Question

1. What is the importance or advantage of studying "Drug Repurposing" for a better understanding of the human disease drug discovery process?

2. Provide two examples of human diseases where researchers used this concept or research strategy. What is the cellular mechanism of disease, or signaling pathway targeted by these researchers? Please cite two sources using PubMed!

3. What are the potential disadvantages or challenges of drug repurposing?

Answer 1

1.

Drugs in development, on the market, or those that are shelved because of lack of efficacy, are excellent starting points for further development. Finding new indications for such drugs will benefit patients who will see a potential new therapy sooner, will maximise their value and will also protect the original IP owner against competitor adjacency moves.

Typically, repositioning is done by accident, or in a limited way. New technologies however, enable the systematic evaluation of any drug or mechanism of action against any disease or adverse event.

From 2007-09, 30-40% of drugs or biologics that were approved or launched for the first time in the US were either drugs repositioned for new indications, reformulations or new combinations of existing drugs (1). This is the lifecycle business with repositioning as a major contributor, and it is rarely given much attention outside of its practitioners.

Yet, why is it practised, why is it such a big percentage of biopharma approvals and what is its future?

How come more than 30% of new market entrants are existing drugs finding commercial success through variations and new uses, and yet this is just recently beginning to be recognised as a high-performance strategy in its own right?

Any business model that relies on product development that takes 10-15 years and costs about $1.3 billion per successful product launch (2) requires constant appraisal and rethinking. How does big pharma make such a model work?

To date, the success that this model has enjoyed is the result of multiple shots on goal, meaning multiple drugs entering trials before one makes it all the way to the market: the one that is successful generates enough revenues to fund the attrition of the rest of the portfolio that occurs because of lack of efficacy or because of unexpected safety concerns in clinical trials.

The attrition is important to keep in mind, as approximately one in 10 mature preclinical candidates will make it to product launch (3), and hundreds of thousands of molecular library members will need to be screened and developed before the mature preclinical candidates themselves are available for first-in-human studies.

This attrition rate puts tremendous pressure on a drug pipeline since it means that one must assume that failure is the default outcome, given that about nine out of 10 candidates will not be launched. Adding to this pressure is the so-called patent cliff, which vividly describes the more than $100 billion in revenues that are due to be lost in the next few years as patents begin to expire and generic versions of drugs take the place of the original branded forms (4).

The patent cliff and attrition rates are considered to be by-products of a broader R&D productivity and innovation challenge. Multiple authors and commentators discuss specific elements of the R&D process itself, with a view towards improving specific steps that will increase the number of drugs that have a higher chance of success in the clinic, while reducing the overall costs of the effort within a pipeline environment (5).

The specific arguments in favour of drug repositioning as a contributor to pipeline growth and as a defence against generics are simple and potent:

1. The safety advantage

Existing drugs that are either approved or have been shown to be safe in late-stage trials, but have failed to meet end points of their originally-targeted indications, can leverage their inherently reduced development risk into potentially new indications. They can do so if they can be proven to be effective in the new indications and also sufficiently differentiated against standard of care.

When such drugs enter clinical trials, they compete with non-repositioned drugs not in terms of safety, but in terms of efficacy. Since safety accounts for approximately 30% of drug failures in clinical trials, this is a significant development advantage that repositioned drugs enjoy.