Nepadutant

Summary

Nepadutant (MEN‑11420) is an investigational, selective antagonist of the tachykinin NK2 (neurokinin‑A) receptor. It is being explored for functional gastrointestinal disorders such as irritable bowel syndrome, for asthma‑related bronchoconstriction, and for infant colic, but it has not received regulatory approval for any indication.

Mechanism of Action

Nepadutant binds competitively to the NK2 G‑protein‑coupled receptor, blocking the actions of neurokinin‑A. NK2 activation normally drives smooth‑muscle contraction in the gut and bronchial airways and contributes to secretory responses. By preventing receptor activation, nepadutant reduces NK2‑mediated motility, tone, and bronchoconstriction, while leaving NK1 and NK3 pathways unaffected.

What the Research Shows

Early‑phase clinical work has evaluated nepadutant in several contexts. In healthy volunteers, an 8 mg intravenous dose antagonised neurokinin‑A‑induced small‑intestinal motility and increased colonic compliance without altering overall bowel habits after repeated dosing. A double‑blind crossover study in mild‑to‑moderate asthmatics showed that 2 mg and 8 mg intravenous nepadutant shifted the dose‑response curve for neurokinin‑A‑induced bronchoconstriction, an effect that was not sustained at 24 h. A population PK/PD analysis in infants with colic (0.1–0.5 mg kg⁻¹ oral for 7 days) demonstrated dose‑related reductions in crying/fussing minutes and characterized clearance variability. Phase IIa trials in Belgium and Sweden have been reported for irritable bowel syndrome and asthma, but detailed efficacy outcomes remain unpublished. Overall, the data indicate target engagement and short‑term functional effects, but larger, longer‑term trials are lacking.

Reported Benefits

Available studies suggest that nepadutant can acutely blunt NK2‑mediated physiological responses: it reduces neurokinin‑A‑driven bronchoconstriction in asthmatic patients and modulates intestinal motor activity in healthy volunteers. In infants with colic, oral dosing produced a statistically significant, dose‑dependent decrease in crying and fussing time, indicating potential benefit for functional gastrointestinal discomfort. These findings support its mechanistic rationale for IBS and colic symptom relief.

Limitations of the Evidence

Evidence is confined to small, short‑duration trials and early‑phase investigations. The asthma study showed no sustained effect 24 h after dosing, and prolonged NK2 blockade did not change bowel habit frequency or stool consistency in healthy subjects. No large, placebo‑controlled Phase III data are available for IBS or asthma, and the infant colic study involved a limited sample with high pharmacokinetic variability. Consequently, the therapeutic value of nepadutant remains uncertain.

Safety Considerations

Across the reported studies, nepadutant was generally well tolerated. Intravenous 8 mg doses prevented neurokinin‑A‑induced adverse events in volunteers, and the asthma trial reported no serious safety signals. The infant colic trial did not highlight major adverse events, but noted a substantial placebo effect and wide inter‑individual clearance variability. Given the limited safety database, caution is advised, especially for repeated dosing or use in vulnerable populations.

How It Is Administered

Nepadutant has been administered intravenously (e.g., 2 mg or 8 mg bolus), orally (0.1–0.5 mg kg⁻¹ daily in infants), and subcutaneously in early‑phase studies. Formulations used in trials were solution preparations suitable for injection or oral suspension; detailed dosing regimens have not been established for clinical use.

Routes of Administration

Goals & Uses

• Visceral PainPain / GastroenterologyModerate
• Asthma / BronchoconstrictionRespiratoryLow
• Chronic PainPainLow
• Irritable Bowel SyndromeGastrointestinalModerate
• Irritable Bowel Syndrome (IBS)GastrointestinalModerate
• Infantile ColicGastrointestinal / PediatricLow
• AsthmaRespiratoryModerate

Contraindications

• Hypersensitivity to nepadutant or excipientsAllergyHigh
• Known hypersensitivity to nepadutantAllergyHigh

Adverse Effects

• Injection site reactionsLocalUncommon
• HeadacheNeurologicUncommonPain in the head or upper neck
• Gastrointestinal discomfortGastrointestinalUncommon
• Injection site erythemaLocalCommonRedness at the injection site

Drug Interactions

• Beta‑agonistsLow
• CYP3A4 substrates / inhibitorsLow

Population Constraints

• PregnancyReproductive SafetyRelative
• Pediatric populations (neonates/infants)AgeRelative
• Severe hepatic impairmentOrgan ImpairmentRelative

Regulatory Status

• European UnionInvestigationalClinical development discontinued.
• United StatesInvestigationalPhase II completed, no NDA filed.
• United KingdomInvestigationalNo MHRA approval; remains investigational

No approved indication; development halted after Phase II trials due to limited efficacy.

Evidence & Sources

• Targeting tachykinin receptors for the treatment of functional gastrointestinal disorders with a focus on irritable bowel syndrome
  Journal ArticleModerateCorsetti M, Akyuz F, Tack J2015-01-01T00:00:00.000000Z
• Nepadutant Menarini Richerche
  Journal ArticleModerateAhluwalia A2001-01-01T00:00:00.000000Z
• Tachykinin receptors antagonists: from research to clinic
  Journal ArticleModerateQuartara L, Altamura M2006-01-01T00:00:00.000000Z
• Population pharmacokinetic and dose-response models of nepadutant, a selective antagonist of the NK(2) receptors, in infants with colic
  Journal ArticleModerateJönsson S, et al.2025-01-01T00:00:00.000000Z
• Tachykinins and tachykinin receptors in the gut, with special reference to NK2 receptors in human
  Journal ArticleModerateLecci A, et al.2006-01-01T00:00:00.000000Z
• The effect of the tachykinin NK(2) receptor antagonist MEN11420 (nepadutant) on neurokinin A-induced bronchoconstriction in asthmatics
  Journal ArticleModerateSchelfhout V, et al.2009-01-01T00:00:00.000000Z

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