Health and Prostate

Among the drugs in the pipeline for benign prostatic hyperplasia, silodosin (Figure 10), also known as KMD-3213, is in the most advanced stage of development. The agent is being codeveloped by Kissei and Daiichi in Japan. In June 2004, a new drug application (NDA) was submitted to the Pharmaceuticals and Medical Devices Agency (PMDA), and in 2004, Daiichi announced an expected launch date of 2006 in Japan. In April 2004, Kissei entered a licensing agreement with Watson Pharmaceuticals, which will develop and market silodosin in Mexico, Canada, and the United States, where Phase III clinical trials were in progress in 2005. In December 2004, Kissei granted Recordati exclusive rights to the development of silodosin in 45 countries in Europe.

Silodosin is a highly selective, twice-daily oral alpha blocker that preferentially inhibits the activity of alpha_1A-adrenergic receptors, which are predominantly located in the prostate. Other alpha blockers that are considered uroselective, such as tamsulosin, block not only alphai A-adrenoceptors but also other adrenergic receptor subtypes found in the prostate, cardiovascular system, spleen, kidney, and lungs. Although silodosin is a late-to-market agent, if it

demonstrates greater efficacy in relieving benign prostatic hyperplasia symptoms than currently available alpha blockers and has fewer side effects related to orthostatic hypotension and retroactive ejaculation, physicians may be willing to use the drug in benign prostatic hyperplasia.

A study published in 2001 compared the uroselectivity of silodosin with that of prazosin and tamsulosin in a dog model. When the drugs were administered intravenously, silodosin was 12-fold more uroselective than prazosin and 7.5-fold more than tamsulosin. When administered intraduodenally (a surrogate to oral administration), silodosin demonstrated at least 3.8-fold higher uroselectivity than tamsulosin. These results indicate that silodosin has the potential to be an effective orally administered, uroselective compound for treating the symptoms of benign prostatic hyperplasia.

Phase III clinical data on silodosin were presented for the first time at the American Urological Association’s (AUA’s) 2005 annual meeting. In a randomized, placebo-controlled, double-blind study, 457 benign prostatic hyperplasia patients from 88 participating centers in Japan received treatment: 4 mg of silodosin twice daily, 0.2 mg of tamsulosin once daily, or placebo. After 12 weeks of therapy, reductions in International Prostate Symptom Scores from baseline were 8.3, 6.8, and 5.3, respectively. Of the patients taking silodosin, 76.4% achieved at least a 25% reduction in symptom score; only 65.6% of patients taking tamsulosin and 50.6% taking placebo achieved the same improvement. Silodosin induced hypotension-related adverse effects similar to those seen with tamsulosin treatment; these events affected 5.1% of the silodosin treatment group and 7.3% of the tamsulosin treatment group. Furthermore, abnormal ejaculation was more frequent in the silodosin group (22.3%) than in the tamsulosin group (1.6%).