Joyclu (diclofenac etalhyaluronate) / Seikagaku, Ono Pharma, Eisai - LARVOL DELTA

Mechanistic Insights into Cartilage Protection and Extracellular Matrix Remodeling: Transcriptome Analysis of Diclofenac Etalhyaluronate-Treated Knee Cartilage in Collagen-Induced Arthritis Rats and Cytokine-Stimulated Human Chondrocytes. (PubMed, Cartilage) - "Pathway analysis was then performed on genes that specifically varied with DF-HA treatment.ResultsIn the cartilage of rats with collagen-induced arthritis, treatment with DF-HA, but not DF or HA, suppressed the extracellular matrix (ECM) remodeling pathway and promoted the parathyroid hormone/parathyroid hormone-related peptide receptor-mediated pathway, which regulates chondrocyte differentiation and bone/cartilage development. In cytokine-stimulated chondrocytes, DF-HA similarly suppressed the ECM remodeling pathway; specifically, gene expression changes in IGFBP4, MMP10, MMP13, and TIMP1 were consistent with those observed in vivo.ConclusionRNA-seq analysis of cartilage in arthritic rats and cytokine-stimulated chondrocytes provided molecular mechanistic insights, indicating that DF-HA treatment induced cartilage protection through the suppression of ECM remodeling."

Journal • Preclinical • Immunology • Osteoarthritis • Pain • Rheumatology • MMP10 • MMP13 • TIMP1

Pain Relief Improves Key Motor Functions in Refractory Advanced Knee Osteoarthritis. (PubMed, Cureus) - "Aggressive pain management with DF-HA significantly improved key motor functions in advanced KOA patients experiencing pain relief. However, balance improvement may involve mechanisms beyond pain reduction. These findings highlight the importance of pain control in improving motor function in refractory KOA."

Journal • Immunology • Orthopedics • Osteoarthritis • Pain • Rheumatology

No relationship between non-IgE-mediated mechanisms (complement activation or direct activation of mast cells and basophils) during diclofenac etalhyaluronate (SI-613/ONO-5704)-induced anaphylaxis. (PubMed, J Immunotoxicol) - "However, the possibility remains that the anaphylaxis might be a non-immunological hypersensitivity reaction due to inhibition of cyclooxygenase-1 by non-steroidal anti-inflammatory drugs (NSAID). Further investigation into the relationship between the non-immunological hypersensitivity and anaphylaxis following DEH administration is warranted."

Journal • Hematological Malignancies • Immunology • Leukemia • Oncology

Impact of Intra-Articular Diclofenac Etalhyaluronate on Pain and Osteoarthritic Changes in Advanced and End-Stage Hip Osteoarthritis. (PubMed, J Orthop Res) - "Intra-articular administration, therefore, contributes to pain relief and improvement of central sensitization in advanced and end-stage osteoarthritis of the hip without subsequent progression of osteoarthritis. These findings highlight the potential of intra-articular administration of diclofenac etalhyaluronate as a conservative treatment option for advanced and end-stage hip osteoarthritis, particularly for patients who may be unsuitable for surgery or have limited response to oral nonsteroidal anti-inflammatory drugs."

Journal • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

Consideration of the EXiLE test for predicting anaphylaxis after diclofenac etalhyaluronate administration. (PubMed, J Immunotoxicol) - "Notably, complement inactivation treatment led to a positive EXiLE result in a BAT-negative patient. In conclusion, it appears that the EXiLE test exhibits promise as an alternative to BAT for predicting JCL-induced anaphylaxis, and in so doing offers a simpler diagnostic approach."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Comparison of effects of intra-articular diclofenac etalhyaluronate and hyaluronic acid in a monoiodoacetate rat osteoarthritis model. (PubMed, J Orthop Res) - "OARSI scores did not differ among treatment groups, Larsen scores indicated lower in the DF-HA than in the vehicle. DF-HA was as effective as HA in joint protection and significantly improved inflammatory pain compared to HA."

Journal • Preclinical • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology • IL6 • TNFA

Anaphylaxis and prolonged allergic reactions caused by intra-articular injection of diclofenac etalhyaluronate in knee osteoarthritis: A case report. (PubMed, Mod Rheumatol Case Rep) - "Thus, further development of appropriate testing methods is necessary. Intra-articular allergic reactions in knee OA may be modified and worsened besides normal allergic reactions; therefore, caution is required."

Journal • Allergy • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

Clinical study on the utility of allergy tests to detect IgE-mediated anaphylaxis after diclofenac etalhyaluronate administration. (PubMed, Mod Rheumatol) - "DEH may be the main factor involved in the development of anaphylaxis. The SPT was more sensitive than the basophil activation and allergen-sIgE tests for identifying factors associated with anaphylaxis."

Journal • Allergy • Dermatology • Immunology • Osteoarthritis • Pain • Rheumatology

Effects of Diclofenac Etalhyaluronate (SI-613/ONO-5704) on Cartilage Degeneration in Arthritic Rats and Inflammatory Cytokine-Stimulated Human Chondrocytes. (PubMed, Cartilage) - "In this study, we demonstrated the chondroprotective effect of DEH in rats with collagen-induced arthritis and in interleukin-1β-stimulated human chondrocytes. Thus, DEH may suppress cartilage degeneration in patients with musculoskeletal diseases, such as OA."

Journal • Preclinical • Immunology • Inflammation • Musculoskeletal Diseases • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology • IL1B • MMP13

Clinical investigation for the mechanisms of anaphylactic symptoms in osteoarthritis patients after diclofenac etalhyaluronate administration. (PubMed, Mod Rheumatol) - "These findings suggest that anaphylaxis occurs after JCL administration via an IgE-mediated mechanism and that DEH may be involved in this mechanism. BAT and DF-specific IgE ELISA may be useful tests for investigating the mechanisms of anaphylactic reactions after JCL administration."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Analgesic effects and arthritic changes following intra-articular injection of diclofenac etalhyaluronate in a rat knee osteoarthritis model. (PubMed, BMC Musculoskelet Disord) - "DF-HA exerted analgesic effects on osteoarthritic pain, but did not affect joint deformity."

Journal • Preclinical • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

Diclofenac-hyaluronate conjugate (diclofenac etalhyaluronate) intra-articular injection for hip, ankle, shoulder, and elbow osteoarthritis: a randomized controlled trial. (PubMed, BMC Musculoskelet Disord) - "Intra-articularly administered DF-HA for hip OA produced a rapid response and was safe, with analgesia maintained for 12 weeks when administered every 4 weeks."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Comments on the Efficacy and Safety of Diclofenac-Hyaluronate Conjugate Trial by Nishida and Colleagues. (PubMed, Arthritis Rheumatol) - "This design allows for the determination of true effects of the active ingredient (diclofenac etalhyaluronate) over that attributable to placebo (contextual) injection effects and non-specific effects (2). My comments on the trial relate to three issues."

Clinical • Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Ono and Seikagaku Announce a Manufacturing and Marketing Approval in Japan for JOYCLU 30mg Intra-articular Injection, a Joint Function Improvement Agent, for the Indication of Osteoarthritis (Knee Joint and Hip Joint) (Ono Pharmaceuticals Press Release) - "Ono Pharmaceutical...and Seikagaku Corporation...announced today that Seikagaku has obtained from the Ministry of Health, Labour and Welfare (MHLW) a manufacturing and marketing approval in Japan for JOYCLU® 30mg Intra-articular Injection (generic name: diclofenac etalhyaluronate sodium; development code: ONO-5704/SI-613; 'JOYCLU') for the indication of osteoarthritis (knee joint and hip joint)...The approval is based on the results of three Phase III clinical studies conducted with ONO-5704/SI-613 in Japan...Seikagaku will manufacture and market JOYCLU, and Ono will be responsible for distribution. We will announce the launch date of JOYCLU following the National Health Insurance drug price listing."

Japanese regulatory • Osteoarthritis • Pain

Efficacy and safety of diclofenac-hyaluronate conjugate (diclofenac etalhyaluronate) for knee osteoarthritis: a randomized phase 3 trial in Japan. (PubMed, Arthritis Rheumatol) - "We achieved the primary objective of a statistically significant improvement in WOMAC pain subscores over placebo during 12 weeks of DF-HA. Anaphylactic reactions were observed, and further safety evaluation is needed."

Clinical • Journal • P3 data • Immunology • Osteoarthritis • Pain • Rheumatology

Open-label phase 3 study of diclofenac conjugated to hyaluronate (diclofenac etalhyaluronate: ONO-5704/SI-613) for treatment of osteoarthritis: 1-year follow-up. (PubMed, BMC Musculoskelet Disord) - "Repeated IA injections of DF-HA every 4 weeks for 1 year were well tolerated with no clinically significant adverse events indicating they might lead to the long-term improvement of OA symptoms. DF-HA might be a useful treatment for patients with OA."

Clinical • Journal • P3 data • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology

Sustained-release diclofenac conjugated to hyaluronate (diclofenac etalhyaluronate) for knee osteoarthritis: a randomized phase 2 study. (PubMed, Rheumatology (Oxford)) - "DF-HA reduced pain in patients with knee OA without major safety concerns."

Clinical • Journal • P2 data • Immunology • Osteoarthritis • Pain • Rheumatology

Eisai now gets rights to Seikagaku’s osteoarthritis candidate SI-613 in South Korea (The Pharma Letter) - Subscription needed.

Licensing / partnership • CNS Disorders • Osteoarthritis • Pain

Residual Property of SI-613, a Novel Drug for Osteoarthritis, in Knee Joint (PubMed, Yakugaku Zasshi) - "These results suggested that intra-articularly administered SI-613 remained for a longer time in the joint as HA linked with DF than when HA was administered. Therefore, SI-613 was considered to prolong the pharmacological effects of both HA and DF by remaining in the joint as HA linked with DF."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Ono and Seikagaku announce the results from a phase III clinical study in Japan of ONO-5704/SI-613 in patients with knee osteoarthritis presented at an Academic Conference (Seikagaku Press Release) - "Ono Pharmaceutical Co., Ltd....and Seikagaku Corporation...announced today that the results from a Phase III clinical study of ONO-5704/SI-613 in Japan in patients with knee osteoarthritis ('the Study') were presented at the 93rd Annual Meeting of the Japanese Orthopaedic Association, an on-line annual meeting being held from Thursday June 11 to Monday August 31, 2020. ONO-5704/SI-613 is being jointly developed in Japan by the companies for the treatment of osteoarthritis....In January 2020, Seikagaku submitted an application for manufacturing and marketing approval of ONO-5704/SI-613 in Japan for the treatment of osteoarthritis (knee joint, hip joint and ankle joint)...and will work together to obtain an approval of ONO-5704/SI-613 as soon as possible."

Japanese regulatory • P3 data • CNS Disorders • Osteoarthritis • Pain

Eisai, Seikagaku to sell osteoarthritis drug in China (Biospectrumasia) - "Japanses firms Eisai Co., Ltd. and Seikagaku Corporation have announced that the companies have entered into an agreement for the co-development and marketing alliance in China for SI-613 (diclofenac conjugated sodium hyaluronate), a therapeutic agent for osteoarthritis....On the basis of this agreement, the companies will jointly develop SI-613 in China for a treatment of knee osteoarthritis. After obtaining approval, Seikagaku will supply products to Eisai, and Eisai will be responsible for distribution. The companies will cover an equal share of the development cost, and Eisai will pay Seikagaku the upfront payment, and development as well as sales milestones."

Licensing / partnership

Effect of diclofenac etalhyaluronate (SI-613) on the production of high molecular weight sodium hyaluronate in human synoviocytes. (PubMed, BMC Musculoskelet Disord) - "The present results clearly demonstrate that SI-613 induces the production of high molecular weight HA in synoviocytes from OA patients, suggesting the long-lasting analgesic and disease modifying effect of SI-613 for OA. Taken together with the anti-inflammatory and analgesic effects we recently reported for the intra-articular administration of SI-613 to experimental animal models, SI-613 holds great promise for the treatment of knee osteoarthritis."

Journal