1899: A Phase 3, 28-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (OA-10) to Evaluate the Efficacy and Safety of a Single Injection of Lorecivivint Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects
Yusuf Yazici1, Christopher Swearingen2, Heli Ghandehari3, Victor Lopez4, ismail simsek5, Mark Fineman6, Sarah Kennedy7, Jeyanesh Tambiah8 and Timothy McAlindon9, 1New York University School of Medicine, La Jolla, CA, 2Samumed LLC, San Diego, CA, 3Biosplice Therapeutics, Inc., San Diego, CA, 4Biosplice Therapeutics, Santa Clarita, CA, 5Alpine Immunesciences, San Diego, CA, 6Biosplice Therapeutics, San Diego, CA, 7Biosplice Therapeutics, Inc, San Diego, CA, 8Biosplice Ther Inc., San Diego, CA, 9Tufts 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, appeared safe and demonstrated patient-reported outcome (PRO) pain and function improvements compared with placebo (PBO) in a Phase 2b knee OA trial (Yazici et al. OAC 2021). The safety and efficacy of 0.07 mg LOR was evaluated in a Phase 3 28-week trial (OA-10, NCT04385303) utilizing PROs.
Methods: Participants with 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, were randomized 1:1 to receive a single IA injection of 2 mL 0.07 mg LOR or vehicle PBO. A portion of the trial was enrolled concurrently with OA-11, a 56-week trial evaluating PRO and radiographic outcomes, utilizing a pre-screening protocol (OA-15) such that participants who met PRO criteria for both trials but had a baseline medial joint space width (mJSW) outside the 1.5-4 mm range (inclusion criteria for OA-11) were enrolled in OA-10. 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], and Patient Global Assessment (PtGA)[0-100]. Adverse events (AEs) were collected through the trial period. Change from baseline was estimated using a mixed-effects model for repeated measures with treatment group, week, treatment × week, and baseline as covariates.
Results: 498 participants (mean age 61.0±8.3 years, BMI 29.8±3.9 kg/m2, female 60.4%, KL2 60.4%, 67.9% bilaterally symptomatic) were randomized and 454 completed The trial did not meet its primary endpoint of change from baseline at week 12 in Pain NRS, LOR -2.24 ± 2.21 vs. PBO -2.20 ± 2.32, NS, in the Full Analysis Set (FAS). There were no meaningful treatment effects observed between LOR and PBO in any FAS PROs. Separation was seen in the KL2 subgroup for all PROs, significant at various timepoints for Pain NRS and PtGA. Enrolled participants' baseline mJSW distributions were skewed towards lower mJSWs (56% mJSW < 3 mm). 164 AEs and 4 SAEs were reported in 91 and 4 LOR participants, with 154 AEs and 1 SAE were reported in 85 and 1 PBO participants; no SAEs were deemed related to LOR.
Conclusion: LOR appeared safe and well tolerated but did not meet the primary or secondary endpoints in this trial. Efficacy signals were identified in participants with less severe structural disease, suggesting earlier intervention may be more effective. 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). Future trials of LOR in knee OA will target less severe structural disease, as well as evaluating a higher dose (0.23 mg LOR).
Disclosures: Y. Yazici, Amgen, Biosplice; C. Swearingen, Biosplice Therapeutics, Inc; H. Ghandehari, Biosplice Therapeutics, Inc.; V. Lopez, None; i. simsek, Biosplice Inc.; M. Fineman, None; S. Kennedy, Biosplice Therapeutics, Inc; J. Tambiah, Biosplice Therapeutics Inc; T. McAlindon, Biosplice Therapeutics, Inc, Remedium-Bio, Organogenesis, Pfizer, Kolon Tissue Gene, Seikugaku.
