How Viagra nearly flopped: a sober tale of drug development

A few days ago Pfizer’s patent on Viagra expired – meaning that any other company can make and sell the drug – even the BBC covered the story! This reminded me of a lecture I was lucky enough to hear at the 2012 UK Pharmaceutical Science conference by Dr David Brown, the project leader during the early stages of the drug’s development program. The fact that Viagra was one of Pfizer’s failed angina drugs is well known (and again covered by the BBC), but David Brown’s talk highlighted just how close the whole project came to failing on several occasions. His talk had three features: he was a good speaker with a great story, but it was also a personal journey.

What was interesting for me (and really anyone else involved in developing new medicines) was the how close this international blockbuster drug (which at one time made more money than the GDP of some countries!) came so close, so often, to being ‘canned’. David Brown’s lecture overturns the ‘Powerpoint-presentation’ concept of systematic ‘straight-line’ drug development – it’s more like a game of snakes and ladders!

How it works

Before the history it might be worth mentioning how Viagra – or to give it it’s proper name sildenafil – actually works. Since most modern drugs are chemicals, it’s significant that science is now at a point of being able to understand the chemistry that controls biology.

Many of the body’s biological ‘systems’ are interlinked and the mechanism that controls penile erections starts with nitric oxide – a short-lived chemical, produced by lots of different cells in the body, but mostly associated with relaxing the ‘smooth muscle’ linings of blood vessels. Once it’s released, nitric oxide ‘switches on’ an enzyme called guanylate cyclase, which in turn  ‘bends’ two parts of the molecule ‘GMP’ into a ring, making cGMP (the ‘c’ standing for cyclic), as shown in the diagram below.

Structure of cyclic guanosine monophosphate (cGMP)

Structure of cyclic guanosine monophosphate (cGMP) (Photo credit: Wikipedia)

cGMP relaxes the smooth muscle in the blood vessels that controls the flow of blood to the ‘corpus cavernosum’ – an inflatable ‘sponge’ within the penis. The body has a clever mechanism for getting rid of unwanted cGMP – because a sustained erection (called a priapism) is medically dangerous – by breaking it down using another enzyme called PDE (the full name is cGMP-specific phospgodiesterase type 5!). Viagra/silenafil blocks (or inhibits) PDE from breaking cGMP down, allowing cGMP levels to stay high, leading to more smooth muscle relaxtion, high blood flows and a larger corpous caverosum.

A simple analogy would be if one man, ‘The cGMP-guy’, had a job stacking bricks and another, ‘The PDE-guy’, was employed to take them away again. If they co-operated they could build a small tower: but if The cGMP-guy gets tired, or The PDE-guy speeds up, nothing will get built. Viagra/sildenafil tells The PDE-guy to take a tea-break, letting The cGMP-guy catch up!

The rocky road to develop Viagra/sildenafil

The project began in the mid-1980’s with the intension of developing a drug for blood pressure. As work progressed the lead compounds in the project were studied as potential angina medications. Nitric oxide, remember, controls the smooth muscle around walls of blood vessels and so is a key component in opening up blood vessels, reducing blood pressure and relieving angina. Glasgow University got involved in the story in 1988 providing the project team access to a FPLC (Fast Protein Liquid Chromatograph) to try and identify which proteins and enzymes Viagra/sildenafil acted upon. (Interestingly enough the academic, Miles Houslay, now works in my ‘hood in SIPBS at Strathclyde Uni.)

In 1990 the compound was put into a pre-clinical animal toxicology study and was reported as ‘lethal’. This result nearly killed the project off, but the Pfizer team eventually found that the external tox lab had mixed the compound up with another one, and that sildenafil was pretty benign! (A very scary story that for any of us professionally involved in clinical development using external labs!).

As part of his role within Pfizer, David Brown was involved in other drug development projects, including one targeting erectile dysfunction (ED) using a neurological stimulant which would act as an aphrodisiac. The project was quickly rejected, but he now had access to a detailed ‘Target Product Profile’ for ED that included data such as medical needs, market size etc, and this knowledge eventually became a keystone in the Viagra/sildenafil story.

Between 1991 and 1993 Viagra/sildenafil progressed through Phase I and II clinical trials, uneventfully, but the data didn’t show it to be particularly effective against angina. With hindsight this seems obvious because although the drug was developed to act on the nitric oxide pathways that control the muscles around blood vessels, sildenafil acts on the closely associated PDE/cGMP systems which are found mainly in the penis and retina. In summer 1993 the project team was given 3 month deadline to prove its effectiveness or the project would be terminated.

Nearly dead

Shortly after the ultimatium was given, a preplanned study was run in health male volunteers. At the end of the study the test group was gathered together for a questionare. To the final ‘any other comments’ question, one guy mentioned sustained erections, to which the rest of the group quietly concurred. When this was reported back to David Brown as a side-effect he had two pieces of crucial information at hand: the market potential for an erectile dysfunction therapy from the work on the abandoned aphrodisiac project, and published scientific information on the role of nitric oxide, cGMP and PDE in dilating blood vessels.

However there was one last challenge – a study in erectile dysfunction patients was need to ‘seal the deal’. The problem was that the Viagra/sildenafil project was just a few weeks away from termination: clinical trials are expensive, what manager would approve spending funds on a study what was known to be for the chop? One of the Pfizer bosses agreed (at, Dr Brown believes, significant professional risk) to fund an additional study. Out of 12 impotence patients, 10 responded and when these findings were reported the project was ‘fast tracked’ through Pfizer, and because it was so successful in subsequent trials, sped through the regulatory process. Even at that it took another 5 years to reach the pharmacies.

So…?

In concluding, David Brown highlighted serendipity but also being prepared, being tenatious, being commited and the effective, trusting and risk taking research structure around him at Pfizer. At the end of the talk I asked  what I suppose is an impossible question: how many other blockbuster therapies currently sit on the pharmaceutical development scrapheap? The answer is no-one knows.

David Brown has moved from Pfizer and is now a freelance consultant, but he also works for charities providing education and healthcare in developing countries: a subject he didn’t get time to talk on. At the end of 2012 I invited him to be the plenary speaker at our local SIPBS Researchers Day, but he declined. In his email he told me would rather look forward to the future than dwell on the past: a powerful statement from a scientist with such an astounding past!

Related links

One World Health: one of the charities Dr Brown is involved with which seeks to provide medicines to developing countries: http://www.oneworldhealth.org

On-line PDF of a similar lecture given by David Brown in Cambridge

http://www.cfel.jbs.cam.ac.uk/resources/presentations/downloads/2012/brown_serendipity.pdf

A research paper on the chemistry and synthesis of sildenafil (which was the subject of another separate patent)

http://www.erowid.org/archive/rhodium/pdf/sildenafil.synthesis.pdf

An interesting schools resource by Pfizer which explains the chemistry and biology of sildenafil in a simple and systematic way http://resources.schoolscience.co.uk/pfizer/viagra/

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