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

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

TREATMENT WITH LORECIVIVINT LEADS TO IMPROVED LONG-TERM PATIENT ACCEPTABLE SYMPTOM STATE (PASS) COMPARED TO PLACEBO: DATA FROM PHASE 3 EXTENSION TRIAL (EULAR 2024) - P3 | "In this analysis of a phase 3 extension study of LOR compared to PBO, patients treated with LOR were significantly more likely to achieve a 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 are safe and may provide long-term benefits for knee OA symptoms."

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

EFFECT OF LORECIVIVINT ON CARTILAGE REPAIR IN A MOUSE MODEL OF JOINT SURFACE INJURY (EULAR 2024) - "These findings indicate that LOR may promote cartilage repair, which could contribute to its OA-protective activity. Further studies with different dosing regimens are needed to confirm."

Preclinical • Immunology • Osteoarthritis • Pain • Rheumatology • CDK1

Treatment with Lorecivivint Leads to Improved Long-Term Patient Acceptable Symptom State (PASS) Compared to Placebo: Data from Phase 3 Extension Trial (OARSI 2024) - P3 | "While clinical outcomes focus on differences between treatment groups, an individual's "acceptable symptom state" may provide a meaningful and clinically relevant assessment (Roos 2019). Year 1 results from a 2-year Phase 3 extension study, OA-07 (NCT04520607), which evaluated LOR 0.07 mg safety and efficacy with clinical outcomes including WOMAC Pain [0-100] and WOMAC Function [0-100] subscales, are reported here within the context of the Patient Acceptable Symptom State (PASS)."

Clinical • P3 data • Pain

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 (OARSI 2024) - P3 | "Lorecivivint (LOR), an intra-articular (IA) CLK/DYRK inhibitor thought to modulate Wnt and inflammatory pathways has previously appeared safe, improved patient-reported outcomes (PROs) and maintained radiographic medial joint space width (JSW) compared with placebo (PBO). A Phase 3 extension study, OA-07 (NCT04520607), evaluated LOR safety and efficacy with outcomes of medial JSW (mm), WOMAC Pain [0-100], and WOMAC Function [0-100] subscales."

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

Biosplice Announces Upcoming Presentation of Successful OA-07 Phase 3 Long-Term Structure and Pain & Function Results for Lorecivivint for Treatment of Knee Osteoarthritis at OARSI Conference, and Completion and Preliminary Analysis of OA-21 Trial 12-Week Pain Results (GlobeNewswire) - P3 | N=700 | STRIDES (NCT05603754) | P3 | N=276 | NCT04520607 | Sponsor: Biosplice Therapeutics, Inc. | "Final analysis of OA-07 results confirmed this structural benefit and further demonstrated that patients also experienced statistically significant reduction in their pain (as measured by WOMAC Pain at Month 6 and Month 12) and significant improvement in function (as measured by WOMAC Function at Month 12). Biosplice will present its OA-07 results at the Osteoarthritis Research Society International ('OARSI') World Congress, April 18-21, 2024, in Vienna, Austria....With respect to the shorter-term OA-21 study, preliminary analysis showed that the study did not meet the primary endpoint of pain reduction at Week 12. The Company observed an unusually high placebo response in this trial compared to published intra-articular OA trials and Biosplice’s prior trials."

P3 data • CNS Disorders • Osteoarthritis • Pain

Chondrocyte membrane-coated nanoparticles promote drug retention and halt cartilage damage in rat and canine osteoarthritis. (PubMed, Sci Transl Med) - "Simulated synovial fluid clearance studies showed that CM-NPs loaded with a Wnt pathway inhibitor, adavivint (CM-NPs-Ada), delayed the catabolic metabolism of rat and human chondrocytes and cartilage explants under inflammatory conditions...OA progression was also mitigated by CM-NPs-Ada in a canine model of anterior cruciate ligament transection. These results demonstrate the feasibility of using chondrocyte membrane-coated nanoparticles to improve the pharmacokinetics and efficacy of anti-OA drugs."

Journal • Preclinical • Developmental Disorders • Immunology • Osteoarthritis • Pain • Rheumatology • CDH1