Drugs developed at the ACSRC

Amsacrine

The anti-leukaemia drug amsacrine was the first drug of its kind to be successfully trialled. Amsacrine is a topoisomerase II inhibitor, which intercalates into DNA and causes cell death. It became available for the treatment of leukaemia in adults in 1983 and is still used in chemotherapy for acute leukaemia and malignant lymphomas today.

Find out more on Amsacrine.

Since amsacrine, four further topoisomerase inhibitors have been developed to clinical trial by the ACSRC in collaboration with various partners: asulacrine (Sparta Pharmaceuticals Inc), DACA/XR-5000 (Xenova Ltd), XR-11576 (Xenova Ltd) and MLN-944 (Millennium Pharmaceuticals Ltd, subsequently shown to be a potent transcription inhibitor). DACA/XR5000 reached Phase II clinical studies, but did not progress.

Vadimezan (DMXAA)

Vadimezan targets and disrupts the immature vasculature of solid tumours, limiting their blood supply and thus survival. It was initially trialled at Auckland Hospital, New Zealand, and Mt Vernon Hospital, UK, in 2000. Phase II trials were conducted by Antisoma in NZ and Europe with positive results. Antisoma on-licensed the drug to Novartis in 2007, who carried out world-wide Phase III trials in non-small-cell lung cancer, the first patients of which were enrolled in Auckland. Unfortunately, vadimezan eventually failed Phase III trials. Vadimezan was subsequently shown to activate the stimulator of interferon genes (STING) protein in mice, and to thereby enhance anti-tumour immunity, but is not effective against human STING.  

Learn more about Vadimezan.

Canertinib (CI-1033)

Canertinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. It was the first irreversible kinase inhibitor to enter clinical trial. The ACSRC developed this drug in collaboration with Pfizer (Ann Arbor, USA), commencing clinical trial in 2000. Development of canertinib was discontinued at the end of Phase II, however the approach pioneered by canertinib has become a template for further development of irreversible kinase inhibitors. Several analogues from different companies have been developed. Of these, afatinib (Gilotrif) was FDA approved in 2013, osimertinib (Tagrisso) in 2015 and dacomitinib (Vizimpro) in 2018 as treatments for non-small cell lung carcinoma (NSCLC).

Learn more on:

• Canertinib
• Pfizer

Dacomitinib (PF-00299804)

Dacomitinib, an optimised analogue of canertinib, was developed by the ACSRC in partnership with Pfizer. The results of a large Phase III trial (ARCHER 1050) in 2017 were positive and the drug gained global approval for the front-line treatment of mutant EGFR-positive NSCLC in September 2018.

Read more about Dacomitinib.

PR-104

PR-104 is a prodrug linked to a potent DNA cross-linking agent (an aniline mustard). It undergoes bioreduction in the hypoxic areas of tumours to become active. PR-104 underwent phase I/II clinical trials, including in solid tumours, advanced acute myeloid leukaemia and acute lymphocytic leukaemia, through the University of Auckland start-up company Proacta Inc. This study demonstrated responses in some patients, but subsequent studies in the ACSRC demonstrated that it was also activated by the enzyme aldoketoreductase 1C3 (AKR1C3) under oxic conditions. Subsequent research has focused on discovery of prodrugs that are more selective for either AKR1C3 or hypoxia.

Learn more on PR-104.

Tarloxotinib Bromide

Tarloxotinib (targeting low oxygen – nib) is a hypoxia-activated irreversible inhibitor of the epidermal growth factor receptor (EGFR) family which are mutated or overexpressed in many cancers. It is the first hypoxia-activated kinase inhibitor to enter human clinical trial. It is currently undergoing Phase II trials for non-small cell lung carcinoma patients harbouring exon 20 insertion mutations in EGFR through partnership with the start-up company Rain Therapeutics.

Learn more on:

• Tarloxotinib
• Rain Therapeutics