A recently published piece in the journal nature reviews: drug discovery outlines the challenges involved with developing new, non-opioid painkillers that target a human sodium ion channel known as Nav1.7. The great promise of Nav1.7 flows from the discovery that individuals who are congenitally insensitive to pain (‘CIP’) feature Nav1.7 deletions. This positioned Nav1.7 as a ‘genetically validated’ target for painkiller discovery efforts, one that many players large and small across the biotech and pharma sector have been pursuing for a number of years.
However, over the years, R&D outcomes have been sobering, for reasons that can be summarized as follows:
- Minimal differentiation of the Nav1.7 pore from those of other sodium ion channels.
- Nav1.7 pore – a transmembrane protein – is hard to express in sufficient quantities for classic drug discovery efforts. As one scientist told me, “expression of sufficient amounts (>0.1 of mg on a regular basis) of well-folded NaV1.7 full-length channel for biochemical studies remains an unsolved problem”.
- While safely inducing allosteric modulation of Nav1.7 might be more feasible with biologics than with small molecules, the former would be less convenient, thus restraining commercial opportunity.
- Small molecule efforts also need to take classic PK/PD considerations into account. Ziconotide, a synthetic conotoxin derivative which targets N-type voltage gated calcium channels, needs to be administered intrathecally.
- Datasets to date suggest that near-complete Nav1.7 blockade may be required for meaningful therapeutic effect, which poses additional challenges around PK/PD & therapeutic practicality.
- Congenitally Nav1.7-null individuals feature additional abnormalities which cannot be mimicked with short-term, drug-induced Nav1.7 blockade.
With all the above caveats in mind, what could a realistic way forward with Nav1.7 look like? As the nature article explains, not all hope is lost, and synergistic effect between Nav1.7 inhibitors with sub-therapeutic doses of opioid painkillers seems like a promising and pragmatic route to explore.
Naturally, such potential synergistic effects would still require any sponsor to develop a viable (effective and safe) Nav1.7 inhibitor in the first place. As both private sector R&D efforts and academic research continue to elucidate the structural components surrounding the Nav1.7 pore, the binding properties of naturally derived inhibitors or additional characterization of CIP phenotypes, I am cautiously optimistic that a therapeutic breakthrough is a matter of when, not if. To get a glimpse of ongoing academic efforts, I suggest watching this video summary of recent findings by McDermott et al. published in Neuron:
While Nav1.7-targeted investment opportunities in listed equities appear sparse at the moment, I will keep an eye on this space both out of intellectual curiosity and with a view on identifying promising drug candidates down the line.