Abarelix: abarelix-depot-F, abarelix-depot-M, abarelix-L, PPI 149, R 3827.

Abstract

Abarelix [Abarelix-Depot-F, Abarelix-Depot-M, Abarelix-L, PPI 149, R 3827, Plenaxis] is a peptide consisting of natural and artificial amino acids. In females, abarelix is an estrogen production antagonist with potential for the treatment of breast cancer, endometriosis and other reproductive hormone diseases. In males it is a testosterone production antagonist and has potential as hormonal therapy of prostate cancer. Depot formulations of abarelix (abarelix-depot-M and abarelix-depot-F) are being developed for hormonally responsive prostate cancer and endometriosis, respectively. Clinical development of the depot formulations is currently being conducted by Praecis Pharmaceuticals, the originators of the agent. A non-depot formulation, abarelix-L, was also being conducted for prostate gland volume reduction. Praecis Pharmaceuticals has entered into a number of licensing agreements covering abarelix. However, all agreements have since been terminated leaving Praecis to develop and commercialise the agent on its own. The terminated agreements include an agreement between Praecis and Roche for the commercialisation of abarelix in the US. This agreement was terminated in November 1998. Praecis Pharmaceuticals also entered into a collaborative agreement with Amgen in March 1999, whereby the companies would develop abarelix and Amgen would commercialise the drug in the US, Canada, Australia, Asia and several secondary markets. However, in September 2001, Praecis and Amgen announced that they were terminating the agreement for all indications. Praecis stated at the time that it remained committed to developing abarelix for both prostate cancer and endometriosis. Amgen had submitted 'Lotestrol' to the US Patent and Trademarks Office as a possible tradename for abarelix-depot-M. Lotestrol may also have been under consideration as a tradename for abarelix-depot-F. Praecis had also sold European, African, Latin American and Middle Eastern rights to abarelix to Sanofi-Synthélabo. However, in October 2001, Sanofi-Synthélabo announced that it had waived its rights to abarelix. Praecis confirmed in December 2000 that it had filed an NDA seeking FDA approval for abarelix in the US. In January 2001, the FDA granted the abarelix application priority review status. However, in June 2001, the FDA rejected the NDA for prostate cancer. The FDA requested that Praecis use existing data from the completed trials to analyse the allergic reactions that occurred in a small subset of patients. The FDA also expressed concerns over the lack of maintenance of testosterone suppression beyond the 3-month timeframe that occurred in a subset of patients. In February 2003, Praecis announced the re-submission of its NDA to the US FDA. The submission seeks approval for the use of abarelix in a defined subpopulation of advanced prostate cancer patients for whom the current hormonal therapies are not appropriate. Praecis plans to submit its regulatory application in Europe during the second quarter of 2003. Following the completion of a phase I/II trial of abarelix-L in prostate gland volume reduction, a phase IIIb study of the depot formulation was initiated in September 2001. The trial is comparing the effects of neoadjuvant hormonal therapy with depot formulations of leuprorelin or abarelix for prostate gland volume reduction. Abarelix-L is no longer mentioned on Praecis' website, suggesting that development of this formulation is no longer being pursued. The Financial Times (ft.com) reported in May 2001 that approximately 12 new anti-cancer agents are expected to be approved by the FDA through to the end of 2002, with the potential to generate total sales of US dollars 2.6 billion--abarelix is one of these products. The paper quoted analysts at Salomon Smith Barney predicting that abarelix could reach sales of US dollars 120 million for the indication of prostate cancer. However, in June 2001 the FDA rejected Praecis Pharmaceuticale FDA rejected Praecis Pharmaceuticals' NDA filing; this was later re-submitted in February 2003. A year earlier, in May 2000, the Financial Times (ft.com) stated that Credit Suisse First Boston had forecast abarelix to reach peak sales of 1 billion US dollars . Other analysts, at SG Cowen, predicted annual sales of US dollars 200 million for the first 3 years; however, this could increase to 1 billion US dollars if abarelix is also approved for the indication of endometriosis. Abarelix' main competitors at the time were said to be Lupron [TAP Pharmaceuticals], Viadur [Alza] and Zoladex [AstraZeneca].