Selective NK1 Research Articles

Identification of an Intravenous Injectable NK1 Receptor Antagonist for Use in Traumatic Brain Injury.

Traumatic brain injuries represent a leading cause of death and disability in the paediatric and adult populations. Moderate-to-severe injuries are associated with blood-brain barrier dysfunction, the development of cerebral oedema, and neuroinflammation. Antagonists of the tachykinin NK1 receptor have been proposed as potential agents for the post-injury treatment of TBI. We report on the identification of EUC-001 as a potential clinical candidate for development as a novel TBI therapy. EUC-001 is a selective NK1 antagonist with a high affinity for the human NK1 receptor (Ki 5.75 × 10-10 M). It has sufficient aqueous solubility to enable intravenous administration, whilst still retaining good CNS penetration as evidenced by its ability to inhibit the gerbil foot-tapping response. Using an animal model of TBI, the post-injury administration of EUC-001 was shown to restore BBB function in a dose-dependent manner. EUC-001 was also able to ameliorate cerebral oedema. These effects were associated with a significant reduction in post-TBI mortality. In addition, EUC-001 was able to significantly reduce functional deficits, both motor and cognitive, that normally follow a severe injury. EUC-001 is proposed as an ideal candidate for clinical development for TBI.

Nausea and vomiting induced by pharmacotherapy: have all issues of maintenance therapy been resolved?

Many patients with various localizations of malignant neoplasms require therapy aimed at preventing or reducing the manifestations of nausea and vomiting induced by anticancer pharmacotherapy. New drugs to prevent the development of complications of chemotherapy are critical to improve the quality of life of patients and their adherence to therapy. Palonosetron, a new generation 5-HT3 receptor antagonist, has a long half-life (up to 40 hours) and a 30-fold higher affinity for 5-HT3 receptors compared to previous generations of 5-HT3 receptor antagonists. Clinical studies have shown the ability of palonosetron in combination with dexamethasone and, if indicated, neurokinin antagonists to effectively prevent the development of nausea and vomiting during single- and multi-day cycles of chemotherapy for both solid tumors and hematological diseases, including high-dose chemotherapy, in preparation for transplantation of auto- and allogeneic stem cells. The innovative oral drug Akynzeo is currently available for use in clinical practice, which includes 2 highly selective NK1 and 5-HT3 receptor antagonists in fixed doses. The drug prevents induced nausea and vomiting during moderate and highly emetogenic chemotherapy in more than 90 % of cases, both in the acute and delayed phases.

A CASE OF ANAPHYLAXIS TO FOSAPREPITANT

<h3>Introduction</h3> Fosaprepitant is a small molecule, intravenously administered antiemetic drug that is a selective NK-1 receptor antagonist. Systemic hypersensitivity reactions to fosaprepitant are rare. <h3>Case Description</h3> A 42-year-old male with Shwachman-Diamond syndrome presents with newly diagnosed myelodysplastic syndrome. He was initiated on chemotherapy with azacitidine and venetoclax. He developed neutropenic fever from a perianal abscess and fistula. Chemotherapy was paused, and cefepime/metronidazole was started. When chemotherapy was restarted, he was pretreated with fosaprepitant 150mg for refractory nausea. Fosaprepitant was administered over 7 minutes. Symptoms of shortness of breath and epigastric pain began during the infusion. Hypoxia developed 17 minutes after the infusion with O2 84% and a new 4L oxygen requirement. Notable signs included wheezing, periorbital/perioral edema, tachypnea, and tachycardia. He received 0.3mg IM epinephrine, nebulized epinephrine, 50mg IV Benadryl, and 125mg IV methylprednisolone. He required intubation for worsening upper lip/tongue edema and recrudescence of wheezing as well as an epinephrine IV infusion for hypotension. A tryptase level was drawn 3 hours after symptom onset and was elevated to 13.2 mcg/L (baseline 6.7 mcg/L). <h3>Discussion</h3> Fosaprepitant is an unusual cause of systemic hypersensitivity reactions with <1% incidence reported in the literature. Our patient represents an unexpected case of anaphylaxis on first exposure to fosaprepitant with the likely mechanism being non-IgE mediated mast cell activation. Chemotherapy and antibiotics were reintroduced without complication. Increased awareness of hypersensitivity reactions to fosaprepitant is critical given the growing use of this antiemetic drug for cases of refractory nausea.

Regional differences of tachykinin effects on smooth muscle and pacemaker potentials of the stomach, duodenum, ileum and colon of an emetic model, the house musk shrews

Background and aimsThe contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus. MethodsThe effects of substance P (SP), neurokinin (NK)A, NKB and selective NK1 (CP122,721, CP99,994), NK2 (SR48,968, GR159,897) and NK3 (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array. ResultsCompared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK3 had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon. ConclusionThis study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms.

Azathioprine therapy induces selective NK cell depletion and IFN-γ deficiency predisposing to herpesvirus reactivation

Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and reducing the numbers of circulating B and T lymphocytes. Case reports indicate increased risk for serious infections that can occur despite regular measurements of lymphocyte counts during azathioprine therapy. We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use. Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients. Azathioprine therapy selectively induced pronounced CD56dimCD16+ natural killer cell depletion and concomitant IFN-γ deficiency. Cytokine profiling revealed a specific contraction of classical TH1 cells during azathioprine treatment. We further observed an increased occurrence of reactivation of endogenous latent herpesviruses in the azathioprine-treated group versus in patients with myasthenia gravis who were not receiving immunomodulatory treatment; this increased occurrence was validated in an independent cohort. Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice.

Second-Generation Camelid Trike Induces Improved NK Cell Mediated Targeting of AML in Pre-Clinical Models

We have shown that IL-2 stimulated NK cell-based immunotherapy can induce remission in 30-50% of patients with refractory acute myeloid leukemia (AML). Although encouraging, the clinical benefit is limited by induction of Tregs and by lack of antigen specificity. Thus we generated a 161533 trispecific killer engager (TriKE) molecule containing an anti-CD16 scFv to engage NK cells, an anti-CD33 scFv to engage myeloid targets, and a modified IL-15 linker. Our pre-clinical data showed that both scFvs were functional and the IL-15 linker induced enhanced survival and selective NK cell expansion. This agent will be tested in a Phase I clinical trial at the University of Minnesota with enrollment planned for Q3 2017. Despite the promising pre-clinical data using the 161533 scFV TriKE molecule, we hypothesized that steric factors, probably mediated by the two scFv arms containing a VH and a VL, were likely hindering maximal functionality in this molecule by mispairing at the time of refolding. Supporting this premise, at equimolar concentrations, the IL-15 moiety in the 161533 first-generation TriKE is 13-fold less potent than monomeric recombinant IL-15. To address this issue we substituted the anti-CD16 scFv arm in the TriKE platform with a novel humanized camelid anti-CD16 single-domain antibody to create a second-generation molecule, named cam161533. The humanized single domain antibody was generated by cloning the CDRs (1, 2 and 3) of a llama anti-CD16 single-domain antibody into a humanized single-domain backbone. Single-domain antibodies have several advantages, including better stability and solubility, more resistance to pH changes, better recognition of hidden antigenic sites, and lack of a VL portion preventing VH/VL mispairing. In our bacterial production system the cam161533 molecule yielded better purities and quantities than the first-generation 161533 molecule. More importantly, the cam161533 TriKE induced a potent increase in NK cell degranulation (Figure 1A), measured by CD107a expression against HL-60 AML tumor targets when compared to the first-generation 161533 molecule (5 nM conc.: 70.75±3.65% vs. 30.75±5.05%). IFNg production (Figure 1B) was similarly enhanced with the cam161533 TriKE against HL-60 cells when compared to the 161533 TriKE (5 nM conc.: 29.2±1.8% vs. 6.55±1.07%). The cam161533 TriKE also exhibited a robust increase in NK cell proliferation (Figure 1C), measured by CellTrace dilution, when compared to the 161533 TriKE (5 nM conc.: 57.65±6.05% vs. 20.75±2.55%). In order to compare binding stability of cam161533 TriKE to the 161533 TriKE we used pre-incubated PBMCs with each molecule for 15 minutes, and after two washes, tested then in functional degranulation assay after incubation with HL-60 tumor targets for 4 hours (Figure 1D). In this assay the cam161533 TriKE induced significantly more degranulation than all other groups tested, while the first-generation TriKE (161533) did not induce any differences compared to either control in this setting (cam161533 = 48.35±3.06% vs. 161533 = 26.35±1.82%, NT = 22.15±2.88%, and IL15 = 23.05±2.59%; P = 0.0153, 0.0045, and < 0.0001 respectively, n = 4). Having shown that the second-generation cam161533 TriKE molecule displays substantially better functional characteristics in vitro, we next tested it in a preclinical AML model. This model consists of NSG mice engrafted with HL-60-luc targets and human NK cells. Both TriKEs significantly reduced tumor burden, tracked by bioluminescence generated by the luciferase gene in the HL-60-luc cells, when compared to tumor alone (Figure 1E). However, the cam161533 TriKE treated mice had 130-fold less tumor luminescence than the 161533 TriKE treated mice (1.86x107±2.76x106 vs 2.45x109±4.26x108 p/sec/cm2/sr, P = 0.0005, n = 5), indicating a strong improvement in AML tumor control with the second-generation TriKE. The camTriKE also yielded better tumor control in a primary AML tumor model. Our data suggest that the second-generation cam161533 molecule has clear functional advantages and warrants clinical testing in direct comparison to the scFV 161533 construct. These promising new findings steer our future molecule development towards camelid TriKEs which show great potential in the tumor immunotherapy setting. [Display omitted] DisclosuresVallera:Oxis Biotech: Consultancy. Miller:Oxis Biotech: Consultancy; Celegene: Consultancy; Fate Therapeutics: Consultancy, Research Funding.

Evaluation of tradipitant, a selective NK1 antagonist, on response to oxycodone in humans.

RationalePreclinical studies demonstrate that the NK1 receptor is involved in opioid reinforcement and withdrawal expression. Few studies have examined the impact of treatment with NK1 antagonists on opioid response in humans.ObjectiveTo explore the potential for a selective NK1 antagonist, tradipitant, to attenuate the abuse liability and reinforcing and analgesic effects of oxycodone in opioid-experienced individuals.MethodsParticipants with recreational opioid use, but without opioid physical dependence, were enrolled as inpatients for ~6 weeks (n = 8). A within-subject, double-blind, randomized, placebo-controlled, crossover design was employed. The pharmacodynamic response to intranasal oxycodone across a range of doses (0 to 30 mg) was examined during two counterbalanced maintenance periods (tradipitant 0 or 85 mg/bid). Oxycodone self-administration was assessed with a modified progressive ratio procedure, and analgesia was assessed with the cold pressor test.ResultsOxycodone produced significant and dose-related increases on a broad array of prototypic opioid measures, including subjective ratings related to abuse liability (e.g., liking) and physiological outcomes (i.e., expired CO2). Oxycodone self-administration increased with increasing dose, as did analgesia. Tradipitant largely did not alter any of these effects of oxycodone, with the exception of producing a reduction in ratings of desire for opioids.ConclusionsGiven that the vast majority of oxycodone effects were unchanged by tradipitant, these data do not provide support for the utility of NK1 antagonists as a potential treatment for opioid use disorder.

Substance P restores spermatogenesis in busulfan-treated mice: A new strategy for male infertility therapy

Male infertility has become an important health problem that is primarily caused by testicular dysfunction with abnormal spermatogenesis. In this study, we demonstrated that the neuropeptide, substance P (SP), is essential for spermatogonia proliferation in a seminiferous tubule culture system. In addition, SP (5 nmol/kg) treatment markedly restored spermatogenesis, improved sperm quality, and increased the number of ZBTB16+ or LIN28+ undifferentiated spermatogonia as well as STRA8+ differentiated spermatogonia in a busulfan-induced non-obstructive azoospermic mouse model. Furthermore, 100 nM SP treatment in vitro significantly stimulated the proliferation of GC-1 spg cells (a spermatogonia cell line) via activation of the Erk1/2 signaling pathway. Moreover, the sperm quality and the number of spermatogonia were significantly reduced after treatment with RP67580, a selective NK-1 receptor antagonist, suggesting that SP-NK1R signaling plays an important role in spermatogenesis. Taken together, these results suggest that SP may be a potential therapeutic agent for male infertility by accelerating the restoration of spermatogenesis.

Opioidergic regulation of contractile activity of lymphatic vessels

The aim is to study the effect of endogenous opioid peptides on the contractile activity of lymphatic vessels in the white rat. Materials and methods . Under isometric conditions, the dynamics of spontaneous contractile activity of isolated annular segments of rat lymphatic vessels under the action of endogenous opioid peptides (beta-endorphin and endomorphin-1) was record; possible mechanisms of opiates action were studied. Results . The range of β-endorphin level 1×10 –11 –1×10 –8 M resulted in a decrease of the minute productivity of the lymphatic vessels, by 22%, mainly due to a decreasing of single contractions frequency. In the presence of blockers of voltage-gated and ATP-sensitive potassium channels and blockers of eNOS, the inhibitory effect was not manifest. Endomorphin-1, used in the concentration range of 1×10 –10 –1×10 –8 M, stimulated the contractile activity of the lymphatic vessels by an average of 15 %. The stimulatory effect was not manifest when using endomorphin-1 in the presence of a selective NK1 receptor antagonist. Conclusions . The inhibitory effect of β-endorphin is associated with the activation of voltage-dependent and ATP-sensitive potassium channels, endothelium-(NO)-dependent mechanisms. The action of endomorphin-1, stimulating lymphangionic motility, can be carry out through interaction with NK receptors.

Gender-Related Differences of Tachykinin NK2 Receptor Expression and Activity in Human Colonic Smooth Muscle.

The tachykinin NK2 receptor plays a key role in gastrointestinal motor function. Enteric neurons release neurokinin A (NKA), which activates NK2 receptors on gastrointestinal smooth muscle, leading to contraction and increased motility. In patients with diarrhea-predominant irritable bowel syndrome, the NK2 receptor antagonist ibodutant had a greater therapeutic effect in females than males. The present study aimed to determine whether gender influences the expression and activity of NK2 receptors in human colonic smooth muscle. In vitro functional studies were performed to examine the contractile responses of colonic muscle strips to NKA and the selective NK2 receptor agonist [Lys5,MeLeu9,Nle10]NKA(4-10). Contractions were also measured in the presence of ibodutant to determine its antagonistic potency. The signal transduction pathways coupled to NK2 receptor activation were investigated using second messenger inhibitors. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localization of NK2 receptors. NK2 receptor-mediated contractility was greater in females compared with males. When against NKA, ibodutant was more potent in females. NK2 receptor expression increased with age in females, but not in males. Phospholipase C-mediated signaling was less prominent in females compared with males, whereas Ca2+ sensitization via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. The distribution of NK2 receptors in the human colon did not differ between the genders. Overall, gender differences exist in the expression and activity of NK2 receptors in colonic smooth muscle. These gender distinctions should be considered in the therapeutic development of NK2 receptor agents. SIGNIFICANCE STATEMENT: The tachykinin NK2 receptor has been identified as a therapeutic target for the treatment of bowel and bladder dysfunctions. The present study has revealed gender-related variations in NK2 receptor activity, signaling transduction pathways, antagonist potency, and changes in expression with age. These factors may underlie the gender differences in the treatment of diarrhea-predominant irritable bowel syndrome with NK2 receptor antagonists. Our findings highlight that gender differences should be considered in the therapeutic development of NK2 receptor agents.

Δ9-THC and related cannabinoids suppress substance P- induced neurokinin NK1-receptor-mediated vomiting via activation of cannabinoid CB1 receptor

Δ9-THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB1 receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT3-and neurokinin NK1-receptors to induce vomiting. Δ9-THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT3 receptor selective agonist, 2-methyserotonin. In the current study, we explored whether Δ9-THC and related CB1/CB2 receptor agonists (WIN55,212–2 and CP55,940) inhibit vomiting evoked by SP (50 mg/kg, i.p.) or the NK1 receptor selective agonist GR73632 (5 mg/kg, i.p.). Behavioral methods were employed to determine the antiemetic efficacy of cannabinoids in least shrews. Our results showed that administration of varying doses of Δ9-THC (i.p. or s.c.), WIN55,212–2 (i.p.), or CP55,940 (i.p.) caused significant suppression of SP-evoked vomiting in a dose-dependent manner. When tested against GR73632, Δ9-THC also dose-dependently reduced the evoked emesis. The antiemetic effect of Δ9-THC against SP-induced vomiting was prevented by low non-emetic doses of the CB1 receptor inverse-agonist/antagonist SR141716A (<10 mg/kg). We also found that the NK1 receptor antagonist netupitant can significantly suppress vomiting caused by a large emetic dose of SR141716A (20 mg/kg). In sum, Δ9-THC and related cannabinoids suppress vomiting evoked by the nonselective (SP) and selective (GR73632) neurokinin NK1 receptor agonists via stimulation of cannabinoid CB1 receptors.

Potency, efficacy, and selectivity of GR64349 at human recombinant neurokinin NK2 and NK1 receptors

The affinity, potency, efficacy, and selectivity of the NK2 receptor agonist GR64349 ([Lys3,Gly8,-R-γ-lactam-Leu9]NKA(3–10)) at human recombinant NK2 and NK1 receptors was examined. In radioligand binding studies, GR64349 displaced [125I]-NKA binding to NK2 receptors with high affinity (pKi 7.77 + 0.10) but only weakly displaced [3H]-septide binding to NK1 receptors (pKi <5). In functional studies examining increases in intracellular inositol-1 phosphate (IP-1) accumulation, calcium levels, and cyclic AMP synthesis, GR64349 was a full agonist by reference to the endogenous agonists NKA (NK2 receptors) and substance P (NK1 receptors). GR64349 increased IP-1 accumulation with 1,400-fold greater potency in cells expressing NK2 receptors (pEC50 9.10 + 0.16) than cells expressing NK1 receptors (pEC50 5.95 + 0.80). For calcium responses, GR64349 was 500-fold more potent in the assay using NK2 receptors (pEC50 9.27 + 0.26) than NK1 receptors (pEC50 6.55 + 0.16). GR64349 also stimulated cyclic AMP synthesis in both cell lines, and was almost 900-fold more potent at NK2 receptors (pEC50 10.66 + 0.27) than NK1 receptors (pEC50 7.71 + 0.41). These findings confirm that GR64349 is the most selective NK2 receptor agonist described to date.

Affinity, potency, efficacy, and selectivity of neurokinin A analogs at human recombinant NK2 and NK1 receptors

A series of peptide NK2 receptor agonists was evaluated for affinity, potency, efficacy, and selectivity at human recombinant NK2 and NK1 receptors expressed in CHO cells to identify compounds with the greatest separation between NK2 and NK1 receptor agonist activity. Binding studies were performed using displacement of [125I]-NKA binding to NK2 receptors and displacement of [3H]-Septide binding to NK1 receptors expressed in CHO cells. Functional studies examining the increase in intracellular calcium levels and cyclic AMP stimulation were performed using the same cell lines. A correlation was demonstrated between binding affinities (Ki) and potency to increase intracellular calcium (EC50) for NK2 and NK1 receptors. Ranking compounds by their relative affinity (Ki) or potency (EC50) at NK2 or NK1 receptors indicated that the most selective NK2 agonists tested were [Lys5,MeLeu9,Nle10]-NKA(4-10) (NK1/NK2 Ki ratio = 674; NK1/NK2 EC50 ratio = 105) and [Arg5,MeLeu9,Nle10]-NKA(4-10) (NK1/NK2 Ki ratio = 561; NK1/NK2 EC50 ratio = 70). The endogenous peptide, NKA, lacked selectivity with an NK1/NK2 Ki ratio = 20 and NK1/NK2 EC50 ratio = 1. Of the compounds selected for evaluation in cyclic AMP stimulation assays, [β-Ala8]-NKA(4–10) had the greatest selectivity for activation of NK2 over NK1 receptors (NK1/NK2 EC50 ratio = 244), followed by [Lys5,MeLeu9,Nle10]-NKA(4-10) (ratio = 74), and NKA exhibited marginal selectivity (ratio = 2.8).

A randomized phase III study evaluating the efficacy of single-dose NEPA, a fixed antiemetic combination of netupitant and palonosetron, versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC)

BackgroundCo-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize chemotherapy-induced nausea and vomiting (CINV) control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a fixed combination of a highly selective NK1 receptor antagonist, netupitant (300 mg), and the pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), has shown superior CINV prevention compared with PALO in cisplatin and anthracycline/cyclophosphamide-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen.Patients and methodsThis randomized, double-blind phase III study conducted in Asia was designed with the primary objective to demonstrate non-inferiority of a single oral dose of NEPA compared with a 3-day oral APR/GRAN regimen in chemotherapy-naïve patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis/no rescue medication) during the overall (0–120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at − 10%. Secondary efficacy endpoints included no emesis, no rescue medication, and no significant nausea (NSN).ResultsTreatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0–1 (98%); lung cancer (58%). NEPA demonstrated non-inferiority to APR/GRAN for overall CR [NEPA 73.8% versus APR/GRAN 72.4%, 95% CI (−4.5%, 7.5%)]. No emesis [NEPA 75.0% versus APR/GRAN 74.0%, 95% CI (−4.8%, 6.9%)] and NSN rates [NEPA 75.7% versus APR/GRAN 70.4%, 95% CI (−0.6%, 11.4%)] were similar between groups, but significantly more NEPA patients did not take rescue medication [NEPA 96.6% versus APR/GRAN 93.5%, 95% CI (0.2%, 6.1%)]. NEPA was well tolerated with a similar safety profile to APR/GRAN.ConclusionsIn this first study comparing NK1RA regimens and DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC.

Phase III safety evaluation of intravenous NEPA, a novel fixed antiemetic combination of fosnetupitant and palonosetron, over multiple cycles.

122 Background: NEPA is an oral fixed combination of the selective NK1 receptor antagonist (RA), netupitant (300 mg), and pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), combining two guideline-recommended antiemetic classes in a convenient single capsule. Oral NEPA has shown superior prevention of chemotherapy-induced nausea and vomiting (CINV) over oral PALO, sustained efficacy over multiple cycles, and well-established safety in &gt;1500 patients (pts). To offer additional convenience for health care practitioners and pts, an intravenous (IV) formulation of the NEPA fixed combination (fosnetupitant 235 mg/PALO 0.25 mg) was developed. Methods: This randomized, multinational, double-blind, stratified (by gender/country) phase 3 study in chemotherapy-naïve pts with solid tumors was designed to assess the safety of a single 30-minute infusion of IV NEPA prior to initial/up to 4 repeated cycles of highly emetogenic chemotherapy (HEC). Patients received either IV NEPA or oral NEPA, both with oral dexamethasone on days 1-4. Safety was assessed by treatment-emergent adverse events (TEAEs), laboratory tests, vital signs and ECGs. Results: 404 pts were evaluated for a total of 1312 exposures. Overall, 53% of pts were male with a mean age of 60 years; 99% of pts were white and cisplatin-containing regimen was the HEC for 96% of pts; lung cancer was the most common tumor (55% pts). The AE profiles were similar for both groups in cycle 1 and across all cycles (See Table), with no increased incidence of AEs in subsequent cycles. No infusion site reactions related to IV NEPA occurred. No clinically relevant changes in QTcor cardiac safety concerns were observed. Conclusions: IV NEPA is safe and well-tolerated over multiple cycles with a similar safety profile to oral NEPA in pts receiving HEC. Clinical trial information: NCT02517021. [Table: see text]

Phase III study of NEPA, a fixed combination of netupitant and palonosetron, versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV).

10090 Background: Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize CINV control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a novel fixed combination of a highly selective NK1 receptor antagonist (RA), netupitant (300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3RA, has shown superior CINV prevention compared to PALO in cisplatin and AC-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen, with the primary objective being to demonstrate non-inferiority in preventing CINV. Methods: This randomized, double-blind, parallel group Phase III study conducted in an Asian population was designed to compare efficacy and safety of a single oral dose of NEPA with a 3-day oral APR/GRAN regimen in chemotherapy-naïve patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at -10%. Secondary efficacy endpoints included no emesis and no significant nausea (NSN: &lt; 25mm on 100mm VAS). Results: Treatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0-1 (98%); lung cancer (58%). NEPA demonstrated non-inferiority to APR/GRAN for overall CR; no emesis and NSN rates favored NEPA. Most frequent study drug-related adverse events (AEs) for NEPA included constipation (8.0%) and hiccups (2.7%). The type/incidence/severity of AEs were similar for NEPA and APR/GRAN. Conclusions: In this first study comparing NK1RA regimens and 4 days of DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC. [Table: see text]

Effect of a Bicyclic Pyrimidine Derivative (KRP-103), a Novel Selective Tachykinin NK1 Receptor Antagonist, on Bladder Function in Guinea Pigs.

We evaluated the pharmacological characteristics of KRP-103, chemically named as ((2-(4-acetylpiperazin-1-yl)-6-[3,5-bis(trifluorometheyl)-phenylmethyl]-4- (2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one), and its effects on lower urinary tract function in guinea pigs. In radioligand binding assay, KRP-103 showed higher selectivity for human NK1 receptor (hNK1R) than for human NK2 receptor (hNK2R) and human NK3 receptor (hNK3R) (Ki for hNK1R, hNK2R and hNK3R=0.126 nM, > 10 000 nM and > 10 000 nM). In distention-induced rhythmic bladder contractions (RBCs) in urethane-anesthetized guinea pigs, intravenous administration of KRP-103 dose-dependently increased the shutdown time of RBCs and slightly decreased the amplitude of RBCs (only about 20%). In acutely spinalized guinea pig cystometory, intraduodenal administration of KRP-103 dose-dependently increased the effective bladder capacity with a minimum effective dose of 1 mg/kg. Furthermore, to clarify the site of action of KRP-103, we evaluated the inhibitory effects of KRP-103 on bladder contractions induced by electrical stimulation (ES) of the central or peripheral cut end of the pelvic nerve (PN). KRP-103 inhibited the bladder contractions induced by ES of the central cut end of PN but not those induced by ES of the peripheral cut end of PN. These results indicate that KRP-103 enhances bladder storage function by inhibiting sensory transmission from the bladder at the level of spinal cord without affecting bladder efferent function, suggesting that KRP-103 may be a suitable therapeutic drug for treatment of overactive bladder.

Netupitant, a Potent and Highly Selective NK1 Receptor Antagonist, Alleviates Acetic Acid-Induced Bladder Overactivity in Anesthetized Guinea-Pigs.

Introduction. Tachykinins potently contract the isolated urinary bladder from a number of animal species and play an important role in the regulation of the micturition reflex. On the guinea-pig isolated urinary bladder we examined the effects of a new potent and selective NK1 receptor antagonist (netupitant) on the contractions induced by a selective NK1 receptor agonist, SP-methylester (SP-OMe). Moreover, the effects of netupitant and another selective NK1 antagonist (L-733,060) were studied in anesthetized guinea-pigs using two experimental models, the isovolumetric bladder contractions and a model of bladder overactivity induced by intravesical administration of acetic acid (AA).Methods and Results. Detrusor muscle strips were mounted in 5 mL organ baths and isometric contractions to cumulative concentrations of SP-OME were recorded before and after incubation with increasing concentrations of netupitant. In anesthetized female guinea-pigs, reflex bladder activity was examined under isovolumetric conditions with the bladder distended with saline or during cystometry using intravesical infusion of AA. After a 30 min stabilization period, netupitant (0.1–3 mg/kg, i.v.) or L-733,060 (3–10 mg/kg, i.v.) were administered. In the detrusor muscle, netupitant produced a concentration-dependent inhibition (mean pKB = 9.24) of the responses to SP-OMe. Under isovolumetric conditions, netupitant or L-733,060 reduced bladder contraction frequency in a dose-dependent manner, but neither drug changed bladder contraction amplitude. In the AA model, netupitant dose-dependently increased intercontraction interval (ICI) but had no effect on the amplitude of micturition (AM). L-733,060 dose-dependently increased ICI also but this effect was paralleled by a significant reduction of AM.Conclusion. Netupitant decreases the frequency of reflex bladder contractions without altering their amplitude, suggesting that this drug targets the afferent limb of the micturition reflex circuit and therefore may be useful clinically in treating bladder overactivity symptoms.

Ca2+ signaling and emesis: Recent progress and new perspectives.

Cisplatin-like chemotherapeutics cause vomiting via calcium (Ca2+)-dependent release of multiple neurotransmitters (dopamine, serotonin, substance P, etc.) from the gastrointestinal enterochromaffin cells and/or the brainstem. Intracellular Ca2+ signaling is triggered by activation of diverse emetic receptors (including tachykininergic NK1, serotonergic 5-HT3, dopaminergic D2, cholinergic M1, or histaminergic H1), whose activation in vomit-competent species can evoke emesis. Other emetogens such as cisplatin, rotavirus NSP4 protein and bacterial toxins can also induce intracellular Ca2+ elevation. Netupitant is a highly selective neurokinin NK1 receptor (NK1R) antagonist and palonosetron is a selective second-generation serotonin 5-HT3 receptor (5-HT3R) antagonist with a distinct pharmacological profile. An oral fixed combination of netupitant/palonosetron (NEPA; Akynzeo(®)) with >85% antiemetic efficacy is available for use in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Cannabinoid CB1 receptor agonists possess broad-spectrum antiemetic activity since they prevent vomiting caused by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, 5-HT3R agonists, and D2R agonists. Our findings demonstrate that application of the L-type Ca2+ channel (LTCC) agonist FPL 64176 and the intracellular Ca2+ mobilizing agent thapsigargin (a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor) cause vomiting in the least shrew. On the other hand, blockade of LTCCs by corresponding antagonists (nifedipine or amlodipine) not only provide broad-spectrum antiemetic efficacy against diverse agents that specifically activate emetogenic receptors such as 5-HT3, NK1, D2, and M1 receptors, but can also potentiate the antiemetic efficacy of palonosetron against the non-specific emetogen, cisplatin. In this review, we will provide an overview of Ca2+ involvement in the emetic process; discuss the relationship between Ca2+ signaling and the prevailing therapeutics in control of vomiting; highlight the evidence for Ca2+-signaling blockers/inhibitors in suppressing emetic behavior in the least shrew model of emesis as well as in the clinical setting; and also draw attention to the clinical benefits of Ca2+-signaling blockers/inhibitors in the treatment of nausea and vomiting.

Abstract P1-10-06: Nausea control and quality-of-life benefit with NEPA, the first combination antiemetic agent, in patients with breast cancer receiving anthracycline/cyclophosphamide (AC) chemotherapy

Abstract Background: Patients (pts) with breast cancer (BC) are at high risk for developing chemotherapy-induced nausea and vomiting (CINV) due to the emetogenicity of chemotherapy (often AC-based) and predisposing risk factors including young age and female gender. For pts receiving AC, antiemetic guidelines recommend prophylactic administration of an NK1 receptor antagonist (RA), a 5-HT3 RA, and dexamethasone (DEX). NEPA is the first fixed combination agent approved in oncology; comprised of a highly selective NK1 receptor antagonist (RA), netupitant (300 mg), and the pharmacologically/clinically distinct 5-HT3 RA, palonosetron (PALO 0.50 mg). NEPA has shown superior complete response (no emesis/no rescue use) rates compared with oral PALO in a Phase 3 trial in pts receiving AC (Aapro, Ann Oncol 2014) and in that study's BC subset. Despite progress in prevention of vomiting, nausea control remains suboptimal, particularly in the delayed phase (days 2-5), and debate exists whether NK1 RAs improve nausea control. The objective of this post-hoc analysis was to evaluate whether NEPA showed nausea and associated quality-of-life (QOL) benefits in the subset of patients with BC in this trial. Methods: The subset of chemotherapy-naïve BC pts from this multinational, randomized, double-blind Phase 3 study were included in this analysis. Patients received either a single dose of NEPA or oral PALO prior to AC along with oral DEX 12 mg (NEPA) or 20 mg (PALO). No significant nausea (NSN: max &amp;lt;25 mm on 100 mm visual analog scale) rates in the acute (0-24h), delayed (25-120h) and overall (0-120h) phases following chemotherapy during cycles 1-4 were calculated. QOL was assessed by the Functional Living Index—Emesis (FLIE) during cycle 1 overall phase; the percentage of pts with "no impact on daily life" (NIDL) was calculated. Comparisons between groups were performed using a Cochran-Maentel-Haenszel test. Results: 1412 patients with BC were included for a total of 5839 AC cycles. NSN rates were similar for both groups in the acute phase, superior for NEPA during cycles 1, 2 and 4 in the delayed phase, and superior for NEPA during cycles 1-4 in the overall phase. Overall NSN (0-120h)NEPA + DEXOral PALO + DEXP ValueCycle 174.2% (N = 708)68.5% (N = 704)0.016Cycle 277.0% (N = 621)71.1% (N = 636)0.015Cycle 378.2% (N = 586)72.7% (N = 594)0.027Cycle 479.9% (N = 542)74.9% (N = 550)0.040 This corresponded with a significantly greater proportion of NEPA patients reporting NIDL compared with PALO due to nausea (71% vs 65%; p=0.007) in cycle 1. Conclusions: While other NK1RAs have not consistently shown benefit in improving nausea control over 5-HT3RA + DEX, in this study NEPA significantly improved prevention of nausea over oral PALO in BC patients receiving AC. In addition, NEPA was superior to PALO in reducing the negative impact of nausea on patients' daily functioning. As the first fixed antiemetic drug combination, NEPA is highly effective and offers the convenience of a single dose administered with DEX on Day 1 only. Citation Format: Rugo HS, Aapro M, Rizzi G. Nausea control and quality-of-life benefit with NEPA, the first combination antiemetic agent, in patients with breast cancer receiving anthracycline/cyclophosphamide (AC) chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-06.