sivopixant (S-600918) / Shionogi - LARVOL DELTA

Targeting P2X receptors for analgesia: Small molecule antagonists in development. (PubMed, Eur J Med Chem) - "For instance, Sivopixant is a highly selective P2X3R antagonist that exhibits potent analgesic efficacy in the rat spinal nerve ligation (SNL) model (ED50 = 0.4 mg/kg p.o.) and possesses favorable pharmacokinetic properties. And NC-2600, as a potent and specific P2X4R antagonist, demonstrated significant analgesic efficacy in a rat model of colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) at oral doses of 10 and 30 mg/kg...Additionally, A-740003 (49) is a potent, selective P2X7R antagonist that demonstrates broad-spectrum analgesic activity in both neuropathic and inflammatory pain models. These findings underline the potential of rational drug design to develop subtype-selective P2XR antagonists as novel analgesics for pain management."

Journal • Review • Addiction (Opioid and Alcohol) • Gastroenterology • Gastrointestinal Disorder • Immunology • Neuralgia • Pain

Selective P2X3 versus dual P2X2/3 receptor antagonists in refractory chronic cough: a systematic review and dose-response meta-analysis of randomized controlled trials. (PubMed, Purinergic Signal) - "While dual antagonists (gefapixant) demonstrate robust antitussive efficacy, their clinical use is limited by taste disturbance resulting from P2X2/3 inhibition in gustatory pathways...Among selective agents, camlipixant (≥ 50 mg BID) achieved clinically meaningful cough reduction (- 34%) with minimal dysgeusia (5-7%). These findings demonstrate a mechanistically defined benefit-risk trade-off in purinergic receptor targeting, supporting selective P2X3 antagonism as a more favourable strategy for modulating ATP-driven airway sensory signalling in RCC while preserving tolerability."

Clinical • Journal • Retrospective data • Review • Chronic Cough • Cough • Pulmonary Disease • Renal Cell Carcinoma • Respiratory Diseases

Safety and Efficacy Study of Sivopixant, Acetazolamide and SASS-001 in Sleep Apnea (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Shionogi | Recruiting ➔ Active, not recruiting | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Enrollment closed • Trial completion date • Trial primary completion date • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Structure of the human P2X3 receptor reveals the basis for subtype-selective inhibition by sivopixant. (PubMed, PLoS Biol) - "Gefapixant, a negative allosteric modulator (NAM) of P2X3 receptors, has been approved in some countries for the treatment of chronic cough; however, its limited selectivity for P2X3 homomers over P2X2/P2X3 heteromers is associated with taste disturbance as a prominent adverse effect. Structural comparisons across P2X subtypes, together with patch-clamp analyses of gain-of-function mutants that confer sensitivity to two investigational drugs, sivopixant and camlipixant, provided a broadly applicable structural framework for subtype selectivity. Furthermore, structural comparisons with apo and ATP-bound open states of P2X3 receptors, together with molecular dynamics simulations, revealed that sivopixant expands the upper-body domain to suppress the lower-body movements required for channel activation, thereby preventing channel opening even in the presence of ATP."

Journal • Chronic Cough • Cough • Pain • Pulmonary Disease • Respiratory Diseases

Investigating Camlipixant P2X3 Selectivity and Taste Disturbance: A Model-Based Dose-Response Meta-Analysis (ATS 2025) - P3 | "Other P2X3 antagonists of different magnitudes of selectivity have been investigated for RCC: sivopixant (262×), eliapixant (13×), gefapixant (1.5×), and filapixant (unknown). In this model-based dose-response meta-analysis, the highly selective P2X3 antagonist camlipixant demonstrated placebo-like rates of dysgeusia over the clinical dose range modelled. After adjusting for relative selectivity, all P2X3 antagonists fell on the same tolerability dose-response curve, and the dosage of camlipixant currently under investigation in the CALM-1 and CALM-2 Phase 3 clinical trials (50 mg BID; NCT05599191, NCT05600777) was predicted to result in substantially lower rates of dysgeusia compared with a similar dosage of gefapixant."

Retrospective data • Chronic Cough • Cough • Renal Cell Carcinoma • Respiratory Diseases

Safety and Efficacy Study of Sivopixant, Acetazolamide and SASS-001 in Sleep Apnea (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Shionogi Apnimed Sleep Science | Enrolling by invitation ➔ Recruiting

Enrollment status • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Safety and Efficacy Study of Sivopixant, Acetazolamide and SASS-001 in Sleep Apnea (clinicaltrials.gov) - P2 | N=60 | Enrolling by invitation | Sponsor: Shionogi Apnimed Sleep Science | Recruiting ➔ Enrolling by invitation

Enrollment status • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Safety and Efficacy Study of Sivopixant, Acetazolamide and SASS-001 in Sleep Apnea (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Shionogi Apnimed Sleep Science | Not yet recruiting ➔ Recruiting

Enrollment open • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Safety and Efficacy Study of Sivopixant, Acetazolamide and SASS-001 in Sleep Apnea (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Shionogi Apnimed Sleep Science

New P2 trial • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Benefit-risk profile of P2X3 receptor antagonists for treatment of chronic cough: Dose-response model-based network meta-analysis. (PubMed, Chest) - "When used at safe doses, gefapixant had a favorable risk-benefit profile compared to the other four agents. Camlipixant showed initial promise, which may be further investigated by phase III trials currently underway."

Benefit-risk assessment • Journal • Retrospective data • Chronic Cough • Cough • Pulmonary Disease • Respiratory Diseases

Evaluation of S-600918 in Adults With Refractory Chronic Cough (clinicaltrials.gov) - P2 | N=406 | Completed | Sponsor: Shionogi | Phase classification: P2b ➔ P2

Phase classification • Chronic Cough • Cough • Pulmonary Disease • Respiratory Diseases

Druggable site near the upper vestibule determines the high affinity and P2X3 homotrimer selectivity of Sivopixant/S-600918 and its analogue DDTPA. (PubMed, Br J Pharmacol) - "Thus, from the receptor-ligand recognition perspective, we have elucidated the molecular underpinnings of novel RCC clinical candidates' cough-suppressing properties and reduced side effects, offering a promising avenue for the discovery of novel drugs that specifically target P2X3."

Journal • Chronic Cough • Cough • Pulmonary Disease • Respiratory Diseases

Safety and efficacy of P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough: A systematic review and meta-analysis of 11 randomized controlled trials. (PubMed, Pulm Pharmacol Ther) - "P2X3 receptor antagonists are promising drugs for treating chronic cough by significantly reducing the frequency, severity, and quality. Some potential side effects may include drug-related adverse events such as hypogeusia, ageusia, and dysgeusia."

Journal • Retrospective data • Review • Chronic Cough • Cough • Pain • Pulmonary Disease • Respiratory Diseases

Potential applications of P2X3 receptor antagonists in the treatment of refractory cough. (PubMed, Respir Med) - "Although review articles summarizing have been published previously, most have focused on their chemical properties rather than their clinical aspects, with some omitting drugs that have been in clinical studies for nearly two years such as Eliapixant and Sivopixant. This article can be used as a reference for the follow-up studies of P2X3 receptor antagonists in chronic cough. Additionally, it also has implications for the clinical focus of the drug and the approaches to relieve some side effects."

Journal • Review • Chronic Cough • Cough • Pulmonary Disease • Respiratory Diseases

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 2b Trial of P2X3 Receptor Antagonist Sivopixant for Refractory or Unexplained Chronic Cough. (PubMed, Lung) - P2b | "Sivopixant did not demonstrate a statistically significant difference vs placebo in change from baseline in 24-h cough frequency. The dose of 300 mg has potential for RCC/UCC, showing the greatest improvements in cough frequency and patient-reported outcomes and dose-related mild to moderate reversible taste disturbance, although further trials are needed."

Clinical • Journal • P2b data • Chronic Cough • Cough • Pulmonary Disease • Respiratory Diseases

Managed care considerations for the treatment of chronic cough. (PubMed, Am J Manag Care) - "New targeted therapies for refractory CC are currently under development, including the purinergic 2X3 receptor antagonists gefapixant, BLU-5937, and sivopixant (S-600918) and the neurokinin-1 receptor antagonist orvepitant. These targeted agents may have improved efficacy and safety profiles, helping fill unmet treatment needs. If approved, managed care organizations must develop formulary placement and utilization management criteria based on clinical guideline recommendations, expert opinion, and cost-effectiveness analyses to support the clinically appropriate use of these targeted therapies for best patient outcomes."

Journal • Chronic Cough • Cough • Pulmonary Disease • Respiratory Diseases

Sivopixant dose-finding study in RCC/UCC (LICS 2022) - "Sponsored by Shionogi"

Chronic Cough

Randomised trial of the P2X receptor antagonist sivopixant for refractory chronic cough. (PubMed, Eur Respir J) - "Sivopixant reduced objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with refractory or unexplained chronic cough."

Clinical • Journal • Chronic Cough • Pulmonary Disease • Respiratory Diseases

Discovery of clinical candidate Sivopixant (S-600918): lead optimization of dioxotriazine derivatives as selective P2X3 receptor antagonists. (PubMed, Bioorg Med Chem Lett) - "In the course of the following study, the molecular structures of the dioxotriazines were modified based on pharmacokinetic/pharmacodynamic (PK/PD) analyses. As a result of these SAR studies, Sivopixant (S-600918) was identified as a clinical candidate with potent and selective antagonistic activity (P2X3 IC, 4.2 nM; P2X2/3 IC, 1100 nM) and a strong analgesic effect in the rat partial sciatic nerve ligation model (Seltzer model) of allodynia (ED, 0.4 mg/kg)."

Clinical • Journal • Pain

Evaluation of S-600918 in Adults With Refractory Chronic Cough (clinicaltrials.gov) - P2b; N=406; Completed; Sponsor: Shionogi; Active, not recruiting ➔ Completed; Trial completion date: May 2021 ➔ Dec 2020; Trial primary completion date: May 2021 ➔ Dec 2020

Clinical • Trial completion • Trial completion date • Trial primary completion date • Respiratory Diseases

Evaluation of S-600918 in Adults With Refractory Chronic Cough (clinicaltrials.gov) - P2b; N=372; Active, not recruiting; Sponsor: Shionogi; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Respiratory Diseases

[VIRTUAL] Results of early phase 2 clinical trial of S-600918 in patients with refractory chronic cough: Correlation between changes in cough frequency and changes in LCQ (WAC 2020) - "The password to see abstracts was announced to registrants by email."

Clinical • P2 data

[VIRTUAL] Design of phase 2b randomised controlled trial of S-600918, P2X3 receptor antagonist for refractory chronic cough (ERS 2020) - P2b | "By using an advanced approach to include the patient-reported outcome measures as well as to assess the onset of the efficacy, this trial will provide useful insights to determine the optimal dose range for the phase 3 pivotal trials and may suggest the potential impacts and the tolerability of the treatment with S-600918 in patients with RCC."

Clinical • P2b data

[VIRTUAL] Dioxotriazine derivatives as a new class of P2X3 receptor antagonists Part 2: Discovery of clinical candidate S-600918 (ACS-Fall 2020) - "Screening criteria were set for the key parameters based on the results of the PK/PD analyses. As a result of these SAR studies, S-600918 has been identified as the clinical candidate with potent and selective antagonistic activity (P2X3 IC50, 4.2 nM; P2X2/3 IC50, 1100 nM) and strong analgesic effect in rat Seltzer model of allodynia (ED50, 0.4 mg/kg)."

Clinical • Pain

[VIRTUAL] Phase 2a Randomized, Double-Blind, Placebo-Controlled, Crossover Study of a P2x3 Receptor Antagonist S-600918: Effects on Health-Related Quality of Life in Patients with Refractory Chronic Cough (ATS-I 2020) - "These observations, combined with the efficacy results to reduce objective cough as previously reported, suggested the positive impact of S-600918 on quality of life in patients with RCC. These findings warrant further investigation with larger population samples."

Clinical • HEOR • P2a data • Immunology