Anti-tumour activity from Adherex

Adherex Technologies, from Research Triangle Park, NC,US, has shown in a Phase I study of the molecularly targeted anti-cancer drug, Exherin, that the drug is generally well tolerated and has shown evidence of anti-tumour activity in three patients following treatment with Exherin, including one objective "partial response," defined as a reduction of at least 50% in tumour size.

The partial response occurred in a 62-year-old woman with N-cadherin positive squamous cell cancer of the esophagus and lung metastases, which had been unresponsive to prior treatment with cisplatinum and 5-fluorouracil chemotherapy, and who was subsequently treated with Exherin. Six weeks after a single dose of Exherin, CT scans showed a 48% reduction in the size of the tumour masses in her lungs. Repeat Exherin treatments resulted in additional tumour regression reaching formal partial response criteria. The tumour regression has been sustained through five dose cycles over a four-month period.

'The data demonstrate not only that Exherin is generally well tolerated over a wide dose range but has also shown evidence of important anti-tumour activity, including an objective partial response,' said Dr William Peters, Chairman and CEO. 'Three out of 14 patients, whose tumours were either N-cadherin positive or unknown, have shown some evidence of anti-tumour activity. This finding is important when you consider these results were seen following a single dose of drug and in patients with advanced resistant disease. The objective partial response underscores the therapeutic potential of Exherin and supports our strategy of developing it as a molecularly targeted therapy. It is our belief that by focusing on patients whose tumours express the N-cadherin protein, we will be able to more effectively select appropriate patients, which will facilitate the systematic and more rapid development of this novel drug. This approach is further supported by the fact that, thus far, the cancers that do not express the N-cadherin protein have not responded to Exherin.'

Exherin has also demonstrated signs of anti-tumour activity in two other patients. In one case, a 56-year old man with an unknown primary cancer and lung metastases showed decreases of 39% and 14% in tumour masses, formally termed a mixed response, on radiologic scans six weeks following a single dose of Exherin. In a second case, a 24-year-old woman with N-cadherin positive cancer of the adrenal glands that were secreting abnormally high hormone levels, experienced a drop in these hormone levels one week after Exherin administration, with subsequent evidence of necrosis (cell death) on MRI scans. She has since received additional doses of Exherin and has shown similar reductions in the tumour biomarker hormone levels.

Dr Peters said: 'While these are important results, I must reiterate that drug development is inherently risky and uncertain, and we are still in the early stages of development with Exherin. We will continue to carefully and systematically evaluate this drug in greater numbers of patients. To complete the development more rapidly, we are now also actively recruiting patients at the M.D. Anderson site for this Phase I study, and are moving forward with Phase Ib/II studies of Exherin, which will investigate the optimal dose and schedule for using the drug. We expect to initiate the first of these Phase Ib/II studies by the end of the year.'

To date, the safety, toxicity, pharmacokinetics and maximum tolerated dose of Exherin have been evaluated in 45 treatment cycles in 29 patients with incurable solid tumours. Results thus far have demonstrated that Exherin is generally well tolerated in all seven tested doses (ranging from 50 to 840 mg/m²) with no maximum tolerated dose reached thus far. The most commonly reported side effects include mild to moderate fatigue, nausea and a bad taste in the mouth (dysgeusia) shortly after drug administration. This bad taste has dissipated quickly and has required no medical treatment.

Two patients developed transient post-infusion symptoms of facial flushing, light-headedness and chest discomfort, within one to two minutes of the rapid IV bolus administration of Exherin. These symptoms completely resolved within five minutes of drug administration, and each patient's vital signs remained stable. One of these patients also developed transient changes in her electrocardiogram (ECG). Within five minutes of drug administration, this patient's ECG returned to baseline. Both patients were given a subsequent dose of Exherin more slowly, by IV infusion over 7 to 10 minutes, and experienced none of the symptoms noted during the previous rapid bolus administration.

'We believe the facial flushing, light-headedness and chest discomfort could be related to the speed of the drug administration and may be eliminated by giving the drug more slowly. We demonstrated this approach worked in each of the patients who reported these symptoms,' said Dr Rajesh Malik, Adherex's chief medical officer. 'It's also important to note that the patient with transient ECG changes had an abnormal baseline ECG, which may indicate some pre-existing heart abnormality, and following Exherin administration, experienced no change in her levels of cardiac troponin, a chemical that increases when there is ongoing damage to the heart muscle. Finally, these transient post-infusion symptoms did not occur in these same two patients with their next treatments when the drug was administered more slowly.'

Exherin is a small peptide molecule that selectively targets N-cadherin, a protein that plays a major role in holding together and stabilising the cells that make up blood vessels and which is also present on certain tumour cells. Exherin works by mimicking the N-cadherin active site, thereby preventing cadherins from binding together. This leads to two possible anti-tumour effects: leakage and rupture of the established tumour blood vessels and tumour cell death (apoptosis). In preclinical studies, Exherin has demonstrated this beneficial therapeutic effect without any apparent adverse impact on healthy blood vessels outside the tumour.

Phase I studies are the first step in human drug development following animal-based research. These studies are typically conducted on a small number of patients and aim to evaluate a drug's safety and toxicity. In some instances, Phase I studies also provide preliminary evidence of drug activity.