Researchers Try to Reverse the Aging Process for Arthritic Joints

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Single intra-articular doses of UBX0101 of up to 4 mg were well-tolerated by patients with painful knee osteoarthritis, according to a study presented at the annual meeting of the American College of Rheumatology in Atlanta on November 12.

UBX0101 is a MDM2/p53 interaction inhibitor in development for osteoarthritis by United Biotechnology. UBX0101 works by destroying senescent cells. In osteoarthritis synovial tissue, senescent cell burden has been shown to correlate with disease severity, inflammation, and knee pain as a result of aging. UBX0101, could, in essence, reduce the effects aging arthitic joints.

“We assessed in a phase 1 study the safety, pharmacokinetics, and clinical outcomes of intra-articular UBX0101 treatment in patients with painful knee OA,” wrote the authors of the study, presented by Benjamin Hsu, M.D., Ph.D., of Unity Biotechnology in Brisbane, Australia.

This single, ascending dose study included 48 patients (mean age 62 years, 67% female, 89.6% white) who were randomized to UBX0101 low (0.1 to 0.4 mg) and high (1 to 4 mg) dose groups or placebo intra-articular. Key eligibility criteria included knee osteoarthritis by ACR criteria, Kellgren-Lawrence grade 1-4, and mean daily pain 4-9 on a Numeric Rating Scale (NRS). The study population was balanced regarding demographic and baseline osteoarthritis characteristics. Clinical outcomes through 12 weeks included WOMAC sub-scores for pain, function, and stiffness derived from the Knee Injury and Osteoarthritis Outcome Score (KOOS) Survey and NRS.

In a sub-study, an additional 30 participants were randomized 2:1 to UBX0101 4 mg or placebo intra-articular to assess the impact of UBX0101 on synovial fluid and plasma senescence-associated secretory phenotype and osteoarthritis disease biomarkers. Synovial fluid collected by arthrocentesis or lavage at baseline and at week four along with plasma were assayed using a custom multiplex panel. 

Single intra-articular doses of UBX0101 up to 4 mg were well-tolerated. Most adverse events were mild, and none led to discontinuation, while no serious adverse events occurred. The plasma pharmacokinetics of UBX0101 following single intra-articular injection demonstrated minor interpatient variability at all dose groups, and systemic concentrations were low and further minimized by a four-hour half-life. 

“Improvements in pain and function were dose-dependent, clinically meaningful, and durable through 12 weeks for the three highest UBX0101 doses of 1, 2, and 4 mg,” the authors wrote.

Meanwhile, 50% of patients in the high dose group achieved a 50% decrease in WOMAC pain sub-score at week 12 compared to 36% of the placebo group and 25% of the low dose group.
Synovial fluid/lavage fluid analyses in the sub-study revealed modulation of multiple plasma senescence-associated secretory phenotype/osteoarthritis markers such as tissue remodeling and inflammatory factors, after one dose of UBX0101 doses compared to placebo.

“The activity of UBX0101 is supported by its effects on multiple biomarkers, as well as the clinically meaningful and durable improvements in pain and function.

“UBX0101 as a senolytic agent may be an important future therapeutic option for patients with knee osteoarthritis,” the authors wrote.

REFERENCE

“LO5 - Safety, Tolerability, Pharmacokinetics, and Clinical Outcomes Following Single-Dose IA Administration of UBX0101, a Senolytic MDM2/p53 Interaction Inhibitor, in Patients with Knee OA.” Benjamin Hsu, M.D., Ph.D., 9 a.m., Tuesday, Nov. 12. 2019 ACR/ARP Annual Meeting, Atlanta