lorecivivint (SM04690) / Biosplice Therap, Samil Pharma - LARVOL DELTA

Efficacy and safety of intra-articular disease-modifying osteoarthritis drugs (DMOADs) for knee osteoarthritis: a Bayesian network meta-analysis of randomised controlled trials. (PubMed, Knee) - "Current low-level evidence indicates that no intra-articular DMOADs provide significant structural or symptomatic benefit. This highlights the need for efficacious agents and optimised trial designs with standardised imaging protocols, clinically relevant endpoints, adequate statistical power, and long-term follow-up to accurately assess disease-modifying effects. Future studies should also evaluate novel DMOADs with improved efficacy and safety."

Journal • Retrospective data • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

UK’s MHRA Accepts Biosplice’s Application for Lorecivivint (LOR) in Knee Osteoarthritis and Begins Assessment (The Manila Times) - "Biosplice intends to submit an application for LOR to the European Medicines Agency ('EMA') later this month....OA-07 demonstrated joint structure benefits rarely observed in OA research: patients treated with LOR in the OA-07 study maintained and ultimately improved their medial JSW, as measured by X-ray at two years following annual injections."

EMA filing • MHRA filing • Immunology • Osteoarthritis

The NPM1/p53 nucleolar stress signaling pathway promotes endometrial receptivity establishment in goats via the Wnt/β-catenin pathway. (PubMed, Biol Reprod) - "Using early-pregnancy goat models, in vitro-induced goat endometrial epithelial cells (gEECs), and low-dose Actinomycin D (ActD) to trigger nucleolar stress, we investigated this signaling axis in goat endometrial receptivity...Pretreatment with the Wnt/β-catenin inhibitor Adavivint markedly reduced ActD-induced upregulation of HOXA10 and HOXA11 proteins but did not affect p53 expression. Together, these results indicate that the NPM1/p53 nucleolar stress pathway promotes endometrial receptivity in goats, at least in part, through the Wnt/β-catenin pathway. This work expands understanding of endometrial receptivity in ruminants and provides a basis for further investigation of nucleolar stress in reproductive regulation."

Journal • CDKN1A • HOXA10 • HOXA11 • MDM2 • NPM1

Efficacy and safety of lorecivivint for the treatment of knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials. (PubMed, J Orthop Surg (Hong Kong)) - "Safety outcomes were also comparable to placebo. Although pain reduction was seen, further long-term studies are required to validate its clinical importance."

Clinical • Journal • Retrospective data • Review • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

The Cilia-Wnt Axis as a Therapeutic Target for Sox9 mRNA-LNP in Osteoarthritis (EULAR 2026) - "Rats received intra-articular injections of Sox9 mRNA- LNPs, Lorecivivint (positive control), or PBS...Furthermore, deconvolution analysis demonstrated that Sox9 therapy restored the cellular landscape by increasing the fractions of regulatory and proliferative chondrocytes while reducing the effector chondrocyte subpopulation compared to OA controls. Conclusions Intra-articular delivery of Sox9 mRNA-LNPs effectively retards OA progression and provides pain relief by enhancing cilium movement and suppressing pathological Wnt signaling, which in turn restores the anabolic balance and modulates chondrocyte subpopulations."

Gene Therapies • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • COL2A1 • IL1B • MMP13 • RUNX2 • SOX9 • TGFB1 • YBX1

SM04690-OA-07: A Long-Term Safety and Efficacy Study of Lorecivivint in Subjects With Osteoarthritis of the Knee (clinicaltrials.gov) - P3 | N=276 | Terminated | Sponsor: Biosplice Therapeutics, Inc. | Completed ➔ Terminated; Study OA-07 was designed to be conducted until the Sponsor closed it. Study OA-07 was administratively closed at Visit 6E (Week 100), with no safety concerns, one year into the open-label study as described in the protocol.

Trial termination • Immunology • Osteoarthritis • Pain • Rheumatology

Cationic liposome-mediated intra-articular delivery of lorecivivint for osteoarthritis treatment. (PubMed, Eur J Pharm Biopharm) - "An in vivo pilot study was conducted using a severe ACLT-hMnX rat model showing preliminary evidence of an alleviated osteophyte formation and reduced cartilage matrix loss in the medial tibial plateau. Overall, Lipo-LOR improved drug solubility, release and cartilage retention, which are critical requirements for implementing a localized intra-articular OA therapy."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • IL6 • TGFB1

Biosplice Announces the Submission of its New Drug Application (NDA) to the FDA for Lorecivivint (LOR) to Treat Knee Osteoarthritis (The Manila Times) - "Results from Biosplice’s Phase 3 OA-07 trial also showed that LOR led to improvements in medial joint space width (JSW) on imaging over multiple years. These results support LOR’s potential as the first disease-modifying therapy for OA, a milestone long sought by patients, physicians and researchers."

FDA filing • Osteoarthritis

Update on clinical trials of intra-articular disease-modifying osteoarthritis drugs inducing cartilage regeneration. (PubMed, Eur J Pharm Sci) - "This review also discussed some pathways of chondrocytes, which boost the transcription of genes involved in the production of extracellular matrix components. Finally, the review also covers some implants in the commercial and clinical phases for cartilage repair."

Journal • Review • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology

Lorecivivint Delayed Time to Pain and Function Worsening Compared to Placebo: Evaluation of Knee OA Symptom Progression Outcomes in a Phase 3 Trial (OA-07) (ACR Convergence 2025) - P3 | "LOR was shown to be safe and efficacious in Study OA-07. Significant reduction in pain and function progression was seen for LOR compared to PBO, with LOR delaying time to progression. PBO patients who crossed to LOR treatment also demonstrated reduced progression."

Clinical • P3 data • Musculoskeletal Diseases • Orthopedics • Pain

Evaluation of a Parent-Trial as a Run-In Period: Efficacy and Safety of Repeat Injections of Lorecivivint over Three Years (ACR Convergence 2025) - P3 | "Examining demographics, outcomes and safety data from the OA-11 trial did not elicit any prediction to patients that enrolled into OA-07 but supports OA-07 as a random sample of the OA-11 population. The impact of COVID on the conduct and results of OA-11 may have relegated the Phase 3 trial into a large run-in, possibly allowing patients to normalize over the course of a year prior to the start of OA-07. In OA-07, improvements in pain and function in LOR compared to PBO were seen at six and twelve months."

Clinical • Novel Coronavirus Disease

Retraction notice to "Effect of lorecivivint on osteoarthritis: A systematic review and meta-analysis" [Heliyon 9 (2023) e18682]. (PubMed, Heliyon) - "[This retracts the article DOI: 10.1016/j.heliyon.2023.e18682.]."

Journal • Retrospective data • Immunology • Osteoarthritis • Pain • Rheumatology

Advances and Challenges in the Pursuit of Disease-Modifying Osteoarthritis Drugs: A Review of 2010-2024 Clinical Trials. (PubMed, Biomedicines) - " Eleven DMOAD candidates are reviewed and critically analyzed for their potential benefit in OA treatment-Lorecivivint (SM04690), TissueGene-C, Cindunistat (SD-6010), Sprifermin, UBX0101, TPX-100, GLPG1972/S201086, Lutikizumab (ABT-981), SAR113945, MIV-711, and LNA043-and relevant challenges to their development are discussed. Six DMOADs have demonstrated statistically significant evidence of a structural or symptomatic benefit without major safety concerns in phase II and III randomized controlled trials post-2010."

Journal • Review • Developmental Disorders • Immunology • Osteoarthritis • Pain • Rheumatology

Comparison of the chondrogenic potential of eBMSCs and eUCMSCs in response to selected peptides and compounds. (PubMed, BMC Vet Res) - "Based on cell response to the positive control, in the conditions employed in the current study, eBMSCs may be preferred over eUCMSCs for chondrogenesis. The current study supports the use of spheroid culture, and the use of dexamethasone over TGF-β or any of the compounds or peptides tested here from the prior literature to drive chondrogenesis with eBMSCs."

Clinical • Journal • Immunology • Osteoarthritis • Pain • Rheumatology • TGFB1 • TGFB3

A Phase 3, 28-week, multicentre, randomised, double-blind, placebo-controlled trial (OA-10) to evaluate the efficacy and safety of a single injection of lorecivivint in the target knee joint of moderately to severely symptomatic osteoarthritis patients. (PubMed, Clin Exp Rheumatol) - "LOR was well tolerated despite not meeting the primary endpoint. Efficacy signals were identified in patients with less severe structural knee OA disease, suggesting earlier intervention may be more effective."

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

Phase 3, 56-week, randomised, double-blind, placebo-controlled study utilising patient-reported and radiographic outcomes evaluating the efficacy and safety of a lorecivivint injection in patients with moderate to severe knee osteoarthritis: OA-11 Study. (PubMed, Clin Exp Rheumatol) - "Incidences, severity, and relationship to study treatment of AEs were similar between LOR and PBO treatment groups. In this study, LOR was well tolerated although it did not meet the primary endpoint of change from baseline in target knee Pain NRS at Week 12."

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

Inhibition of the canonical Wnt/β-catenin pathway interferes with macropinocytosis to suppress pseudorabies virus proliferation. (PubMed, Vet Microbiol) - "In this study, the antiviral activities of the Wnt inhibitors (Adavivint, CCT251545, FH535, and iCRT14) were identified...On the contrary, LiCl treatment significantly stimulated the protrusion formation and the PRV entry. Together, these findings suggest that suppression of the Wnt/β-catenin pathway inhibits the macropinocytosis-dependent entry of PRV, thereby providing potential targets for developing antiviral agents against PRV."

Journal

A Novel Small Molecule Screening Assay Using Normal Human Chondrocytes Toward Osteoarthritis Drug Discovery (ACR Convergence 2024) - "This included lorecivivint, used as a positive control...Staurosporine inhibited MMP-13 in chondrocytes but was cytotoxic in synovial fibroblasts while edicotinib inhibited MMP-13 and IL-6 but with considerable variability between donors. We have successfully tested a novel HTS for OA drug discovery. We have successfully tested a novel HTS for OA drug discovery. Potential targets for OA therapeutic development were identified including CDK1 which inhibited MMP-13 and IL-6 production by OA chondrocytes and synovial fibroblasts. Given the lack of effective drugs on the market, the discovery of novel OA therapeutics that eliminate catabolic and inflammatory signaling in multiple joint tissue cell types would be a tremendous benefit to public health."

Immunology • Osteoarthritis • Pain • Rheumatology • CDK1 • IL6 • MAP2K1 • MMP13

Targeting the NOTCH2/ADAM10/TCF7L2 Axis-Mediated Transcriptional Regulation of Wnt Pathway Suppresses Tumor Growth and Enhances Chemosensitivity in Colorectal Cancer. (PubMed, Adv Sci (Weinh)) - "Furthermore, use of adavivint or blockage of ADAM10/NOTCH2/TCF7L2 signaling enhances the chemosensitivity of CRC cells. Overall, this study provides a promising candidate for the development of small-molecule inhibitors and reveals a potential therapeutic target for CRC."

Journal • Colorectal Cancer • Hepatology • Oncology • Solid Tumor • ADAM10 • CCND1 • NOTCH2 • TCF7 • TCF7L2

Treatment of Advanced Knee OA with Lorecivivint Leads to Improved Long-Term Patient Acceptable Symptom State (PASS) Compared to Placebo: Data from Phase 3 Extension Trial (ACR Convergence 2024) - P3 | "In this analysis of a phase 3 extension study of LOR compared to PBO, LOR-treated patients were significantly more likely to achieve a positive patient acceptable symptom state 12 months after a second injection. Pain and function outcomes showed greater improvement for those subjects reporting an acceptable symptom state. These data suggest that multiple once-yearly doses of LOR may provide long-term benefits for knee OA symptoms."

Clinical • Metastases • P3 data • Pain

Treatment Effect of Lorecivivint Across Multiple Trials in Patients with Knee OA: A Meta-analysis (ACR Convergence 2024) - P=N/A, P2, P3 | "In this meta-analysis of knee OA trials, LOR showed significant improvement in both pain and functional outcomes over 6 and 12 months after a single injection compared to placebo. LOR continues to show promise as a safe and effective treatment for knee OA with benefits across pain, function and structure."

Retrospective data • Pain

Radiographic and Pain Outcomes from a Phase 3 Trial (OA-07) Evaluating the Efficacy and Safety of Repeat Lorecivivint Injections over 3 Years in Subjects with Knee OA (ACR Convergence 2024) - P3 | "The OA-07 trial met its objective as repeat LOR 0.07 mg injections appeared to be safe and efficacious. Significant improvements in pain and function compared to PBO were seen at 6 and 12 months. Significant improvement in medial JSW was seen after repeat LOR injections compared to PBO."

Clinical • P3 data • Pain

Impact of Structural Severity on Outcomes in Knee Osteoarthritis: An Analysis of Data from Phase 2 and Phase 3 Lorecivivint Clinical Trials. (PubMed, Rheumatology (Oxford)) - P2, P3 | "Baseline medial JSWs were heterogeneous across trials despite KL inclusion criteria. LOR demonstrated greater symptomatic improvements in patients with less structurally advanced disease, indicative of an association between OA structural damage and pain. Early treatment interventions may improve outcomes and provide insight for future OA trial inclusion criteria development."

Journal • P2 data • P3 data • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression. (PubMed, Mol Oncol) - "Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • ARSI • CDK1 • CLK2 • SRSF9

RADIOGRAPHIC AND PAIN OUTCOMES FROM A PHASE 3 EXTENSION STUDY (OA-07) EVALUATING THE SAFETY AND EFFICACY OF REPEAT LORECIVIVINT INJECTIONS OVER 3 YEARS IN SUBJECTS WITH SEVERE KNEE OSTEOARTHRITIS (EULAR 2024) - P3 | "In this advanced knee OA cohort, LOR 0.07 mg appeared safe and OA-07 met its primary objective with repeat LOR injections showing medial JSW improvement compared to PBO after 3 years (3 injections). Beneficial LOR effects compared to PBO were also seen across pain and function PROs and were more pronounced in KL2 patients. PBO patients who crossed to LOR treatment showed similar benefits after 12 months, providing further evidence of potential efficacy."

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