Out-licensing

Phase I Clinical Development of PX-478 for the Treatment of Cancer: A Small Molecule Inhibitor of Hypoxia-inducible Gactor (HIF)-1 Alpha

Introduction/Background

HIF-1a is a component of a transcription factor, hypoxia inducible factor (HIF-1). The levels of HIF-1a are elevated in a wide variety of human tumours, including brain, bladder, pancreatic, prostate, ovarian, colon, breast, and kidney cancers. HIF-1a is an important regulator of tumour response to certain stress factors. Under stress conditions, e.g. tumour hypoxia, the regulatory breakdown of HIF-1a protein is inhibited, resulting in HIF-1 induced increase in angiogenesis and glycolytic metabolism as well as resistance to apoptosis. HIF-1a levels have been shown to correlate with tumour grade and vascularity and are considered a marker of highly aggressive disease. Elevated HIF-1a levels are linked to poor prognosis and treatment failure in a number of cancers.

Aims/Hypothesis

We are developing a novel agent for the treatment of cancer.

Results

PX-478 is a small molecule HIF-1a inhibitor with outstanding market potential. PX-478 decreases both HIF-1a gene expression and protein synthesis, resulting in a significant reduction of HIF-1a in tumour tissue. PX-478 is highly specific for HIF-1a.This inhibitory effect is independent of the tumour suppressor genes VHL and p53.

PX-478 has been shown to have efficacy against a number of human cancer xenograft models, with significant regressions and growth delays in OvCar-3 (ovarian), SHP-77 (small cell lung), PC-3 (prostate), DU-145 (prostate), MCF-7 (breast), and Caki-1 (renal). PX-478 suppresses constitutive and hypoxia induced levels of HIF-1a in cancer cells, while leaving other ubiquitin regulated proteins unaffected. Through HIF-1a inhibition , PX-478 inhibits the expression of VEGF and the glucose transporter Glut-1, resulting in massive tumour apoptosis When tumours (xenograft models in mice) are being treated with PX-478, the efficiency of tumour killing correlates with inherent tumour HIF-1a expression. PX-478 is highly water soluble and is effective when administrated orally. PX-478 decreases tumour vascular permeability in a xenograft model. PX-478 potentiates the effect of radiation in xenograft models and has shown synergistic anti-tumour effect with Avastin (bevacizumab).

PX-478 is effective in a preclinical model of human lung cancer. The study employed a model of lung cancer in mice, which closely mimics the disease in humans. Treatment with oral PX-478 for five days resulted in significant inhibition of tumour growth, marked reduction in lymph nodes metastases, decreased volume of pleural effusions, and significantly improved survival. PX-478 was effective in models of both non-small cell lung cancer and small cell lung cancer that express HIF-1 alpha.

PX-478 has been shown to enhance the antitumour effects of radiation therapy in preclinical models of pancreatic and brain cancer. The data demonstrate that PX-478 enhances the effect of radiation therapy in xenograft models of both glioma, a form of brain cancer, and pancreatic cancer.

A multi centre Phase 1 trial is being conducted in the US in patients with advanced metastatic cancers (solid tumours or lymphoma) that have failed conventional
therapy. The trial is a single arm dose escalation study with PX-478 administered orally on days 1 to 5 of a 21 day cycle. Primary endpoints are determination of the maximum tolerated dose, safety profile, pharmacokinetic profile, and pharmacodynamic effects of the drug on the HIF-1a pathway and related tumour markers. Enrolment is expected to be completed in 2008. Other trials will initiate in 2008.

Conclusion

PX-478 is currently in phase I clinical development at two major US cancer centres. The clinical development plan includes use as a stand alone therapy in a number of major cancers, as well as combination therapy. The drug is being developed as an oral formulation.

Relevance/Opportunity

There are currently five families of pending and issued patent cases for PX-478. One patent with claims covering PX-478 composition of matter has issued in the United States. Oncothyreon has an active development program for PX-478. We are seeking a partner with significant oncology experience to accelerate the late stage development and commercialization of PX-478.

Phase I

Talks KL, et al. The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers and tumor associated macrophages. Am J Pathol 2000; 157; 411. Zhong H, et al. Over-expression of hypoxia-inducible factor 1α in common human cancers and metastases. Cancer Res 1999; 59; 5830. Welsh SJ, et al. PX-478, a potent inhibitor of hypoxia-inducible factor-1 (HIF-1) and antitumor agent. Eur J Cancer 2002; 38; 294. Powis G and Kirkpatrick L. Hypoxia inducible factor-1α as a cancer drug target. Mol Cancer Ther 2004; 3; 647. Kojima H, et al. HIF-1 depresses cytotoxic function of T-lymphocytes and blocks B-cell development in bone marrow. Current Pharmaceutical Design 2003; 9; 1827. Mecklenburg KI, et al. HIF-1 up-regulation accompanies inhibition of neutrophil apoptosis. Blood 2002; 100; 3008.