Patents, regulations and manufacturing issues have long undermined the case for repurposing established biological therapeutics for new indications. Novel technologies, however, promise to transform the commercial manufacture of repurposed biological therapeutics. This opens the door to breakthroughs in efficacy, side-effect reduction and dosing, while lowering the risk of commercial failure.
Repurposing risks are high
The pre-clinical and clinical development cycle for new biological therapeutic candidates is a long and expensive process. Problems with safety and ADME (absorption, distribution, metabolism and excretion) add to an already high attrition rate. Currently approved therapeutics, by contrast, benefit from having already passed the safety test of regulators, and possessing known ADME properties. Thus, in theory, their use in new indications reduces the risk of failure and potentially shortens the development cycle.
However, this promise is impeded by commercial and technical realities. How likely is it that a drug developed for one purpose turns out to be the ideal candidate for another application?
Chances of success are low
Various attempts have been made to unlock value and advance medical capabilities by repurposing biological therapeutics. Some involve searching for approved compounds, including biological therapeutics, that might bind to a promising target. The hypothesis here is that tighter binding affinity to a defined target is likely to deliver greater efficacy.
Under this hypothesis, however, the likelihood that a biological therapeutic designed for one target is also the ideal candidate for another target is low. Developing a commercial means of manufacture also carries risks, even when using tried and tested methods. Process patents frequently persist long after the composition of matter and use patents of the original molecule have expired, raising the possibility of litigation.
Promising multi-valent mechanisms of action
Complex degenerative and metabolic diseases represent an area of significant unmet need in medicine. Their pathologies expand beyond single cells, manifesting across tissues and systems. Increasingly, researchers acknowledge that treatment based on a single target within a defined pathway is unlikely to be capable of slowing and arresting the pathology of such diseases. This has led to a growing realisation that the mechanisms of action required for efficacy are likely to be highly targeted and multi-valent.
Multi-valent mechanisms of action harness the synergistic nature of a combination of targets to have the desired effect on relevant biological systems. This becomes less about seeking tight binding affinity to a given target, and more about finding the correct spectrum of binding to the multiple targets of interest, at a lesser binding affinity.
Circumventing patents and know-how
Manufacturing multi-valent biological therapeutics becomes easier by creating a bespoke and optimised strain using QTL technology. This enables a new basis of manufacture that circumvents the need to have access to know-how associated with the original regulated biological therapeutic, with such know-how often being closely guarded by the original manufacturer. The process of creating a bespoke and optimised strain with QTL technology uses Saccharomyces cerevisiae (Baker’s yeast), which benefits from an extensive track record of being accepted by regulators.
Strains optimised for a repurposed biologic are by definition bespoke, meaning that they can also incorporate upstream adjustments to alter processing requirements, thereby avoiding any breach of incumbent processing methods and the patent thickets that surround them. Furthermore, the optimised strains created by QTL technology can be patented, providing a much-needed extra layer of protection.
Scaling at pace with new technology
A Phenotypeca customer had previously locked into an archaic, suboptimal production strain and process which was sufficient to meet its existing current regulated indication. They have now established that this biological therapeutic has promising efficacy in the treatment of several new indications with much larger markets. Their current process cannot meet the requirements of these new markets for several reasons: low titre, expensive media, a downstream process that cannot scale, and loss of product due to post-translational modifications that requires complex and unscalable downstream processing (DSP). This is a prime example of how the creation of a bespoke optimised strain (optimised for increased titre, reduced post-translational modifications and therefore DSP, defined media and high cell density production), can allow rapid development of the repurposed therapeutic, first through provision of material for clinical trials and then for a scalable process for ultimate production for the new markets.
Unlocking the potential of repurposed therapeutics
New research approaches are enabling a better understanding of the systems that drive biology at the tissue level, and of how a pathology alters them. The development of novel multi-valent mechanisms of action offers a step change in efficacy that places a different emphasis on the search criteria for suitable candidates. In particular, adopting a spectral perspective of potential candidate molecules based on seeking to establish the correct combination of target interactions, instead of focusing on tight binding to a single target, promises to transform the discovery approach to repurposed biological therapeutics. Aside from the discovery of new uses, potential benefits include shorter and radically cheaper development cycles, and significantly lower risks of failure in addition to a patent protected optimised strain offering the lowest possible cost of manufacture.
