BioXell says 'ciao' to enlarged prostates

BioXell is an Italian pharma company that was spun out of Roche by Dr Francesco Sinigaglia and Dr Luciano Adorini in 2002.

Now, its lead drug candidate, elocalcitol, is in the latter stages of Phase II clinical development and if approved could provide a significant boost to men with enlarged prostates, or benign prostatic hyperplasia (BPH).

According to the National Institutes of Health, that is some 55m men in the seven major industrialised countries and more than 50 per cent of men over the age of 60.

Furthermore approximately 90 per cent of men over 70 have some symptoms of BPH.

Most of these patients currently take a combination of two drugs: one to treat their symptoms, and a second to try and slow the growth of the prostate.

Adorini, now scientific director at BioXell, told DrugResearcher.com that the firm is trying to create a single drug that can do both of these jobs; stop prostate growth and treat the symptoms at least as well as current drugs.

The result is elocalcitol, which is a vitamin D3 (cholecalciferol, VD3) analogue that exerts a three pronged attack on BPH.

The idea is that it stops new prostate cells from growing, kills off some of the extra cells and also blocks the prostate inflammatory response.

Firstly, it blocks the effects of some growth factors, such as keratinocyte growth factor (KGF) and insulin growth factor (IGF), by preventing their receptors from being phosphorylated.

Adorini said that it may also inhibit other growth factors but these are the two that BioXell has analysed.

Elocalcitol also inhibits Bcl-2 expression, a target that can prevent cells from dying.

By clocking this, more of the excess prostate cells die off.

Lastly, the drug also inhibits the inflammatory response in BPH cells through blocking cyclooxygenase 2 (COX-2) and nuclear factor-kappa B (NF-kB).

If approved, BioXell hopes its therapy could replace the multiple drug regimen or surgery currently recommended for BPH patients.

The treatment typically consists of taking one or both of finasteride or tamsulosin.

The first is a type II 5-alpha reductase inhibitor, the enzyme that converts testosterone to dihydrotestosterone (DHT), the latter being a key mediator of prostate growth.

Testosterone has a permissive effect on BPH - it needs to be there for the disorder to occue but, on the other hand, it doesn't necessarily directly cause the problems.

Finasteride had sales of $733m in sales in 2004, yet is associated with several sexual side effects and has a slow onset of action.

The second drug, tamsulosin, is an alpha-1a-selective alpha blocker that made $1.5bn in sales in 2004.

It is a purely symptomatic treatment, acting by relaxing the smooth muscle in the prostate and the bladder neck, thus decreasing the degree of blockage of urine flow.

However it has sexual and cardiovascular side effects.

A combination therapy of these two type of drug also clearly combines their side-effects and so treatment of BPH can be unpleasant.

As well as replacing multiple drugs, BioXell believes elocalcitol has a better safety profile than existing treatments.

In the latest trial, although 77 of 134 people suffered an adverse event from any cause, this was less than the 98 of 133 people who had such an event on placebo.

Of those seven and two adverse events were classified as serious, with placebo and with elocalcitol respectively.

Adorini asserts that neither of those two was related to the drug itself.

Elocalcitol is also being tested in Phase II trials as a treatment for overactive bladder.

Here it exerts its positive effect through blocking RhoA/Rho kinases, which induce involuntary bladder contractions.

Vitamin D analogues have been used by doctors for 30 years for many conditions, including osteoporosis and psoriasis, but Adorini said these are completely new uses for this type of molecule.

Around 3 per cent of the human genome can be modulated with vitamin D analogues, but Adorini explained that which targets are hit depends on the pathology.

For example, in patients with hypertension the molecules can decrease blood pressure, but this effect doesn't occur in those with normal blood pressure in the first place.

When designing a drug, the scientists at BioXell will first conduct in vitro assays on products of primary response genes and then in selected genes specific for a given tissue type.

That way, they can avoid the impractical task of testing all 3 per cent of the genome that could potentially be targeted.

When asked, Adorini did admit the company may look to expanding their use of computational tools to look at more targets in the future, but that the company's existing projects were too advanced for it to be useful at this stage.

As this week's research and development (R&D) update, BioXell also said that BXL746, another Vitamin D3 analogue, has been shown to be highly effective in preclinical models of post-surgical adhesions.

Its primary target is the vitamin D receptor and is expected to enter Phase IIa trials in the first half of next year.

The company is also developing MNAC13, a humanised monoclonal antibody (MAb) therapy for the treatment of pain.

It has shown efficacy is several different pain models, such as arthritis and neuropathic pain and a clinical candidate will be selected by the end of this year, although the drug won't make it to the clinic until late 2009.