Personalised Analgesia? Why have researchers waited so long?


A recent study in Science Translational Medicine (http://stm.sciencemag.org/content/8/335/335ra56) has received much attention both in the scientific literature and on other science blogs (http://relief.news/moving-toward-the-dream-of-precision-pain-medicine/) The paper describes a clinical study in a small group of patients with the rare condition Inherited Erythromelalgia which is caused by again of function mutation in the gene SCN9A which encodes the voltage gated sodium channel Nav1.7. The patients were treated with a selective Nav1.7 inhibitor developed by the Neusentis group. It might have been expected that all individuals would experience a large reversal of the phenotype, however results were highly variable among the individuals with some experiencing near total relief from symptoms where in others the drug barely worked at all In parallel with the clinical study the authors generated neuronal cells from the individuals in the study. Cells isolated from the patients’ blood samples were genetically reprogrammed into induced pluripotent stem cells (iPSCs). The iPSCs were then differentiated into nerve cells which functioned in a similar way to the native neurons in the patients. The drug used in the clinical study was then tested on the nerve cells. Intriguingly the compound showed different responses in each cell tested and the degree of effect corresponded closely with the response seen in the clinical trial. Even though the number of people treated is small the correlation of clinical effects and results from electrophysiological studies is striking and has rightly generated a great deal of excitement.

What will become of the results of this study remains to be seen. It would be reasonable to hope and expect that pharma companies would adopt this strategy in future clinical studies and if successful in marketing strategies. However the proposal to use iPSCs in analgesic drug discovery was proposed some years ago (http://www.nature.com/nm/journal/v16/n11/abs/nm.2230.html) but until now it has not been truly tested. Indeed the author proposed using patient derived cells throughout the drug discovery process.

Using this strategy has great potential; both for patients where it offers promise to provide better pain relief by matching the right individual with the correct medicine thereby overcoming a major issue with current analgesics which fail to show efficacy in the majority of patients (http://www.bmj.com/content/346/bmj.f2690), and for future treatments. Virtually all experimental analgesics fail in clinical studies and whilst a number of recent successes in phase 2 have been highlighted (most notable Nav1.7 blockers and angiotensin 2 receptor antagonists) it is highly unlikely any will reach the market using current clinical trial paradigms.

Clearly there is a long way to go and iPSC technology is currently expensive and has been slow to develop. Additionally it may not be suitable for assessing all pain targets, but this recent study is both very exciting and promising in that it does provide hope that new analgesic medicines will reach the market in the coming years. For this to happen those engaged in analgesic drug discovery need to abandon the existing and broken model and be prepared to embrace these new methodologies.

Blog written by Paul Beswick

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