The introduction of Viagra in the Spring of 1998 revolutionized the treatment of erectile dysfunction (ED) and prompted an amazingly public discussion of what had previously been a very private and seldom-mentioned sexual issue. Suddenly, everyone was talking about male impotence and "the little blue pill." Former senator and presidential candidate Bob Dole even hired on as spokesman for Viagra.

Lost in the flood of news reports and late-night TV punch lines, however, was the fact that Viagra doesn't work for approximately 30% of men who need it. For others, Viagra is not safe because it interacts with their nitrate-based heart medications. And some may have problems with Viagra's side effects, including headache, facial flushing, stomach upset, and vision disturbances.

Given the potential unmet need in the ED market, up to 30 million men by some estimates, a number of companies have rushed, hard on the heels of Viagra, into the field of ED therapy. Among the contenders for a share of the ED market are several PDE5 inhibitors (the class of drugs to which Viagra belongs), and a number of older drugs now being re-examined for potential use in treating ED.

Coming soon (maybe)—the first centrally-acting ED therapy

A novel approach to ED therapy has been taken by the developers of Uprima (TAP Pharmaceutical Products Inc.), a proprietary formulation of apormorphine. Up until now, most of the therapies developed for ED have been locally-acting drugs or mechanical devices that focus on circulatory problems in the penis. By contrast, Uprima works by stimulating receptors in the brain for dopamine, a neurotransmitter linked with pleasure signals in the central nervous system. Thus, it is classified as a centrally-acting ED therapy.

Uprima is a sublingual tablet of apomorphine. 'Sublingual' means it's placed under the tongue to dissolve and be absorbed. Apomorphine is used as an emetic in veterinary medicine (i.e., to induce vomiting). Not surprisingly, the chief side effect associated with Uprima is mild-to-moderate nausea.

In trials for ED, Uprima has shown promise. In one large placebo-controlled study, apomorphine was effective in about 50% of men with ED, compared with 35% of the men taking a placebo. Uprima was recommended for approval by the FDA's Urology Subcommittee in April of 2000, but as of this writing (March 2001), it is still not on the market.

New alprostadil-based treatments and an oral phentolamine

Alprostadil is a synthetic form of prostaglandin E1, a substance found in human semen that has the effect of dilating blood vessels. Alprostadil helps enlarge the diameter of diseased arteries in the penis to improve the inflow of blood during sexual arousal and facilitate erection. Currently available treatments for ED include direct injection of alprostadil into the erectile tissue of the penis or insertion of an alprostadil pellet into the urethra at the end of the penis so that the medication can be absorbed through the urethra (MUSE). But the push now is for topical formulations such as creams or gels for ED, and at least two manufacturers are in the race.

NexMed is currently testing Alprox-TD cream, which combines alprostadil with the company's patented transdermal drug delivery system to enhance absorption through the skin. In recently completed phase II studies, 73% of men using Alprox-TD reported improvement in erectile function, compared with 23% of men in the placebo group.

MacroChem Corporation has completed phase II studies of Topiglan, a gel formulation of alprostadil that also includes a patented absorption enhancer. An early study indicates Topiglan may be effective in up to 75% of men with ED. The hope of MacroChem and NexMed is that their topical ED therapies will be just as effective as Viagra with fewer side effects. The next round of clinical studies (phase III) should reveal a good deal more about the safety, effectiveness, and tolerability of these topical alprostadil formulations.

Rounding out the development picture for alprostadil-based therapies is Alibra from VIVUS, Inc., the marketer of MUSE, the above-mentioned alprostadil therapy using a tiny pellet inserted into the urethra. Alibra combines alprostadil with the vasodilator prazosin hydrochloride. Intended to be an enhanced version of MUSE, the new drug has been shown to work in men who are unresponsive to alprostadil alone. As of October 2000, however, VIVUS had withdrawn its application for approval of Alibra, pending further meetings and negotiations with the FDA.

Finally, among the old familiar products with new faces, Vasomax, an oral version of phentolamine, is being developed by Zonagen and Schering-Plough. Phentolamine has previously been used to treat ED by direct injection into the erectile tissues of the penis. Clinical development of Vasomax was suspended in the Fall of 2000 pending further animal studies to determine whether phentolamine can cause cancer.

The many sons of Viagra

Viagra and other phosphodiesterase (PDE) inhibitors work by way of a complicated process that centers on two compounds. The first is the enzyme phosphodiesterase type 5 (PDE5), which is a sort of barrier to erections. In the erectile tissues of the penis, PDE5 breaks down the second key agent, a compound called cyclic guanosine monophosphate (cGMP), which helps to promote erections. Cyclic GMP relaxes the smooth-muscle walls of blood vessels in erectile tissue so that the penis can more easily become distended with blood. What Viagra does is curb the action of PDE5. This, in turn, sustains the action of cGMP, allowing men with ED to achieve and maintain an erection.

To understand the current developmental vogue for second-generation PDE5 inhibitors, it's necessary to understand that there are other PDEs that play key roles in such diverse organs as the eyes, brain, heart, and kidneys. Viagra is a selective inhibitor of PDE5, which means it inhibits the action of PDE5 to a much greater extent than it does the other PDEs. For example, Viagra is more than 4,000 times more potent an inhibitor of PDE5 than PDE3, which is good because PDE3 is involved in controlling the contraction of heart muscle. On the other hand, Viagra is only 10 times more potent an inhibitor of PDE5 than PDE6, which is found in the retina. Partial inhibition of PDE6 is believed responsible for the temporary vision disturbances sometimes reported as side effects of Viagra: blurred vision, sensitivity to light, a bluish tinge to objects, or difficulty distinguishing blue and green objects. (Viagra has nonetheless been shown to be safe opthalmologically in numerous published studies.)

A number of companies are working to develop more highly selective PDE5 inhibitors with the idea that a more selective drug will be that much less likely to cause side effects. In a joint venture with ICOS Corporation, Eli Lilly & Company is developing Cialis—a highly selective, second-generation PDE5 inhibitor. In one large phase II study, 88% of men taking Cialis reported significantly improved erections, compared with 28% of men taking a placebo. The most common side effects were headache, back pain, muscle pain, and stomach upset after meals. These effects were generally mild to moderate and tended to go away after continued use of Cialis. Commenting on the selectivity of Cialis, the lead investigator on this study noted that it would take approximately 700 times more Cialis than the normal dose to inhibit PDE6 (found in the retina), which suggests Cialis is unlikely to cause the vision disturbances associated with Viagra.

Other selective PDE5 inhibitors in the post-Viagra pipeline include FR229934, recently in-licensed by TAP Pharmaceutical Products Inc. from the Japanese drug company Fujisawa, and vardenafil, which is being developed by Bayer. In one phase II study, vardenafil was effective for 74.6% of men with ED, compared with 24.2% of men taking a placebo. Side effects were generally mild and included headache in 13%, flushing in 10%, and rhinitis (inflammation of the nasal mucous membranes) in 5%.

The broadest foray into PDE inhibitor research may be that of VIVUS Inc., which has embarked on a program to develop locally administered inhibitors of PDE3, PDE4, and PDE5 for the treatment of ED. Local administration of these PDE inhibitors would be transurethral or transdermal, which would reduce or eliminate the risk of side effects at other body sites where PDEs play key roles.

Conclusion

Time will tell, of course, which if any of these contenders make it market or have a major impact when they do. Experts say, however, that the potential market for these products remains substantial. For one thing, there's a need for safe, effective, and tolerable ED therapy for a broader range of patients, especially those for whom Viagra and other current therapies are not an option. In addition, it's possible that further public education about the problem of ED will help to remove some of the stigma that still surrounds this condition.

"The new drugs will offer improvement and also will serve to increase awareness of both male and female sexual dysfunction," says Andrew McCullough, MD, assistant professor of urology at New York University and director of NYU's Male Sexual Health and Fertility Clinic. "I am seeing a spectrum of men in my office from age 18 to 87, and men in all age groups will potentially benefit.