The co-inventors of the compound TH-4000, Dr Adam Patterson and Dr Jeff Smaill, senior academics from the Auckland Cancer Society Research Centre and the Maurice Wilkins Centre, have collaborated with a NASDAQ-listed American bio-technology company, Threshold Pharmaceuticals, to advance the compound to this stage.
TH-4000 is described by Threshold as a molecular-targeted, hypoxia-activated irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that may overcome resistance to therapy from conventional EGFR-TKI compounds.
The data was reported today at the annual meeting of the American Association for Cancer Research (AACR) in Philadelphia by Drs Patterson and Smaill.
“We are grateful for the funding support from the Ministry of Business Innovation and Employment, the Health Research Council of New Zealand and the Maurice Wilkins Centre over the years,” said the co-inventors, Drs Patterson and Smaill.
In September 2014, Threshold licensed exclusive worldwide rights to a clinical development program based on TH-4000 from Auckland UniServices, the technology transfer company of the University of Auckland.
The new compound has shown positive results in limiting tumour growth in Non-Small Cell Lung Cancer (NSCLC) models resistant to conventional EGFR-TKIs.
“Certain tumour types are addicted to EGFR signalling and current EGFR-TKI therapies are ineffective in shutting down that signalling due to dose-limiting toxicities of rash and diarrhoea,” says Dr Adam Patterson, head of the Translational Therapeutics Team at the University’s Auckland Cancer Society Research Centre (ACSRC).
“At the same time, we know that these tumours are hypoxic, and that hypoxia drives the overexpression of EGFR, “he says. “Therefore, a molecularly-targeted, hypoxia-activated irreversible EGFR-TKI is expected to deliver greater efficacy with fewer side effects than available treatments.”
His co-inventor, Dr Jeff Smaill, a senior medicinal chemist at the University of Auckland, says “Leveraging knowledge that the hypoxic tumour microenvironment enhances aberrant, wild-type EGFR signalling, we designed TH-4000 to selectively release an irreversible EGFR inhibitor upon encountering tumour hypoxia.”
“Given Threshold’s expertise in developing therapies that target tumour hypoxia, it’s exciting for us to be working together on this next generation approach of combining molecular and hypoxia targeting in a single drug candidate,” he says.
Aberrant EGFR signalling is implicated in the growth and spread of certain tumour types including NSCLC and Head and Neck cancers. Clinical studies indicated that mutant EGFR-positive NSCLC with wild-type EGFR present (heterozygous) was associated with reduced response rates, progression free survival and overall survival outcomes on conventional EGFR-TKIs.
In Head and Neck cancer, wild-type EGFR signalling drives tumour growth. Both types of tumours are known to be hypoxic; thus, hypoxia-induced activation of wild-type EGFR signalling may be a mechanism of EGFR-TKI resistance.
Data from a previous Phase 1 clinical trial of patients with advanced solid tumours were also reported at the AACR. The maximum tolerated dose of TH-4000 administered as a 1-hour weekly intravenous infusion was established at 150 mg/m2.
The most common treatment-related adverse events were dose-dependent and included rash, QT prolongation, nausea, infusion reaction, vomiting, diarrhoea and fatigue.
“We believe the data presented at AACR support our clinical development plans for TH-4000 in patients with tumours that are not candidates for conventional EGFR-TKI therapy,” says Dr Tillman Pearce, Chief Medical Officer of Threshold.
“In particular, we believe the data support the development of TH-4000 in patients with mutant EGFR-positive, T790M-negative NSCLC after conventional EGFR-TKI therapy has failed as well as in patients with head and neck cancer for which EGFR over-expression is associated with worse outcomes, both of which represent a significant unmet medical need.”
“We are delighted to join forces with our friends and experts in the field of tumour hypoxia and Hypoxia-Activated Prodrug technology at the University of Auckland, and look forward to our collaborative efforts in the development of TH-4000 as a potential new therapy that has potential to overcome the limitations of currently available EGFR-TKI therapies,” says Dr Pearce.
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