Recovering the Value of Repurposed Drugs

Repurposing drugs-redeveloping drugs that have already been approved for one use, for another-has been going on for decades. Pfizer’s Viagra was originally developed to treat high blood pressure and angina; Celgene redeveloped the infamous teratogen thalidomide, as a treatment for leprosy and multiple -myeloma.

In the past, repurposing efforts were usually ad hocor the results of serendipity. Within the past few years, as the cost and time required for coming up with new drugs has risen to new heights, efforts are becoming more systematic and focused. In addition, more companies are exploring the development of repurposed drugs via the 505(b)(2) pathway of the US Food, Drug, and Cosmetic Act, and orphan drug indications.

A number of companies, including S M Bioech (Barcelona, Spain) and Biovista (Charlottesville, VA), are focusing on drug repurposing, using in-vitro and animal studies to evaluate potential candidates. In addition, patient groups and nonprofits, notably Chicago-based Cures Within Reach, are working with medical researchers on key projects.

In the United Kingdom, HealX matches potential repositioning targets to rare diseases. The company recently set up the Cambridge Rare Diseases network to advance this work. Transparency Life Sciences, which calls itself an “open innovation” company is working to crowdsource repurposed drug projects.

The only way to make a connection between a potential candidate for repurposing, and applications, is by checking the patent literature and data. A number of commercial da-tabases are available, in addition to databases on patented drugs. Consultant Hermann Mucke, based in Vienna, Austria, is a specialist in drug repurposing. He is currently developing the Discontinued Drug and Candidate Database (DDCD) as a reference tool to facilitate the identification of potential repurposing candidates.

The DDCD uses information going back to the early 1990s, and includes data on APIs discontinued from development or pulled from the market. In addition to chemical structure, international non-proprietary names (INN) and/or research codes, pharmacological activities, key literature, and patent references, the database contains developer statements and analyst assessments. Currently, Mucke’s H.M. Pharma Consultancy is using the database as an internal tool, but he hopes to secure funding to develop and publish the database-ideally, as an open-access tool that would facilitate drug repurposing. Mucke recently shared his insights into repurposed medicines with Pharmaceutical Technology.

The repurposing processPharmTech: How did you get into the field of repurposed medicine?

Mucke: I have been in the field since long before the term ‘drug repurposing’ was even used. I was involved in the repurposing of galantamine, a drug originally sold in Eastern Europe in the 1950s and 1960s to treat myopathy. The drug also inhibited cholinesterase, which made it an interesting candidate for repurposing when the cholinergic hypothesis of Alzheimer’s disease was advanced in the 1980s. It was only available in small quantities and was very expensive. Eventually, Janssen Pharmaceuticals launched it as Reminyl (later, Razadyne), a treatment for Alzheimer’s disease, in 2000.

PharmTech: How large is the potential market for repurposed drugs? Has anyone come up with an estimate?

Mucke: It’s very difficult to attach a monetary size or market volume/ unit volume to repurposing. My impression, however, is that the market could grow by a factor of 10 without a problem within the next decade. We are going to see developments that we can’t even imagine now. I’d say that, taken altogether, perhaps 10% of the entire pharmaceutical market is in some way related to repurposing.

PharmTech: How do you find potential candidates for repurposing? What data are already out there?

Mucke: There are some good subscription databases, such as those offered by Thompson Reuters and GVK Biosciences, which leverage these companies’ huge data pools for repurposing. H.M. Pharma Consultancy approaches the challenge bottom-up. We are trying to develop a database that would theoretically look at each and every compound that has been reported on. Right now, we have a few hundred core compounds with structures, activities, and research and development history summarized and annotated. We’re using it internally now, and haven’t begun the programming and development work.

PharmTech: What is the general process, at the start, for repurposing a drug?

Mucke: You have the basic strategy of looking for candidates, you have the structure of the molecule, and you build on structural and pharmacological similarities and use your knowledge about biological and biochemical pathways and their interconnections to see where you might pitch your candidate. You try to achieve something that hasn’t been recorded for this particular drug.

You have to be a clever pharmacologist and connect the dots in new ways. Very often, you just try to think of a new application where you know that the known pharmacological activity should be of some use.

Repurposing drugs is a universe unto itself, and we have barely scratched its surface. There are enough APIs, in theory, for many, many years, if not decades. This is why repurposing has become such an important strategy in drug development.

Outsourcing opportunity?PharmTech: What role do contract research organizations (CROs) and contract manufacturing organizations (CMOs) play in drug repurposing? Are there any new business models that you are seeing in CMOs that work in this area?

Mucke: Right now, I think the potential of CROs in drug repurposing is not sufficiently well utilized, which is a shame.

PharmTech: So, how would a contract services partner fit in?

Mucke: With drug repurposing, you have a different starting point than you do for new drug entities, one that calls for a stronger partnership between sponsor and CRO.

Of course, you can just ask for specific studies from different contract companies and choose the least expensive one. A better strategy is to find a CRO or CMO with a clear understanding of what you want to do and make that company your partner.

You will want to change the route of administration, or at least the presentation, to prevent cross prescription problems. In most cases, you switch to a new target population, and you don’t know what the acceptable dose is. This is what CROs and CMOs do best.

CROs’ expertise could be much better utilized if repurposing projects could be treated as true joint development projects, particularly if the repurposing company is a university institute, or a newly established academic spin-off.

PharmTech: What mistakes are typically made in drug repurposing projects?

Mucke: The most important thing to realize is that repurposing a drug does not automatically make its development cheaper or quicker. It reduces risk of failure because the drug has already been investigated, or even approved, in humans. You are not starting from ground zero.

PharmTech: Where do you see outsourcing service companies working in in repurposing, in the future?

Mucke: Many CROs have picked up on the repurposing trend, but they are not typically the largest ones. They are well acquainted with life science aspects of repurposing, from discovery to animal testing and clinical trials. Generally, they are also experienced with regulatory issues. In most cases, however, they are not familiar with the challenges of patenting.

Questions to ask are: what sort of timeline can you offer? Will this project follow the 505(b)(2) pathway? Will it be for an orphan drug project? You should also know the people at regulatory agencies who have worked on cases like this in the past. Before considering all this, however, you must establish that the patent situation allows, not only for freedom to operate, but also to develop any new intellectual property.

On the clinical trial side, you might run into some of the same problems that you would have with a new drug, even if you know the mechanism and what the acceptable dose in healthy humans is.

In theory, you should be able to start at Phase I/II, but you will typically change the route for administration, which will require a new formulation. In any case, you’ll also be targeting a new patient population, which could have quite different pharmacokinetics and pharmacodynamics (PK/PD properties) when compared to the population for which the original drug was first investigated. You must be prepared for surprises all the way along. In the end, it is still less risky to do than a new chemical entity (NCE), but it is not, a priori, cheaper or quicker.

A repurposed business modelPharmTech: Is there an issue globally with different regulations?

Mucke: Not really. Much has been harmonized. There are two basic ways for repurposing a drug that have been approved, 505(b)(2) in the US, or the hybrid application in Europe. There are some differences between these two approaches, but they share many characteristics, so you can often request a common review, which may involve a few additional studies.

Also, if the compound had never been approved before, there is no longer a significant difference between Europe and the US, although I don’t know about Japan.

PharmTech: What business models are you seeing, and where do you see innovation on the business side?

Mucke: Smaller companies often work the classical NCE strategy: to develop the drug candidate to the point where they have the greatest leverage they can manage financially (i.e., to the conclusion of Phase II). Then they can try to outlicense it.

This approach requires high capital investment, but it is still manageable to work with a CRO to get to Phase II. Unless they are working towards an orphan indication, or perhaps a tropical disease where the World Health Organization (WHO) might help with financing, they will not advance to Phase III.

Another small-company strategy is to work in silico, to develop unique algorithms and run them against compounds with known structures. They can then work with a CRO to try to substantiate these initial in-silico hits in animal studies. This approach doesn’t require much investment, but doesn’t provide much leverage either.

And then there are those who work with Big Data--they mine the literature, patents, and side effect data to identify potential repurposing candidates. If you are with a large pharma company, you might want to repurpose your own universe of unexplored compounds. Big Pharna has the patents, undisclosed test results, and the expertise.

So, unless you are with Big Pharma the options are not so different from what you would have with a NCE: -identify and sell early-stage repurposing candidates, or push the work to clinical proof-of-principle, and then attempt to out-license it, perhaps to the original developer.

PharmTech: Are foundations showing any interest in repurposing drugs?

Mucke: There is Cures Within Reach, a foundation that is focused on drug repurposing. There are also companies such as Transparency Life Sciences, that try to crowdsource drug repurposing, or just put out a repurposing idea and see what creative life-science people can contribute. This approach, however, requires settling any unresolved patent problems early.

PharmTech: Are there any particular therapeutic areas where you’re seeing a lot of potential for repurposing?

Mucke: There are several hot spots, including tropical and orphan diseases, because these are relatively neglected fields where a project can be advanced to initial stages without investing too heavily. These would include malaria, West Nile, and the Coronavirus.

In more conventional applications, a big area would be in neurology, the next most popular would be cardiovascular drugs. Any neglected diseases would also be a ripe area for focus.

Article DetailsPharmaceutical Technology Outsourcing Resources Supplement
Vol. 39, No. 17
Pages: s44-s47

Citation: When referring to this article, please cite it as A. Shanley, " Recovering the Value of Repurposed Drugs," Pharmaceutical Technology Outsourcing Resources Supplement 39 (17) 2015.