Have we ever considered who is looking for what, in whom and why? The immediate assumption is that the pharmaceutical industry is driving the whole ‘pink Viagra’ process, as much to benefit shareholders as patients. It would appear that the impetus has come from several ‘penis-envy, pressure groups’ campaigning along the lines of ‘what men have we must have’, but would industry react to this type of pressure or has the hunt for pink Viagra been ‘created’ by the pharmaceutical industry?
Assuming that the pharmaceutical industry is driven by profit, does the maths indicate that a drug for the treatment of ‘female sexual dysfunction (FSD)’ would be commercially viable? In today's terms it costs £400–700 million to take a product to market (the actual cost of any one successful drug is actually much less, but the cost of the ≈ 92% of drugs that do not make it from bench to bedside have to be ‘re-absorbed’ against marketed products). It costs considerably less to develop a drug for a second indication, e.g. doxazosin, which was originally developed for hypertension and subsequently for BPH, and duloxetine, an anti-depressant also being developed for stress incontinence.
Potentially the commercial opportunity for FSD could be modelled on that of erectile dysfunction (ED). In 2004 the worldwide legal prescription market for ED is going to be close to $2.7 billion with sildenafil retaining a 60–65% market share, tadalafil retaining 20–30% and vardenafil retaining the rest. Although it has been calculated that the prescription market represents as little as 40% of total sales, it is the only component that the pharmaceutical industry has access to and can generate revenue from. When we factor in the development costs (above), profitability on each tablet (generally 70–85% for new drugs), annual marketing costs and patent life, the economics of the ED market can be interpreted in another way; sildenafil would be considered a ‘blockbuster’ by industry and stock market analysts alike, tadalafil might just about fit that description, and vardenafil would not even come close, with a <10% share of the ED market (in other areas, e.g. hypertension, such a market share would give rise to a ‘blockbuster’). Any other phosphodiesterase inhibitors are likely to fare less well, and given the overall satisfaction with this drug class it is by no means certain that the entry of a new drug class in the future will either expand the market or even take market share.
The situation in FSD is even more complex; if nothing else because of the incomplete clinical definition and corresponding lack of consensus on clinical trial design. The scientists may well tell us that the prevalence of FSD is equivalent to that of ED, the degree of bother comparable, and potentially an analogous situation to that in ED could apply, with two or possibly three drugs becoming commercially successful. However, when we superimpose the heterogeneity encompassed within FSD, the economics become totally different for a drug reaching the marketplace. An effective drug, that is first to market and gains over 70% of the share for the arousal component of the FSD market (for the sake of argument let's say this represents 25% of the total FSD market), would become much less attractive. Peak sales incidentally would be ≈ £500 million, with the third drug to the market gaining less than £50 million worldwide sales annually.
Based on this type of calculation, which is mandatory in the pharmaceutical industry when considering a new therapeutic area, by and large the FSD opportunity would be considered unattractive, at least for initiating de novo research programmes. An additional negative factor is that, as relatively little is known about the pathophysiology of FSD, it would be almost impossible to select a mechanism on which to work. However, as described above, if FSD represented another indication for a product already marketed or soon to be marketed, the economics become considerably more attractive!
Not surprisingly, the pharmaceutical industry, or more correctly clinical investigators, started with the obvious, i.e. the use of sildenafil. Trials by Berman et al. showed a 17% increase in clitoral blood flow, and this translated into great expectations (and AUA abstracts) for the drug in FSD. Only with the completion of carefully controlled clinical trials by Pfizer has the true clinical potential of the drug been unravelled. Essentially the drug does not work in the general FSD population but could offer certain individuals some degree of benefit. Should we be surprised? I think not. At the clinical laboratory level, clitoral smooth muscle bears some resemblance, at least embryologically and biochemically, to corporal smooth muscle, and in both organs some degree of change in local blood flow and engorgement would be expected. As we do not know the inter-relationship between these physiological changes and FSD, the negative clinical trials data should not be surprising.
An approach with a more credible scientific pedigree has been the evaluation of various formulations of apomorphine in the arousal- and desire-deficient FSD clinical subpopulations. At least in terms of clinical anecdote, based on investigator-stimulated studies, some degree of benefit may be apparent with apomorphine sublingual (SL). However, the issue will be the risk in the benefit-risk equation, with the Food and Drug Administration holding particularly strident and negative views about the potential for syncope and fainting. Although the original developers for ED (Takeda, TAP and Abbott) are no longer pursuing the FSD indication for apomorphine SL, several other companies are, and with novel formulations, e.g. Nastech have a nasal delivery and Vectura a pulmonary delivery form of the drug. The wisdom of speeding up the absorption rate of a vasoactive agent with respect to orthostasis will, I am sure, be a subject of much debate with the regulatory authorities.
Not surprisingly, several companies with marketed hormone-replacement products (both oestrogenic and androgenic) have got in on the act and are undertaking some highly original clinical trials. These endocrine-based agents undoubtedly have as much scientific justification as any other approach (because of space and potential litigation issues these are not listed). However, Proctor and Gamble are to be applauded on completing two phase III studies on the use of their testosterone-replacement patch (Intrinsa) in women with hypoactive sexual desire disorder (HSDD). Presumably the use of androgens circumvents the negative perception of oestrogen-based hormone replacement therapy strategies. It remains to be seen whether the use of this testosterone delivery system, in the eyes of the regulators, avoids aromatisation to oestrogens.
I leave the reader to decide whether or not they feel that the pharmaceutical industry will: a) continue to try to develop products for FSD; b) base any such development on rational research programmes.
Next month I will review the pharmaceutical industry in China (PRC).