKU-Shenzhen Hospital) and Asia (via National University Cancer Institute Singapore and National University Hospital, Singapore) to develop the use of oral-ATO. This multicentre research team demonstrated a three-year OS and relapse-free survival (RFS) rate of 99% and 97%, respectively.

Oral-ATO has been approved by the Guangdong Provincial Medical Products Administration (GDMPA) for clinical use in the GBA via the HKU-Shenzhen Hospital. Under the aegis of the Asian APL Consortium, oral-ATO is available for research and clinical use on APL patients in Singapore, Malaysia and Taiwan.

United Kingdom
The UK AML Research Network and the University of Cardiff, UK, in collaboration with the HKUMed research team, obtained funding from Blood Cancer UK for oral-ATO. A nation-wide Phase 3 study incorporating oral-ATO will be investigated in the frontline management of APL in the UK. This is a historic landmark for medicinal development in Hong Kong.

USA and Europe
ODDs granted by the US FDA and the EMA provide the regulatory requirements for studies of oral-ATO in the USA and Europe. The HKUMed researchers will team up with industry partners to conduct these clinical studies, which are set to commence in Hong Kong, North America and Europe this year.

APL as a curable disease
‘We take great pride in seeing our research translated into practice in Hong Kong and around the world,’ said Dr Harinder Gill. ‘The development of oral-ATO is a game-changer for APL patients. It offers a convenient and effective treatment option that can significantly improve their quality of life. We are proud to play a pioneering role in bringing this innovation to the world and are committed to ensuring that all APL patients have access to this life-saving and cost-effective therapy. In this way, we aim to make APL a curable disease for patients around the world. As doctors, this will be our greatest achievement.’

About the research team
Invention: Oral arsenic trioxide (ARSENOL®)
Inventors: Professor Cyrus Kumana, Emeritus Professor; Professor Kwong Yok-lam, Chair Professor
Current lead investigator: Dr Harinder Gill, Clinical Associate Professor
(All from the Department of Medicine, School of Clinical Medicine, HKUMed)

Acknowledgements
The research was funded by the ITF-Partnership Research Programme of the Innovation and Technology Commission of the HKSAR Government. Other collaborating parties include the Technology Transfer Office and Versitech of HKU, Jacobson Pharma Corporation, SDK Therapeutics Inc., USA, the National Cancer University Cancer Institute Singapore, National University Hospital, Singapore, the UK AML Research Network, the University of Cardiff, U.K, and Blood Cancer UK.

Media enquiries
Please contact LKS Faculty of Medicine of The University of Hong Kong by email (medmedia@hku.hk).