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The addictive properties of opioids and the lives shattered by their misuse and overprescription are heavily chronicled chapters of the early 21st century. For over 2 decades, scientists in academia and industry have been trying to design nonaddictive painkillers by turning to key proteins involved in neuron function: voltage-gated sodium channels. Now, Vertex Pharmaceuticals is on the cusp of crossing the finish line.
Vertex’s new compound, dubbed suzetrigine—pronounced “soo-ZEH-trih-jeen”—targets a specific protein channel that is expressed in pain-signaling neurons in the peripheral nervous system. If the drug is approved by the US Food and Drug Administration for the treatment of acute pain in January as expected, the drug could set the stage for the development of further compounds that target this and similar channels.
“It’s time for a precision medicine in pain,” says Paul Negulescu, a cell biologist who leads Vertex’s pain program. “That’s what’s so exciting about these selective inhibitors.”
In the body, there are proteins that create channels in cell membranes and facilitate molecules crossing from the outside of a cell to the inside. Voltage-gated sodium channels are membrane proteins that contribute to pain, and to neuron signaling more generally, by generating electrical impulses that travel along the length of a neuron (called its axon). These impulses are called action potentials.
During the generation of an action potential, a voltage-gated sodium channel opens a pore in the cellular membrane of a neuron or other excitable cell, allowing sodium ions to pass through. When the channel is in a resting state, it is closed off to positively charged sodium ions located outside the cell. But when domains called voltage sensors shift the channel to an open position, sodium ions rush through the pore into the cell. This rapid influx of sodium ions continues until an inactivation gate caps the pore.
The quick influx of sodium ions into the cell depolarizes the cell membrane and causes adjacent voltage sensors to open their corresponding sodium channels. A wave of opening and closing sodium channels carries an electrical signal (the action potential) from its start point to other areas of the body.
Scientists have discovered nine subtypes of human sodium channels, which are expressed in skeletal and cardiac muscles as well as neurons in different areas of the nervous system. Drugs that target sodium channels already exist. Lidocaine, the local anesthetic that is likely familiar to people who have had their mouth numbed for a dental procedure, inhibits sodium channels.
The barrier to using drugs like lidocaine to treat pain is that they target conserved regions on sodium channels. This means they are not specific toward certain sodium channel subtypes over others. That’s great for knocking out sensation in a localized area after injection. But systemic administration of the drugs—say, through a pill—not only would inhibit the channels generating a pain signal but could also interfere with those involved with brain and heart function, leading to severe side effects.
By the mid-1990s, researchers surmised that if they could identify sodium channels that are expressed primarily in pain-signaling neurons, they might be able to target pain without affecting critical bodily functions. In 1996, researchers in neurobiologist John Wood’s laboratory at University College London announced that they had discovered a sodium channel that is expressed in pain-signaling neurons from the peripheral nervous system (Nature, DOI: 10.1038/379257a0). The channel, which is now called NaV1.8, is the target for Vertex’s suzetrigine.
Meanwhile, a team led by Gail Mandel, a molecular neuroscientist at the Vollum Institute at Oregon Health and Science University, stumbled upon a different sodium channel when the researchers were treating rat cell lines with nerve growth factor. In a paper published in 1997, they reported that the channel—now known as NaV1.7—is also preferentially expressed in peripheral pain-signaling neurons (Proc. Natl. Acad. Sci. U.S.A., DOI: 10.1073/pnas.94.4.1527). It’s these cells that sense harmful stimuli and deliver the ouch that scientists call nociceptive pain.
“Since nothing was really known about peripheral nerve channels, we predicted it would be a target for nociceptive pain,” Mandel says.
NaV1.7 and NaV1.8 work largely in tandem. They are located on the same nerve axons in the peripheral nervous system, where they both contribute to producing an action potential. They differ, though, in their roles. Whereas NaV1.7 is responsible for producing smaller depolarizations that kick off the action potential, NaV1.8 is behind the larger depolarization that brings the action potential from threshold to its peak.
“For lay audiences, I describe 1.7 as being the fuse and 1.8 being the firecracker,” says Stephen Waxman, a neurologist and molecular neuroscientist at Yale University.
In 1998, members of Waxman’s lab reported that they had found a third peripheral sodium channel, now called NaV1.9 (Proc. Natl. Acad. Sci. U.S.A., DOI: 10.1073/pnas.95.15.8963). It remains the most elusive of the three peripheral subtypes. Researchers have had difficulty inducing the expression of the channel in cells, limiting the types of studies that can be done on it. Still, scientists hope that NaV1.9 might serve as another target to treat pain.
“[NaV1.8] is difficult to work with in heterologous systems, but the 1.9 is another order of magnitude [of] difficulty to get it to express,” says Sulayman Dib-Hajj, a Yale neuroscientist who led efforts to identify NaV1.9 in Waxman’s lab. “My belief is that I think it will catch up as we learn how to express it in these heterologous systems.”
After the identification of the three peripheral sodium channels, scientists in both academia and the pharmaceutical industry began looking for pain treatments that target them. They believed that creating selective inhibitors for the channels would offer alternatives to opioids that lack some of their side effects, notably their addictive potential.
Scientists figured that sodium channel inhibitors would block the signal in pain-signaling neurons at the source rather than act on parts of the brain where pain is perceived like opioids do.
Attention around the development of inhibitors for the channels came to a head around 2 decades ago, when scientists discovered humans with a rare form of chronic pain as well as people who didn’t feel pain. Both groups had mutations in their NaV1.7 channels.
For example, many members of a family based primarily in Alabama had a condition called inherited erythromelalgia. The pain caused by their condition made them feel as though they were on fire—some members elected to walk barefoot, since wearing shoes was too painful.
In 2005, Waxman and his colleagues published a paper that showed that a mutation to the gene SCN9A, which codes for NaV1.7, was behind the family’s condition (Brain, DOI: 10.1093/brain/awh514). The mutation made the channel hyperexcitable, causing their pain-signaling neurons to fire repeatedly even when there was no outside source of pain.
The next year, a group at the University of Cambridge published a study suggesting that loss-of-function mutations to NaV1.7 were also related to pain (Nature, DOI: 10.1038/nature05413). The scientists described members of three related families in Pakistan who had mutations that meant they didn’t generate functioning NaV1.7 channels. Unlike people with inherited erythromelalgia, who felt intense, persistent burning pain, members of the Pakistani families didn’t seem to feel pain at all.
The discovery of humans with mutations to NaV1.7 further suggested to the drug industry that targeting subtype-specific inhibitors could translate to effective treatments in humans. Researchers also later discovered people with gain-of-function mutations to NaV1.8 and NaV1.9, though the phenotypes of these people were less pronounced. Still, much of the focus remained on NaV1.7.
“If you weren’t working on NaV1.7, it was like, Why not? You’re not in neuroscience at that point,” says Bryan Moyer, a neuroscientist and senior vice president for discovery at Latigo Biotherapeutics. “And that was kind of the way it went for a number of years.”
Despite many years of investment, pharmaceutical companies have struggled to identify NaV1.7-targeting compounds that translate to success in the clinic. Compounds developed by Pfizer and Genentech, for example, were discontinued after discouraging clinical trial results.
“Maybe somewhat surprisingly, the initial clinical trials didn’t show robust efficacy,” Moyer says. “They weren’t repeating, at face value, the human genetics in terms of knocking people’s socks off with reduced pain-rating scales in the patients.”
Vertex was among the companies working to develop NaV1.7 inhibitors in the wake of the channel’s genetic validation in humans. But at the same time, the company kept up efforts to find compounds that selectively inhibited NaV1.8.
“There was nothing in the evidence for 1.7, as compelling as it was, to indicate that 1.8 wasn’t still a good target. So we continued to work on 1.7, and we continued to work on 1.8,” Negulescu says. “I think that ended up perhaps helping our program a bit.”
In the early 2000s, Vertex scientists designed a system called the electrical stimulation voltage ion probe reader (E-VIPR) to help screen for sodium channel–inhibiting compounds. Similar to how voltage-gated sodium channels rapidly alternate from closed to open configurations depending on the neuron’s voltage, E-VIPR uses electrical stimulation to create an electric field in wells that mimic sodium channel activity in cells.
“That’s been important because a lot of ion channel inhibitors will only inhibit under certain conditions, but not others, because the channel changes its shape fairly dramatically during its cycling,” Negulescu says. “The binding site for any given compound may be only transiently available. So you need a compound that can get on and stay on, keep the channel closed, and not fall off as the channel goes through its cycles.”
Negulescu says the company’s high-throughput screening, which uses fast detectors to locate dyes that indicate compounds that inhibit sodium channels, can perform up to 50,000 tests per day. To identify compounds that are selective for NaV1.8 and not other sodium channels, the company ran concurrent counterscreens. Once the compounds were identified, Vertex scientists could chemically optimize them and test their efficacy in pain-signaling dorsal root ganglion neurons isolated from human donors.
Vertex’s NaV1.8-targeting compound VX-150 advanced to human clinical trials in 2015. The compound was shown to reduce pain in patients with acute pain in a Phase 2 clinical trial. VX-150 also had an effect across two types of chronic pain.
“It was the first example ever of a selective NaV inhibitor having a robust pain effect in people in the clinic,” Moyer says. “That kind of brought NaV1.8 back into, I think, the attention of the industry as a whole as being meritorious of attention.”
Still, a relatively high dosage of VX-150 was needed to produce an effect in patients. As the compound progressed through clinical trials, Vertex scientists kept searching for more-potent NaV1.8-inhibiting leads. Their efforts eventually led to the development of VX-548, which superseded VX-150. The company would later name VX-548 suzetrigine.
In a paper published earlier this month in Pain and Therapy, Vertex scientists describe how suzetrigine inhibits NaV1.8 by binding to one of the channel’s voltage-sensing domains and stabilizing the channel’s closed state (DOI: 10.1007/s40122-024-00697-0). This is different from the action of local anesthetics, which block the channel’s open state.
Suzetrigine—a name chosen to evoke the word soothing, according to Negulescu—showed promise through Phase 2 clinical trials for treating both acute pain and a chronic pain condition called painful diabetic neuropathy. In January 2024, Vertex announced positive Phase 3 clinical trial results in treating acute pain after abdominoplasty surgery or bunionectomy surgery. People who received the compound reported having a clinically meaningful reduction in pain and less pain than those who received a placebo.
“The Vertex suzetrigine story really is a triumph, to make an orally active pill that blocks 1.8,” says Wood, whose team had also looked into creating NaV1.8 inhibitors before running out of funding for the efforts.
The FDA gave suzetrigine priority review and designated Jan. 30 as the date for approving or not approving the drug for the treatment of moderate to severe acute pain.
Meanwhile, Phase 3 clinical trials are ongoing to test suzetrigine’s effectiveness in people with painful diabetic neuropathy. Results of a Phase 2 trial for another form of chronic pain, painful lumbosacral radiculopathy, released in December 2024 showed that suzetrigine reduced pain compared with baseline levels (though questions were raised about similar levels of within-group pain reduction shown in the placebo arm, causing the company’s stock to fall). Another NaV1.8-targeting compound, VX-993, is also in clinical trials.
Vertex also continues to search for compounds that target NaV1.7, Negulescu says. The company hopes to explore treatments that target NaV1.7 alone or in combination with a NaV1.8 inhibitor.
Whether in academia or industry, scientists are eagerly awaiting the potential approval of suzetrigine. Not only might the drug provide a new treatment option, but many in the field credit Vertex with bringing renewed attention to sodium channel inhibitors.
“Vertex are pretty heroic, actually, because they plowed on,” Wood says. “They’ve had their reward. I think it’s going to be great for them.”
John Mulcahy, an organic chemist and the CEO of SiteOne Therapeutics, agrees that Vertex’s compound has been meaningful in boosting enthusiasm for the nonopioid pain relief space. But he says there are many questions about how suzetrigine might perform commercially. Existing generic pain medications are relatively inexpensive, which he says may make it a challenge to get payers to cover the new drug despite the safety and tolerability benefits.
“Certainly the better suzetrigine does, from a commercial perspective, the more it will pull other companies in to invest in this space,” Mulcahy says, adding that he feels strongly that making suzetrigine and other nonopioid analgesic options broadly available “is the right thing to do for patients.”
SiteOne is among a number of companies that are working to advance sodium channel inhibitors. The firm, which was founded in 2010, started by modifying a natural product called saxitoxin to make analogs specific for NaV1.7. The company has since expanded to focus on NaV1.8 as well, Mulcahy says.
Latigo Biotherapeutics launched in early 2024 after over 4 years in stealth. The company, which was founded by Amgen veterans after the pharmaceutical giant exited neuroscience in 2019, has developed a number of NaV1.8-targeting compounds. One of them, LTG-001, was well tolerated in a Phase 1 clinical trial. The company announced in October 2024 that a second compound, LTG-305, had been given to the first patient in a Phase 1 clinical trial.
But while suzetrigine’s success could help boost work on NaV1.8, questions remain about the future of NaV1.7 inhibitors. On top of being expressed in pain-signaling neurons, the channel is found in neurons in the autonomic nervous system, including some that regulate cardiovascular function. Scientists at Merck & Co. revealed in April 2024 that some primates and humans treated with a NaV1.7 inhibitor had experienced autonomic side effects, including lowered blood pressure and effects on heart rate variability, after the treatment (Circulation, DOI: 10.1161/CIRCULATIONAHA.123.06733). Genentech and SiteOne scientists have also published data that suggest possible autonomic side effects of NaV1.7 inhibitors (J. Physiol. 2024, DOI: 10.1113/JP286538; Br. J. Pharmacol. 2024, DOI: 10.1111/bph.16398).
Wood says he thinks that NaV1.7 is “dead” as a target. Other scientists remain optimistic, figuring that more research into the channel can uncover new ways to inhibit it while sidestepping autonomic effects.
Rajesh Khanna, a molecular neurobiologist at the University of Florida, and colleagues at his start-up Regulonix have focused on an untraditional approach: designing small molecules that indirectly target NaV1.7 by binding to a regulator protein for the channel. Khanna says the approach could avoid side effects, as the protein seems to be specific to pain-signaling neurons. He argues that Vertex’s suzetrigine has put new energy into the field, including by turning attention toward NaV1.7.
“It’s going to make a huge impact,” Khanna says. “It’s already starting to do that. We see a lot more renewed conversation about not just 1.8 but also on 1.7.”
Overall, scientists remain enthusiastic about the potential of achieving lasting pain relief by targeting voltage-gated sodium channels. For Latigo’s Moyer, who has been studying the channels for over 15 years, suzetrigine’s potential approval marks an “important first step” in bringing nonopioid analgesics to patients in need.
“This is not trivial, and the impact is severe. If you have chronic pain, you can’t sleep, you can’t work, you can’t go to your kid’s soccer games, you can’t socialize. So the mental toll is heavy,” Moyer says. “So making a dent in that—VX-548 being the first dent; there will be more dents after that—I think it’s admirable. It really gives me, as a scientist, motivation to give back and help.”
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