The NK1 receptor antagonist serlopitant for treatment of chronic pruritus

ABSTRACT

Introduction: Pruritus is a common symptom associated with several potential underlying causes, including both dermatologic and systemic diseases; it can also occur without an identifiable cause. Current treatment options are limited and most patients experience impaired quality of life. Serlopitant is a neurokinin 1 (NK₁) receptor antagonist under development for the treatment of pruritus associated with various dermatologic conditions and chronic pruritus of unknown origin.

Areas covered: This review describes the epidemiology and unmet needs of patients with chronic pruritus, focusing specifically on patients with prurigo nodularis, psoriatic itch, and chronic pruritus of unknown origin; the rationale for targeting the NK₁ receptor for treatment of chronic pruritus; and the clinical development of serlopitant, including efficacy and safety data from completed phase II studies.

Expert opinion: There is an unmet need for novel, safe, and effective therapies to treat chronic pruritus. Serlopitant has shown promising efficacy, safety, and tolerability across different patient populations, including adolescents and elderly patients. In contrast to less convenient administration options, serlopitant is a once-daily oral tablet, which is expected to facilitate compliance.

Trial registration: ClinicalTrials.gov identifier: NCT00290563.

Trial registration: ClinicalTrials.gov identifier: NCT00835718.

Trial registration: ClinicalTrials.gov identifier: NCT03282591.

Trial registration: ClinicalTrials.gov identifier: NCT01951274.

Trial registration: ClinicalTrials.gov identifier: NCT02196324.

Trial registration: ClinicalTrials.gov identifier: NCT02975206.

Trial registration: ClinicalTrials.gov identifier: NCT03343639.

Trial registration: ClinicalTrials.gov identifier: NCT03546816.

Trial registration: ClinicalTrials.gov identifier: NCT03677401.

Trial registration: ClinicalTrials.gov identifier: NCT03540160.

Trial registration: ClinicalTrials.gov identifier: NCT03841331.

KEYWORDS:

• Chronic nodular prurigo
• chronic pruritus
• neurokinin 1 receptor
• NK₁ receptor
• prurigo nodularis
• psoriasis
• serlopitant

1. Introduction

1.1. Epidemiology of chronic pruritus

Pruritus is the most frequent presenting symptom in dermatology [1,2]. Studies have estimated the point prevalence of chronic pruritus at 14% to 17%, with a lifetime prevalence of 22% to 26% [3–6]. These data indicate that approximately 1 in 4 people experience chronic itch at some point in their lifetime. Chronic pruritus can be associated with a variety of underlying causes, including dermatologic, systemic, neuropathic, psychogenic, mixed, and unknown origin. Many inflammatory skin conditions cause itch; there is currently an unmet need to develop itch-specific drugs that target nonhistaminergic itch [7–9]. In addition, prurigo nodularis (PN) occurs with a lower frequency but is characterized by therapy-refractory pruritus. Patients with chronic pruritus of any etiology experience impaired quality of life comparable to that of patients with chronic pain [10].

2. Overview of the market

2.1. Current treatment paradigms for chronic pruritus

For patients with chronic pruritus, treatment typically consists of initial measures to improve the condition of the skin; avoidance of potential triggers; treatment of the underlying cause, if known; and symptomatic treatment with topical or systemic therapies [1,11,12].

Regardless of the etiology of pruritus, therapies that are frequently recommended include emollients, topical corticosteroids, topical calcineurin inhibitors, systemic antihistamines, phototherapy, gabapentinoids, antidepressants, biologics, and immunosuppressants [1,12,13]. However, no drugs are approved specifically for the treatment of chronic pruritus, and many of these modalities have limited efficacy and can be associated with significant side effects [14–17]. Thus, patients often experience long-lasting pruritus without improvement, and with markedly reduced quality of life [17,18].

A number of novel treatment targets are currently under investigation for the management of chronic pruritus. This review will focus on evidence supporting the use of the neurokinin 1 (NK₁) receptor antagonist, serlopitant.

3. Rationale for NK₁ receptor blockade in pruritus

3.1. Role of the substance P and NK₁ receptor pathway in transmission of itch

Itch signals are transmitted via both histamine-dependent and histamine-independent pathways; however, the nonhistaminergic pathway appears to have a greater role in chronic pruritus except in pruritus associated with urticaria [19,20]. Substance P (SP) is a neuropeptide involved in mediating itch signaling in the peripheral and central nervous systems [21–24]. SP binds to the NK₁ receptor and another class of receptors, the Mas-related G protein–coupled receptors (Mrgprs), which are involved in itch signaling in mice [25,26]. The NK₁ receptor is expressed on multiple skin cell types involved in the initiation and transmission of itch, including keratinocytes, fibroblasts, and mast cells, and in the superficial lamina I dorsal horn neurons of the spinal cord [22,24]. Although further research is needed to clarify the role of SP and the NK₁ receptor in the skin, their role in transmission of the itch signal in the peripheral and central nervous systems is supported by a growing body of evidence [19,22–24,27–30].

3.2. Role of SP and the NK₁ receptor in chronic pruritic conditions

Studies have demonstrated that SP and the NK₁ receptor are overexpressed across multiple chronic itch-inducing conditions and that NK₁ receptor antagonism disrupts itch signaling and reduces pruritus [19,23,31–34]. In a recent study, SP and the NK₁ receptor were identified as genes that were overexpressed in the pruritic skin of patients with psoriasis or atopic dermatitis [32]. Immunohistochemical analysis also showed that the NK₁ receptor was overexpressed and the number of SP-expressing nerve fibers was increased in pruritic skin of these patients [32]. Preclinical studies support the functional role for increased expression of SP and the NK₁ receptor in pruritic conditions and the potential to reduce pruritus by targeting the NK₁ receptor. Intradermal injection of SP is reported to cause dose-dependent increases in scratching at the injection site in mice [35] and to be associated with pruritus in healthy volunteers and patients with psoriasis [36]. Animal studies have shown that scratching behaviors are reduced by blocking NK₁ receptor signaling [19,23], and intradermal injection of an NK₁ receptor agonist induces scratching, which can be attenuated by the administration of NK₁ receptor antagonists [33,34]. These data suggest that disrupting the itch signal by NK₁ receptor antagonism could be a rational treatment approach for chronic pruritus. This concept was supported by several case series and a small (N = 20) proof-of-concept study that showed that the NK₁ receptor antagonist, aprepitant, reduced pruritus intensity in patients with chronic pruritus or PN [15,37].

4. Clinical development of serlopitant

Serlopitant is an oral once-daily NK₁ receptor antagonist (Box.1). The clinical development for serlopitant was initiated by Merck in January 2005 and included 13 phase I studies and 2 phase II studies in patients with overactive bladder (N = 557) and alcohol dependence (N = 162) [38,39]. In 2012, the serlopitant clinical development program was licensed to Menlo Therapeutics, formerly Tigercat Pharma, where phase II clinical studies have been completed in patients with chronic pruritus, pruritus associated with PN, pruritus associated with atopic dermatitis, pruritus associated with psoriasis, and chronic cough [39–43]. In addition, an exploratory phase II investigator-initiated study was completed in patients with epidermolysis bullosa by researchers at Stanford University [44]. Serlopitant is currently being developed for the treatment of pruritus associated with PN, pruritus associated with psoriasis, and chronic pruritus of unknown origin (CPUO).

4.1. Pharmacokinetics and metabolism

In pharmacokinetics studies, dose-proportional increases in plasma concentrations were observed with serlopitant doses up to 35 mg, with no differences observed between male and female participants [39]. Peak plasma concentrations were observed at 2 to 4 hours postdose, apparent elimination half-life ranged from 45 to 85 hours, and steady state was achieved at about day 14. Three long-lived active metabolites of serlopitant are observed in humans: M1/M1a, M2/M2a, and M3. Exposure of the metabolites was <1% to 5% of the parent molecule after a single 10-mg dose and increased to up to 7% to 36% after 3 weeks of daily dosing. In central nervous system receptor occupancy studies, dose-dependent NK₁ receptor occupancy was observed at serlopitant doses ranging from 0.1 mg to 10.0 mg, with mean receptor occupancy >90% observed with the 5-mg dose [38]. Serlopitant is metabolized by CYP3A4 and coadministration with a strong CYP3A4 inhibitor (ketoconazole) resulted in a 4.8-fold, 6.3-fold, and 1.2-fold increase in serlopitant half-life, exposure (AUC_0-inf), and maximum concentration, respectively [39]. In contrast with aprepitant, a moderate CYP3A4 inhibitor that has Ki values of approximately 10 μM for the 1ʹ- and 4-hydroxylation of midazolam, serlopitant had no significant effect on the pharmacokinetics of midazolam [39,45].

4.2. Nonpruritus clinical studies

Serlopitant was originally developed for use in the treatment of overactive bladder. In preclinical studies, stimulation of NK₁ receptors was associated with smooth muscle contraction, and NK₁ receptor antagonism reduced inflammatory bladder hyperactivity [22,46]. A pilot study of the NK₁ receptor antagonist aprepitant demonstrated activity in women with urge urinary incontinence [47]. In the phase II study of 557 adults with overactive bladder (ClinicalTrials.gov identifier: NCT00290563), serlopitant at doses of 0.25 mg and 4 mg significantly decreased daily micturitions after 8 weeks compared with placebo; however, tolterodine 4 mg demonstrated superior efficacy [38]. The data support the tolerability of serlopitant and its potential for chronic use, as some patients received serlopitant 4 mg for up to 1 year.

In addition, a phase II placebo-controlled study was intended to evaluate serlopitant in adults with alcohol dependence (ClinicalTrials.gov identifier: NCT00835718); however, the study was prematurely terminated by Merck, the study sponsor, for business reasons.

Substance P is present in the sensory nerves, smooth muscle, and blood vessels of the lower respiratory tract [48]. In preclinical studies, inhibition of neutral endopeptidase, the major enzyme degrading SP, enhanced cough whereas an NK₁ receptor antagonist inhibited cough in response to various stimuli. Serlopitant for the treatment of chronic cough was evaluated in a phase II randomized controlled trial (ClinicalTrials.gov identifier: NCT03282591; EudraCT number: 2017–003250-16). Adults with chronic cough (N = 185) were treated with serlopitant 5 mg or placebo orally once daily for 12 weeks. Although serlopitant was well tolerated, there was no treatment benefit relative to placebo in the reduction in cough frequency.

5. Efficacy of serlopitant for treatment of pruritus

Serlopitant has been evaluated in 4 phase II studies in patients with chronic pruritus across 4 different populations. Serlopitant met the primary endpoints in 3 of the 4 studies and showed improvement compared with placebo at all assessed time points (Figure 1). The 4-point responder rate was also significantly higher with serlopitant than placebo in 3 of the 4 studies (Figure 2).

Figure 1. Efficacy of serlopitant in meeting primary endpoints across phase II pruritus trials: TCP-101 (NCT01951274), TCP-102 (NCT02196324), MTI-103 (NCT02975206), and MTI-109 (NCT03343639). *Primary endpoint. Avg, average; VAS, visual analog scale; WI-NRS, worst-itch numeric rating scale.

Figure 2. Serlopitant 5 mg responder rate across phase II pruritus studies: TCP-101 (NCT01951274), TCP-102 (NCT02196324), MTI-103 (NCT02975206), and MTI-109 (NCT03343639). NRS or WI-NRS 4-point responder analysis. *Primary endpoint. NRS, numeric rating scale; WI-NRS, worst-itch NRS.

5.1. Chronic pruritus

The first phase II study of serlopitant for the treatment of pruritus was a multicenter, randomized, placebo-controlled study (ClinicalTrial.gov identifier: NCT01951274) that evaluated 3 once-daily oral doses of serlopitant (0.25 mg, 1 mg, and 5 mg) in 257 patients with severe treatment-refractory chronic pruritus of various or unknown etiologies [41]. In this study, the effect of serlopitant on pruritus was dose dependent, with the 1- and 5-mg doses achieving significant reductions in visual analog scale (VAS) pruritus scores compared with placebo at week 6, the primary endpoint (Table 1). The percentage change from baseline in VAS at week 6 was −42.5% for serlopitant 5 mg compared with −28.3% for placebo (P = 0.013). A similar result was observed for numeric rating scale (NRS) pruritus scores. In addition, efficacy outcomes were similar in the prespecified subgroup analysis of patients with a history of atopic diathesis. These data demonstrated the clinically meaningful activity of serlopitant for the treatment of chronic pruritus derived from multiple primary causes and support ongoing clinical development.

Table 1. Efficacy of serlopitant in patients with chronic pruritus.

Study (ClinicalTrials.gov identifier)	Study design	Population	Treatment	VAS percentage change from baseline	WI-NRS mean change from baseline	NRS percentage change from baseline	4-point NRS responder rate
TCP-101 (NCT01951274) [41]	Phase II RPCT	Adults (age range, 18–65 years) with CP (N = 257)	Serlopitant 0.25 mg, 1 mg, or 5 mg vs placebo orally once daily for 6 weeks	Serlopitant: -34.1 ± 4.1 for 0.25 mg; −41.4 ± 4.0* for 1 mg; -42.5 ± 4.1* for 5 mg Placebo: −28.3 ± 4.1	N/A	Serlopitant: -35.8 ± 3.5 for 0.25 mg; −39.4 ± 3.5* for 1 mg; -39.0 ± 3.5* for 5 mg Placebo: −28.7 ± 3.5	Serlopitant: 38.5% for 0.25; 32.7%* for 1 mg; 46.2%* for 5 mg Placebo: 22.6%
TCP-102 (NCT02196324) [42]	Phase II RPCT	CP in adults (age range, 25–78 years) with prurigo nodularis (N = 128)	Serlopitant 5 mg vs placebo orally once daily for 8 weeks	Serlopitant: -48.3 ± 30.7* Placebo: −26.3 ± 34.9	Serlopitant: -3.2 ± 2.8 Placebo: −2.3 ± 2.5	Serlopitant: -37.2 ± 37.1* Placebo: −26.4 ± 28.0	Serlopitant: 46.5%* Placebo: 25.6%
MTI-103 (NCT02975206) [39,43]	Phase II RPCT	CP in adults and adolescents (age range, 13–84 years) with atopic dermatitis (N = 484)	Serlopitant 1 mg or 5 mg vs placebo orally once daily for 6 weeks	N/A	Serlopitant: -2.32 for 1 mg and −2.25 for 5 mg Placebo: −2.01	N/A	Serlopitant: 22.4% for 1 mg and 20.6% for 5 mg Placebo: 16.5%
MTI-109 (NCT03343639) [16,39]	Phase II RPCT	CP in adults (age range, 20–77 years) with psoriasis (N = 204)	Serlopitant 5 mg vs placebo orally once daily for 8 weeks	N/A	Serlopitant: -2.8 ± 2.5* Placebo: −2.0 ± 2.3	N/A	Serlopitant: 33.3%* Placebo: 21.1%

*P < 0.05 compared with placebo.

CP, chronic pruritus; N/A, not available; NRS, numeric rating scale; RPCT, randomized placebo-controlled trial; VAS, visual analog scale; WI-NRS, worst-itch NRS.

5.2. Pruritus associated with PN

In a randomized, double-blind, placebo-controlled study (ClinicalTrial.gov identifier: NCT02196324), serlopitant 5 mg was evaluated in 128 patients with chronic, topical corticosteroid- or antihistamine-treatment-refractory PN [42]. Serlopitant significantly reduced average-itch VAS pruritus scores, the primary endpoint, compared with placebo. The mean change from baseline in average-itch VAS was −3.6 for serlopitant vs −1.9 for placebo at week 8 (P < 0.001; Table 1). Differences between serlopitant and placebo were also statistically significant at weeks 2 and 4. Similar results were obtained for multiple additional secondary endpoints, with serlopitant providing greater reduction in pruritus than placebo as measured by worst-itch VAS, average-itch NRS, worst-itch NRS (WI-NRS), and the verbal rating scale (each 24-hour recall period). In addition, patients treated with serlopitant showed greater improvement in the percentage of healed or excoriated PN lesions from baseline to week 8 compared with placebo, though the differences were not statistically significant.

5.3. Pruritus associated with psoriasis

To study the effects of serlopitant on psoriatic itch, a randomized, double-blind, placebo-controlled trial (ClinicalTrial.gov identifier: NCT03343639) evaluated serlopitant 5 mg compared with placebo in 204 adults with plaque psoriasis and severe pruritus. In this study, the WI-NRS 4-point responder rate (percentage of participants who achieved a 4-point reduction from baseline itch score) at week 8, the primary endpoint, was 33% with serlopitant versus 21% with placebo (P = 0.028; Table 1) [40]. Similar results were obtained for the key secondary endpoint of the WI-NRS 4-point responder rate at week 4, and additional secondary endpoints of the WI-NRS 3-point responder rate at weeks 4 and 8.

5.4. Pruritus associated with atopic dermatitis

Serlopitant was evaluated for treatment of severe pruritus in adults (n = 439) and adolescents (n = 45) with a diagnosis of atopic dermatitis in a phase II randomized, placebo-controlled study (ClinicalTrials.gov identifier: NCT02975206). The study showed numeric differences in pruritus scores favoring serlopitant compared with placebo at all time points; however, the differences were not statistically significant (Table 1) [43]. Although these data indicated that serlopitant had activity in patients with pruritus associated with atopic dermatitis, the results were not sufficient to warrant further development in this patient population.

6. Safety and tolerability of serlopitant

6.1. Overview of adverse events

Serlopitant has been evaluated in approximately 1600 patients across multiple indications, including patients who received treatment for up to 1 year. Overall, serlopitant has been well tolerated across multiple disease states and dose levels [39]. The most common treatment-emergent adverse events (AEs) across all completed phase II studies (Table 2) were urinary tract infection (serlopitant, 4.8%; placebo, 2.5%), nasopharyngitis (serlopitant, 4.8%; placebo, 3.7%), diarrhea (serlopitant, 4.7%; placebo, 3.4%), and headache (serlopitant, 4.4%; placebo, 6.3%). Somnolence was infrequent and occurred at similar rates in patients treated with serlopitant (1.7%) and placebo (1.5%) [39]. In the phase II studies, most AEs were mild or moderate in severity [39,41,42,44]. Serious AEs assessed as possibly or likely related to serlopitant were reported in 5 patients across all phase II studies, and included transient ischemic attack, cardiac syndrome, (recurrent) depression, dizziness and vertigo (presenting concurrently), and a fatal pulmonary embolism [39].

Table 2. Treatment-emergent adverse events reported for ≥2% of patients treated with serlopitant or placebo in completed phase II studies.

System organ class/preferred term	All serlopitant (N = 1261)	Placebo (N = 670)
Infections and infestations
Urinary tract infection	61 (4.8%)	17 (2.5%)
Nasopharyngitis	60 (4.8%)	25 (3.7%)
Upper respiratory tract infection	42 (3.3%)	23 (3.4%)
Gastrointestinal disorders
Diarrhea	59 (4.7%)	23 (3.4%)
Nausea	30 (2.4%)	13 (1.9%)
Dry mouth	26 (2.1%)	9 (1.3%)
Nervous system disorders
Headache	55 (4.4%)	42 (6.3%)
Dizziness	38 (3.0%)	10 (1.5%)
General disorders and administration- site condition
Fatigue	43 (3.4%)	16 (2.4%)
Skin and subcutaneous tissue disorders
Pruritus	20 (1.6%)	17 (2.5%)

7. Future directions

Based on results of the completed phase II studies, the efficacy and safety of serlopitant will be further evaluated in phase III development programs in patients with PN and with psoriatic pruritus, including a long-term safety study, and in a phase II study in patients with CPUO (Table 3).

Table 3. Ongoing studies of serlopitant for treatment of chronic pruritus.

Study (ClinicalTrials.gov identifier)	Study design	Population	Treatment	Primary outcome(s)	Status as of April 2019
MTI-105; US study (NCT03546816)	Phase III RPCT	Adults (age ≥18 years) with pruritus associated with PN (N = 280)	Serlopitant 5 mg vs placebo orally once daily for 10 weeks	WI-NRS 4-point responder rate at week 10	Recruiting
MTI-106; EU study (NCT03677401; EudraCT number: 2017–004210-25)	Phase III RPCT	Adults (age ≥18 years) with pruritus associated with PN (N = 280)	Serlopitant 5 mg vs placebo orally once daily for 10 weeks	WI-NRS 4-point responder rate at week 10	Recruiting
MTI-107 (NCT03540160; EudraCT number: 2017–004211-40)	Phase III open-label long-term safety study	Adults (age ≥18 years) with pruritus associated with PN, AD, or psoriasis (N = 700)	Serlopitant 5 mg orally once daily for 57 weeks	TEAEs and SAEs; mean change from baseline in clinical laboratory parameters, vital signs, and ECG parameters	Recruiting
MTI-117 (NCT03841331)	Phase II RPCT	Adults (age 18–120 years) with CPUO (N = 200)	Serlopitant 5 mg vs placebo orally once daily for 10 weeks	WI-NRS 4-point responder rate at week 10	Recruiting

AD, atopic dermatitis; CPUO, chronic pruritus of unknown origin; ECG, electrocardiogram; PN, prurigo nodularis; RPCT, randomized placebo-controlled trial; SAE, serious adverse event; TEAE, treatment-emergent adverse event; WI-NRS, worst-itch numeric rating scale.

7.1. Ongoing phase III studies

7.1.1. Pruritus associated with PN

Two phase III studies were initiated in the United States and Europe to evaluate the efficacy, safety, and tolerability of serlopitant for the treatment of pruritus in adults with PN (ClinicalTrials.gov identifiers: NCT03546816 and NCT03677401). The studies are currently recruiting adults with PN involving at least 10 lesions on at least 2 different body surface areas. If the cause of the pruritic condition associated with PN is known, the pruritus must be persistent despite at least 6 weeks of optimized and stable treatment of the underlying condition. Patients will be randomized to oral once-daily administration of serlopitant 5 mg or placebo. The primary outcome measure is WI-NRS 4-point responder rate at week 10.

7.1.2. Long-term safety

A long-term safety study was initiated to further evaluate the safety of serlopitant for chronic use (ClinicalTrials.gov identifier: NCT03540160). This open-label study is currently recruiting adults with pruritus associated with PN, atopic dermatitis, or psoriasis to evaluate the safety of orally administered serlopitant 5 mg once daily. Primary outcome measures at 57 weeks include the incidence of treatment-emergent AEs and serious AEs, and the mean change from baseline in clinical laboratory parameters, vital signs, and electrocardiogram parameters.

7.1.3. Pruritus associated with psoriasis

A phase III study to evaluate the efficacy, safety, and tolerability of serlopitant in patients with psoriasis is planned.

7.2. Ongoing phase II studies

7.2.1. Chronic pruritus of unknown origin

A phase II study has been initiated to evaluate the efficacy and safety of serlopitant in patients with CPUO (ClinicalTrials.gov identifier: NCT03841331). The study is currently recruiting adults with chronic pruritus assessed by the investigator to be of unknown origin that is not localized and is unresponsive to prior treatment with emollients. Patients receive orally administered serlopitant 5 mg or placebo once daily for 10 weeks. The primary endpoint is the WI-NRS 4-point responder rate at week 10.

8. Conclusion

Chronic pruritus is a common symptom associated with multiple potential underlying causes. Current treatment options are limited, and most provide only short-term relief. The NK₁ receptor pathway is involved in the transmission of itch signals in the peripheral and central nervous systems, and studies indicate that targeting this pathway with NK₁ receptor antagonists could be an effective strategy for the treatment of pruritus. Serlopitant is an NK₁ receptor antagonist that has demonstrated good tolerability and reduced pruritus in patients with chronic pruritus, PN, and psoriatic itch in well-controlled clinical studies. Efficacy and safety of serlopitant is under further evaluation in robust clinical safety and efficacy studies in patients with pruritus associated with various underlying conditions and CPUO.

Box 1. Drug summary box.

Drug name (generic)	Serlopitant (VPD-737; MK-0594)
Phase	III
Indication	In development for pruritus associated with prurigo nodularis (PN), psoriatic pruritus, and chronic pruritus of unknown origin
Pharmacology description/mechanism of action	NK1 receptor antagonist
Route of administration	Oral
Chemical structure
Pivotal trials	PN phase III US study (ClinicalTrials.gov identifier: NCT03546816) PN phase III EU study (ClinicalTrials.gov identifier: NCT03677401; EudraCT number: 2017–004210-25) Psoriasis phase III study (study number not yet available)

9. Expert opinion

There is an urgent need for novel, safe, and effective therapies to treat chronic pruritus. The multifactorial nature of pruritus, which can include neuroimmune and/or pruritogen-related mechanisms, presents therapeutic challenges. Accordingly, drugs that target distinct mechanisms of itch induction or transmission show promise as effective treatments for different types of pruritus. NK₁ receptor antagonists, such as serlopitant, inhibit itch signaling via NK₁ receptors in spinal neurons and regions of the brain associated with itch signaling, and block the efferent function of SP in the skin, two important pathways for diminishing pruritus [23,24,27–30]. These data support a role for NK₁ receptor antagonism for treatment of itch associated with dermatoses, as well as with nondermatologic diseases.

Current data indicate serlopitant is a potent NK₁ receptor antagonist for the treatment of pruritus, with a good safety profile, and no clinical evidence of significant drug–drug interactions. Clinical studies of serlopitant support its use in elderly patients, a population particularly at risk of itch; the use of serlopitant for pre-adolescent children needs to be further elucidated. The oral once-daily administration of serlopitant is beneficial, as it facilitates medication adherence, and in contrast with intravenous or subcutaneous therapies, can be self-administered by patients. Thus, compared with existing antipruritic therapies, serlopitant may provide a more effective and better tolerated treatment for patients with chronic pruritus. If the promising results showing efficacy in reduction of pruritus associated with PN and psoriasis from the phase II studies are confirmed in the phase III studies, quick uptake and acceptance of serlopitant among both patients and physicians is anticipated after approval. Availability of a safe and effective therapy specifically evaluated in robust clinical studies for the treatment of pruritus could also have a health economic benefit if less effective (eg, antihistamines) or less tolerable (eg, immunosuppressants such as oral corticosteroids and cyclosporine, and sedating drugs such as gabapentinoids and oral antidepressants) therapies can be replaced in the future. Regulatory approval for the use of serlopitant for the treatment of pruritus associated with various underlying conditions potentially including PN, psoriasis, and CPUO is expected to be requested within the next few years. It is anticipated that approval of serlopitant for the pruritic indications will help address a significant unmet need for these patients, and possibly also patients with less common etiologies, by disrupting the itch signal through NK₁ receptor antagonism.

Declaration of interest

Prof. Sonja Ständer is a principal investigator for Dermasence, Galderma, Kiniksa, Menlo Therapeutics Inc., Trevi Therapeutics, Novartis, Sanofi, and Vanda, and a member of scientific advisory boards and consultant for Almirall, Bayer, Beiersdorf, Bionorica, Cara, Celgene, DS Biopharma, Galderma, Kiniksa, Kneipp, Maruho, Menlo Therapeutics Inc., NeRRe Therapeutics, Novartis, Nuformix, Perrigo, Sanofi, Sienna, Toray, and Trevi Therapeutics. Dr. Mary Spellman was previously an employee of Menlo Therapeutics Inc. Dr. Paul Kwon is an employee of Menlo Therapeutics Inc. Prof. Gil Yosipovitch is a principal investigator for Menlo Therapeutics Inc., Trevi Therapeutics, Regeneron, Pfizer, Sun Pharma, Kiniksa, Vanda, and Novartis, and a member of scientific advisory boards for Menlo Therapeutics Inc., Trevi Therapeutics, Sienna, Novartis, Galderma, Sanofi Regeneron, Pfizer, Kiniksa, Eli Lilly, and Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Acknowledgments

Medical writing/editorial support was provided by Amy Agbonbhase, PhD, of The Lockwood Group (Stamford, CT), in accordance with good publication practice guidelines (GPP3), and was funded by Menlo Therapeutics Inc.

Additional information

Funding

This paper was funded by Menlo Therapeutics Inc.