Unity Biotechnology says UBX0101 was safe, well-tolerated in Phase 1 study
UNITY Biotechnology announced results from its first-in-human Phase 1 study of UBX0101 in patients with moderate to severe osteoarthritis of the knee. The study demonstrated that UBX0101 was safe and well-tolerated. Improvement in several clinical measures, including pain, function, as well as modulation of certain senescence-associated secretory phenotype factors and disease-related biomarkers was observed after a single dose of UBX0101. The Phase 1 clinical trial of UBX0101 is a randomized, double-blind, placebo-controlled study evaluating the safety, tolerability and pharmacokinetics of a single intra-articular injection of UBX0101 in patients diagnosed with moderate to severe painful OA of the knee. UBX0101 is a p53/MDM2 interaction inhibitor that targets selective elimination of senescent cells. In Part A, 48 patients were randomly assigned to receive one of six dose levels of UBX0101 or placebo in a 3:1 randomization. Primary endpoints were safety and tolerability. Secondary and exploratory endpoints included plasma pharmacokinetics, synovitis as measured by MRI, pain, and measurement of SASP factors and disease-related biomarkers present in synovial fluid and plasma. In Part B, 30 patients were randomized to receive UBX0101 or placebo in a 2:1 randomization. Primary endpoints were safety and tolerability. Secondary and exploratory endpoints included changes in the levels of SASP factors and disease-related biomarkers present in synovial fluid and plasma, and pain. Synovial fluid samples were obtained at baseline and four weeks post-treatment. In Part A, UBX0101 was well tolerated up to the maximum administered dose of 4 mg. There were no serious adverse events and no patients discontinued because of an adverse event. There were no dose-dependent adverse events or relevant clinical laboratory findings. The majority of adverse events were mild. In Part B, UBX0101 was well tolerated at the 4 mg dose. There were no serious adverse events and no patients discontinued because of an adverse event. The majority of adverse events were mild and there were no relevant clinical laboratory findings. UBX0101 demonstrated dose-proportional plasma pharmacokinetics. Model-based predicitons of concentrations within the knee suggested that doses at or above 1 mg may be pharmacologically active. This informed the prospectively defined low dose and high dose groupings for analyses. In Part A, evaluation of pain by NRS measured at 12 weeks demonstrated a dose-dependent and clinically meaningful reduction. The range of mean baseline values was between 5.90 to 6.76. In Part A, evaluation of pain by WOMAC-A mean item score measured at 12 weeks demonstrated a dose-dependent and clinically meaningful reduction. The range of mean baseline values was between 1.80 to 2.36. In Part B, WOMAC-A, measured at 4 weeks, showed a numerical reduction that was not significantly different from placebo. In Part A, evaluation of function by WOMAC-C mean item score demonstrated a dose-dependent and clinically meaningful improvement. The range of mean baseline values was between 1.40 to 2.47. There were no observed changes in stiffness as measured by WOMAC-B. Evaluation of Patient Global Impression of Change with treatment demonstrated a higher proportion of patients being "much improved" or "very much improved" versus placebo. Evaluation of synovial inflammation by MRI detected no significant placebo adjusted change at any dose level. In Part A, an insufficient number of matched samples were collected due to a lack of adequate levels of synovial fluid in patients for sampling. Therefore, an analysis of change in biomarkers from baseline to 12 weeks was not performed. In Part B, 19 biomarkers were analyzed across 20 matched pair samples. In approximately half the biomarkers measured in synovial fluid modulation was observed consistent with elimination of senescent cells and potential improvement in the tissue environment. Changes were observed in MMPs, tissue remodeling factors, and inflammatory cytokines. These biomarkers were: MMP-3, MMP-10, MMP-12, MMP-13, IL-6, IL-10, CCL20, A2M, ICAM-1 and VEGF-C.