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With the expiration of the last patents of the drug for erectile dysfunction, the interest in finding new treatments has renewed. David Cox reports.
Are we witnessing the end of an era for Viagra and Pfizer?
Since the famous "little blue pill" burst onto the market in 1998, becoming the fastest selling drug in history, the pharmaceutical giant has made huge sales of it to erectile dysfunction sufferers worldwide.
Within three months of launching, Viagra had already earned Pfizer $ 400 million, and in the last two decades it has consistently generated annual sales of $ 1.8 billion.
However, this will be over soon, as Pfizer's remaining Viagra patents expire forever in 2020.
Over the last six years, a whole range of common versions have emerged, often in strange shapes, such as mint strips or breathing sprays, as Pfizer's power over the rights to the drug slowly loosens.
They are soon expected to flood the market as manufacturers clash with a slice of pie.
This will make Viagra, which is made at the Pfizer plant in Ringaskidi, Co Cork, more affordable and cheaper, but for millions of men worldwide with erectile dysfunction, it can also write good news in the form of much needed innovations in the treatment.
Since Viagra was launched, several truly new therapies have been developed, and while Viagra and similar drugs such as Cialis and Levitra – all of which increase blood flow to the penis by blocking an enzyme known as PDE5 – are effective in about 70% of patients, they come with significant disadvantages.
For starters, there are often side effects ranging from headaches to stomach pains.
In addition, if Viagra takes more than an hour to work, there is a need for prior sexual planning, and in older patients, medications can often be inappropriate due to potentially dangerous interactions with high blood pressure or hypertension drugs,
For patients with the most severe forms of erectile dysfunction, often as a result of nerve damage due to diabetes or surgery for prostate cancer, Viagra usually does not work at all.
The need for better treatments is especially urgent as erectile dysfunction seems to be becoming more common, with global prevalence reaching 300 million by the middle of the next decade.
Scientists have long argued whether this is simply because men become more open about their problems or whether it is a byproduct of other health problems. One thing is clear: the market is growing.
"There is a tremendous need for new treatments to work in the widest possible population of patients, while having a longer-lasting effect on improving spontaneity and reducing the stress of having to be scheduled," says Dr. Samit Sonny, urologist at Baylor College of Medicine in Houston, Texas.
Many patients would like to be able to take something and then not worry about it for 30 days.
But at the moment there are several options.
The only viagra alternatives are medicines that need to be injected directly into the penis shaft to improve blood flow, or complicated surgery to fit penis pumps or prosthetic implants. None of them are particularly pleasant.
So why is that? While a handful of pharmaceutical companies try and fail to bring competing drugs into the clinic, the full scale of Viagra's profit machine creates a monopoly, with most companies deflecting the challenge, taking it as too great a risk.
But experts believe this may be about to change.
"For many years after Viagra was developed, there was little change in our understanding of erectile dysfunction and how to correct it," says Sony.
"But with the expiration of the patent, interest in alternative avenues for the treatment of erectile dysfunction and their use to develop new ideas that can be patented and to secure a sustainable profit for the industry is definitely renewed."
Viagra 2.0
In the early 2000s, scientists at the pharmaceutical company Futura Medical, a pharmaceutical company in Surrey, came across stories of heart disease medications that seem to have triggered an erection.
"There have been some anecdotal reports that people intentionally spray this product on their penises," said Ken James, head of research and development at Futura. "These observations have been reported in the scientific literature and the company believes there may be a commercial opportunity."
The effects reported are due to a particular molecule known as glyceryl trinitrate or GTN, which causes the blood vessels to expand into the penis, increasing blood flow.
The reason Futura was so intrigued was that while Viagra, Cialis and other medicines should be taken orally – meaning that they reach the target area through the bloodstream and thus interact with other systems in the body – GTN can rapidly absorbed into erectile tissue through the skin.
This means that it can potentially be applied directly as part of a gel or cream, with almost instant results and none of the problematic side effects associated with Viagra.
"Viagra and Cialis are pretty effective drugs, but 50% of people stop using them within a year," James says.
"60% -70% of people have some dissatisfaction with them. This shows that there is an opportunity if we can market something that addresses many of these problems. "
Over the past decade, Futura has developed a GTN-based gel called Eroxon that appears to be able to erect an erection in patients with mild to moderate erectile dysfunction in five to ten minutes.
Already headed by the new Viagra by some, it looks like it has the potential to be the first truly new cure for erectile dysfunction in two decades, and Futura even tentatively set its potential market value at $ 1 billion.
After investors showed new interest in supporting new treatments for erectile dysfunction, Futura completed a clinical trial of 232 patients last year and now begins the last phase III trial of 1,000 patients, which will be completed by the end of 2019.
If successful, Eroxon may become clinically available within the next few years, although urologists remain cautious.
"The biggest question from this Phase III study will be how they compare in clinical efficacy with Viagra," says Sony.
"We have seen in the past that it is difficult to achieve such efficacy with topical administration, but at the same time our understanding of how drugs can be absorbed through the skin in the bloodstream has improved massively."
Supporting the most severe cases
But even Futura scientists admit that Eroxon is unlikely to help the worst cases of erectile dysfunction, affecting about 20-30% of patients, usually due to nerve damage to the lower abdomen.
There have been few opportunities for these people in the past, but over the past five years, renewed interest in erectile dysfunction has seen research programs spend more time and money on clinical trials of a technology known as shockwave therapy.
Unlike Viagra or Eroxon, this seeks to reverse the problems that cause dysfunction by passing low-intensity sound waves through erectile tissue.
Scientists are still not entirely sure how or why it works, but so far, they believe it leads to a form of erectile tissue regeneration, promoting the growth of new blood vessels and clearing the plaque from existing vessels.
"Improving the function of these vessels leads to improved blood flow and erection in these patients," explains George Hatsihristodulu, who studies shock wave therapy at the University of Wurzburg in Germany.
However, because there is such a wide range of causes for erectile dysfunction, shockwave therapy is currently only known in a subset of these patients, especially in those with diabetes or hypertension.
Hatzichristodoulou points out that further data are still needed and a series of shock wave trials are currently underway in Europe and the US.
But compared to Viagra or Herxon, one of the great promises of treatment is that it will not be needed on a regular basis. Instead, patients can simply undergo maintenance therapy at half yearly or yearly intervals.
The most excruciating attempt to restore the natural function of the penis is directing the eventual treatment, a hope that can still be realized in the years ahead.
Look for a completely cured cure
Even when Viagra works, one of the problems for people who have to take it indefinitely is that it becomes less effective over months or years.
"It's quite common. Most patients will experience a worsening of their erection after being on Viagra for some time, "says Hatzichristodoulou.
"They have been taking Viagra for five, six, ten years, and some days think there is little improvement in function."
The despair has pushed many patients to unscrupulous private clinics around the world that promise end-to-end treatment, offering treatments such as shockwaves, stem cell infusions and unregulated platelet-rich plasma injections.
But all of these therapies are highly experimental – as an example, shockwave therapy is currently only approved by the US Food and Drug Administration to promote wound healing, as scientists are still working to determine the best doses for efficacy and examine long-term safety.
"There is some particularly convincing evidence of shockwave therapy, especially in certain patients," says Sony. "But it's still in its early stages."
Although scientists hope that shockwave therapy may be ready for the first time within the next five to 10 years, progress is also being made with longer-term treatments, such as gene therapy that may offer full treatment.
At the Kaiser Permanente Research Unit in Northern California, a group of scientists have identified a genetic switch that is considered unique to sexual function.
They believe that this switch plays a crucial role in controlling the brain signals that trigger erection, and new genome-editing technologies like Crispr-Cas9 may one day allow scientists to activate this switch in patients.
"This genetic location is part of a pathway that is involved in a number of different systems in the body, from pigmentation to weight to sexual function," explains project manager Eric Jørgenson.
"But what's exciting about it is that it looks very specific to sexual function, which would allow it to target that location and not disturb anything else in the body. But there is a long way to go. We need to understand the exact part of the brain where this switch is active and then try to point it at mice. "
Because genome editing is still such an experimental concept, Jørgenson says it will take time for regulators to make sure it can be safe.
"The first applications of Crispr-like technology are likely to be in patients who have a more immediate medical need for experimental therapies," he says. "You will need to have very safe treatment before people resolve it for erectile dysfunction."
Although gene therapy may be a bit distant, there are still new treatments for erectile dysfunction on the horizon for the first time in decades. With the end of the Viagra era and the increase in available research funding, the field has been in its healthiest state for years.
"There has been no real innovation in erectile dysfunction for many years," says Sony.
"These new breakthroughs and treatments offer excitement in the realm of healthcare that has long been dormant."
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