Neurokinin-1 antagonist orvepitant for EGFRI-induced pruritus in patients with cancer: a randomised, placebo-controlled phase II trial.

OBJECTIVE: To evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus. DESIGN: Randomised, double-blind, placebo-controlled clinical trial. SETTING: 15 hospitals in Italy and five hospitals in the UK. PARTICIPANTS: 44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment. INTERVENTION: 30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus. RESULTS: The trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was -2.78 (SD: 2.64) points in the 30 mg group, -3.04 (SD: 3.06) points in the 10 mg group and -3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity. CONCLUSIONS: Orvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible. TRIAL REGISTRATION NUMBER: EudraCT2013-002763-25.

The Neurokinin-1 Receptor Antagonist Orvepitant Is a Novel Antitussive Therapy for Chronic Refractory Cough: Results From a Phase 2 Pilot Study (VOLCANO-1).

BACKGROUND: Substance P and the neurokinin-1 (NK-1) receptor are implicated in chronic refractory cough pathophysiology. We assessed the efficacy and safety of orvepitant, a brain-penetrant NK-1 antagonist, in an open-label study in CRC patients with chronic refractory cough. METHODS: Thirteen patients with daytime cough frequency >3 to <250 coughs/h took orvepitant 30 mg once daily for 4 weeks. Objective cough frequency was measured over 24 h at baseline and weeks 1, 4, and 8. The primary end point was change from Baseline in daytime cough frequency at week 4. Secondary end points included cough severity visual analog scale (VAS) score, global ratings of change for cough frequency and severity, and Cough-specific Quality of Life Questionnaire score. RESULTS: All patients completed the study. Mean baseline cough frequency was 71.4/h. A statistically and clinically significant improvement in objective daytime cough frequency was observed at week 4: reduction from baseline of 18.9 (26%) coughs/h (95% CI, 9.6-28.3; P < .001). This effect was apparent at week 1 (reduction from baseline of 27.0 [38%] coughs/h [95% CI, 11.4-42.7; P = .001]) and sustained after drug discontinuation at week 8 (reduction from baseline of 20.4 [29%] coughs/h [95% CI, 3.2-37.5; P = .020]). Statistically significant improvements were seen for severity VAS and quality of life. Orvepitant was safe and well-tolerated. CONCLUSIONS: Orvepitant resulted in a significant and sustained improvement in objective cough frequency, severity VAS, and quality of life; appeared safe; and merits further clinical investigation. TRIAL REGISTRY: EU Clinical Trials Register; No.: 2014-003947-36; URL: www.clinicaltrialsregister.eu.

NK-1 Receptor Antagonists and Pruritus: Review of Current Literature.

The discovery of the first neurokinin 1 (NK-1) receptor antagonist was a turning point in the prevention of chemotherapy-induced nausea and vomiting. The NK-1 antagonists are a novel class of drugs that possess antidepressant, anxiolytic, and antiemetic properties. Recently, clinicians have also described an anti-itch activity of NK-1 antagonists. We present herein results from currently available data on use of NK-1R antagonists in dermatology. For this purpose, a systemic electronic literature search of the PubMed and CINAHL databases, Cochrane Library, and clinicaltrials.gov website was performed. Based on currently available data, it can be concluded that NK-1 inhibitors show significant antipruritic potential for treatment of chronic pruritus in different dermatological conditions, but further studies are needed to establish the best indications and dosage of these drugs.

Therapeutic Effect of Novel Antidepressant Drugs Acting at Specific Receptors of Neurotransmitters and Neuropeptides.

BACKGROUND: Major depression is a frequent psychiatric disease. One- third of the depressive patients remain treatment-resistant; thus, it is urgent to find novel antidepressant drugs. OBJECTIVE: In major depression, in several brain areas the neural networks involved and the alterations of neurotransmitters and neuropeptides are updated. According to these networks, new pharmacological agents and effective combinations of antidepressant drugs achieving a more efficacious antidepressant treatment are suggested. RESULTS: In the neural networks, the prefrontal cortex has been included. In this brain area, glutamatergic neurons, which receive an activating potential from D2 dopaminergic neurons, presynaptically inhibit M1 muscarinic cholinergic neurons via NMDA receptors. Medium spiny GABAergic/somatostatin neurons, which receive projections from M1 muscarinic cholinergic neurons, presynaptically inhibit D2 dopaminergic neurons via GABAA/somatostatin1 receptors. The combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist can achive a rapid, long-lasting antidepressant effect. CONCLUSION: In preclinical studies, the antidepressant effect of orvepitant, an NK1 receptor antagonist, has been demonstrated: this antagonist reaches a complete blockade of NK1 receptors. In clinical studies, the combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist should be investigated indepth as well as the therapeutic effect of orvepitant. In clinical studies, the antidepressant effect of a triple reuptake inhibitor should be examined and compared to current antidepressant drugs.

Neurokinin-1 receptor antagonist orvepitant is an effective inhibitor of itch-associated response in a Mongolian gerbil model of scratching behaviour.

Data suggest that substance P could play an important role in pruritus, and therefore, blockade of the neurokinin (NK)-1 receptor might be antipruritic. Thus, we explored in the Mongolian gerbil the effect on scratching behaviour, induced by intra-dermal injection of the NK-1 receptor-specific agonist GR73632, of oral administration of the NK-1 receptor antagonist orvepitant. Orvepitant at all doses tested (0.1-10 mg/kg p.o.) produced a profound inhibition of GR73632 (30 nmol i.d.) induced hindlimb scratching; the minimum effective dose of orvepitant in this model was identified as ≤0.1 mg/kg. The data generated supported the proposition that the antipruritic potential of orvepitant should be evaluated in clinical trials.