Nature’s review of April 8, 2019 is a further supportive piece of evidence for Topical Innovation’s strategy of developing a broad-acting sodium channel blocker as a topical treatment for neuropathic pain.
Author Kingwell points out that despite compelling genetic validation, drug developers are still struggling to unlock the therapeutic promise of the Nav1.7 sodium channel as a pain target.
But after several failures in the phase II development, skepticism is rising whether such a selective target has a therapeutic potential in the real world. Andrea Houghton, executive director of pharmacology at Merck & Co pointed out that “Just because a target is genetically validated, it doesn’t necessarily mean to say it’s very druggable, Nav1.7 as a target is very hard to drug.”
When researchers reported in 2006 that patients with null mutations in the voltage-gated sodium channel Nav1.7 were impervious to pain, they kicked off an industry-wide hunt for novel analgesics. Genetic target validation was gaining traction as a means of improving drug development success rates, and Nav1.7 promised to be a poster child example of the drug development future. Instead, a slew of failures attest to how hard it can be to translate even the most compelling targets into therapeutics.
“Just because a target is genetically validated, it doesn’t necessarily mean to say it’s very druggable,” says Andrea Houghton, executive director of pharmacology at Merck & Co. “Nav1.7 as a target is very hard to drug.”
The most recent setbacks failure in this field was announced in October 2018, when Biogen pulled its Nav1.7 blocker vixotrigine in painful lumbosacral radiculopathy, due to a a failed phase II trial. phase III trial is still planned in trigeminal neuralgia and a phase II trial is ongoing in small fibre neuropathy. But the perspectives are now dim.
Interestingly, many other selective ligands failed in the recent past:
PF-05089771 from Pfizer was discontinued in 2015 after failed phase II trial in painful diabetic peripheral neuropathy;
TV-45070 from Teva/Xenon was discontinued in 2017 after failed phase II trial in post-herpetic neuralgia;
RG-6029/GDC-0310 from Roche/Genentech/Xenon was discontinued in 2018 prior to phase II initiation.
Topical Innovations (TI) has started their development of a topical formulation of the broad acting sodium channel blocker some years ago, and collected an impressive safety package, as well proof of concept in peripheral neuropathic pain, and is currently, after consultation with the Dutch MEB, starting preparations for two pivotal studies in diabetic painful neuropathy.
David Hackos, senior scientist at Genentech, pointed out that with the current huge unmet need for new pain relief options, and with the ongoing opioid crisis going on in the United States and starting in Europe: “many drug companies remain committed to Nav1.7. But they have tempered their views.” He now thinks this inroad is really difficult, but still possible.
The director of pharmacology at Merck & Co points out that there are fairly limited small-molecule opportunities, looking at all the screening people have done, most of the publications and structures are quite closely related to each other. There’s not a lot of novelty here.
It was further pointed out that non-selective Nav blockers can provide useful pain relief but the generalized nerve block and unwanted side effects such as dizziness underscore the need for enhanced selectivity to tap wider pain markets. The other option to decrease the side-effects has been explored by Topical Innovations and clearly directs us in a different direction: broad acting sodium blockage, but not entering the bloodstream, and acting locally.
To date, TI approach is seen as a new innovative approach, potentially creating a block-buster based on an old repurposed drug in a new formulation and in a field of a new indication. TI is currently discussing with potential partners who would take over phase III development of the treatment on a world-wide or regional scale.