Editor

Erectile dysfunction (ED) used to be called impotence, until doctors decided on what the Merck Manual of Diagnosis and Therapy refers to as a "less pejorative" and more specific phrase.

But a rose by any other name smells the same and this one stinks, for 10 million to 20 million men over age 18 afflicted with the condition in the U.S.

The common form of ED (which some persist in calling "male erectile dysfunction") is secondary, notes the Merck handbook. This means the loss of a previous ability to attain and sustain erections. It's almost always due to an organic cause: vascular trouble in many cases (atherosclerosis, or venous leaks causing blood to flow out of the penis prematurely); hormonal disorders; drugs; or neurological problems.

Primary ED, which is rare, means a lifelong inability to get an erection, probably traceable to psychological factors and therefore not treatable with drugs.

ED can hardly be mentioned without Pfizer Inc.'s blockbuster Viagra (sildenafil citrate) coming up right away. The diamond-shaped blue pill, which inhibits the enzyme phosphodiesterase 5, has proven for many to be pure gold sexually. It has demonstrated value to Pfizer on the bottom line, too, last year chalking up sales of $1.5 billion, or 4.7 percent of the pharmaceutical giant's revenue.

Viagra's mechanism of action is fairly simple. In a healthy, aroused male, nerve cells near the penis release nitric oxide, which triggers the making of cyclic guanosine monophosphate (cGMP), which causes the penile blood vessels to expand.

Blood rushes in; an erection happens. Produced along with cGMP is PDE5, which ideally balances the first chemical until the sexual main event is complete. Then, PDE5 "cleans up" the remaining cGMP, and the penis returns to a flaccid state.

By blocking PDE5, Viagra lets cGMP do its work with less impediment, resulting in erections for many men who had previously complained of difficulty. Although they might be tempted to call it magic, Viagra's efficacy is based on pure science.

But Pfizer's headliner could face challenges if several other ED products two of them also PDE5 inhibitors edging toward approval can penetrate the market.

That "if" got bigger last week. One of the front-runners in the PDE5 inhibitor race, Cialis (taladafil, from ICOS Corp., which is partnered with Eli Lilly and Co.), was the subject of an FDA letter that called the drug approvable but asked for three issues to be cleared up first.

One of those issues is pharmacology, which means more studies. ICOS "for competitive reasons" would not be specific about what the FDA wants, but news of the delay sent the firm's stock into a 34 percent tailspin.

Analysts are estimating the NDA for Cialis, which boasts a quicker onset, 24-hour duration of action, and lack of food interaction, will go back to the FDA by the end of the year, and could win approval by mid-2003.

Word from the FDA prompted speculation that Cialis could fail to reach the market before a close runner-up: vardenafil, filed with the FDA three months behind Cialis, by Bayer AG and GlaxoSmithKline plc.

Agency officials might require the same from Bayer and GlaxoSmithKline that it's asking from ICOS and Lilly and probably will, said Adam Greene, analyst with Dresdner Kleinwort Wasserstein. That's the "competitive reason" the FDA's concerns weren't disclosed by ICOS and Lilly: Tipping Bayer and GlaxoSmithKline about the agency's questions would only give the rival pair of companies more time to prepare their response.

"Usually, second or third products in a class [such as PDE5 inhibitors] don't have a problem getting approved," Greene noted. "We don't know whether the issue is more with Lilly's manufacturing or more with clinical [matters]."

Greene told BioWorld Financial Watch he'd heard speculation that the FDA is concerned about use of PDE5 inhibitors by men who don't need it, but are interested in enhancing their sexual performance.

"Clearly, a lot of it is recreational use," he said. "But, if that's their concern, wouldn't they call a panel meeting to remove Viagra from the market?" Instead, Greene wrote in a research note, the FDA knowing the abuse of Viagra may be asking for more data regarding Cialis in non-ED patients.

Todd Nelson, analyst with RBC Capital Markets, said he found "nothing wrong" with the so-called recreational use of Viagra, which is widely acknowledged.

"I don't think there's any reason to pull the drug from the market," he said. "The issue is, since [Cialis also would be] used much more broadly, you want to make sure you have a real good handle on safety."

He noted Cialis' 24-hour duration is its "best point of commercial adoption," but potentially its weakest point as well (since the side effects could last), and one that ICOS and Lilly already have addressed.

"In none of the clinical trials has there ever been a statistically significant difference in the frequency, incidence or duration of side effects between those who got the drug and those who didn't," Nelson told BioWorld Financial Watch.

There are also two ways to think about the possibility of Bayer and Glaxo running into the same snares as ICOS and Lilly. It seems inevitable, in one sense, but the safety profile of vardenafil is much more similar to Viagra than to Cialis, so depending on the nature of the FDA's concerns vardenafil could slide past.

Lilly is clearing up its manufacturing issues, too, Nelson said, and now that the launch of Cialis has been pushed back, the company has even more time to get approval of its manufacturing processes and facilities.

"No one should be expecting [Cialis] to get a label that says it's in any way superior," Nelson said. "There've been no head-to-head trials." However, Cialis' longer action and relative lack of slowing by food in the stomach give it a clear edge over Viagra and vardenafil.

Having the same mechanism, "both drugs should be 80 [percent] to 85 percent efficacious, but in reality, Viagra only works in 55 percent of patients," Nelson said, noting that Cialis should be particularly important "for the younger crowd" or those who insist on spontaneity.

PDE5 is not the only route being explored for ED drugs. Zonagen Inc. is developing phentalomine-based Vasomax, but Zonagen got bad news last week, too. In the latest in a series of unfortunate developments regarding the drug, partner Schering-Plough Corp. is scrapping its marketing application in the United Kingdom.

Vasomax, an immediate-release oral formulation of phentolamine mesylate, blocks the alpha-adrenergic receptor for short periods, thus stimulating smooth muscle relaxation and causing vasodilation. Phentolamine has long been used for hypertension and used more recently in diagnosing adrenal tumors, and doctors have deployed it off-label for ED.

In the U.S., Zonagen's drug is on clinical hold due to suspicions it causes in mice a proliferation of brown fat, a type that is common to hibernating animals, but very rare in humans. Brown fat wasn't the source of the snag overseas, Zonagen said, but the move by worldwide partner Schering-Plough to withdraw the filing package dashed hopes of using it as the basis for applications in all of Europe. Zonagen's stock tanked by 57.1 percent on the news.

Then there's alprostadil. A type of prostaglandin, it also works along the same lines as phentolamine. Smooth muscles in the penis are relaxed, thereby letting in more blood.

MacroChem Corp. hasn't had luck recently with its alprostadil-based gel Topiglan, which failed to hit endpoints in a Phase III trial. The company also disclosed in September that it had made a mistake in dosing, and Topiglan might not reach consumers until 2004.

MachroChem's share value fell by about 47 percent on the news.

NexMed Inc. also has an alprostadil cream, called Alprox-TD, in Phase III studies, and launched the product in Hong Kong last month under the trademark Befar. In the U.S. barring such hurdles as brown fat surprises and dosing boners NexMed aims to finish two pivotal Phase III studies by the end of this year, and submit a new drug application in the first half of 2003.

Phentolamine and alprostadil already are available as injection treatments for ED, but few men favor the prospect of jabbing themselves in the genitals hence the oral and topical formulations.

Because of Viagra's huge success, though, the PDE5 inhibitors are inspiring much talk among analysts and investors. Greene, speaking of the mystery behind the FDA's holdup of Cialis, might have been describing one of the vascular causes of ED itself, when he predicted details of the agency's concern will surface eventually.

"Over time, it leaks out," he said.

Whatever the concern, Greene and Nelson agree that Cialis is the best in the PDE5 class of treatments. Said Nelson: "Whether it's second-to-market best in class or third-to-market best in class isn't going to matter."

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