In the 12-month period to the end of June 2005, according to IMS, the global benign prostatic hypertrophy/hyperplasia (BPH) treatment market (G4C ATC therapy class) was worth almost $4 billion and grew by 12% in fixed-rate US dollar terms.

What is BPH?
The prostate is a gland about the size of a walnut that is only present in men. It is located just below the bladder and surrounds the urethra. One of its main functions is to produce an important liquefying component of semen, which allows the sperm to move freely. An enlarged prostate is caused by an overgrowth of prostate cells, and leads to a constriction of the urethra. This in turn reduces the flow of urine, making it increasingly difficult to empty the bladder.

BPH is very common, affecting about one-third of men aged 50+, and may be treated with drugs and surgery. As any treatment can have unwanted effects, however, some men with mild symptoms opt for “watchful waiting”, where no treatment is undertaken, but they are closely monitored. If symptoms deteriorate, it is then possible to opt for treatment.

Current drug treatments
Two main classes of drugs are prescribed for BPH: alpha-blockers and 5-alpha-reductase inhibitors.

Alpha-blockers (or alpha-1 antagonists) work by relaxing the muscles at the neck of the bladder and in the prostate. In this way they reduce the pressure on the urethra and so help increase the flow of urine. They do not cure BPH but help to alleviate some of the symptoms. Around 60% of men find symptoms improve significantly after 2-3 weeks of treatment with an alpha-blocker, which are also used for hypertension. Common side-effects include tiredness, dizziness and headaches.

Major drugs in this class include:

• tamsulosin – marketed by developer Astellas as Harnal, and licensor Boehringer Ingelheim as Flomax or Alna. Abbott will co-market Flomax in the US until the end of 2005
• alfuzosin – sanofi-aventis’ Xatral. A long-acting version is available as UroXatral/Xatral OD
• doxazosin – Pfizer’s Cardura
• and terazosin – Abbott’s Hytrin

5-alpha-reductase inhibitors inhibit production of the hormone dihydrotestosterone, produced from testosterone, which contributes to prostate enlargement. Merck & Co’s Proscar (finasteride) is the main drug of this type for BPH, although it is now being challenged by a newer product, GlaxoSmithKline's Avodart (dutasteride). Proscar was first launched in the US in 1998 and is also used for the treatment of male-pattern baldness.

Unlike alpha blockers, 5-alpha-reductase inhibitors are able to reverse BPH to some extent and so may delay the need for surgery. Potential side-effects of finasteride, however, include a reduced sex drive and difficulty in maintaining an erection. In addition, it takes several months of treatment before any benefit is noticed.

Certain plant-based products are also used in the treatment of BPH and there is some evidence that an extract of saw palmetto (Serenoa repens) can be beneficial. Pierre Fabre markets this plant extract as Permixon, and it was the sixth best-selling product in the class for the 12 months to June 2005, according to IMS.

Tamsulosin dominates the market
The major compound used in the treatment of BPH is the alpha-1 antagonist tamsulosin, originally developed by Yamanouchi (now Astellas). In the 12-month period to the end of June 2005, tamsulosin had almost half the G4C BPH market. It was first launched in Japan in 1993 as Harnal, and in 1994, Yamanouchi licensed it out to BI for co-marketing in certain European countries and in North and South America. Astellas co-markets with BI in France, Italy and Greece. BI mainly sells it as Flomax, which is also co-promoted in the US by Abbott, though this agreement is due to cease at the end of 2005. Astellas claims that tamsulosin has high selectivity for the lower urinary tract, making it better suited to BPH therapy than previous alpha-1 antagonists.

Global BPH therapy sales (G4C therapy class)

Source: IMS MIDAS Quantum

Behind tamsulosin in terms of sales is Merck & Co's Proscar, the leading 5-alpha-reductase inhibitor, with an 18% market share. Its share has fallen since 2001, perhaps because of the launch of GSK’s similar product, Avodart, which hit the major markets in 2003. Avodart was number five in the G4C class for the 12 months to June 2005, with a 4% share, but 150% fixed-rate US dollar growth. Number four in the class was sanofi-aventis' Xatral, with 10% of the market.

The top five products together accounted for 80% of the BPH market. The remainder is mainly made up by plant-based products such as Pierre Fabre's Permixon and older alpha-1 antagonists. Also, the alpha-1 adrenergic antagonist, naftopidil, is used for BPH in Japan. Originally developed by Roche, it is sold by Asahi Chemical and Akzo Nobel in Japan as Flivas and Avishot, but development outside Japan has stopped.

New products in R&D

Various new compounds for BPH are in research and development. In addition, some compounds marketed for other indications are in trials for BPH, notably Lilly Icos’ tadalafil, which is marketed for erectile dysfunction as Cialis.

Major new compounds in R&D for BPH

Source: IMS LifeCycle R&Dfocus /IMS Company Profiles

Of the new BPH compounds in development, the most advanced is Kissei and Watson's silodosin, which was filed for approval in Japan by originator Kissei in 2004. Watson has rights in the US, Canada and Mexico and Recordati holds European rights. It is in Phase III studies in the US with Watson, with an FDA filing forecast in 2008, and in Phase II trials in Europe.

Threshold is investigating lonidamine, an old compound (first patented in 1972), which was launched in 1987 by the Italian firm Angelini for the treatment of a variety of cancers, but was withdrawn in 2003, when Threshold acquired the regulatory dossier for the compound. Threshold initiated a European Phase III trial in BPH in August 2005.

QLT uses photodynamic therapy (PDT) to make lemuteporfin, a ‘light-activated’ drug. An instrument is put into the urethra to inject lemuteporfin into the prostate, and then another is used to shine light into the urethra and activate the therapy. When the cool laser light activates the lemuteporfin, the overgrown prostate tissue is destroyed.

BioXell announced in July 2005 the initiation of a Phase IIb trial of BXL 628 in BPH, to take place at 60 urology centres across Italy, enrolling more than 500 patients. BioXell is also planning to evaluate BXL 628 for an additional indication of non-bacterial chronic prostatitis. The company expects to initiate a proof-of-concept study in this indication by the end of 2005. BioXell has also confirmed that Phase IIa trials are ongoing, in Italy, in patients with over-active bladder.

In October 2005, Lilly and Icos announced positive results from a Phase II study of tadalafil in the treatment of lower urinary tract symptoms in men with BPH. The companies have a joint venture to develop tadalafil and are reported to be planning Phase III studies for this new indication. Lilly Icos notes that many men with BPH also suffer from erectile dysfunction, so it is well-poised to capitalise on Cialis’ existing marketing and promotional tactics.

This article was written by Susan Murray, Senior Editor of IMS Company Profiles.

To make any comments on this article, or to ask a question of the author, please contact the publisher. If you would like to submit an article please subscribe to our PL Intelligence service.

The opinions expressed in the articles published in this section do not necessarily reflect those of Pharmalicensing or UTEK Corporation. No actions including proposals to or agreements with other companies should be taken by any reader without obtaining specific business or legal advice. Neither the publisher nor the authors accept any liability for any actions or activities undertaken by any reader or other third party as a consequence of these articles or for any errors or omissions therein.