Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101

Abstract

Purpose: To report the Results of a Phase 1 study that assessed the safety, pharmacokinetics (PK), and clinical outcomes of single dose, intra-articular (IA) UBX0101 in patients (pts) with painful knee osteoarthritis (OA). In a previous observational biomarker study of patients with painful knee OA, the percentage of senescent cells (SnCs) in synovial biopsies positively correlated with disease severity, synovitis severity, and knee pain. UBX0101 is an MDM2/p53 interaction inhibitor that can induce apoptosis of senescent synovial fibroblasts. Reducing the number of SnCs from painful OA joints with UBX0101 may reduce pain and create a pro-regenerative environment. Methods: This was a Phase 1, double-blind, randomized, placebo-controlled, single, ascending dose (SAD) study in 48 pts randomized 3:1 to IA UBX0101 (dose range of 0.1 to 4.0 mg) or placebo IA. Key eligibility criteria included knee OA by ACR criteria, Kellgren-Lawrence (KL) grade 1-4, and mean daily pain between 4-9 on a Numeric Rating Scale (NRS, 0-10). Clinical outcomes through 12 weeks included NRS and total WOMAC with pain, function, and stiffness sub-scores derived from the Knee Injury and Osteoarthritis Outcome Score (KOOS) Survey. PK modeling was used to pre-define low (0.1 to 0.4 mg) and high (1.0 to 4.0 mg) dose groups, predicted to achieve knee concentrations below and above 50% effective concentration (EC50) pharmacological thresholds for senolysis, respectively. The SAD study design and sample size were chosen for evaluation of safety. Statistical significance for efficacy endpoints in this Phase 1 SAD study size was considered to be p<0.1. WOMAC sub-scores were item-averaged (i.e., each was normalized to a 0-4 Likert scale). A minimal clinically important difference (MCID) for the WOMAC pain sub-score was considered to be a within-subject reduction in the pain sub-score of ≥0.5. In addition, the rate and extent of pain reduction was determined using the area under the effect curve (AUC) for both NRS and WOMAC pain sub-score. Odds ratios for achieving response were determined using logistic regression models controlling for baseline NRS score and baseline WOMAC sub-score. Results: The SAD study population was balanced regarding patient characteristics and baseline outcome measure values; mean age was 62 years, 67% were female, 89.6% white, mean WOMAC pain sub-score at baseline was 1.96 ± 0.46. Single IA doses of UBX0101 up to 4 mg were well-tolerated. Most adverse events (AEs) were mild. No serious AEs occurred and no AEs led to discontinuation. The plasma PK of UBX0101 following single IA injection demonstrated minor inter-patient variability at all dose groups and systemic concentrations were low and further minimized by an estimated 4-hour elimination half-life. Improvements in pain and function were dose-dependent, clinically meaningful, and durable through 12 weeks for the high doses group of UBX0101 (table). Greater proportions of pts in the high doses group achieved decreases from baseline in the WOMAC pain sub-score equivalent to the MCID, and twice the MCID, at Week 12 compared to the placebo and low dose groups. The odds ratio of 3.68 versus placebo of having a 70% reduction from baseline in the WOMAC pain sub-score in the high doses group was nearly statistically significant (p=0.106, alpha=0.1). The magnitude and duration of pain reduction as measured by the mean (standard deviation) WOMAC pain AUC from baseline to Week 12 was 4.94 (3.66) in the high doses group (p=0.034 vs placebo), 3.32 (3.62) in the low doses group, and 2.28 (2.35) in the placebo group. Conclusions: Single IA doses of UBX0101 up to 4.0 mg were well-tolerated by patients with painful knee OA. Systemic exposure was well described by a one-compartment model with first order absorption. The activity of UBX0101 is supported by the dose-dependent, clinically meaningful, and durable improvements in pain and function observed. Senolysis with IA UBX0101 may be an important future therapeutic option for pts with knee OA.Tabled 1Clinical Outcomes at Week 12UBX0101EndpointPlaceboInjection(n=14)Low doses,0.1-0.4mg (n=16)High doses,1.0-4.0mg (n=18)WOMAC Pain (0-4)Baseline, mean1.872.141.86LSM Change from BL to Week 12 (95% CI)-0.74 (-1.14, -0.34)-0.49 (-0.89, -0.10)-1.09 (-1.38, -0.80)p-value0.430.07Mean Daily Pain NRS (0-10)Baseline, mean6.476.296.31LSM Change from BL to Week 12 (95% CI)-1.96 (-3.14, -0.77)-2.66 (-3.78, -1.55)-3.95 (-4.74, -3.16)p-value0.42<0.01WOMAC Function (0-4)Baseline, mean1.932.051.94LSM Change from BL to Week 12 (95% CI)-0.72 (-1.12, -0.31)-0.49 (-0.88, -0.10)-1.05 (-1.36, -0.74)p-value0.430.13WOMAC= Western Ontario and McMasters Universities Osteoarthritis Index (Likert) 0-4, LSM= Least-squares mean, BL=Baseline, CI=Confidence Interval, NRS=Numeric rating scale 0-10 Open table in a new tab WOMAC= Western Ontario and McMasters Universities Osteoarthritis Index (Likert) 0-4, LSM= Least-squares mean, BL=Baseline, CI=Confidence Interval, NRS=Numeric rating scale 0-10