21 February 1999
3,325 words

Science and sales of sildenafil:
NO strikes again in the corpora cavernosa;
Pfizer's cost-benefit pitch for Viagra
Buy it on the web: "Online consultation" $85

NEW YORK--A trio from Pfizer, Inc. actually came up with some new story ideas about sildenafil (Viagra).

Pfizer realized that sildenafil had a "tremendous potential to be trivialized and marginalized," said Michael Magee, MD, senior medical adviser. They identified this and every other problem before the drug's launch, and prepared responses, he said. The only surprise was that the demand for information was even greater than expected. "We missed it by an order of 2 or 3," he said, although "we had all the issues right."

On the basic research side, the blockbuster drug was one more benefit of the discovery of the nitric oxide (NO) mechanism, explained Pierre Wicker, M.D., director of clinical research, Pfizer central laboratories.

They spoke at a meeting of Science Writers in New York (SWINY) on 9 February 1999 at the New York Academy of Sciences on E. 63 St.

Rounding up the group was Marianne Caprino, from Pfizer public relations, ready to jump in should there be any confusion over sensitive FDA-regulated issues like deaths in "temporal association" with sildenafil. But there weren't any glitches. They've been speaking around the country since the 27 March FDA approval of Viagra. Even by the high standards of cost-is-no-object pharmaceutical company presentations, this was a smooth, professional job. Behind every statement you could hear the admonitions of regulatory lawyers to avoid product claims that go beyond the package insert, without conceding much to their critics. The critical marketing goal, insurance coverage for Viagra, depended on public reaction (and the absence of adverse events and abuse). As a urologist, Magee understood the awkwardness and importance of erectile dysfunction (ED), and addressed the subject with seriousness. There were no Viagra jokes throughout the entire meeting--except for some ridicule of the managed care companies.

Nobel-winning discovery

On the clinical side, Wicker traced the development of Viagra at the Pfizer central research facility in Sandwich, England. Sildenafil was a failed angina drug with a serendipitous side effect of improving ED.

It's a good lesson in several important themes in pharmacology--the application of basic research to cardiovascular disease, the mechanism by which receptors in the vascular muscles cause blood vessels to expand and contract, the significance of NO in the vascular system, and the search for drugs that affect certain organ systems more specifically and avoid undesirable side effects. Once the biochemists understand a biological cascade, the pharmacists look for someplace in the cascade where a drug can alter the balance.

Nitric oxide (NO, not to be confused with nitrous oxide, N2O) is created in the endothelium of arteries. A gas, NO diffuses to the arterial smooth muscle cells and causes them to relax. This increases the blood flow and lowers the blood pressure. Nitroglycerine works by stimulating the release of NO in the coronary arteries. The discovery of this important mechanism won the 1998 Nobel Prize for Robert F. Furchgott, Louis J. Ignarro and Ferid Murad. (None of them worked for Pfizer, though Furchgott works in Brooklyn.) (For additional background, on the mechanism of NO on the protein, organelle, cellular and embryological level, in p53, capsases, mitochondria, apoptosis, cell motility, and angiogenesis, see Nitric Oxide research group, St. George's Hospital Medical School, U. London.)

Triphosphate to monophosphate

Phosphate groups are the ping-pong balls of biochemistry. The way to get an erection, in biochemical terms, is to knock off 2 phosphate groups from guanosine triphosphate (GTP) and turn it into cyclic guanosine monophosphate (cGMP). cGMP relaxes and expands the blood vessels in the penis, fills the corpus cavernosum with blood, and produces an erection. How do you knock off a phosphate group? With an enzyme: guanylate cyclase (GC). How do you get rid of the cGMP when you're done? With another enzyme: phosphodiesterase (PDE). The GC and PDE are in balance. That gives Pfizer a place to attack: PDE. There are non-toxic compounds that can inhibit PDE, and cause the cGMP to accumulate, in enough of a concentration to produce an erection. One of them is sildenafil.

(This mechanism is described with illustrations on the Nobel Prize web site, using the example of an even more important organ: the coronary arteries of the heart.)

Just say NO

The whole process, explained Wicker, starts with NO. The nervous system can release NO (with another enzyme). As the Nobel laureates discovered, NO activates GC. GC converts GTP to cGMP, which produces vasodilitation. PDE breaks down the cGMP--sometimes too quickly. Viagra inhibits PDE, and helps the patient get an erection.

But the NO-cGMP pathway is a widespread mechanism, found in many other places in the body, such as the heart and the eye, and PDE inhibition would cause side effects in those other organs. Actually, there are several different types of PDE: PDE3 in the heart, PDE5 predominently in the penis, and PDE6 in the retina. Sildenafil is fortunately selective for PDE5. PDE5 is 4,000 times as sensitive to sildenafil as PDE3, and 1,000 times as sensitive as PDE1, 2, 3 and 4. However, PDE5 is only 10 times as sensitive as PDE6, and that's the reason for Viagra's distinctive side effect--the "purple haze," a transient blue-tinged vision with about 3% incidence, which seems to be harmless. PDE5 is distributed in other vessels throughout the body, and sildenafil caused a blood pressure drop of about 10 mm Hg. That's harmless, and sometimes beneficial, but combined with other drugs, sildenafil can produce dangerously low blood and possibly fatal blood pressure--but more of that later.

Measuring improvement

In 1994, Pfizer started testing sildenafil for efficacy, but they needed quantifiable data for the FDA. In one laboratory test, placebo-randomized patients are "visually stimulated" while wearing a plethysmograph, which is like a blood pressure cuff for the penis. But there was no way to measure real-world sexual functioning. And so, said Wicker, Pfizer developed its own scale, a questionnaire called the International Index of Erectile Dysfunction (IIEF), which asks patients to record their ability to achieve and maintain an erection capable of intercourse. The IIEF, which has been adopted by urologists worldwide, is a source of great pride for Wicker, and is representative of similar scales in many disciplines of medicine, such as ophthalmology, where it is necessary to quantify the ability to perform activities of daily life.

With the IIEF in hand, Pfizer was able to demonstrate efficacy in the peer-reviewed literature and to the FDA. "There was efficacy in 2/3 of the men," said Wicker. They got an NDA in 1997, FDA gave sildenafil priority review, and approval 6 months later. With 380 patients on the highest dose (100 mg), 82% reported improvements, compared to 24% placebo, according to the package insert. With 268 diabetic patients, 48% of intercourse attempts were successful, compared to 12% placebo. With 178 spinal cord injured patients, 59% were successful, compared to 12% placebo. Unfortunately only 43% of the patients with radical prostatectomy for prostate cancer reported improvements. (These numbers would vary greatly with the degree of disability of the men selected for the study.) Studies are now ongoing with different subsets of patients.

Viagra in women?

There were several questions in the audience about the effect of Viagra on women. "There are preliminary studies, too early to tell," said Wicker, mindful of the FDA. Female sexual dysfunction is more subtle and complex, he said. There isn't that much known about it. The experts who best understand what little that is known, the speakers said, are Ellen Loan, in Amsterdam; Ray Rosen, in New Jersey, and Julia Heimann, in Seattle.

Clinical perspective

Magee, a professor of surgery at Jefferson Medical College, continued the presentation from the perspective of his day-to-day clinical experience. A disarmingly folksy country doctor with a knack for arithmetic, Magee entertained the audience with stories of HMO stupidity. Such tales of outsmarting managed care companies are always a big hit among doctors at medical meetings. But Magee gave a few tips that would be useful to skeptical journalists as well.

Sildenafil is a "safe, effective, natural alternative" to previous treatments for ED, said Magee. Instead of an injection, or a urethral insert, or surgery, Viagra is a pill. It's natural in the sense that it doesn't stimulate sexual activity, but enhances the response to a partner. The abuse potential is low. Higher doses produce more frequent side effects, but not a more intense effect.

Laughing at the disabled

So they had good, favorable data on safety and efficacy, so they could adopt a strategy of simply presenting the facts, said Magee. That wasn't as easy as it sounds, since they started with a lot of misinformation out there.

The Governor of Arkansas, for example, said, "I don't think people who are poor deserve any better sex than people who are rich," paraphrased Magee. Besides, said the Governor, "I don't think it's safe."

Kaiser-Permanente said that it was going to "break the bank," recalled Magee. Besides, they said, "We don't think it's safe."

Kaiser appealed to the Department of Corporations of the State of California for an exemption to the medical necessity rule. Magee didn't think that was rational or justified. "ED was already covered by methods that were more expensive," he said.

"We appealed," said Magee. There were public hearings in San Francisco and Los Angeles. He appeared at the hearings to rebut the HMOs.

Rebutting the HMOs

Kaiser claimed that sildenafil would cost them $150 million annually. "That's about 25% of the total revenue we project for the entire country," said Magee. The actual cost was "more like $10 or $15 million."

Blue Shield claimed that Viagra would cost $35 billion this year. Where did they get that number? That was extrapolated from the 30 million men in the U.S. with ED. But that turned out to be based on several unlikely worst-case assumptions.

Rebutting Kaiser was easier. "Kaiser decided not to give any data," said Magee.

Ancillary benefits

But when you get 15% of ED men to come in for treatment, you're getting a chance to treat the underlying disease. In 1 million men age 40-70, you will find 40,000 cases of untreated diabetes, 50,000 cases of untreated heart disease, and a similar number for untreated hypertension. "If you're going to do a cost-benefit analysis," said Magee, "consider treating diabetes early instead of having a man come in with a leg that has to be cut off."

At the Los Angeles hearings, the Commissioner asked the representative from Blue Cross whether they had taken account of this preventative health benefit. Blue Cross responded that they don't do cost-benefit analysis, said Magee. "The Commissioner was shocked."

"The numbers that were being thrown out and accepted were very weak," said Magee. Cost-benefit analysis was in a "much more primitive state than we had imagined."

The National Governors' Association said that Viagra was going to cost $100 million. "The figure proved to be more like $7 or $8 million."

Minnesota approved Viagra for Medicaid after a "thorough analysis," said Magee. It will cost about $150,000 for this year.

Suggestions for journalists

Magee has followed the press coverage very carefully. "We've visited every major editorial board in every major newspaper in the U.S.," he said. Ironically, the massive coverage worked against them. "This drug was so well covered, there was a sense that they really understood this product," when they actually didn't, he said.

The other impressive observation was that journalists, and everyone else, tended to accept the claims of the managed care companies unquestioningly, said Magee. Most people, he said, did not ask, "Where did you get these numbers?"

Magee suggested that journalists ask companies like Kaiser for their prescribing data. "Could you give us your scrip data for the first 5 months?"

"Why are people not doing a thorough cost benefit analysis?" said Magee. Someone should force them to justify their numbers.

Viagra is only the first, said Magee. There will be lots of drugs presenting these same problems "coming up the pike very quickly."

"If the business people are going to say that we don't have the capacity, the resources," to provide the newest medical care, said Magee, "let's just throw up our hands and go back to 1950s medicine."

(If I were getting paid for this story, I would give a response from Blue Shield and Kaiser here.)

3 case histories

One of Pfizer's strongest cards in promoting Viagra was case histories of patients who were successfully treated. In a twist, Magee gave 3 case histories of patients who had ED in the days before Viagra, with tragic results.

Today, with treatment for ED, "the first guy would have been married, the second guy wouldn't have divorced and lost his job, and the third guy would have been alive," said Magee.


"Did you anticipate those deaths?" asked Larry Katzenstein, author of Viagra: The Potency Promise (St. Martin's), and of a recent New York Times article on PSA testing for prostate cancer.

"There are adverse effects with all drugs," said Caprino. The difficulty is separating the deaths in "temporal association" with sildenafil from the deaths, if any, that are caused by sildenafil. Pfizer's position is that no cause-effect relationship has been established, although Mark Litwin, cited below, says that sildenafil is "partially responsible."

For the controlled studies, said Wicker, "the size of the database is pretty large." There was no differences in deaths between sildenafil and placebo, he said.

However, men who take sildenafil tend to be older, with cardiovascular problems that may or may not be related to their underlying conditions. Exercise alone may precipitate a heart attack. "Heart patients die a lot more [often] than other patients," said Wicker.

"Sexual activity is equivalent to climbing up 2-3 flights of stairs," said Wicker. "There is a risk."

"The American public realized for the first time," said Magee, "that if you had sex you can die."

There were 133 reported deaths on the FDA web site, said Magee, "after 3 1/2 million men on the product." There were "some temporal associations with intercourse." The actual mortality "falls quite short" of what would be expected in that population. Then again, there is no procedure in place to assure that doctors will report sildenafil-related deaths to the FDA's Medwatch program, and Medwatch officials openly admit that adverse events of drugs and devices are generally under-reported, in some estimates by 90%.

"It's not a perfect process," said Magee. Yet, sildenafil was administered to 3,700 patients worldwide at the time of FDA approval, and some patients continue to be monitored. "Viagra did not seem to be pushing the button," he said. "We know that there were not major crazy things."

Everyone, including the package insert, agrees that nitrate drugs, such as nitroglycerine, can be additive with sildenafil, and cause a fatal lowering of blood pressure. The nightmare scenario is that a man taking sildenafil will have a heart attack, be taken to an emergency department, and be given nitrate drugs by the emergency room staff.

Sold on the Internet

Viagra is widely sold and even prescribed on the Internet. For example, the Medical Center offers to give you a prescription for sildenafil after you take an $85 "online consultation", in which you promise to answer all questions truthfully, and agree to a lengthy waiver of liability.

"We were absolutely opposed to Internet prescribing because they bypass the doctor-patient relationship," said Magee. "There are reasons you should not give a Viagra prescription without seeing a doctor." ED is a marker disease, he noted, and as he repeatedly stressed, ED is a marker disease for other life-threatening diseases that will be treated or even diagnosed when the patient sees the doctor for a prescription.

The Lancet (352(9130), 5 September 1998, "Viagra's licence and the internet") reported illegal sales of Viagra, but Magee didn't think it was extensive. "There are no police reports," he said. The Internet prescriptions, which are legal in some states, at least allows them to monitor the activity.

Sildenafil does not enhance sexual activity in normal men without underlying pathology, said Magee. It restores dysfunction but does not improve normal function, he said. The evidence of that is the absence of a black market; normal men who try it don't continue to buy it.

Geriatricians are challenging the notion that men have a normal sexual decline with age, said Magee. (Although in the JAMA Laumann study cited below, ED increased with age.) So a doctor should prescribe Viagra after diagnosing an underlying pathology. But sometimes, he admitted when pressed, you can't find an underlying pathology, and sometimes those patients improve with sildenafil.

Web links

This week was urology week at the Journal of the American Medical Association. The 10 February 1999 JAMA published the first population-based assessment of sexual dysfunction since Kinsey, "Sexual Dysfunction in the United States: Prevalence and Predictors," Edward Laumann, et al., which is in full text on the web. This gold mine of data documented, for example, the relationship between sexual dysfunction and forced sexual contact in women or children; and with deteriorating economic status. One of the great innovations of former JAMA editor George Lundberg was the Contempo articles, which summarize the year's most important research in each specialty. This week's Contempo, by Mark Litwin, is on urology, covering sildenafil, the Nobel Prize, benign prostatic hyperplasia, and prostate cancer. (JAMA's site requires a free registration.)

Wicker's 14 May 1998 article in the New England Journal of Medicine has a linked editorial; the 3 September NEJM has letters reporting side effects.

The British Medical Journal recommended several sildenafil sites: Viagra Talk, Pfizer, the Pillbox pharmacy, and the U.S. FDA.

Free, full-text articles on the BMJ's site can be found by searching for "sildenafil". Noteworthy are stories including other methods of treating sexual dysfunction besides Viagra are ABC of sexual health: Erectile dysfunction and Update on male erectile dysfunction.

The Lancet has selected articles in full text and can also be searched after a free registration.

--Norman Bauman


The next meeting of SWINY is tomorrow, 23 February, 6:30pm (dinner), 7:30pm (tour) at the "Epidemic!" exhibit, American Museum of Natural History, CPW and W. 86 St. Be sure to bring a $15 check. If you haven't reserved your place already, it's too late. However, you can go to the regular media preview from 11:00am-1pm.

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