AZ hoping its prostate cancer drug will succeed where Abbott's failed

ZD4054 is a small molecule drug designed to combat prostate cancer tumours that have become resistant to hormone treatment. It is about to enter the final phase of clinical development and if it is eventually approved, it would be a real breakthrough for patients. Although the drug did not meet the primary endpoint of progression-free survival in its Phase II trial, it did extend overall survival by 45 per cent compared to placebo (24.5 months compared to 17.3 months), and AZ is pushing ahead with a Phase III programme. The data from the proof of concept trial were presented at this week's European Congress of Clinical Oncology (ECCO) meeting in Barcelona, Spain. It is only three years since chemotherapy - Taxotere (docetaxel) - was first proved to have any effect in prostate cancer but its usefulness is still limited. It remains the only option for late-stage, metastatic disease though and life expectancy at this stage is only two years at most. "Once a patient has been classed as needing hormonal treatment, it is inevitable they will become hormone resistant, although how long that takes varies a great deal"​ said Dr Tom Morris, medical science director at AstraZeneca. "Although there are a lot of options, nothing has been shown to control the disease in the same way as first-line hormonal treatment. A lot more research needs to be done in this area as these men do need more options,"​ he continued. ZD4054 inhibits the endothelin A receptor (ETAR), which not only acts as a very potent vasoconstrictor in the vascular system, it has also been shown to independently promote the growth and spread of tumours (metastasis), the growth of new blood vessels (angiogenesis) and also stimulate osteoblasts - which can cause aberrant new bone formation. When targeting this receptor, it is important not to also block the related endothelin B receptor (ETBR), as this protein stimulates cell death (apoptosis) in tumours. Abbott's Xinlay (atrasentan) also inhibited ETAR, but the US Food and Drug Administration (FDA) refused to approve the drug following lukewarm trial results and its current status is unknown. Although the reasons it failed are not known for certain, it did bind to ETBR albeit not as strongly as it stuck to ETAR. "Whereas that drug could be described as 'selective', ours is 'specific',"​ Morris told DrugResearcher.com. So far, AZ has seen "no detectable effect"​ of ZD4054 on the B receptor, he explained, leading them to believe that if it does bind to it at all, it must attach itself at least 10,000 times more strongly to ETAR. He added that another Phase II trial, expected to finish by the end of this year, is looking at the drug in combination with placebo. The news that another drug is entering Phase III trials will come as a boost for the 670,000 patients diagnosed with prostate cancer every year. It is estimated that 221,000 people die from the disease annually. Professor Nick James from the University of Birmingham was the principal investigator in the Phase II trial of ZD4054. He explained that the study looked at two different doses of the drug - 10mg and 15mg - and that, perhaps surprisingly, it was the lower dose that had the greater effect. The 15mg dose extended survival by a month less than 10mg - still an increase of 35 per cent over placebo. "The fact that the substantial increase is seen in both arms of the study suggests this wasn't a fluke,"​ he said. Prof. James went on to say that perhaps the reason why no improvement in progression free survival was seen was down to the trial design. It is difficult to quantify progression and there is no 'standard' trial design. In the case of ZD4054, the definition of progression in the study did not include worsening on a bone scan or levels of prostate specific antigen (PSA). Although this might seem an unusual decision, he explained that cancer both destroys bone and initiates other reactions which case new bone to grow, so it is difficult to work out which bone processes are due to the cancer. For example, more cancer could lead to more bone damage and therefore an increase in bone repair processes or less cancer could also lead to the same result as the body has more opportunity to affect repairs once the cancer is under control. He also explained that since the drug is modulating the behaviour of the cancer, rather than seeking to cure it, the age old technique of using the maximum tolerated dose might not be applicable. Finally, he pointed out that analyses of the drug's effect have shown it may work better on cancer in the bone rather than in soft-tissue, which would make it more useful as a late stage treatment of several cancers where bone metastasis is one of the main drivers of death. These two drugs are believed to be the only two that have targeted the A receptor for the treatment of cancer. Spectrum Pharmaceuticals do have a anticancer drug, SPI-1620, that targets ETBR, utilising its vascular dilation effects as a means to deliver more chemotherapy drugs to the tumour. SPI-1620 is currently in Phase I clinical trials. Verus sells paediatric asthma programme ​ In other news, earlier this week AstraZeneca agreed to pay up to $310m (€220m) for Verus Pharmaceuticals paediatric asthma development programmes. The deal includes the North American rights to Captisol enabled budesonide solution, a short-acting beta agonist solution and, thirdly, a customised version of eFlow, a nebuliser delivery device. Other intellectual property and related assets were also included.