Proacta Inc, a San Diego based biotechnology company, and Yakult Honsha Co. Ltd, a leading Japanese company focused on the development and marketing of pharmaceuticals, foods, beverages, and cosmetics, today announced that the two companies will be working together in the ongoing research, development and commercialization of PR-509, a hypoxia-activated pro-drug for the treatment of cancer.

By targeting and killing hypoxic tumor cells, researchers hope to dramatically improve the outcome of patients with various forms of cancer. The compounds being studied are designed to be activated and converted to active cancer drugs in areas of tumors that are hypoxic.

Hypoxia-activated irreversible multi-kinase inhibitor
PR-509 is Proacta’s proprietary hypoxia-activated irreversible multi-kinase inhibitor discovered at the Auckland Cancer Society Research Centre (ACSRC), University of Auckland, New Zealand.

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 the use of higher doses. PR-509 utilizes an irreversible MKI that is activated only in areas of severe hypoxia, a characteristic of most solid tumors. Localized release of the irreversible MKI leads to higher concentrations in the tumor relative to normal tissues, which should result in improved efficacy and fewer side effects. In addition, irreversible MKI inhibitors are not subject to some of the resistance mechanisms applicable to reversible MKI inhibitors.

Clinical trials
The drug candidate is currently targeted for development in non-small cell lung cancer resistant to reversible tyrosine kinase inhibitors such as erlotinib and /or gefitinib, where an effective treatment has yet to be established. In addition to NSCLC, Proacta expects to evaluate PR-509 in other cancers such as gastric, breast, and pancreatic that are currently treated with first-generation reversible tyrosine kinase inhibitors.

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“We have worked diligently to arrive at this significant agreement with Yakult and we are very pleased to announce its execution,” said John C. Gutheil, MD, Proacta’s CEO. “This achievement underscores the commitment that our two companies have to a long-term, mutually rewarding relationship. It also exemplifies the ability of Proacta to leverage relationships with pharmaceutical partners to foster the likelihood of market success for its proprietary line of hypoxia-activated pro-drugs. We view this partnership with Yakult as further validation of the hypoxia-activated pro-drug platform and its potential as a novel therapeutic agent for patients suffering from cancer.”

Mr. Shigeyoshi Sakamoto, Head, Pharmaceutical Division/ Managing Director, Member of the Board of Yakult, said, “We are delighted to have reached an agreement with Proacta regarding their PR-509 for the research, development, and commercialization in Japan. The unique mechanism of action and well-developed preclinical data provide Yakult with the confidence necessary to join with Proacta in completing the preclinical and early clinical studies in the US in a collaborative manner. This collaboration should allow us to more quickly bring promising new treatments to patients suffering from cancer. We look forward to our work with Proacta through the collaborative research and development of PR-509.”

Other oncology trials
Proacta is also conducting a phase II study of PR-104, a hypoxia activated alkylator, in patients with relapsed or refractory leukemia. PR-104 is a bioreductive prodrug that is activated to a toxic DNA cross-linking agent (aniline mustard or [N,N-di-(2-Chloroethyl)-aniline]) in the hypoxic (oxygen-deprived) areas of tumors which contribute to its cytotoxicity.

Earlier this month Proacta announced a new Phase I/II trial of PR104 in Acute Myeloid Leukemia (AML). This study is designed to evaluate PR104 in patients with refractory/relapsed AML, and determine a range of optimal individualized doses based on a patient’s important prognostic factors. At the same time, the company announced the closure of a randomized phase II trial of PR104 in Non-Small Cell Lung Cancer (NSCLC), and one in patients with Hepatocellular carcinoma (HCC). The trial in patients with NSLC evaluated the combination of PR104 with docetaxel in patients with relapsed/refractory NSCLC. This trial failed to demonstrate sufficient efficacy for the PR104/docetaxel combination to justify further development. The trial in HCC evaluated the toxicity of PR104 when combined with sorafenib. In this trial the combination of PR104 and sorafenib was not sufficiently well tolerated.

For more information:
PR-104 in Treating Patients With Refractory/Relapsed Acute Leukemia.
PR-104 and Docetaxel or Gemcitabine in Treating Patients With Solid Tumors.

– Denny WA Hypoxia-activated prodrugs in cancer therapy: progress to the clinic. Future Oncol. 2010 Mar;6(3):419-28.
– Gu Y, Atwell GJ, Wilson WR. Metabolism and excretion of the novel bioreductive prodrug PR-104 in mice, rats, dogs, and humans. Drug Metab Dispos. 2010 Mar;38(3):498-508. Epub 2009 Dec 17.
– Gu Y, Guise CP, Patel K, Abbattista MR, Lie J, et al. Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice. Cancer Chemother Pharmacol. 2010 May 15. [Epub ahead of print]
– Guise CP, Abbattista MR, Singleton RS, Holford SD, Connolly J, Dachs GU, et al. The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3. Cancer Res. 2010 Feb 15;70(4):1573-84. Epub 2010 Feb 9.
– Jameson MB, Rischin D, Pegram M, Gutheil J, Patterson AV, Denny WA, Wilson WR. A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors. Cancer Chemother Pharmacol. 2010 Mar;65(4):791-801. Epub 2009 Dec 10.

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