Health and Prostate

Overview

The active form of vitamin D3 is calcitriol. Initially, this steroid was shown to control bone metabolism and calcium equilibrium; it has the ability to induce hypercalcemia and hyperphosphatemia. Further research proved that calcitriol also moderates cell proliferation, differentiation, and apoptosis. Vitamin D3 analogues have been developed for benign prostatic hyperplasia treatment with the intention of preserving regulatory activity without causing hypercalcemic side effects. The class of vitamin D3 analogues is novel in the treatment of benign prostatic hyperplasia, so elucidating its mechanism of action to practicing physicians will be necessary for this class to achieve commercial success.

Mechanism Of Action

Vitamin D3 binds to vitamin D receptors, which are expressed in the human prostate gland. Vitamin D receptors are responsible for hyperproliferation of cells and are implicated in diseases such as psoriasis, cancer, and benign prostatic hyperplasia. In addition to reacting directly with vitamin D receptors, vitamin-D-receptor ligands have been shown to antagonize growth factor (GF) receptors. In combination, these actions have influential regulatory effects on tissue expansion and cell death.

Synthetic analogues of vitamin-D-receptor ligands have been modified in their side chains so as to improve their therapeutic effects. Side effects related to hypercalcemia can be reduced by use of vitamin D3 analogues instead of natural vitamin D3 agents.

BXL-628

Roche has granted exclusive worldwide development and marketing rights to the novel vitamin D3 analogue BXL-628 to BioXell, an Italian company spun off from Roche Milano Richerche. BXL-628 is the company’s most advanced developmental drug. BioXell’s U.S. subsidiary is currently conducting clinical trials for BXL-628 in patients with benign prostatic hyperplasia. A Phase lib, dose-ranging study was initiated in July 2005.

BioXell’s new agent offers a novel approach to the treatment of benign prostatic hyperplasia. BXL-628 is significantly less hypercalcemic than cacitriol and other analogues in the vitamin D3 analogue class. It works by inhibiting the activity of growth factors involved in prostate proliferation. This action occurs downstream from the adrenergic receptors, which BXL-628 does not bind. Furthermore, BXL-628 does not interact with 5-alpha-reductase type 1 or type 2. Therefore, BXL-628 does not affect sex hormone secretion and potentially avoids sexual dysfunction and other side effects associated with 5-ARIs.

In September 2004, BioXell announced the results of a three-month, double-blind, randomized, placebo-controlled Phase Ha study that involved 120 men with benign prostatic hyperplasia. Patients taking BXL-628 exhibited an average 7.2% reduction in prostate volume, compared with no reduction in patients taking placebo (p < 0.0001). Furthermore, 92% of patients treated with BXL-628 had no prostatic growth at all, compared with only 48% of patients treated with placebo who experienced no prostate enlargement (p < 0.0001).