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European Biopharmaceutical Review
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Intelligent Approaches
Commercial pressures are forcing companies to look at alternative strategies for drug discovery and development. Drug repurposing or reprofiling has proven to be an efficient and lower risk route to bringing patentable drugs to market
Pharmaceutical pipelines have traditionally been fed by the discovery of new chemical entities (NCEs). NCEs typically cost a minimum of $400 million to bring from discovery to market. Factoring in the costs of failed development projects, the R&D spend per marketed drug is far higher, in the region of $5 billion (1). To recoup this cost, a pharmaceutical company must be certain of two things: that they can secure exclusive rights over the compound; and that there is a large enough market to bring in enough income per annum over the patentable lifetime of the compound.
In recent years, NCEs have been failing to arrive in the market place at the rate required to sustain the industry. There is a high attrition rate at all stages of the development pipeline; the scientific and medical reasons for this are many and varied and include a lack of efficacy, poor pharmacokinetics and toxicology issues. However, a significant number of compounds are dropped from the development pipeline each year due solely to commercial considerations. In other words, no issues have been found with the compound itself, but the market conditions indicate that there would not be a viable return for continued costs of development. The result is that the project is then halted and the compound is not brought to market.
In response to commercial pressure, the pharmaceutical industry is looking at alternative approaches to drug discovery and development. Compound reprofiling – also referred to as repurposing – is an intelligent, proven and profitable method of lowering the costs and risks associated with traditional NCE discovery.
Reprofiling Benefits
Reprofiling draws primarily on known drugs, but also on pipeline drugs, to find new applications for compounds that have already been progressed part or all of the way through the development process.
A prime benefit of reprofiling existing drugs is that the toxicology, safety and pharmacokinetics are generally well understood because they have already been tested in a patient population for another disease indication. These compounds, therefore, offer a lower risk route for development with a far higher chance of succeeding through the regulatory approval process. When developing a repurposed drug, it is often possible to construct much smaller Phase 1 trials since previously gathered safety data can be taken into consideration. In some cases, Phase 1 may be omitted completely and an agent may transition directly into Phase 2 proof of principle trials. It may also be possible to scale back the side effect profiling required in a Phase 3 trial, all of which leads to a shorter development path, with lower costs and associated risk of failure. This ability to ‘cash in’ on previous clinical and non-clinical experience, and thus advance through a de-risked, more rapid, cost-effective early stage development, is a key attraction of reprofiling.
Pipeline compounds can also be a rich source of reprofiling opportunities. Of the attrition rate of compounds at each stage of clinical trials, roughly 30 per cent is due to commercial decisions rather than clinical results. For example, if a competing drug is launched that would limit the market, it is not uncommon for a company to stop development on a compound, even though it may have reached the clinical trials stage. In addition, numerous compounds, although proven safe, fail to achieve sufficient efficacy in the initial indication. However, it may well be worth the incremental investment needed to bring the compound to market for a different disease indication.
Sourcing Good Candidates
Reprofiling strategies vary from the evidence-based to the serendipitous. Some companies specialise in a large-scale wet screening approach, whereby all known drug compounds are screened for different disease indications. This comes at a high cost, but can yield interesting, one-off results.
A common strategy to identify a promising candidate for reprofiling is through a search of the scientific literature for indications of unexpected effects or for off-label prescription use of a known and marketed drug. In a literature search the goal is to find an unexpected correlation between a disease and a drug.
For example, patients might have been taking medication for shingles during a trial. A good percentage of these patients may also happen to have high blood pressure and it may transpire that these patients find that their blood pressure decreases. Now, this could prove to be a coincidence, it could be a statistical error, or it could be a real side-effect that can be exploited.
On the basis of this, a researcher could go ahead and trial a compound for blood pressure-reducing effects. Alternatively having identified a promising group of 5-10 papers that indicate that there could be a connection between a known drug and a new disease indication, a more intelligent step is to try to understand the biological pathways that are causing the beneficial side-effect. In other words, the goal is to find out how and why compound A interacting with target B gives result C that affects disease D. This knowledge-driven and intelligent approach to reprofiling means that it yields new information that can be fed back into discovery research.
Structural Understanding
Computational chemistry software is a great aid in helping to gain a structural understanding of the compound of interest. Interestingly, computational chemistry can also be used to discover related reprofiling candidates by chemotype switching to find back-up series and possibly avoid conflicting patent issues.
Chemotype switching is the process of finding biologically equivalent compounds by screening large databases. The first step is to analyse the electrostatic and shape properties of a known active to derive a molecular fingerprint or field pattern. Analysing the molecular field of a compound is highly relevant to the interactions between drug molecules and proteins, and therefore sheds light on the mechanism of action of the drug.
This field pattern is then used as a query to search databases to identify other compounds with a similar field pattern. These compounds have a high probability of showing similar activity to the query and are good candidates for confirmation by wet screening. This field-based approach provides far more accurate results than other methods in identifying likely active compounds.
A successful reprofiling approach is to start with the literature to identify possible areas of interest, then to screen known actives in silico to find biologically equivalent compounds. The best candidates are evaluated and screened in an in vitro assay, with positives being potentially progressed to testing in animal models. When successful, the advantages to this approach are twofold: not only can it identify a new indication for existing agents, but the structural understanding that drives the approach also provides a platform for potential NCE discovery and new generations of highly optimised compounds.
Intellectual Property Issues
Intellectual property (IP) issues are a major factor in reprofiling. There is a dilemma inherent in the reprofiling approach, which is that compounds identified through literature searching may be impossible to patent due to the existing prior art. In essence, the literature may teach us too much. Equally, a compound which is identified as active in a new indication may not be patentable or commercially viable due to competition from off-label use of the existing treatment.
Space does not allow a complete discussion here, but typical strategies to gain an IP position include reformulation – for example, switching from systemic to topical applications – or pro-drugging – such as creating a compound which itself is not active, but will be metabolised within the body to the active form. It should also be noted that structure-based approaches may provide a means of escaping the IP ‘trap’.
Understanding how to generate IP in a potentially congested landscape is a human skill that requires experience and expertise in pharmacology and a working knowledge of patent law, and is a key constituent of a successful reprofiling team.
As an example of the approach, one of our academic collaborators has elucidated a hitherto poorly understood mechanism in inflammatory conditions. This discovery enabled us to identify a series of compounds which we predicted to have activity against the newly elucidated target. From a series of 50 initially identified compounds we further triaged that down to 12 compounds that were purchased and tested. Of these 12, one has shown sufficient activity to be progressed through further animal studies. That compound is now the subject of two filed patents.
Orphan Conditions
Many conditions have a restricted patient population and are referred to as orphan diseases. In the US the formal definition is a patient population of less than 200,000 or approximately 1 in 1,500. For example, Duchenne’s Muscular Distrophy, an
X chromosome-linked genetic disease, affects about 1 in 3,600 boys. With such a small potential market, it is extremely unlikely that a pharmaceutical company could recoup the cost of developing a drug for this condition, despite there being tax breaks and lower developmental hurdles for compounds given orphan drug status.
On the other hand, some diseases have a large patient population, but in a part of the world where the patients have very limited economic means and would not be able to pay high treatment costs. Commercial pressures dictate that companies are unlikely to commit to the high development costs of finding NCEs to treat these diseases.
If an indication can be found for an existing drug for an orphan condition, the development costs are dramatically decreased. Therefore, reprofiling represents a very promising development strategy for such conditions.
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