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Introduction There is a high unmet need for safe and effective non-opioid medicines to treat moderate to severe pain without risk of addiction. Voltage-gated sodium channel 1.8 (Na V 1.8) is a genetically and pharmacologically validated pain target that is selectively expressed in peripheral pain-sensing neurons and not in the central nervous system (CNS). Suzetrigine (VX-548) is a potent and selective inhibitor of Na V 1.8, which has demonstrated clinical efficacy and safety in multiple acute pain studies. Our study was designed to characterize the mechanism of action of suzetrigine and assess both nonclinical and clinical data to test the hypothesis that selective Na V 1.8 inhibition translates into clinical efficacy and safety, including lack of addictive potential. Methods Preclinical pharmacology and mechanism of action studies were performed in vitro using electrophysiology and radiolabeled binding methods in cells recombinantly expressing human Na V channels, human proteins, and primary human dorsal root ganglion (DRG) sensory neurons. Safety and addictive potential assessments included in vitro secondary pharmacology studies, nonclinical repeat-dose toxicity and dependence studies in rats and/or monkeys, and a systematic analysis of adverse event data generated from 2447 participants from phase 3 acute pain studies of suzetrigine. Results Suzetrigine is selective against all other Na V subtypes (≥ 31,000-fold) and 180 other molecular targets. Suzetrigine inhibits Na V 1.8 by binding to the protein’s second voltage sensing domain (VSD2) to stabilize the closed state of the channel. This novel allosteric mechanism results in tonic inhibition of Na V 1.8 and reduces pain signals in primary human DRG sensory neurons. Nonclinical and clinical safety assessments with suzetrigine demonstrate no adverse CNS, cardiovascular or behavioral effects and no evidence of addictive potential or dependence. Conclusions The comprehensive pharmacology assessment presented here indicates that suzetrigine represents the first in a new class of non-opioid analgesics that are selective Na V 1.8 pain signal inhibitors acting in the peripheral nervous system to safely treat pain without addictive potential.

Many patients experience inadequate pain control due to limited options that are both efficacious and safe for treating moderate-to-severe acute pain; therefore, opioids are still frequently prescribed for their effectiveness despite known tolerability issues and safety concerns. Suzetrigine, an oral, non-opioid, offers a promising alternative by selectively inhibiting the voltage-gated sodium channel 1.8 (NaV1.8), a novel therapeutic target for pain management. Given the high selectivity of suzetrigine for NaV1.8 (does not bind to other sodium channels/receptors with CNS activity), suzetrigine does not have CNS side effects or addictive potential associated with opioids. In the largest randomized, controlled phase 3 trials in established acute pain models, suzetrigine monotherapy demonstrated statistically significant and clinically meaningful reduction in moderate-to-severe acute pain compared to placebo.BackgroundMany patients experience inadequate pain control due to limited options that are both efficacious and safe for treating moderate-to-severe acute pain; therefore, opioids are still frequently prescribed for their effectiveness despite known tolerability issues and safety concerns. Suzetrigine, an oral, non-opioid, offers a promising alternative by selectively inhibiting the voltage-gated sodium channel 1.8 (NaV1.8), a novel therapeutic target for pain management. Given the high selectivity of suzetrigine for NaV1.8 (does not bind to other sodium channels/receptors with CNS activity), suzetrigine does not have CNS side effects or addictive potential associated with opioids. In the largest randomized, controlled phase 3 trials in established acute pain models, suzetrigine monotherapy demonstrated statistically significant and clinically meaningful reduction in moderate-to-severe acute pain compared to placebo.To evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe-acute surgical and non-surgical pain conditions, we conducted a phase 3, single-arm study in adults with moderate or severe acute pain on the verbal categorical rating scale and ≥4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with moderate or severe acute pain of new origin. Participants received suzetrigine (100mg then 50mg every 12hrs) for 14 days or pain resolution, whichever came first. The primary endpoint was safety. The secondary endpoint was participant perception of suzetrigine's effectiveness in treating acute pain at the end of treatment using a patient global assessment.MethodsTo evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe-acute surgical and non-surgical pain conditions, we conducted a phase 3, single-arm study in adults with moderate or severe acute pain on the verbal categorical rating scale and ≥4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with moderate or severe acute pain of new origin. Participants received suzetrigine (100mg then 50mg every 12hrs) for 14 days or pain resolution, whichever came first. The primary endpoint was safety. The secondary endpoint was participant perception of suzetrigine's effectiveness in treating acute pain at the end of treatment using a patient global assessment.Suzetrigine was generally safe and well-tolerated in participants (N=256) with a range of surgical and non-surgical acute pain conditions; the maximum severity for most participants who had adverse events was mild (71 participants; 27.7%) or moderate (21 participants; 8.2%). Most participants (213 participants; 83.2%) rated suzetrigine's effectiveness for treating pain on a patient global assessment as good, very good, or excellent.ResultsSuzetrigine was generally safe and well-tolerated in participants (N=256) with a range of surgical and non-surgical acute pain conditions; the maximum severity for most participants who had adverse events was mild (71 participants; 27.7%) or moderate (21 participants; 8.2%). Most participants (213 participants; 83.2%) rated suzetrigine's effectiveness for treating pain on a patient global assessment as good, very good, or excellent.Suzetrigine provides a safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain.ConclusionSuzetrigine provides a safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain.NCT05661734.Clinicaltrialsgov RegistrationNCT05661734.

Background: Many patients experience inadequate pain control due to limited options that are both efficacious and safe for treating moderate-to-severe acute pain; therefore, opioids are still frequently prescribed for their effectiveness despite known tolerability issues and safety concerns. Suzetrigine, an oral, non-opioid, offers a promising alternative by selectively inhibiting the voltage-gated sodium channel 1.8 (NaV1.8), a novel therapeutic target for pain management. Given the high selectivity of suzetrigine for NaV1.8 (does not bind to other sodium channels/receptors with CNS activity), suzetrigine does not have CNS side effects or addictive potential associated with opioids. In the largest randomized, controlled phase 3 trials in established acute pain models, suzetrigine monotherapy demonstrated statistically significant and clinically meaningful reduction in moderate-to-severe acute pain compared to placebo. Methods: To evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe-acute surgical and non-surgical pain conditions, we conducted a phase 3, single-arm study in adults with moderate or severe acute pain on the verbal categorical rating scale and [greater than or equal to]4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with moderate or severe acute pain of new origin. Participants received suzetrigine (100mg then 50mg every 12hrs) for 14 days or pain resolution, whichever came first. The primary endpoint was safety. The secondary endpoint was participant perception of suzetrigine's effectiveness in treating acute pain at the end of treatment using a patient global assessment. Results: Suzetrigine was generally safe and well-tolerated in participants (N=256) with a range of surgical and non-surgical acute pain conditions; the maximum severity for most participants who had adverse events was mild (71 participants; 27.7%) or moderate (21 participants; 8.2%). Most participants (213 participants; 83.2%) rated suzetrigine's effectiveness for treating pain on a patient global assessment as good, very good, or excellent. Conclusion: Suzetrigine provides a safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain. Clinicaltrials.gov Registration: NCT05661734. Keywords: suzetrigine, VX-548, non-opioid, NaV1.8 inhibitor, moderate-to-severe acute pain, surgical/nonsurgical acute pain

Many patients experience inadequate pain control due to limited options that are both efficacious and safe for treating moderate-to-severe acute pain; therefore, opioids are still frequently prescribed for their effectiveness despite known tolerability issues and safety concerns. Suzetrigine, an oral, non-opioid, offers a promising alternative by selectively inhibiting the voltage-gated sodium channel 1.8 (Na 1.8), a novel therapeutic target for pain management. Given the high selectivity of suzetrigine for Na 1.8 (does not bind to other sodium channels/receptors with CNS activity), suzetrigine does not have CNS side effects or addictive potential associated with opioids. In the largest randomized, controlled phase 3 trials in established acute pain models, suzetrigine monotherapy demonstrated statistically significant and clinically meaningful reduction in moderate-to-severe acute pain compared to placebo. To evaluate the safety and effectiveness of suzetrigine for the treatment of moderate-to-severe-acute surgical and non-surgical pain conditions, we conducted a phase 3, single-arm study in adults with moderate or severe acute pain on the verbal categorical rating scale and ≥4 on the numeric pain rating scale following surgical procedures or after presenting to a medical facility with moderate or severe acute pain of new origin. Participants received suzetrigine (100mg then 50mg every 12hrs) for 14 days or pain resolution, whichever came first. The primary endpoint was safety. The secondary endpoint was participant perception of suzetrigine's effectiveness in treating acute pain at the end of treatment using a patient global assessment. Suzetrigine was generally safe and well-tolerated in participants (N=256) with a range of surgical and non-surgical acute pain conditions; the maximum severity for most participants who had adverse events was mild (71 participants; 27.7%) or moderate (21 participants; 8.2%). Most participants (213 participants; 83.2%) rated suzetrigine's effectiveness for treating pain on a patient global assessment as good, very good, or excellent. Suzetrigine provides a safe and effective non-opioid, non-addictive treatment with broad applicability for moderate-to-severe acute pain. NCT05661734.

There is a high unmet need for safe and effective non-opioid medicines to treat moderate to severe pain without risk of addiction. Voltage-gated sodium channel 1.8 (Na 1.8) is a genetically and pharmacologically validated pain target that is selectively expressed in peripheral pain-sensing neurons and not in the central nervous system (CNS). Suzetrigine (VX-548) is a potent and selective inhibitor of Na 1.8, which has demonstrated clinical efficacy and safety in multiple acute pain studies. Our study was designed to characterize the mechanism of action of suzetrigine and assess both nonclinical and clinical data to test the hypothesis that selective Na 1.8 inhibition translates into clinical efficacy and safety, including lack of addictive potential. Preclinical pharmacology and mechanism of action studies were performed in vitro using electrophysiology and radiolabeled binding methods in cells recombinantly expressing human Na channels, human proteins, and primary human dorsal root ganglion (DRG) sensory neurons. Safety and addictive potential assessments included in vitro secondary pharmacology studies, nonclinical repeat-dose toxicity and dependence studies in rats and/or monkeys, and a systematic analysis of adverse event data generated from 2447 participants from phase 3 acute pain studies of suzetrigine. Suzetrigine is selective against all other Na subtypes (≥ 31,000-fold) and 180 other molecular targets. Suzetrigine inhibits Na 1.8 by binding to the protein's second voltage sensing domain (VSD2) to stabilize the closed state of the channel. This novel allosteric mechanism results in tonic inhibition of Na 1.8 and reduces pain signals in primary human DRG sensory neurons. Nonclinical and clinical safety assessments with suzetrigine demonstrate no adverse CNS, cardiovascular or behavioral effects and no evidence of addictive potential or dependence. The comprehensive pharmacology assessment presented here indicates that suzetrigine represents the first in a new class of non-opioid analgesics that are selective Na 1.8 pain signal inhibitors acting in the peripheral nervous system to safely treat pain without addictive potential.

Adolescent alcohol abuse is a substantive public health problem that has been the subject of intensive study in recent years. Despite reports of a wide range of effects of adolescent intermittent ethanol (AIE) exposure on brain and behavior, little is known about the mechanisms that may underlie those effects, and even less about treatments that might reverse them. Recent studies from our laboratory have indicated that AIE produced enduring changes in astrocyte function and synaptic activity in the hippocampal formation, suggesting the possibility of an alteration in astrocyte-neuronal connectivity and function. We utilized astrocyte-specific, membrane restricted viral labeling paired with immunohistochemistry to perform confocal single cell astrocyte imaging, three-dimensional reconstruction, and quantification of astrocyte morphology in hippocampal area CA1 from adult rats after AIE. Additionally, we assessed the colocalization of astrocyte plasma membrane labeling with immunoreactivity for AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor 1, an AMPA receptor subunit and established neuronal marker of excitatory synapses, as a metric of astrocyte-synapse proximity. AIE significantly reduced the colocalization of the astrocyte plasma membrane with synaptic marker puncta in adulthood. This is striking in that it suggests not only an alteration of the physical association of astrocytes with synapses by AIE, but one that lasts into adulthood - well after the termination of alcohol exposure. Perhaps even more notable, the AIE-induced reduction of astrocyte-synapse interaction was reversed by sub-chronic treatment with the clinically used agent, gabapentin (Neurontin), in adulthood. This suggests that a medication in common clinical use may have the potential to reverse some of the enduring effects of adolescent alcohol exposure on brain function. All animal experiments conducted were approved by the Duke University Institutional Animal Care and Use Committee (Protocol Registry Number A159-18-07) on July 27, 2018.

R453%R364%R749; Adolescent alcohol abuse is a substantive public health problem that has been the subject of intensive study in recent years. Despite reports of a wide range of effects of adolescent intermittent ethanol (AIE) exposure on brain and behavior, little is known about the mechanisms that may underlie those effects, and even less about treatments that might reverse them. Recent studies from our laboratory have indicated that AIE produced enduring changes in astrocyte function and synaptic activity in the hippocampal formation, suggesting the possibility of an alteration in astrocyte-neuronal connectivity and function. We utilized as-trocyte-specific, membrane restricted viral labeling paired with immunohistochemistry to perform confocal single cell astrocyte imaging, three-dimensional reconstruction, and quantification of astrocyte morphology in hippocampal area CA1 from adult rats after AIE. Additionally, we assessed the colocalization of astrocyte plasma membrane labeling with immunoreactivity for AMPA-(α-amino-3-hydroxy-5-methyl-4-isoxaz-olepropionic acid) glutamate receptor 1, an AMPA receptor subunit and established neuronal marker of excitatory synapses, as a metric of astrocyte-synapse proximity. AIE significantly reduced the colocalization of the astrocyte plasma membrane with synaptic marker puncta in adulthood. This is striking in that it sug-gests not only an alteration of the physical association of astrocytes with synapses by AIE, but one that lasts into adulthood - well after the termination of alcohol exposure. Perhaps even more notable, the AIE-in-duced reduction of astrocyte-synapse interaction was reversed by sub-chronic treatment with the clinically used agent, gabapentin (Neurontin), in adulthood. This suggests that a medication in common clinical use may have the potential to reverse some of the enduring effects of adolescent alcohol exposure on brain function. All animal experiments conducted were approved by the Duke University Institutional Animal Care and Use Committee (Protocol Registry Number A159-18-07) on July 27, 2018.

IL-17R signaling is required for control of extracellular pathogens and is also implicated in development of chronic inflammatory processes. The response to the human pathogen Helicobacter pylori results in Th1 and Th17 cell activation and a chronic inflammatory process that can lead to adverse outcomes, such as gastric cancer. Previously, we identified IL-17RA as a requirement for the recruitment of neutrophils and control of H. pylori colonization in the gastric mucosa. Unexpectedly, H. pylori–infected Il17ra−/− mice had significantly more chronic inflammation than H. pylori–infected wild-type mice. In this study, human epithelial cell lines and murine models were used to investigate differential roles for IL-17A, IL-17F, and IL-17A/F during H. pylori infection. Moreover, the hypothesis that IL-17RA signaling, specifically in lymphocytes, provides an autocrine feedback loop that downregulates Th17 cytokine production was investigated. The data indicate that epithelial cells exhibit a stronger response to IL-17A and IL-17A/F than IL-17F, and that IL-17A and IL-17A/F can synergize with TNF and IL-22 to induce antimicrobial genes of gastric epithelial cells. In vivo deficiencies of IL-17A or IL-17F alone did not significantly change the immunopathological response to H. pylori, but if both cytokines were absent, a hyperinflammatory lymphocytic response developed. Using a cre/flox targeting approach for IL-17RA combined with infection, our findings demonstrate that increased chronic inflammation in Il17ra−/− mice was not attributed to a T cell–intrinsic defect. These data imply that IL-17A and IL-17F may have overlapping roles in maintenance of the gastric mucosal response to infection.

Interleukin-17 receptor (IL-17R) signaling is required for control of extracellular pathogens and is also implicated in development of chronic inflammatory processes. The response to the human pathogen Helicobacter pylori results in Th1 and Th17 cell activation and a chronic inflammatory process which can lead to adverse outcomes such as gastric cancer. Previously, we identified IL-17RA as a requirement for the recruitment of neutrophils and control of H. pylori colonization in the gastric mucosa. Unexpectedly, H. pylori infected Il17ra−/− mice had significantly more chronic inflammation than H. pylori infected WT mice. In this study, human epithelial cell lines and murine models were used to investigate differential roles for IL-17A, IL-17F and IL-17A/F during H. pylori infection. Moreover, the hypothesis that IL-17RA signaling, specifically in lymphocytes, provides an autocrine feedback loop that downregulates Th17 cytokine production was investigated. The data indicate that epithelial cells exhibit a stronger response to IL-17A and IL-17A/F than IL-17F and that IL-17A and IL-17A/F can synergize with TNF and IL-22 to induce antimicrobial genes of gastric epithelial cells. In vivo deficiencies of IL-17A or IL-17F alone did not significantly change the immunopathological response to H. pylori, but if both cytokines were absent, a hyper inflammatory lymphocytic response developed. Using a cre/flox targeting approach for IL-17RA combined with infection, our findings demonstrate that increased chronic inflammation in Il17ra−/− mice was not attributed to a T cell intrinsic defect. These data imply that IL-17A and IL-17F may have overlapping roles in maintenance of the gastric mucosal response to infection.