POS0278\u2005A MULTICENTER, OBSERVATIONAL, EXTENSION STUDY EVALUATING THE SAFETY, TOLERABILITY, AND EFFICACY OF A SINGLE LORECIVIVINT INJECTION IN KNEE OA SUBJECTS

Abstract

Lorecivivint (LOR), a novel intra-articular (IA) CLK2/DYRK1A inhibitor that modulates the Wnt pathway, is in development as a knee osteoarthritis (OA) treatment.Subjects from two consecutive Phase 2 trials were followed up in a 5-year, pooled, observational study that evaluated the safety and exploratory efficacy of a single LOR injection that was previously administered into the target knee joint of subjects with moderate to severe knee OA. The study was terminated in its third year, as relevant long-term safety information became limited in the absence of repeated LOR administration. The primary objective evaluated the incidence of serious adverse events (SAEs). Safety data for all doses and a post hoc efficacy analysis for the pivotal dose (0.07\u2009mg LOR) are reported.This was a Phase 3, multicenter, observational, extension study of completer subjects (OA-05; NCT02951026) from two Phase 2 trials of LOR: a 12-month Phase 2a trial (OA-02; NCT02536833)1 and a 6-month Phase 2b trial (OA-04; NCT03122860)2. Subjects received a single LOR or control (placebo or vehicle) injection at their parent-study baseline visit (OA-02 or OA-04 Visit 0 in this analysis). Pooled data from clinic visits at 6, 12, 24, and 36 months contributed to the extension-study (OA-05) analysis. SAEs, knee-related adverse events (AEs), and AEs of newly diagnosed conditions requiring treatment were collected as safety outcomes. Efficacy was assessed by target knee WOMAC Pain and Function subscores and radiographic medial joint space width (mJSW). A post hoc analysis was performed for 0.07\u2009mg LOR versus control to assess responses in a subject subgroup (unilateral symptoms, no widespread pain, 18-month post-injection radiograph at study termination). Baseline-adjusted ANCOVA was performed using data from both the current and parent studies at 0, 3, 6, 12, and 18 months.Of 703 subjects, 119 (17%) subjects discontinued prior to study termination. Subjects had a mean age of 60.7 years and mean BMI of 29.1\u2009kg/m2, and 61% were female. The majority of subjects had KL 3 (61.2%) OA. The safety analysis set included 495 LOR-treated subjects and 208 control subjects. There were 169 AEs reported by 110 [15.6%] subjects. Four AEs were considered to be related to study drug and were reported by 3 (0.6%) subjects across LOR groups; no subjects withdrew from the study due to a treatment-related AE. The most common AEs were osteoarthritis (28 [4.0%] subjects) and arthralgia (25 [3.6%] subjects); incidence was similar between LOR and control groups. During the study, 68 SAEs were reported by 38 (5.4%) subjects, and no SAEs were considered to be related to treatment by investigator. One death occurred in the control group. Post hoc efficacy analyses demonstrated that subjects in the 0.07\u2009mg LOR group (n=59) showed greater improvements from baseline in both WOMAC Pain and Function at 6 and 12 months versus subjects in the control group (n=70) (Figure 1; Day 0):6 months:Pain: -8.16, 95% CI [-15.60, -0.71], P=0.032Function: -9.47, 95% CI [-17.09, -1.84], P=0.01512 months:Pain: -8.51, 95% CI [-15.17, -1.85], P=0.013Function: -9.62, 95% CI [-16.83, -2.42], P=0.009No mJSW progression was observed in any group over 18 months.Limitations to this analysis include 1) subjects from LOR and control groups were “completers,” therefore, more likely to be responders, and 2) subjects could have been on any medication or treatment in the extension study.From these data, LOR appeared to be safe and well tolerated. A post hoc-analyzed subset of completer subjects treated with a single 0.07\u2009mg LOR injection reported durable symptom improvements in WOMAC Pain and Function for up to at least 12 months versus control subjects.[1]Yazici Y, et al. Arthritis Rheumatol. 2020.[2]Yazici Y, et al. ACR meeting. 2019. Abstract L03.Ismail Simsek Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Christopher Swearingen Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Heli Ghandehari Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Sarah Kennedy Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Jeyanesh Tambiah Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Yusuf Yazici Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Nebojsa Skrepnik Consultant of: Pfizer, Regeneron, Orthofix, Grant/research support from: Samumed, LLC