ASCOA leuprolide (Lupron) implant that provides continuous testosterone suppression for up to a year has been shown to be safe and effective in patients with advanced prostate cancer. The experimental implant spares patients the need for frequent injections of the LHRH (luteinizing hormone-releasing hormone) agonist.
The implant (Viadur) makes use of Alzas DUROS implant technology, an osmotically driven system that enables continuous, steady-state delivery of the drug contained in the implants small titanium alloy cylinder (4.5 cm long and 4 mm in diameter) (see Figure 1 and Figure 2). The cylinder protects the drug from degradation in the body and, in conjunction with Alzas proprietary formulation technology, enables the product to remain stable for extended periods of time.
The implant is inserted subcutaneously into the upper arm under local anesthesia. Each implant is designed to deliver leuprolide at a rate of 120 µg/day over a period of 1 year.
This is an exciting and unique product that will provide an important new therapeutic option in the treatment of advanced prostate cancer, said James Gottesman, MD, of Seattle Urological Associates and clinical professor of urology, University of Washington Medical School, Seattle.
Dr. Gottesman was a co-investigator of both the phase I/II study of Viadur presented at the 1999 American Urological Association annual meeting and the phase III study (1999 Proceedings of the American Society of Clinical Oncology, abstract 1288, page 334a).
In the ASCO paper, Dr. Gottesman and his colleagues provided a preliminary report on 50 patients with advanced prostate cancer enrolled in the ongoing multicenter, open-label, single-dose phase III trial.
A Single Implant Effective
The previous phase I/II study showed that a single leuprolide implant effectively suppressed serum testosterone to castration levels (50 ng/dL or less) within 2 to 4 weeks of treatment, and these levels were maintained throughout 60 weeks of treatment.
In the phase III trial, after a 12-month treatment phase, the implant is removed and replaced with a new implant for a 12-month safety extension phase. Periodic biochemical evaluations include total serum testosterone, luteinizing hormone (LH), prostate-specific antigen (PSA), and leuprolide concentrations. In a subgroup of 21 patients, blood was drawn more frequently during the first treatment week to acquire pharmacokinetic data.
The study showed that mean serum testosterone initially increased from baseline on day 3 after insertion of the implant and then rapidly decreased, with castration levels achieved between weeks 2 and 4, as occurred in the phase I/II trial, Dr. Gottesman said.
Through week 40, serum testosterone had remained suppressed in all evaluable patients with a mean level of 7.2 ng/dL. Similar effects on serum LH levels were seen, and PSA levels normalized or decreased in all patients during treatment.
In the group evaluated for leuprolide pharmacokinetics, immediate leuprolide release was shown by peak levels of leuprolide and LH at 4 hours after implantation.
The safety profile of Viadur was consistent with androgen deprivation. The implantation and reimplantation procedures were well tolerated and highly acceptable to patients and physicians, Dr. Gottesman said.
New Drug Application
Alza Corporation (Palo Alto, California) has submitted a New Drug Application to the FDA for Viadur, which is being developed by Alza on behalf of Crescendo Pharmaceutical Corporation.