It is rare for biology to deliver such a seamless positive-negative effect within a single gene. In man on fire patients, one SCN9A mutation leads to a hyperactive Nav1.7 channel, which causes extreme discomfort. In those with insensitivity to pain, another SCN9A mutation leads to an inactive Nav1.7 channel, which results in total numbness. Given that the teams at Xenon and Yale were working on opposite coasts, and on conditions that fell on opposite sides of the pain spectrum, they only learned of each other’s discoveries through published reports and journal articles. (Sherrington first learned about Waxman’s study at Yale in 2004; Waxman only read about Sherrington’s work at Xenon after the company published its results in 2007.) Both teams arrived at the same clinical destination from a totally different direction, surprised as anyone that people like Pam Costa and Steven Pete had anything in common. “I was overwhelmed when we saw both sides of the genetic coin,” Waxman remembers. “SCN9A really is a master gene for pain.”
NOT LONG AFTER their discovery, technicians at Xenon set to work putting Nav1.7 channels into tissue cultures, then testing each with a compound from their vast library of molecules. They were looking for a blocker that would shut off or at least turn down the faucet on Nav1.7 without affecting the body’s other eight sodium channels. If you block Nav1.4, for example, you might block muscle movement. Blocking Nav1.5 can inhibit the heart. Blocking Nav1.6 might impact the brain, causing double vision, confusion, balance problems, or even seizures. One by one, they experimented with thousands of combinations until they got a hit—a compound that plugs up Nav1.7 without major side effects. From that, researchers then created a drug called TV-45070 and conducted pilot tests on four erythromelalgia patients. In three of the four, “these individuals’ pain responses were markedly blunted, and in one case we couldn’t elicit pain at all,” says Simon Pimstone, president and CEO of Xenon. Now TV-45070 is being used in a phase 2 clinical trial on 330 patients who suffer from nerve pain.
As for Waxman, he and his researchers at Yale helped Pfizer test five erythromelalgia patients with another Nav1.7 blocker. Scientists triggered the subjects’ pain with heating blankets and asked them to rate their feelings before and after taking the drug. Last year Pfizer and Waxman’s team reported that three of the five patients described a decrease in pain with the blockers.
There are other, less conventional approaches under way too. At Amgen, a pharmaceutical company in Thousand Oaks, California, scientists test up to 10,000 molecules against Nav1.7 each week. In 2012 they discovered that the toxin of a Chilean tarantula can target Nav1.7 with minimal impact on other sodium channels. They’ve since engineered a synthetic version of the spider’s toxin that’s more potent than the original.
These findings, while significant, are still small steps forward. Over the next few years, with larger pools of patients suffering from arthritis, sciatica, shingles, and many other kinds of pain, researchers will continue to test the practical applications of these discoveries. “At least a half dozen companies are trying to develop sodium-channel blockers that preferentially or selectively block 1.7,” Waxman says. And while obstacles remain—ensuring that only the Nav1.7 channel is affected; creating compounds that will allow some pain to register without cutting it off altogether; surviving the rigors of FDA approval—he and many others see a way forward.
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