1639: A Phase 3, 56-Week, Multicenter, Randomized, Double-Blind, Placebo Controlled Trial (OA-11) to Evaluate the Efficacy and Safety of a Single Injection of Lorecivivint Injected in the Target Knee Joint of Moderate to Severe Osteoarthritis Participants
Yusuf Yazici1, Christopher Swearingen2, Heli Ghandehari3, Jon Britt4, ismail simsek5, Mark Fineman6, Sarah Kennedy2, Jeyanesh Tambiah7 and Timothy McAlindon8, 1New York University School of Medicine, La Jolla, CA, 2Biosplice Therapeutics, Inc, San Diego, CA, 3Biosplice Therapeutics, Inc., San Diego, CA, 4Biosplice Therapeutics, Inc., Los Angeles, CA, 5Alpine Immunesciences, San Diego, CA, 6Biosplice Therapeutics, San Diego, CA, 7Biosplice Ther Inc., San Diego, CA, 8Tufts Medical Center, Arlington, MA
Background/Purpose: Knee osteoarthritis (OA) is a common joint disorder associated with pain, disability, and joint damage. There remains a large unmet need for treatments that are safe and efficacious for treatment of signs and symptoms and structure modification. Lorecivivint (LOR), a novel intra-articular (IA) CLK/DYRK inhibitor that modulates Wnt and inflammatory pathways, has previously appeared safe and demonstrated patient-reported outcome (PRO) improvements compared with placebo (PBO) and maintenance of medial joint space width (mJSW). The safety and efficacy of LOR was evaluated in a 56-week trial (OA-11, NCT03928184) utilizing PRO and radiographic outcomes.
Methods: Participants were randomized 1:1 to receive a single IA injection of 2 mL 0.07 mg LOR (n=249) or vehicle PBO (n=252). Enrolled participants had ACR-defined (clinical and radiographic) knee OA, Kellgren-Lawrence (KL) grades 2-3, and Pain Numeric Rating Scale (NRS) [0-10] ≥4 and ≤8 in the target knee and < 4 in the contralateral knee. To enrich for participants who may show structural progression, OA-11 allowed BMI up to 40 and restricted enrollment to those with baseline mJSW [1.5-4.0] mm. Primary endpoint was change from baseline in Pain NRS at week 12. Additional outcomes included change from baseline in WOMAC Function [0-100], WOMAC Pain [0-100], Patient Global Assessment (PtGA) [0-100], and mJSW. Adverse events (AEs) were collected throughout the trial. Change from baseline was estimated using a mixed-effects model for repeated measures with treatment group, week, treatment×week, and baseline as covariates.
Results: 501 participants (mean age 60.9 ± 8.3 years, BMI 31.5 ± 4.7 kg/m2, female 65.5%, KL2 51.5%, 67.7% bilaterally symptomatic, mean baseline mJSW 2.61±0.72 mm) enrolled. The trial did not meet its primary endpoint. At week 12, change from baseline in Pain NRS was LOR -2.20 ± 2.20 vs. PBO-2.58 ± 2.24, NS. There were no meaningful treatment effects observed between LOR and PBO in any FAS PROs. Despite enrichment for progression, neither group showed mJSW narrowing over 52 weeks, PBO -0.07 ± 0.50 vs. LOR -0.10 ± 0.52, NS. 307 AEs were reported in 127 PBO participants and 311 AEs were reported in 136 LOR participants. There were 15 SAEs in 12 LOR and 19 SAEs in 13 PBO; no SAEs were deemed treatment related.
Conclusion: LOR appeared safe and well tolerated but did not meet the primary endpoint of change from baseline in Pain NRS at week 12 in this trial. Multiple potential reasons for discrepancies between this and other LOR trials were identified. These participants had the most structurally advanced disease enrolled in the program to date, with baseline mJSW < 3 mm for 68%. As is the case with most chronic conditions, earlier intervention may be more effective, and these more severe subjects may require higher or more frequent dosing. This trial was conducted during the COVID pandemic, and while its impact was difficult to quantify, effects on activity levels and pain PROs in knee OA patients have been reported (Larghi et al., Acta Biomed 2020; Endstrasser et al., ESSKA 2020). These participants are being followed for an additional year (OA-07) to evaluate the effects of a second dose on PROs, as well as longer duration to evaluate structural progression.
Disclosures: Y. Yazici, Amgen, Biosplice; C. Swearingen, Biosplice Therapeutics, Inc; H. Ghandehari, Biosplice Therapeutics, Inc.; J. Britt, Biosplice Therapeutics; i. simsek, Biosplice Inc.; M. Fineman, Biosplice Therapeutics; S. Kennedy, Biosplice Therapeutics, Inc; J. Tambiah, Biosplice Therapeutics; T. McAlindon, Biosplice Therapeutics, Inc, Remedium-Bio, Organogenesis, Pfizer, Kolon Tissue Gene, Seikugaku.
