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Exploring the potential of drug repurposing

pharmafile | June 30, 2021 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | drug repurposing

Drug repurposing is a little like recycling. It is the process of finding new therapeutic uses for drugs that already exist, rather than creating something new.

This makes drug repurposing an effective strategy to discover existing drug molecules with new pharmacological or therapeutic indications.

The drugs that can be repurposed range from substances that are already used for specific illnesses or conditions, old drugs that aren’t used anymore, drugs that didn’t meet their primary endpoint in clinical trials, and shelved drugs.

It has been estimated that it costs approximately $1 billion to bring a drug from the laboratory to market, and this can take as many as 12 years. Additionally, when the costs of failed projects are considered, the real cost rises to about $2.6 billion.

Taking this into account, as well as pressure on revenues from generics as patents begin to expire, the interest in drug repurposing has unsurprisingly grown significantly.

Those involved in drug repurposing, also known as drug repositioning or drug reprofiling, range from charities, academic institutions, biopharmaceutical companies, and government divisions.

In theory, drug repurposing should cut down the time it takes to get a drug to market to as few as one to three years, as well as reduce the cost and risk involved.

Less time, money, and resources are needed to discover new uses for existing drugs, but how does drug repurposing work in reality?

How are repurposed drugs found?

In many cases, repurposed drugs are discovered completely by accident. When drugs are in clinical trials, many side effects are reported. These side effects are often negative, but sometimes they may prove themselves to be useful.

There are several famous examples of this, one being sildenafil. Sildenafil was first tested clinically for hypertension. During clinical trials, patients reported a rather interesting side effect that seemed worth noting. This side effect − persistent erections during the clinical trials − led sildenafil to be repurposed as Viagra for the treatment of erectile disfunction.

The same compound drug has also been further repurposed under a different dosing schedule as Revatio for pulmonary arterial hypertension. More recently, it is being explored for the treatments of certain types of cancers.

These discoveries don’t always happen by luck, some drugs fail in what they were first intended for, such as thalidomide. It was developed in the 1950s as a sedative and treatment for morning sickness in pregnant women, but was quickly withdrawn once serious birth defects in newborn babies became clear.

A closer look at the chemical structure of the compound demonstrated that thalidomide was in fact an effective treatment for leprosy. Even more recently the drug has been approved for the treatment of multiple myeloma.

What makes drug repurposing appealing?

New drug discoveries have significantly high failure rates, high costs, and a longer time to market.

Because pre- and early-clinical trials provide important information on the toxicity and tolerability, it can cost as much as 60% less to repurpose drugs compared to new drugs that enter the market, as well as a greater than 30% success rate, compared to the less than 10% success rate of new drugs entering the clinical stage of development.

Pharmafocus spoke to Lydie Meheus, PhD, Managing Director of the Anticancer Fund, about drug repurposing, she said: “There’s the term hard repurposing and soft repurposing, the term drug repurposing is used for, on the one hand, hard drug repurposing, meaning that you’re finding a new use outside the scope of the original medical indication for existing drugs.

“Hard repurposing means that a new use is outside the field of the original indication, for example, a drug from the field of cardiology that you repurpose in oncology. And then soft repurposing is when you stay within the same indication. If you’re within the oncology field, there is a lot of repurposing, meaning from one oncological indication to another.

“You have existing drugs that are in the market, but you also have existing drugs which are shelved, have been in Phase II or even Phase III, but that were never approved for human use. That’s what we called shelved drugs. Of course, you have a lot of the companies who own those drugs, have a lot of information on them, and a big part of the development work has been done.

“It’s certainly cheaper, but also for commercial development it’s cheaper, so there’s more activity where people try to find new targets for drugs that are already quite developed. It makes it a cheaper development, and you have companies specialising to buy those drugs from companies who have shelved them.”

Limitations

Bessi Qorri, a published researcher pursuing a PhD in Experimental Medicine at Queen’s University in Kingston, explained in a Tedx Talk: “Drug repurposing is still associated with its own set of challenges, the first and potentially most important is a long-standing scepticism.

“People, particularly patients, can be reluctant or sceptical to believe that a drug, especially a generic drug, can do anything other than what they believed it to do for years. It’s important that we adopt a more open-minded approach to drug repurposing as patient education is a crucial component for therapy success.”

Qorri continued: “We’re at the point where generic drug repurposing is considered to be in a state of purgatory. And this is likely due to the lack of financial incentive, which is a major driving force for getting a drug to the market.

“There is no current way for a pharmaceutical company to charge a higher price for a drug to treat a new condition, while patients can continue paying a lower price to treat the original condition. And this is likely why no generic drug has been repurposed without modification of its dose or its dosing schedule, both of which would provide patent protection.

“However, most of the repurposing uses for generic drugs have already been reported in the literature, and this public disclosure reduces patentability. And no patent means no profit, and no profit means no incentive.

“Even if a method-of-use patent can be secured for a new use for a generic drug, there still might not be any profit, especially if this drug is available from many manufacturers, as a physician can just as easily prescribe another manufacturer’s drug.

“Until a payment system is implemented that allows the company to reasonably recover its investment on repurposing a generic drug, generic drug repurposing will not effectively take place in the pharmaceutical industry.

“Now, it’s evident that these challenges cannot be overcome by quick fixes, and rather require a collaborative effort between the pharmaceutical industry and regulatory officials. But it’s important that we don’t let these challenges distract us from the main issue at hand, and the main goal of healthcare, which is to get effective treatment to patients faster.”

Hopes for the future

Meheus also spoke about the future of drug repurposing, as well as its limitations. She said: “There will be more drug repurposing, first of all because more drugs will become off patent.

“But, what we urgently need is a better framework for drug repurposing, because, in terms of the inconveniences of using drugs off label, besides reimbursement issues and liability, you also have supply issues.

“Because the original indication is not of interest anymore for the pharma company, they stopped producing the drug. We’ve seen a problem like that with an antiviral drug called nelfinavir. It’s not used and there is even for the time being no generics, because as an antiviral product it’s not that popular anymore, it was used for AIDS, but there are some really interesting indications in cancer.

“Therefore, I think it’s important that we make efforts. If there are new indications, with solid evidence, that in the end, it’s brought on label. And therefore, we need a new regulatory frame to make it possible, even if the market authorisations are not really interested that there is a way of regulating off label use, I don’t expect the market authorisation holders to be interested in spending money when there is no guarantee of decent return.

“I think we have to find solution by the private public collaborations, and so on, because the permission has been worked and we contributed to that during two years to define framework, it’s called the Commission Expert Group on Safe and Timely Access to Medicines for Patients (STAMP), here really the idea is still that as a third party, champion, and non-profit organisation of a collaborative group it can do all the clinical development work, and then provide a data package to the market authorisation holder, who then has to submit it to the regulator, and the company can add that indication to the label. I understand that even if they receive, let’s say the data package for free, they still may be reluctant to take action.”

Qorri finished off by commenting: “Fortunately, though, we’re moving in the right direction. We need to continue to push for preliminary findings of repurposed generic drugs into the clinic where they can continue to help people. And this is where advocacy groups, non-profits, and foundations play a big role.

“We’ve come up with innovative ways to even further expedite this process. It’s the breadth and depth of scientific knowledge available to us from pre-clinical and clinical trials, in combination with technological advancements that now actually permit us to mine information. And in this way, we can engineer those happy accidents that match a generic drug to a new target as opposed to relying on the serendipitous process that it once was.”

Final thoughts

In theory, drug repurposing is a great idea. It can offer a faster, cheaper, and more effective way of discovering new drugs that could potentially save many lives, particularly those with hard-to-treat cancers and rare diseases. However, it can be hard to fund for a number of reasons, such as scepticism and a lack of financial incentive. A system is needed to allow drug repurposing to be a more viable option, such as through collaboration, and technological advancements. If this happens, there is huge potential to find new treatments in the future by repurposing the tools already at pharma’s disposal.