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Autonomic Dysfunction Linked to Inhibition of the Na v 1.7 Sodium Channel

2024; Lippincott Williams & Wilkins; Volume: 149; Issue: 17 Linguagem: Inglês

10.1161/circulationaha.123.067331

1524-4539

Christopher P. Regan, Pierre Morissette, Richard L. Kraus, Erjia Wang, Leticia Arrington, Marissa Vavrek, Jan de Hoon, Marleen Depré, Thomas Lodeweyck, Ignace Demeyer, Tine Laethem, Aubrey Stoch, Arie Struyk,

Epilepsy research and treatment

HomeCirculationVol. 149, No. 17Autonomic Dysfunction Linked to Inhibition of the Nav1.7 Sodium Channel Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBAutonomic Dysfunction Linked to Inhibition of the Nav1.7 Sodium Channel Christopher P. Regan, Pierre Morissette, Richard L. Kraus, Erjia Wang, Leticia Arrington, Marissa Vavrek, Jan de Hoon, Marleen Depre, Thomas Lodeweyck, Ignace Demeyer, Tine Laethem, Aubrey Stoch and Arie Struyk Christopher P. ReganChristopher P. Regan Correspondence to: Christopher P. Regan, PhD, Merck & Co., Inc., 770 Sumneytown Pike WP81-200, West Point, PA 19486. Email E-mail Address: [email protected] https://orcid.org/0000-0002-3201-5878 Nonclinical Drug Safety (C.P.R., P.M., E.W.), Merck & Co., Inc., West Point, PA. , Pierre MorissettePierre Morissette https://orcid.org/0009-0000-4906-4716 Nonclinical Drug Safety (C.P.R., P.M., E.W.), Merck & Co., Inc., West Point, PA. , Richard L. KrausRichard L. Kraus https://orcid.org/0000-0002-3250-3812 Neuroscience (R.L.K.), Merck & Co., Inc., West Point, PA. , Erjia WangErjia Wang Nonclinical Drug Safety (C.P.R., P.M., E.W.), Merck & Co., Inc., West Point, PA. , Leticia ArringtonLeticia Arrington https://orcid.org/0000-0001-7272-1657 Pharmacokinetics, Pharmacodynamics and Drug Metabolism (L.A., M.V.), Merck & Co., Inc., West Point, PA. , Marissa VavrekMarissa Vavrek https://orcid.org/0000-0003-0240-2583 Pharmacokinetics, Pharmacodynamics and Drug Metabolism (L.A., M.V.), Merck & Co., Inc., West Point, PA. , Jan de HoonJan de Hoon Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven; Belgium (J.d.H., M.D., T. Lodeweyck). , Marleen DepreMarleen Depre https://orcid.org/0009-0005-1318-6574 Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven; Belgium (J.d.H., M.D., T. Lodeweyck). , Thomas LodeweyckThomas Lodeweyck https://orcid.org/0000-0002-6137-7931 Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven; Belgium (J.d.H., M.D., T. Lodeweyck). , Ignace DemeyerIgnace Demeyer https://orcid.org/0009-0008-0294-2460 Burn Center, Military Hospital Queen Astrid, Brussels, Belgium (I.D.). , Tine LaethemTine Laethem Translational Medicine, Merck & Co., Inc., Upper Gwynedd, PA (T. Laethem, A. Stoch, A. Struyk). , Aubrey StochAubrey Stoch Translational Medicine, Merck & Co., Inc., Upper Gwynedd, PA (T. Laethem, A. Stoch, A. Struyk). and Arie StruykArie Struyk https://orcid.org/0000-0003-0189-1004 Translational Medicine, Merck & Co., Inc., Upper Gwynedd, PA (T. Laethem, A. Stoch, A. Struyk). Originally published22 Apr 2024https://doi.org/10.1161/CIRCULATIONAHA.123.067331Circulation. 2024;149:1394–1396Human genetic phenotypes associated with loss or gain of function implicate the Nav1.7 channel as a promising target for novel analgesics.1,2 However, the expression of NaV1.7 on autonomic afferent c-type fibers, on sympathetic efferent fibers, and cardiovascular–related autonomic adverse effects reported in gain-of-function mutation phenotypes2,3 create concern for potential Nav1.7 antagonists. Recent clinical assessment of a Nav1.7 antagonist suggested that cardiovascular adverse events could be related to on-target activity.4 The clinical pharmacodynamic relationship between efficacy and cardiovascular adverse events or the predictive value of nonclinical models has not been fully explored. As such, the effects of MK-2075,5 a small-molecule selective Nav1.7 inhibitor (human and rhesus half-maximal inhibitory concentration [IC50]=85 and 161 nmol/L, respectively), were assessed in rhesus monkey (non-human primate [NHP]) and in phase I clinical studies to understand the pharmacodynamics and cardiovascular safety of Nav1.7 blockade.MK-2075 was highly selective against peripheral Nav channels (Nav1.4 and Nav1.6 IC50 >300 µmol/L), cardiac ion channels (hERG, IKs, and Nav1.5 IC50 >30 µmol/L), a broad panel of 114 potential off-targets (IC50 >10 µmol/L). Moreover, NHP whole-body autoradiography demonstrated no brain penetrance. The Figure shows the concentration-dependent decrease in heart rate variability (HRV, Figure B) and spontaneous baroreceptor sensitivity (Figure C) with physiologically meaningful trends occurring at unbound plasma concentrations as low as 0.18 µmol/L (0.3 mg/kg) and statistically significant decreases at 2.3 µmol/L (6 mg/kg). Frequency domain HRV analysis (Figure D) showed concomitant decreases in both high- and low-frequency domains, suggestive of an MK-2075–dependent effect on sympathetic and parasympathetic tone. Supratherapeutic exposures of MK-2075 (50 mg/kg; maximum plasma concentration after rest article administration=169 µmol/L or 16 µmol/L unbound; 100-fold over the rhesus in vitro Nav1.7 IC50) demonstrated complete loss of all HRV indices, paradoxical decreases in heart rate and blood pressure on animal handling (Figure E and F), and one animal exhibited a brief loss of consciousness on postural change; all are indicative of compromised cardiovascular reflexes. Consistent with these being on-target effects, a Nav1.7 inhibitory peptide analogue of JzTx-V with greater NaV1.7 specificity elicited similar effects on HRV in NHPs. In situ hybridization (RNAscope, Figure G–L) on NHP or commercially sourced human tissue demonstrated Nav1.7 colocalized with markers for cardiac and stellate ganglia but not sinoatrial node (NHP) and cardiac/sympathetic ganglia and sinoatrial node/right atrium (human). Clinical testing of MK-2075 was conducted on healthy adult male participants in 2 protocol number (PN) studies: PN001 where participants were given up to 30 mg IV over 8 hours and PN005 where participants were given up to 8 mg IV over 2 hours. Overall, adverse events were generally mild, with the most frequently reported being paresthesia, and there was a low incidence of cardiovascular-related observations. One PN001 participant experienced orthostatic hypotension 5 hours into the 30 mg/8 h IV infusion. Maximum plasma concentration after rest article administration exposures (0.36 µmol/L unbound) was ≈4-fold the in vitro NaV1.7 IC50 at that time. The orthostatic hypotension resolved after the completion of drug administration. Five other reports of self-limited, presyncope symptoms at lower doses were reported but were often associated with study procedures and without concomitant changes in vital signs. One PN005 participant lost consciousness during protocol-driven orthostatic hypotension testing 1 hour after the start of the 8 mg/2 h IV infusion (≈126 nmol/L unbound). The participant spontaneously regained consciousness after ≈20 seconds. Review of the temporal telemetry ECG showed a period of severe bradycardia with two episodes of sinus arrest of ≈4 to 5 seconds each, followed by a brief junctional escape rhythm and then return to normal sinus rhythm. The MK-2075 infusion was stopped immediately, and the participant remained asymptomatic thereafter. One additional participant receiving 8 mg MK-2075 exhibited a ≈70% reduction in spontaneous baroreceptor sensitivity slope at the 2-hour measurement point that was unaccompanied by clinical signs and resolved 2 hours later. In PN005, there were no mean changes in HRV or spontaneous baroreceptor sensitivity nor were there any effects on afferent sensory function to cold (cold water bath)- or heat (Peltior thermode)-induced painful stimuli, or olfactory sensory function assessed by Sniffin' Sticks.Download figureDownload PowerPointFigure. Effects of MK-2075 on cardiac autonomic nervous system balance and reflex control through the assessment of HRV and sBRS in telemetered rhesus monkey at 2 to 6 hours postdose (A–D). Adult male rhesus monkeys (n=4) were given increasing subcutaneous doses of MK-2075 and continuous ECG was evaluated for changes in heart rate (HR, A), the time domain HRV parameter, standard deviation of N-N intervals (SDNN, B), baroreceptor effectiveness index (sBRS, C), and both high-frequency (HF) and low-frequency (LF) domain heart rate variability (HRV, D). To further clarify persistent effects during the diurnal phase, continuous data extracted as 15-minute means were aggregated into a 4-hour time period (2–6 hours postdose). A dose-dependent trend in SDNN, sBRS, and HRV decreases can be observed with a statistically significant (P<0.05) difference in all parameters at the 6 mg/kg SC dose. Statistical significance from vehicle was determined for change from baseline data using a linear mixed-effects model (Y=Group×Time+ID+error) where Group×Time capture the fixed group and time effects and their interactions; ID characterizes the between-subject random effects. E and F, Effect of supratherapeutic doses of MK-2075 on heart rate and diastolic blood pressure. Adult male rhesus monkeys (n=5) were given a continuous 8-hour intravenous infusion through jacketed infusion pumps to determine the effect of MK-2075 on HR (E) and diastolic blood pressure (F) parameters at supratherapeutic exposures (50 mg/kg over 8 hours). Increased HR and no change in diastolic pressure were observed during the infusion. Note that postinfusion handling procedures (noted as "room entry" on the graphs) caused an expected increase in HR and diastolic blood pressure in vehicle-treated animals (VEH), but the HR increase was attenuated and the diastolic blood pressure paradoxically decreased after administration of MK-2075 suggestive of compromised cardiovascular autonomic regulation. G through L, In situ hybridization Nav1.7 mRNA expression in rhesus and human tissues. G, H, and I represent Nav1.7 staining in formalin-fixed paraffin-embedded rhesus sinoatrial node, cardiac ganglia, and dorsal root ganglia, and J, K, and L represent Nav1.7 staining in human sinoatrial node, cardiac ganglia, and dorsal root ganglia, respectively. Nav1.7 is not detected in rhesus sinoatrial node, but mildly expressed in human sinoatrial node (40×). It highly expressed in cardiac ganglia and dorsal root ganglia of both rhesus and human subjects (20×).This study reports for the first time that acute Nav1.7 inhibition could lead to autonomic effects in NHP and human subjects, and that these may be observed with no therapeutic margin to analgesic pharmacology on the basis of quantitative sensory testing. Dose-dependent decreases in HRV and spontaneous baroreceptor sensitivity occurred in NHPs, and clinical events of syncope were observed that were suggestive of Nav1.7-dependent cardiac autonomic dysfunction.It is tempting to speculate that these results and those of others,4 which contrast the lack of effects in NaV1.7 null individuals, serve as a reminder of the potential phenotypic differences between acute pharmacological block versus genetic deficiency and the important role developmental compensation may play in the latter.Animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (2011) and received facility approval. Clinical studies were approved by an institutional ethics review committee and subjects gave informed consent. Nonclinical data may be available on reasonable request and completion of required agreements.ARTICLE INFORMATIONAcknowledgmentsThe authors thank A. Houghton, D. Henze, R. Briscoe, and C. Burgey for their helpful scientific dialog and perspective, H. Regan, T. Detwiler, S. Gruver, B. Rockafellow, and M. Syrylo for the conduct of the telemetered non-human primate experiments, P. Fanelli for help with data analysis, S. Wang for the conduct of the statistical analysis, and D. Gilberto and A. Bone for veterinarian surgical support and care.Author contributions:Conceptualization, Drs Regan, Morissette, and A. Struyk; Investigation, Drs Regan and Kraus, M. Vavrek, Drs Wang and A. Struyk; Supervision, Dr A. Stoch; Writing – original draft, Drs Regan, Morissette, and A. Struyk; Writing – review and editing, Drs Regan, Morissette, and Kraus, M. Vavrek, Drs Wang, de Hoon, Depre, T. Lodeweyck, Demeyer, Laethem, A. Stoch, and A. Struyk.Sources of FundingNone.Nonstandard Abbreviations and AcronymshERGhuman ether-a-go-go ion channelHRVheart rate variabilityIC50half-maximal inhibitory concentrationNHPnon-human primateDisclosures Drs Regan, Morissette, and Kraus, M. Vavrek, and Drs Wang, T. Laethem, A. Stoch, and A. Struyk are employed by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ. L. Arrington is employed by Amgen Inc. but was employed by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, at the time of the study. Drs de Hoon, Dupre, and T. Lodeweyck are employed by the University of Leuven, Belgium. Dr Demeyer is employed by the Military Hospital Queen Astrid, Belgium.Footnotes*C.P. Regan and P. Morisette contributed equally.For Sources of Funding and Disclosures, see page 1396.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Christopher P. Regan, PhD, Merck & Co., Inc., 770 Sumneytown Pike WP81-200, West Point, PA 19486. Email christopher_regan@merck.comREFERENCES1. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, et al. An SCN9A channelopathy causes congenital inability to experience pain.Nature. 2006; 444:894–898. doi: 10.1038/nature05413CrossrefMedlineGoogle Scholar2. Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, et al. Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy.Ann Neurol. 2012; 71:26–39. doi: 10.1002/ana.22485CrossrefMedlineGoogle Scholar3. Minett MS, Nassar MA, Clark AK, Passmore G, Dickenson AH, Wang F, Malcangio M, Wood JN. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons.Nat Commun. 2012; 3:79.CrossrefGoogle Scholar4. Rothenberg ME, Tagen M, Chang JH, Boyce-Rustay J, Friesenhahn M, Hackos DH, Hains A, Sutherlin D, Ward M, Cho W. Safety, tolerability, and pharmacokinetics of GDC-0276, a novel NaV1.7 inhibitor, in a first-in-human, single- and multiple-dose study in healthy volunteers.Clin Drug Investig. 2019; 39:873–887. doi: 10.1007/s40261-019-00807-3CrossrefMedlineGoogle Scholar5. Ballard JE, Pall PS, Vardigan J, Zhao F, Holahan MA, Zhou X, Jochnowitz N, Kraus RL, Klein RM, Henze DA, et al. Translational pharmacokinetic-pharmacodynamic modeling of NaV1.7 inhibitor MK-2075 to inform human efficacious dose.Front Pharmacol. 2021; 12:786078. doi: 10.3389/fphar.2021.786078CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails April 23, 2024Vol 149, Issue 17 Advertisement Article InformationMetrics © 2024 The Authors.Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.https://doi.org/10.1161/CIRCULATIONAHA.123.067331PMID: 38648272 Originally publishedApril 22, 2024 Keywordsbaroreflexclinical studyheart rate controlNAV1.7 voltage-gated sodium channelpainPDF download Advertisement SubjectsAutonomic Nervous SystemBasic Science ResearchClinical StudiesHemodynamicsTranslational Studies