Threshold's hypoxia success is notable for field that has disappointed


Positive results from Threshold Pharmaceuticals’ TH-302 this week marked a rare win in hard-to-treat pancreatic cancer, as well as encouraging progress for a long-studied mechanism of action that has struggled to produce viable products.

The hypoxia-targeted agent – designed to strike at oxygen deprived regions of a tumour believed responsible for drug resistance and mutation – significantly extended progression free survival when combined with gemcitabine. The trial was small and the real test will come replicating those results in a larger study, in this and other cancers. But as one of the few hypoxia-targeting agents in clinical development, its progress will be watched with interest.

The root of resistance

Tumour hypoxia occurs as a result of the chaotic vasculature of a tumour, the fast growth of which causes an uneven distribution of blood vessels. This leads to regions deficient in oxygen and nutrients, microclimates that contain slowly dividing cells prone to mutation. Given that most cancer-killing agents target areas of fast cell division, and many drugs do not penetrate cells far removed from the vasculature, it is believed that these hypoxic zones lie at the root of resistance to chemotherapy and radiotherapies.

Highly hypoxic tumours are thought be more invasive and mestastatic and are associated with poor prognosis for survival. These regions have long been a focus of drug development although no specific hypoxia targeting agent is currently available. Niacinamide, the active form of vitamin B3 that enhances blood flow and therefore reduces hypoxia, is used as a sensitising agent for chemo and radiotherapies.

Current clinical research is mostly focused on what have been termed hypoxia activated pro-drugs, agents that are activated on reaching the low oxygen zones, leaving normal cells unharmed. Their potential is seen in combination with standard chemotherapy or radiotherapy, allowing all areas of a tumour to be targeted.

Past failures

Merck KGaA’s deal over TH-302 earlier this month marked the return of big pharma to a space that few are publically working in (Threshold brings on Merck KGaA as validation approaches, February 3, 2012). This has not always been the case, both Sanofi and Boehringer Ingelheim took agents into phase III; both were scrapped some time ago.

Boehringher’s porfiromycin, a derivative of the antineoplastic antibiotic mitomycin, made it into phase III in head and neck cancers, but was scrapped a decade ago due to lack of efficacy. Sanofi meanwhile finally abandoned tirapazamine in 2007, after disappointing results in head and neck and other solid tumours.

Another agent, AQ4N or banoxantrone, showed promise but work dwindled when owner Novacea was brought down by other clinical failures in 2008. The drug, which converted to a cytotoxic agent under hypoxic conditions, was being tested in brain cancer and other solid tumours.

Notable success

As such, Threshold’s success with TH-302 in such a hard-to-treat cancer is notable, although excitement should be tempered by the fact that pancreatic cancer is renowned for defeating promising agents in larger studies.

The trial in 214 patients produced median progression free survival of 5.6 months for patients treated with TH-320 plus gemcitabine compared with 3.6 months for gemcitabine alone. Given the lack of options in this cancer, repeating that result in phase III would be good enough for approval.

A phase III study is already ongoing in sarcoma; with Merck now shouldering 70% of the development costs this result should provide confidence to push on with a broad development programme for TH-302.

Seeking partners

One company likely to be encouraged by both Threshold’s clinical and commercial success is Proacta, a private drug developer focused on hypoxia. Its lead product, PR-104, is currently undergoing a phase I/II study in acute leukaemia. Blood cancers and bone marrow cancers are particularly hypoxic and as such are thought likely to benefit from hypoxia activated agents.

The study, seeking to recruit 50 patients, is due to complete in June this year, according to PR-104 is a pro-drug that is converted to an alkalating agent in hypoxic zones.

The company is also working on other pre-clinical agents. A hypoxia activated irreversible pan-erbB inhibitor is being tested in lung cancer, for example, while a class of compounds called hypoxia-selective multi-kinase inhibitors are also in the pipeline. According the company’s website an IND under this project was due to be filed in late 2011 although news on that has not emerged.

Partnered with Yakult Honsha in Japan on several hypoxia projects, the California company is seeking partners elsewhere.

Fading appetite?

It remains to be seen whether Threshold and Proacta will succeed where others have failed, and manage to extract efficacy from this mechanism of action. To a certain extent these attempts to exploit hypoxia should benefit from the growing attention being paid to cancer metabolism, a hot area of research right now.

Attempts to find therapeutics to target the unique metabolic pathways found in fast growing tumours will inevitably address hypoxia. Kancera, for example, is investigating inhibition of the enzyme PFKFB3, which results in decreased metabolism and cell growth in hypoxic cancer environments. Blocking the mechanisms that enable cancer cells to overcome periods of hypoxia may pave the way for new treatment strategies, the company believes, by starving and weakening the tumour cells.

These techniques are still a long way behind the hypoxia activated agents being tested by Threshold and Proacta, and may ultimately be more effective at exploiting this unique tumour characteristic. It seems likely, however, that should TH-302 and PR-104 fail, the appetite to further test this mechanism of action will fade.

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