Therapy required for sexual medicine research?

Mike G. Wyllie, Global Pharma Consulting Ltd, PO Box 189, Sandwich, Kent, CT13 3AB, UK.

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The approval of sildenafil (ViagraTM), now over a decade ago, resulted in kick-starting (or should it be initiating) research interest in the physiology and pharmacology of sexual function and dysfunction within the pharmaceutical industry. Until then, research into sexual medicine was a Cinderella-like investment, i.e. everyone could see the potential but there was no corporate sponsor. Consequently, a positive phalanx of pharmaceutical company investors appeared; the genie was out of the bottle. Everyone knew the key to success was the pharmacological equivalent of the glass slipper, a phosphodiesterase-5 inhibitor (PDEi). Subsequently, to continue the Cinderella analogy, with the advent of Cialis and Levitra, the industry has been able to alter the shoe size but do little about the product attributes. All this is likely to change within the next ≈18 months with the arrival of the legal ‘bootleggers’, i.e. the generic companies. The most important product attribute to the consumer (literally, in the case of a drug) being price.

The impact of this can already be seen in the scientific literature, both in peer group-reviewed articles and congress abstracts and presentations. There are fewer industry-sponsored articles, and these are almost invariably presentations on clinical data and not basic research. This is mirrored and/or reflected in the magnitude of industry’s presence at scientific meetings. The exhibition halls at both the European Society of Sexual Medicine (ESSM) and Sexual Medicine Society of North America (SMSNA) held this month were relatively sparsely populated. Although this was previously often the case for delegate ‘population density’, the field-force headcount could create an illusion of a hive of activity, at least round the coffee stalls and those exhibitor stands well furnished with easily removable ‘physician aids’. A note to the organisers of ESSM and SMSNA: the choice of overlapping dates and venues (Lyon and San Diego) were not helpful. One travel company actually suggested that the best route was Lyon to San Diego via Singapore, and that by crossing the International Date Line you could arrive before your left. Otherwise, via OneWorld or Star Alliance, 23.5 hours would be a good target (excluding check in times and transit to and from airports).

Those attending both meetings might come to the conclusion that they could have saved at least one airfare. Most of the clinical data was recycled, as were the debates. The classic example was the JSM debates at ESSM and SMSNA, a few days apart. Are we really running out of ideas?

This is not to suggest that the pharmaceutical industry should be doing more in the way of sponsoring basic research or developing drugs in sexual medicine. It merely illustrates that there is little basic research sponsored directly or indirectly by industry, and few if any drugs under development in sexual medicine. In the context of the latter, the situation does not appear to be improving for potential clinical trial investigators.

At the ESSM and SMSNA there were signs of life. The J&J Group was promoting its designer selective serotonin-reuptake inhibitor (SSRI) for premature ejaculation (PE), dapoxetine [1], at least in Europe. Sciele/Shionogi had several ‘late breaking’ abstracts on the locally-acting desensitising agent, PSD 502 [2], which is scheduled for world-wide regulatory submission within the first half of next year. In theory, this should result in a considerable degree of copy cat activity. However, the pharmaceutical industry might be reluctant as the exact magnitude of the commercial opportunity is unknown, and could be like the corresponding market in erectile dysfunction (ED) becoming saturated after three drugs have been approved. Another potential stumbling block is that it is unlikely that SSRIs will have efficacy (percentage of responders and magnitude of response) equivalent to that of the PDEi in ED. Another concern for new entrants is that the regulatory route for drug approval in PE by the Food and Drug Administration (FDA) is unclear, although the declaration of dapoxetine as being ‘unapprovable’ can give a few clues on what not to do.

However, it is likely that the use of SSRIs, either approved or ‘off label’, and desensitising agents such as PSD 502, will become the mainstay in the treatment of PE. However, in the case of the latter, this will depend on regulatory approval. Beyond these mechanistic approaches there are few obvious physiological or pharmacological intervention points for new therapeutic agents for PE. Biovail has an extended-release version in late-stage development. The regulatory authorities’ (particularly the FDA) attitude to an opiate being developed for a non-analgesic indication, in my view, is fairly predictable, given they are not particularly keen on fairly benign SSRIs.

The situation for novel oral therapy in ED would appear to be even bleaker; the PDEi group seems to be the only contender. Apomorphine SL is now only available in a few countries, and the next generation of dopamine (D4) agonists from inter alia Abbott and Pfizer never made it further than phase 1. Ironically, apomorphine could have taken an important position in those patients not responding to a PDEi (one study in Viagra failures shows this convincingly), or where they were contraindicated. Unfortunately, the positioning as front-line therapy in the period after Viagra was inappropriately optimistic and created failed expectations in the eyes of patients and physicians. The melanocortin-based approaches came and went with PT 141. Perhaps not surprisingly, the pharmaceutical industry is now committing little or no resources to this therapeutic area. Industry has concluded that there is no major residual commercial opportunity in ED. This is unfortunate, as there is definitely a medical need.

Many hundreds of thousand of men with ED are excluded from the routine use of a PDEi, either because the response is poor (particularly in diabetics) or use of PDEi inhibitors is contraindicated, e.g. in nitrate-using patients with angina. To a certain extent, both classes of patient are served by vacuum therapy (Timm Medical) and intracavernous or intra-urethral variants of alprostadil administration (Pfizer and Vivus, respectively). The availability of the injectable form of alprostadil has become substantially reduced of late. The only new arrival is intracavernous Invicorp (aviptadil plus phentolamine) (Senetek/Plethora) which, given favourable regulatory review, could re-enter the marketplace by mid-2010. Beyond Invicorp, the relatively modest commercial potential, coupled with development costs, will probably mean that no new agents will be developed for this segment of the ED market. Commercial return, unfortunately, almost invariably trumps medical need.