And my prostate just keeps growing!

M.G. Wyllie, Global Pharma Consulting Ltd, 61 Abbey Street, Faversham, Kent, ME13 7BN, UK.

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This statement is true at many levels, which could be a cause for concern to the increasingly many men of 50+ years in the global population. On one hand we get the impression that, at least in the USA, there is increasingly less prostatic surgery with which to train the future generation of urologists, and yet the epidemiologists say that the population is ‘greying’ and will potentially present with age-related symptoms of prostatic disease. ‘Never mind’ you say (at least if you are from the USA), robotic surgery will be our salvation. Not so in Europe, where there are few systems and many of these are literally still in the wrapping paper.

In therapeutic terms the treatment of both benign and malignant prostatic growth is one of our more mature areas; drugs for both prostate cancer and BPH have been around for over three decades. At least for BPH they provide adequate symptomatic relief but not a ‘cure’. As such, they have been described as ‘surgical sticking plaster’ with most patients eventually progressing to a stage requiring surgical intervention. Even the much re-analysed long-term study of a combination of 5α-reductase inhibitors and α-adrenoceptor antagonist therapy (MTOPS) and its clones has failed to convince the healthcare providers of the economic benefit of disease prevention. A case perhaps of the accountant’s pen being much greater than the statistician’s tables? In MTOPS it was a case of ‘something for everyone’, irrespective of whether you were a devotee of monotherapy (both α-blocker and 5α-reductase inhibitor zealots could find solace in the data) or combined therapy. Unfortunately, in the case of the latter it would appear that the proponents were just as likely to word-process an abstract as put pen to prescription pad.

To summarize BPH, we have a situation where most men (at least defined by the epidemiologists) still do not receive ‘effective’ therapy. One would assume, as such, that this would be an area of considerable interest to the pharmaceutical industry, where several ‘blockbuster’ drugs have made it to the market. Using a definition of ‘blockbuster’ of worldwide sales of >$1 billion, doxazosin, tamsulosin and terazosin were all ‘medal winners’, with finasteride just off the podium. So are industry interested? Yes and no!

The pharmaceutical industry is sufficiently motivated to bring new formulations of existing drugs to the market. Over the years we have seen extended- or modified-release versions of alfuzosin, prazosin, doxazosin and tamsulosin arriving in the marketplace. In the case of the latter two there is little evidence of improved clinical performance over the existing molecule, and they represent potentially an opportunistic way to extend patent life and thereby maintain revenue. The development of a new formulation is dependent largely on the demonstration of ‘bioequivalence’ and costs considerably less to develop than a novel chemical entity (<10%).

Exploitation of a novel formulation as a tactic has been around for several years; indeed the Flomax, Omnic and Harnal formulation of tamsulosin are all improved versions of the originally released version, which never left clinical development in Japan due to profound orthostatic hypotension. In this situation, delivering both less of a drug and delivering it more slowly will improve the side-effect profile. In theory, BPH should still constitute a viable commercial opportunity for the pharmaceutical industry; in practice it does not for various reasons (explore below).

The development of a new mechanistic approach is very expensive and risky. This is not medical risk to the patient but risk to the company’s investment. The cost of drug development is well documented and can be absorbed by major pharmaceutical companies. Inter alia Abbott, BMS, GSK, J&J, Pfizer, Ranbaxy, Roche and Schwartz have all been involved in failed programmes in BPH, without too serious a detriment to their stock price. The impact of a failed approach on a one-product biotechnology company can be catastrophic; caveat emptor.

The selection of a new mechanistic approach to treating BPH is not obvious. Most of the above pharmaceutical companies have tried a selection from genuinely uroselective α-blockers, uroselective potassium-channel openers, neurokinin modulators and growth factor inhibitors, and failed. However, several smaller biotechnology companies are persevering in this area; caveat emptor.

The economic equation is less compelling for the pharmaceutical industry. Although the ‘greying’ of the population could potentially increase sales volume, pricing is less attractive. In most healthcare environments the cost of BPH medication is capped and being reduced. This incidentally is probably the single major reason that combined therapy is not more widely used. Unfortunately, on the other side of the equation, the cost of drug development is increasing yearly (currently >$0.5 billion) and will continue to do so due to increasing regulatory requirements for novel chemical entities.

There are increasingly more options, ranging from natural products (‘urbals in the USA, herbals elsewhere) to alternative forms of surgery (minimally invasive and robotics). In the context of the former, given the well-documented placebo response, ≈ 30% of all individuals taking natural products are likely to be satisfied. That there is little supportive clinical data showing efficacy is of little or no interest to this type of patient; they are more motivated by availability and low cost. Surveys regularly show that in the USA up to half of all patients will have tried a plant extract before arriving in the urologist’s office.

There is still an impression that any benefit from drugs will still be transient and ultimately many patients will require surgery. Given the increasing spectrum of ‘minimally-invasive’ procedures and the improved precision of robotic surgery, increasingly many patients could well avoid the drug-controlled phase of disease management. This is despite the durability of some of the procedures being somewhat ephemeral, having a lifespan in some cases of no longer than the time between successive years of AUA abstracts!

Ultimately, future advances in BPH might well depend on activities in small entrepreneurial biotechnology companies, where risk is encouraged. Just now there appears to be a particular focus, with companies such as Ardana Biosciences, Lectus and Xention. Indeed Ardana have recently announced encouraging clinical data on their LHRH analogue, teverelix.

Next month I will examine the activities of the pharmaceutical industry over the conference circuit (EAU and AUA).