Pharmaceutical R&D does not always start with soup and end with nuts, although by analogy this is the classic route followed by what is now the large multinational sector of the industry.
A shortcut version of the full programme is followed by generics companies and specialty pharma, who prefer to delay until the entrée is finished, joining the table in time for the dessert and digestif.
On the other hand, drug repurposing projects commonly require bespoke project designs. To repeat the culinary analogy, they may call for the entrée first, then the soup and then the dessert.
The order of events in a complete development project should reflect the development of knowledge alongside the progressive reduction in risk. By their nature, drug repurposed projects start with some knowledge about the active moiety, and this data can be incorporated in the overall plan, so that the areas of greatest risk can be tackled far earlier.
However, bridging from a past programme to a new development is not straightforward, nor is there always a clear pathway. Previous information may have been obtained under a less stringent regulatory regime that is not sufficiently rigorous by current standards.
Repurposed pharmaceutical developments typically involve a differentiated presentation for the product. So, a partially or substantially repeated set of toxicology and pharmaceutical development studies is the norm rather than the exception.
If studies need to be repeated, the cost and time advantages of drug repurposing are (partially) lost, but the risk advantage is not — and the risk profile improvement alone is worth far more than the cost and time advantages together.
In some cases, it may make sense to undertake some of the clinical development programme before fully defining the details of the final pharmaceutical product. Behind this type of thinking is the use of drug repurposing as a means of target validation. Let me explain.
Most development programmes fail because of lack of (sufficient) clinical efficacy in Phase II. This is particularly so for programmes towards first-in-class new medicines; given the enormous time and cost spent in bringing a new molecule through preclinical development, Phase I and into Phase II, this is a major cause of process inefficiency. And lest we not forget, under 5% of first-in-class programmes are successful.
Repurposing takes as its drug substrate an active substance that has been optimised during its previous discovery campaign for another indication. The drug’s lead optimisation was not specifically directed towards the secondary use, but can deliver a substrate for establishing clinical utility via a shortcut development. Once established, the discovery programme can start afresh with a mechanism of known validity and substantially reduced risk of Phase II failure. The output of such a programme is an optimised new chemical entity, tailored specifically for the new indication as a first-in-class therapeutic.
Even if it means we have to have the soup in the middle of the meal, this way of ordering events promises a better chance of leaving us with a rather fuller stomach.
