Local cancer drug approved for first clinical trial in United States and New Zealand
30 August 2012
The US Food and Drug Administration (FDA) has granted approval for PR610, an anticancer “stealth” drug invented in New Zealand, to move forward to human clinical trials through its approval of an Investigational New Drug (IND) Application for the drug.
The first clinical trial, a phase I/II study, will be conducted at Auckland City Hospital, Waikato Hospital and sites in the United States.
Patient enrolment is expected to commence in the coming weeks. Initially, the trial will recruit small groups of study-eligible patients to different dose levels of PR610 followed by monitoring of its side-effects, blood levels and anti-tumour activity.
PR610 belongs to an exciting new class of hypoxia-activated pro-drugs for the treatment of cancer, designed by Dr Jeff Smaill and Dr Adam Patterson from the Auckland Cancer Society Research Centre (ACSRC) and Maurice Wilkins Centre for Molecular Biodiscovery.
It is licensed to Proacta Incorporated, a San Diego based biotechnology company that last year engaged in the collaboration for research, development, and commercialisation of PR610 in Japan with Yakult Honsha Co., Ltd. (Tokyo: 2267). Proacta announced today that the IND had been approved, allowing this novel first-in-class treatment to enter human trials.
Initial development of PR610 will focus on patients with non-small cell lung cancer who have become resistant to reversible tyrosine kinase inhibitors such as erlotinib and /or gefitinib. Currently there is no effective treatment when these patients relapse. The phase I part of the phase I/II trial will investigate suitable doses in patients with solid tumours, before moving on to focus on patients with this type of cancer in the phase II part of the trial.
PR610, which specifically targets low-oxygen (hypoxic) regions in tumours, has shown promising activity in the laboratory. “The tumour dose intensity achieved by this hypoxia targeting technology results in striking anti-cancer activity,” says Dr Smaill. “We were particularly impressed when we compared PR610 to existing clinical candidates,” adds Dr Patterson. “Only PR610 was able to shrink the drug-resistant lung cancer models.”
“PR610 will be the second novel hypoxia prodrug from the Auckland Cancer Society Research Centre to be taken to clinical trial by Proacta, and speaks to the continued innovation achieved by our staff in cancer chemotherapy,” says ACSRC Co-Director Distinguished Professor Bill Denny.
“It’s especially pleasing to see clinical trials of new drugs being held in New Zealand,” says John Loof, CEO of the Cancer Society Auckland Division. “Local patients can be some of the first involved in furthering our understanding of how these targeted medicines can make such a difference. Cancer Society donors and supporters can feel well satisfied that they have underpinned yet another exciting step forward in cancer medicine.”
“This exciting new therapy ushers in a new era of personalised medicine in New Zealand. For the first time we will be screening patients for the genetic mutation that causes drug resistance and then enrolling them in a trial of a New Zealand drug designed to target that mutation,” says ACSRC Co-Director, Associate Professor Mark McKeage, the Clinical Oncologist leading the Auckland City Hospital trial, referring to the phase II part of the phase I/II trial.
“Our scientists are inventing drugs at the forefront of the international fight against cancer,” says Professor Rod Dunbar, Director of the Maurice Wilkins Centre. “The progression of this first-in-class cancer drug to clinical trials is a great credit to New Zealand and offers further hope for our cancer patients.”
Auckland Cancer Society Research Centre
The Auckland Cancer Society Research Centre (ACSRC) was established in 1956 by the Auckland Cancer Society. Based in the Faculty of Medical and Health Sciences at The University of Auckland, the ACSRC is regarded internationally as one of the world's leading anti-cancer drug development laboratories. The Centre houses over 80 scientists dedicated to discovering new treatments to help improve the lives of patients diagnosed with cancer.
PR610 is a hypoxia-activated irreversible multi-kinase inhibitor discovered at the ACSRC. Reversible multi-kinase inhibitors (MKI) are currently in use for the treatment of several types of cancer. However, resistance often develops to reversible MKI’s. In addition, reversible MKI’s have side effects that limit their use at higher doses. PR610 utilizes an irreversible MKI that is activated only in areas of severe hypoxia, a characteristic of most solid tumours. Localised release of the irreversible MKI leads to higher concentrations in the tumour relative to normal tissues, which should result in improved efficacy and fewer side effects. In addition, irreversible MKI’s are less susceptible to some of the resistance mechanisms that limit use of reversible MKI’s. In subsequent studies, PR610 will be evaluated in other cancers such as gastric, breast, and pancreatic, conditions that are all currently treated with first-generation reversible tyrosine kinase inhibitors.
PR610 research team
A multidisciplinary team of scientists at the ACRSC collaborated to discover and develop PR610. Medicinal chemistry was led by Dr Jeff Smaill, with drug design and synthesis performed by Drs Guo-Liang Lu, Ho Lee and Amir Ashoorzadeh. Cancer biology and lead discovery was led by Dr Adam Patterson with Drs Maria Abbattista, Steve Jamieson and Jagdish Jaiswal supporting the biological evaluation of drug analogues. Radiation chemistry was performed by Associate Professor Robert Anderson and Dr Andrej Maroz. Technical support was provided by a large team including Kendall Carlin, Sisira Kumara, Alexandra Mowday and Denis Simonov. Drs Jeff Smaill and Adam Patterson, Professor Bill Denny and Associate Professor Mark McKeage are all Maurice Wilkins Centre investigators.
Proacta is a San Diego based biotechnology company dedicated to the development and commercialization of hypoxia-activated oncology drugs. Proacta has a pipeline of hypoxia-activated prodrugs that it is developing for the treatment of cancer and which are licensed to them from the University of Auckland in New Zealand.
Yakult is a leading Japanese company focused on the development and marketing of pharmaceuticals, foods, beverages, and cosmetics. With respect to its pharmaceutical business, Yakult has an emerging presence in oncology.