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Repurposed drugs can offer real clinical benefits to patients with unmet needs

In recent years, the pharmaceutical industry has experienced a difficult period whereby productivity has not kept pace with increases in R&D investment. To counter this issue, an increasing number of companies have been focusing on drug repurposing - the development of novel uses for existing drugs.

Although repurposing of drugs is not new to the pharmaceutical sector, large companies using classical life cycle management strategies often extend drug use into new indications to preserve or extend the value of a particular brand. A clear example of such a classic approach can be seen with Seroxat and the extension of the product's original licence for the treatment of depression, to a much broader range of uses including: treatment of social anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder and panic disorder.

Of the 50 top selling brands in 2004, 84 per cent have had additional indications approved since their initial launch in the US, and a further 6 per cent are known to have subsequent indications in development. However, the appearance of companies founded exclusively on drug repurposing reflects a general trend today that seeks to maximise the investment in R&D and reduce the risks of drug development to the industry.

The benefits to the R&D organisation of repurposing are clear: there is a significant reduction in risk as you are starting with an approved compound with established safety and bioavailability profiles, proven formulation and manufacturing routes, and well-characterised pharmacology. Repurposed compounds can enter clinical trials quickly, and at a lower investment cost than completely new chemical entities (NCEs), while avoiding two of the common areas for failure of NCEs; namely, human safety issues and pharmacokinetic profiles.

What are the options?
Drug repurposing is based on two core principles. The first is that a single molecule often acts on multiple targets. Taking advantage of this, one repurposing approach focuses on the identification of secondary or so-called 'off-target' drug actions, followed by the development of the compound in a new indication where the secondary target is relevant. Historically, compounds with such marked off-target effects have been considered 'dirty' because of the side effects they induce. However, the undesirable side effect of a compound in one indication may sometimes provide a desirable effect in another indication. This is the 'known compound - new target' approach.

The second principle is that mechanisms relevant to one disease or biological process are often involved in several biological processes. So, the alternative repurposing approach is to establish the relevance of a known drug to a new disease. Sometimes scientific links have been established between the mechanism and the disease, and between the mechanism and the compound, but not between the compound and the disease.

At other times, the link between the compound and the mechanism is well established, but the new medical significance of the target is discovered by chance during clinical studies of the compound's original indication. Repurposing efforts based upon the new medical potential of a known compound are a 'known mechanism - new indication' approach.

One of the most significant and well-known examples of the 'known compound - new target' approach is the revitalisation of thalidomide by Celgene in the US. Thalidomide was originally prescribed in the 1950s for nausea and insomnia in pregnant women. However, as has been well documented, its use caused severe birth defects in children whose mothers took the drug in the first trimester of pregnancy.

In a surprising 1965 article, an Israeli doctor reported the remarkable effects thalidomide had in alleviating complications of leprosy. It was later discovered that, in addition to its sedative effect, thalidomide had antiangiogenic and immunomodulatory effects, including the inhibition of TNF alpha.

In 1998, Celgene received approval from the Food and Drug Administration (FDA) to market Thalomid (thalidomide) as a treatment for leprosy. Since its release, Thalomid has become the flagship product for Celgene, now with an additional indication for multiple myeloma. Through controlled clinical trials and FDA compassionate-use programmes, the drug has been found to be effective in treating myriad disorders, including certain mycobacterial and autoimmune diseases, HIV and AIDS-related afflictions, cancer and miscellaneous skin conditions.

Merck's finasteride, originally prescribed to treat prostate enlargement and marketed in the UK under the name Proscar, presents a clear example of the 'known mechanism - new indication' approach to repurposing. In the early 1990s, finasteride, which blocks conversion of testosterone to dihydro-testosterone, was also discovered to prevent male pattern baldness,  when administered at much lower doses (1mg rather than 5mg) than used to treat prostate conditions. As a result, in December 1997, the FDA approved finasteride for the treatment of hair loss in men under the brand name Propecia.

Marketing challenges
Many people may have the incorrect perception of repurposed products as 'me-too' drugs, with all the negative associations linked to such molecules. However, this is not necessarily the case; not least if they offer a solution to a previously untreated or untreatable condition, or where current treatments do not meet customers' needs, such as with thalidomide and its use in the treatment of leprosy. Conversely, when they are perceived as 'lifestyle' drugs, for example Propecia, the challenge to make the medical profession consider them relevant can be significant.

Market exclusivity
The essential issues that face repurposed medicines are market exclusivity (in the face of possible generic competition), differentiation (from the original indication) and the issue of being known as a 'dirty' molecule. However, although there can be exclusivity benefits to line extensions, US and EU regulatory reform has reduced effectiveness of indication expansion as a stand-alone generic protection strategy.

An additional indication only extends exclusivity for one year in the EU. Indication expansion must therefore be paired with a method to differentiate the product in the new use, preventing off-label uptake of generics in the new indication (see figure 1)

As a consequence, the challenge for the brand originator is to establish a sufficiently strong presence in the market to be able to withstand generic competition, if it comes. Even if direct competition does not occur, there is always the risk of off-label use of the generic. Combating this requires planning well ahead of the loss of exclusivity.

Marketing alone may not provide the necessary brand protection, hence the need for formulation or other additional barriers, such as new method of use patents.For example, Requip was first launched for use in Parkinson's in 1996 and then for Restless Legs Syndrome (RLS) in 2004 in the EU and 2005 in the US. Requip is not due to lose protection for the active ingredient until 2007 in the US and 2008 in Europe, and GSK has filed a new application for Requip CR, which should help to maintain the brand's position in the market.

Differentiation
A truly differentiated value proposition is the classic marketing challenge in our increasingly competitive markets, and is no less an issue for a repurposed drug as it is for the original molecule. Without demonstrable 'value' then, as ever, it will fall foul of National Institute for Health and Clinical Excellence and or Primary Care Trust prioritisation.

If there is a clear and recognised unmet medical need that the newly repurposed molecule can satisfy better than existing treatments, then initially differentiation is not an issue. In some cases it may even be easier for the repurposed drug than the original molecule as it may be first into an undeveloped market. Hence Propecia had limited competition when originally launched for male pattern baldness.

However, the challenge is often to overcome the cynicism that the pharmaceutical industry is 'creating a disease' if the new indication is not well recognised. RLS has suffered from this stigma even though the condition was clearly described in 1944 by Professor Karl-Axel Ekbom, is common and may be under-diagnosed. It is now well recognised by such bodies as the National Institute of Neurological Disorders and Stroke in the US, has been reviewed by Bandolier in the UK and has a definitive guideline for treatment.

In many cases the real marketing challenge is to develop the market from a relatively low base, while also differentiating and positioning the brand effectively. When pursuing drug repurposing, companies need to recognise that while they will be marketing the same molecule, it will be aimed at meeting very different needs and represents a very distinct opportunity with its own unique challenges. Companies need to undertake a thorough process of analysis and strategic thinking to thoroughly understand the unique challenges they face, rather than simply thinking of it is an 'add-on' to the original business.

In many ways the repurposed drug needs to be treated as a separate business opportunity, while ensuring the marketing in the new therapy area does not undermine that in the original.Subsequently, the usual marketing challenges will be applicable to the repurposed drug, namely the need for differentiation, and clear positioning and targeting to relevant healthcare professionals, particularly since the molecule is likely to be known for treating another, potentially very different problem and possibly used by a different group of prescribers.

There is also the additional challenge of market exclusivity if the molecule has lost its patent protection already, however few companies are likely to undertake repurposing without some degree of protection. 

30th April 2007

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