grapiprant (RQ-00000007) / HaiHe Biopharma, AskAt, ImageneBio, Maruishi Pharma, Newbay Pharma, 3DMed - LARVOL DELTA

Single-Dose Pharmacokinetics of Grapiprant in Rhesus Macaques (Macaca mulatta). (PubMed, J Am Assoc Lab Anim Sci) - "Significant age effects were not observed, although a positive correlation between Cmax and AUClast with age in males was noted. Our data suggest that higher doses should be explored in rhesus macaques, with a need for further investigation into the pharmacodynamics of grapiprant to establish an efficacious therapeutic dose in this species and other NHPs."

Journal • PK/PD data • Immunology • Osteoarthritis • Pain • Rheumatology

Biopharmaceutical Characterization of Grapiprant Within the BCS Framework Under Canine-Relevant Conditions: Solubility and Caco-2 Permeability Assessment. (PubMed, Pharmaceutics) - "Efflux ratios were greater than 1, and verapamil reduced the efflux ratio, suggesting possible P-glycoprotein (P-gp) involvement. Accordingly, this study provides a biopharmaceutical characterization of grapiprant within the BCS framework rather than a definitive canine BCS classification, highlighting the importance of considering canine gastrointestinal conditions when interpreting its solubility and permeability. The results may support future optimization of dosing conditions and oral formulations."

Journal • Gastrointestinal Disorder • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology

Evaluation of clinical effects and plasma metabolomic profiles after the administration of grapiprant in dogs affected by osteoarthritis: a prospective, off-on-off, clinical study. (PubMed, Front Vet Sci) - "Grapiprant improved mobility and pain control in dogs with OA and induced metabolomic shifts consistent with reduced inflammation and improved energy metabolism. This is the first study to integrate clinical outcomes with metabolomics in canine OA, supporting the translational value of metabolic biomarkers for monitoring therapeutic response."

Journal • Immunology • Inflammation • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology

Variations in the management of canine osteoarthritis: a cross-sectional survey of veterinary practices. (PubMed, Front Vet Sci) - "Non-steroidal anti-inflammatory drugs (NSAIDs) were the most prescribed drug class, and gabapentin, bedinvetmab, and polysulfated glycosaminoglycan (Adequan®) were the most prescribed non-NSAID medications...American College of Veterinary Sports Medicine and Rehabilitation (ACVSMR) diplomates and rehabilitation-certified veterinarians were less likely to use glucosamine/chondroitin and bedinvetmab and more likely to use ketamine, amantadine, polysulfated glycosaminoglycan, green-lipped mussel, CBD, undenatured type II collagen, eggshell membrane, curcumin, and Boswellia serrata...The differences highlight opportunities for further research into the safety and efficacy of commonly used therapies. Reported perceived adverse events associated with bedinvetmab and grapiprant underscore the need for pharmacovigilance and further research investigating safety."

Journal • Ataxia • Immunology • Movement Disorders • Osteoarthritis • Pain • Rheumatology

Assessment of safety profile and analgesia provided by grapiprant and metamizole alone or combined for postoperative analgesia of queens undergoing elective ovariohysterectomy. (PubMed, Top Companion Anim Med) - "While metamizole and grapiprant were well tolerated in this study either given alone or in combination, postoperative analgesia was insufficient in healthy queens subjected to elective ovariohysterectomy. Neither drug was associated with any significant changes on laboratory variables over 24 hours of postoperative evaluation."

Journal • Gynecology • Pain

Does grapiprant reduce osteoarthritic pain in dogs? (PubMed, Vet Evid) - "How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient's circumstances and owners' values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care."

Journal • Review • Immunology • Orthopedics • Osteoarthritis • Pain • Rheumatology

3D1002 in Combination With Oxycodone Hydrochloride Sustained-release Tablets in Patients With Moderate to Severe Cancer Pain (clinicaltrials.gov) - P2 | N=177 | Not yet recruiting | Sponsor: 3D Medicines | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Oncology • Pain

A noninferiority trial evaluating the efficacy of bedinvetmab compared to grapiprant for osteoarthritis-pain in dogs using force plate gait analysis. (PubMed, Sci Rep) - "Adverse events were in line with respective label expectations. These data support both bedinvetmab and grapiprant are appropriate first-line treatments for OA pain in dogs."

Clinical • Head-to-Head • Journal • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

Azoheteroarene-Modified Grapiprants Serving as Photoswitchable EP4 Antagonists. (PubMed, Chemistry) - "All compounds were resistant to photobleaching and showed impressive stability for reduction with glutathione (10 mM). This study constitutes a proof-of-concept to design photoswitchable EP4 antagonists, and the structure-activity relationship revealed herein may help design more potent grapiprant derivatives."

Journal • Oncology

Structural insights into selective and dual antagonism of EP2 and EP4 prostaglandin receptors. (PubMed, EMBO J) - "In this study, we present cryo-electron microscopy (cryo-EM) structures of human EP2 and EP4 receptors in complex with selective antagonists PF-04418948 and grapiprant, as well as with the dual antagonist TG6-129...Furthermore, comparisons of active and inactive receptor structures elucidate the mechanisms underlying EP2 activation and antagonism. Overall, these findings provide a structural framework for understanding prostanoid receptor pharmacology and offer valuable insights for the rational design of improved selective and dual antagonists targeting EP2 and EP4 receptors."

Journal • Oncology • Pain

EXPRESS: Efficacy of combined grapiprant and tapentadol for analgesia in cats undergoing elective ovariohysterectomy. (PubMed, J Feline Med Surg) - "At 3 hours postoperatively, FGS scores differed significantly between CON and GT groups (p = 0.0363). Rescue analgesia requirements also varied among groups (p = 0.0110): GT required rescue at 3 hours, compared with 1 hour in CON (p = 0.0007) and 2 hours in GRA (p = 0.0058).The results of this study showed that the analgesic effect of the grapiprant-tapentadol combination lasted up to 3 hours in the postoperative period, which was longer than the 2 hours of grapiprant and tapentadol alone, without compromising intraoperative physiological stability."

Journal • Anesthesia • Gynecology • Pain

EP4/ANXA2 axis in pulmonary arterial hypertension: therapeutic implications. (PubMed, Eur Heart J) - "This study reveals a crucial pathway involving EP4 and ANXA2 in PAH development and progression. Targeting EP4 and its downstream effector ANXA2 represents promising therapeutic strategies for PAH management."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ANXA2

Targeting the mPGES-PGE2-EP4 pathway with MF63, MK886, and Grapiprant as a potential therapeutic strategy for Escherichia coli-induced endometritis in dairy cows. (PubMed, Theriogenology) - "Furthermore, these treatments decreased pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and the chemokine IL-8 while increasing IL-10 expression. In conclusion, targeting the mPGES-PGE2-EP4 pathway may offer a safer, more effective alternative for managing E. coli-induced endometritis in dairy cows."

Journal • Endometriosis • Infectious Disease • CXCL8 • IL10 • IL1B • IL6 • TNFA

Early postoperative angiogenic imbalance may identify patients at risk of colon cancer recurrence (ESCP 2025) - P | "Fifty-five angiogenesis-related proteins were analyzed in serum collected on postoperative day 4 using the Proteome Profiler Human Angiogenesis Array (ARY007)...In multivariate analysis adjusted for age, sex, nodal status, and chemotherapy, Serpin B5 was independently associated with lower recurrence risk (HR 0.46 [0.24–0.86], p=0.015). Conclusion Our findings suggest that an insufficient postoperative anti-angiogenic response may play a relevant role in colon cancer recurrence, highlighting the need for a deeper understanding of angiogenic mechanisms in tumor progression."

Clinical • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • SERPINB5

Investigating the role of the mPGES-PGE₂-EP4 pathway in Escherichia coli-induced mastitis in dairy cows: insights for non-antibiotic therapeutic strategies. (PubMed, Front Vet Sci) - "This study employed in vitro cultured bovine bone marrow-derived macrophages (BMDMs) to systematically assess the potential of microsomal prostaglandin e synthase-1 (mPGES-1) inhibitors (MF63, MK886) and EP4 receptor inhibitor (Grapiprant) in modulating inflammatory responses and reducing tissue damage...Based on the role of PGE₂ in mediating immune and inflammatory responses via the EP4 receptor, inhibiting the mPGES-1-PGE₂-EP4 signaling axis to reduce inflammation and tissue damage will facilitate further investigation into the regulatory mechanisms of the PGE₂ signaling axis in the pathogenesis of mastitis. This approach provides a theoretical foundation and experimental basis for the development of alternative anti-inflammatory therapies to replace antibiotics."

Journal • Infectious Disease • Inflammation • CXCL8 • IL1B • IL6 • TNFA

A phase I dose-escalation and expansion study of RMX1002, a selective E-type prostanoid receptor 4 antagonist, as monotherapy and in combination with anti-PD-1 antibody in advanced solid tumors. (PubMed, Invest New Drugs) - "RMX1002 was well tolerated and showed a best response of stable disease. RMX1002 500 mg BID with toripalimab 240 mg every 3 weeks is the recommended dose for future trials."

Journal • Monotherapy • P1 data • Oncology • Solid Tumor

Targeting the E Prostanoid Receptor EP4 Mitigates Cardiac Fibrosis Induced by β-Adrenergic Activation. (PubMed, Adv Sci (Weinh)) - "Furthermore, double knockout of the CM- and CF-EP4 or administration of EP4 antagonist, grapiprant, markedly improves ISO-induced cardiac diastolic dysfunction and fibrosis. Collectively, this study demonstrates that both CM-EP4 and CF-EP4 contribute to β-adrenergic activation-induced cardiac fibrosis. Targeting EP4 may offer a novel therapeutic approach for cardiac fibrosis."

Journal • Cardiovascular • Fibrosis • Immunology • S100A4 • TGFB1

The haemocyte highly-expressed E-type prostanoid receptor regulates TNF expression during immune response of oyster Crassostrea gigas. (PubMed, Fish Shellfish Immunol) - "When the EP4 antagonist Grapiprant was added with PGE2 treatment in vivo, the p-JNK in haemocytes significantly increased, concomitant with the up-regulation of expressions of CgTNF-1 and CgTNF-2, which were 2.86-fold (p < 0.05) and 1.31-fold (p < 0.05) of that in control group at 24 h. Collectively, these results provides the experimental evidence of a haemocyte highly-expressed EP4 receptor CgEP4 regulating TNFs' expression through MAPK pathway in the innate immune response in C. gigas, and it could be used as a surface marker to type and sort a subset of agranulocyte subpopulation among haemocytes."

Journal

3D1002 in Combination With Oxycodone Hydrochloride Sustained-release Tablets in Patients With Moderate to Severe Cancer Pain (clinicaltrials.gov) - P2 | N=177 | Not yet recruiting | Sponsor: 3D Medicines | Phase classification: P2a/2b ➔ P2 | Trial completion date: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Jun 2025 ➔ Dec 2025

Combination therapy • Phase classification • Trial completion date • Trial primary completion date • Oncology • Pain

Response to treatment with grapiprant as part of a standard multimodal regimen in young dogs with appendicular joint osteoarthritis associated pain. (PubMed, Front Vet Sci) - "This study demonstrates a clinically meaningful benefit of a multimodal treatment regimen over a 4-month period for young dogs (<4 years old) with OA-pain. Future work should determine if early, effective treatment is of long-term benefit."

Journal • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology

Grapiprant and Eribulin for the Treatment of Metastatic Inflammatory Breast Cancer (clinicaltrials.gov) - P1/2 | N=6 | Terminated | Sponsor: M.D. Anderson Cancer Center | N=25 ➔ 6 | Trial completion date: Dec 2025 ➔ Sep 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ Sep 2024; The sponsor terminated support for this study

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CD4 • HER-2 • PGR

Comparison of grapiprant and meloxicam for management of postoperative joint pain in dogs: A randomized, double-blinded, prospective clinical trial. (PubMed, J Vet Intern Med) - "Our study supports the use of grapiprant as an alternative analgesic to meloxicam for management of postoperative joint pain in dogs."

Clinical • Journal • Anesthesia • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology

Evaluation of the analgesic efficacy of grapiprant compared with robenacoxib in cats undergoing elective ovariohysterectomy in a prospective, randomized, masked, non-inferiority clinical trial. (PubMed, J Feline Med Surg) - "These results indicate that grapiprant was non-inferior to robenacoxib for mitigating postsurgical pain in cats after OVH performed via ventral celiotomy. The impact of grapiprant for analgesia in OVH via the flank is unknown."

Head-to-Head • Journal • Gynecology • Pain

3D1002 in Combination With Oxycodone Hydrochloride Sustained-release Tablets in Patients With Moderate to Severe Cancer Pain (clinicaltrials.gov) - P2a/2b | N=177 | Not yet recruiting | Sponsor: 3D Medicines | Trial completion date: Sep 2024 ➔ Sep 2025 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Combination therapy • Trial completion date • Trial primary completion date • Oncology • Pain

KEYNOTE-878: Grapiprant and Pembrolizumab in Patients With Advanced or Progressive MSS Colorectal Cancer (clinicaltrials.gov) - P1b | N=54 | Completed | Sponsor: Arrys Therapeutics | Active, not recruiting ➔ Completed | Trial completion date: Sep 2022 ➔ Mar 2023 | Trial primary completion date: Jun 2022 ➔ Mar 2023

Combination therapy • Metastases • Trial completion • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CEACAM5 • MUC16