The Oncology Drug Advisory Committee ( ODAC ) to the U.S. Food and Drug Administration ( FDA ) did not recommend approval of the oral investigational agent Xinlay ( Atrasentan ) for the treatment of patients with hormone-refractory prostate cancer ( HRPC ) that has spread to the bone.

" Eighty-five percent of the men with hormone-refractory prostate cancer have disease that spreads to the bone," said Joel Nelson, at University of Pittsburgh School of Medicine. " Debilitating bone pain is the cardinal symptom of this stage of the disease and there are currently limited choices to delay this in men."

Xinlay is an investigational, oral, once-daily, non-hormonal, non-chemotherapy, agent that belongs to a class of compounds known as selective endothelin-A receptor antagonists ( SERA ).
SERAs antagonize the effect of endothelin-l ( ET-l ), one of the proteins thought to be involved in the stimulation of the growth and spread of cancer cells.

Abbott Laboratories submitted a New Drug Application ( NDA ) in December 2004 seeking approval.
The NDA for Xinlay supplied data on time to disease progression and delay in time to onset of bone pain.

U.S. Food and Drug Administration staff report did not find clear evidence of effectiveness for Abbott Laboratories’ experimental prostate cancer drug, Xinlay.

The FDA reviewed design, efficacy and safety of two randomized studies of Xinlay for men with metastatic, hormone-refractory prostate cancer.
One of these studies is a phase III study ( M00-211 ) and the other is a phase II study ( M96-54 ).

Xinlay seems to be associated with severe adverse effects.
There were more deaths on the Atrasentan arm ( n=166, 41% ), compared to the placebo arm ( n=158, 39% ) on the phase III study. This arm also had more deaths from cardiovascular causes ( Atrasentan N=8; placebo N=2 ).
Atrasentan is known to cause congestive heart failure ( CHF ) from previously performed Phase II trials.
In phase III study an increase in number of arrhythmias and cardiovascular events ( myocardial infarction, angina pectoris and stent placements ) was observed on the Atrasentan arm in addition to an increase in CHF ( Atrasentan 40%, placebo 13% ).
Twenty patients on the Atrasentan arm experienced 24 arrhythmia events, and 5 patients on the placebo arm were reported to have 5 events of arrhythmias.
Six patients on the Atrasentan arm had grade 3 or 4 coronary artery disease ( CAD ) toxicity ( myocardial infarction, angina pectoris or stent placement ) as opposed to 2 patients on the placebo arm with grade 3 or 4 toxicity.

" Abbott respects the committee's vote on Xinlay; however, we continue to believe that Xinlay represents an important option for patients with advanced prostate cancer who currently have limited options," said Eugene Sun, vice president, Global Pharmaceutical Clinical Development, Abbott. " The company is encouraged by committee member statements regarding the activity of Xinlay and the value of continuing development of the drug. We await FDA's decision on Xinlay."

Xinlay is being studied in earlier stage prostate cancer patients in an ongoing Phase III study in hormone-refractory prostate cancer patients without metastasis. This study to expected to be completed in 2006.

Source:

1) FDA, 2005

2) Abbott Laboratories, 2005


XagenaMedicine2005