Viagra (sildenafil), Pfizer’s blockbuster drug for erectile dysfunction, is a classic example of how a drug developed for one thing can turn out to be successful for another.
Viagra (sildenafil), Pfizer’s blockbuster drug for erectile dysfunction, is a classic example of how a drug developed for one thing can turn out to be successful for another.
Sildenafil, a PDE-5 inhibitor, was originally being developed for hypertension and angina. During clinical trials, they noticed it caused erections, and the company was quick to develop the drug for that market.
“In some ways, repurposing is a standard part of drug development,” Pan Pantziarka, from Brussels’ Anticancer Fund, told Pharmaceutical Journal. “Once [a pharmaceutical company] has a license, they then seek to repurpose [the drug].”
Pantziarka is director of the Repurposing Drugs in Oncology (ReDO) project. This is an international collaboration between the Anticancer Fund and GlobalCures, a Massachusetts-based not-for-profit drug development group.
PDE-5 inhibitors have potential applications in cancer, heart failure, neurodegenerative disease, circulatory disorders and infectious diseases. There are, according to the U.S. Food and Drug Administration (FDA)’s trials registry, more than 650 trials for PDE-5 inhibitors. Pharmaceutical Journal writes, “But with the first generation PDE-5 inhibitors off-patent since 2013, and limited interest from the pharmaceutical industry, there is no clear path to repurposing.”
ReDO came into existence, in part, because of the problems in running clinical trials with off-patent drugs. “I became involved because my son had osteosarcoma, and he didn’t respond to standard treatments,” Pantziarka told Pharmaceutical Journal. “I found that there were people who were looking at non-cancer drugs which had some evidence of activity in cancer.”
He went on to say, “Our intention is to find treatments we can get to patients quickly and repurposing really fits the bill very well. You can bypass the early stages of trials, so in theory the path should be clear to rapid adoption, should we have positive results.”
Three of the cancer drugs that come to mind when thinking of repurposing drugs are Celgene’s Thalomid, Revlimid and Pomalyst. All are highly successful cancer drugs and all derive from thalidomide. Thalidomide was first marketed as an over-the-counter sedative in West Germany in the 1950s under the trade name Contergan. It was later marketed as an anti-nausea medication and to alleviate morning sickness in pregnant women, although in 1960, the FDA rejected it for morning sickness over concerns about side effects.
It was also marketed in the UK, Australia and New Zealand as Distaval. Not long after approval in Germany, children began being born with phocomelia, a malformation of the arms and hands. Approximately 40 percent of those afflicted survived. Worldwide, about 10,000 cases were reported, with a global survival rate of 50 percent. The most common defects were “flipper-like hands” or even stumps. There were other deformities as well.
After being pulled from the market, thalidomide was studied in a number of different diseases. Eventually, it was used to treat leprosy in other parts of the world. In 2005, Celgene received approval for its version of thalidomide, Revlimid, for mantle cell lymphoma, and a year later, for multiple myeloma.
ReDO has created a database of about 270 drugs that have the potential to be repurposed for cancer therapies. Some are PDE-5 inhibitors. In cancer, they seem to have an immunological effect. One suggestion has been they could be used in cancer patients post-surgery to decrease the risk of cancer reoccurrence. They also appear to enhance patient response to chemotherapy.
Paul Dent, with the Virginia Commonwealth University, told Pharmaceutical Journal, “PDE-5 inhibitors have really proven to be excellent drugs for repurposing in anti-cancer therapeutics. We were able to show that Viagra enhanced the lethality of breast cancer chemotherapy doxorubicin against prostate cancer cells.”
The role of PDE-5 inhibitors in cancer appears to be broadly related to its improvements in cardiovascular blood flow, which allows the drugs faster access to tumors. More obviously, they would have benefits in cardiovascular disease, since they dilate arteries and improve blood flow. Pfizer also markets Revatio (sildenafil) and Eli Lilly and Company markets Adcirca (tadalafil) for pulmonary arterial hypertension. Lilly markets tadalafil as Cialis for erectile dysfunction.
“But newer lines of evidence are saying that they’re actually having a direct effect on the [heart] tissues,” David Hutchings, honorary clinical lecturer in cardiovascular sciences at the University of Manchester, UK, told Pharmaceutical Journal.
However, some PDE-5 inhibitors haven’t fared as well in cardiovascular clinical trials.
There is other work involving PDE-5 inhibitors in neurological disorders, such as vascular cognitive impairment, a type of dementia caused by insufficient blood flow to deep brain areas. There has also been work at the use of these drugs to treat traumatic microvascular brain injury in American football players.
And although not as obvious, PDE-5 inhibitors may have antiviral and antibiotic properties, although the work is yet unpublished.
The disincentive for developing these drugs, however, is that many have become generic and are manufactured by dozens of different companies. Companies are cautious to invest in clinical trials for drugs they don’t have major control of or for which there’s already potential competition. And, Pantziarka notes, in Europe, “if you want to license a drug for a new medical indication you need to be a manufacturer, you need to have the marketing authorization. So a not-for-profit organization can’t turn up at the European Medicines Agency (EMA) or the Medicines and Healthcare Products Regulatory Agency and say, look, we have got evidence that sildenafil is an anti-cancer drug.”
