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

Q: What are the key findings of this study?

Acute inhibition of Nav1.7 with MK-2075 led to dose-dependent decreases in heart rate variability in primates and clinical events of syncope and orthostatic hypotension in healthy human subjects.

Q: What is the clinical evidence from this study?

Population: Healthy. Intervention: MK-2075. Primary outcome: Cardiovascular autonomic dysfunction (heart rate variability, baroreceptor sensitivity, and clinical adverse events).

Q: What does this research mean for the field?

Inhibition of the Nav1.7 voltage-gated sodium channel is linked to autonomic dysfunction and altered heart rate control. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

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

doi:10.1161/circulationaha.123.067331

April 22, 2024CirculationOpen Access

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

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Key result

Nav1.7 inhibition with MK-2075 triggers acute autonomic dysfunction, causing syncope and orthostatic hypotension.

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Why the study?

The clinical pharmacodynamic relationship between efficacy and cardiovascular adverse events of Na v 1.7 antagonists and the predictive value of nonclinical models had not been fully explored.

Key Points

Determine the cardiovascular safety, autonomic effects, and pharmacodynamics of selective Nav1.7 sodium channel inhibition in non-human primates and healthy human participants.
Evaluated the selective Nav1.7 inhibitor MK-2075 in adult male rhesus monkeys using subcutaneous dose escalation (n=4) and supratherapeutic intravenous infusions at 50 mg/kg over 8 hours (n=5) with continuous ECG telemetry.
Administered MK-2075 intravenously to healthy adult male volunteers in two phase I clinical trials at doses up to 30 mg over 8 hours (PN001) or up to 8 mg over 2 hours (PN005) while assessing vitals, heart rate variability, and sensory thresholds.
Mapped Nav1.7 mRNA expression across dorsal root ganglia, cardiac ganglia, and sinoatrial node tissues in human and rhesus monkey samples using in situ hybridization.
In rhesus monkeys, MK-2075 caused concentration-dependent reductions in heart rate variability and spontaneous baroreceptor sensitivity, reaching statistical significance at 6 mg/kg (P<0.05), with 50 mg/kg producing paradoxical drops in heart rate and diastolic blood pressure upon handling.
In clinical testing, one participant receiving 30 mg over 8 hours experienced orthostatic hypotension at 5 hours, while one participant receiving 8 mg over 2 hours developed severe bradycardia with two sinus arrest episodes of ≈4 to 5 seconds and transient syncope.
Human and primate cardiac ganglia showed high Nav1.7 expression, and human participants showed no analgesia to cold or heat stimuli at doses that provoked cardiovascular and autonomic adverse events.

PICO

P

Population

Healthy adult male participants evaluated in two Phase I clinical studies to assess the safety and autonomic effects of the Nav1.7 inhibitor MK-2075.

I

Intervention / Comparator

MK-2075 (Up to 30 mg IV over 8 hours or up to 8 mg IV over 2 hours)

O

Primary Outcome

Cardiovascular autonomic dysfunction (heart rate variability, baroreceptor sensitivity, and clinical adverse events)

Limitations

Potential phenotypic differences between acute pharmacological block versus genetic deficiency and the role of developmental compensation.

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Implication

Preclinical and phase I trial demonstrates cardiovascular autonomic dysfunction in primates and healthy humans, indicating narrow therapeutic margins for Nav1.7-targeted analgesics.

Abstract

heart rate control NAV1.7 voltage-gated sodium channel pain

Discussion

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Cite This Study

Regan et al. (2024) studied Healthy. MK-2075 was evaluated on Cardiovascular autonomic dysfunction (heart rate variability, baroreceptor sensitivity, and clinical adverse events). Acute inhibition of Nav1.7 with MK-2075 led to dose-dependent decreases in heart rate variability in primates and clinical events of syncope and orthostatic hypotension in healthy human subjects.

synapsesocial.com/papers/6a73547234af997f9774fc62 https://doi.org/10.1161/circulationaha.123.067331

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

Figures

Key Points

PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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

Figures

Key Points

PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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