Background/Purpose: TPX-100, a peptide derived from matrix extracellular phosphoglycoprotein (MEPE), is in development as a potential disease-modifying osteoarthritis drug (DMOAD) for mild to severe knee osteoarthritis (KOA). While total knee replacement (TKR) remains the FDA’s “gold standard” outcome measure for this regulatory pathway, it presents practical and ethical limitations as a trial endpoint. Surrogate markers predictive of TKR would enable more efficient clinical trials. Data from the Multicenter Osteoarthritis Study demonstrate that poor WOMAC Physical Function scores (40–68) are associated with a >15-fold increased risk of TKR, with a clear dose-response gradient across impairment levels. Longitudinal analyses from the Osteoarthritis Initiative (OAI) have shown that MRI-derived femoral bone shape predicts TKR risk over 48 months. Study TPX-100-5 was designed to evaluate these measures and their interrelationships in order to explore the idea of a surrogate marker for TKR.

Methods: Participants in TPX-100-5 met ACR diagnostic criteria for bilateral KOA based on history, examination and imaging. All had previously completed a randomized, double-blind, placebo-controlled Phase 2 study (TPX-100-1), and received four weekly injections of TPX-100 (200 mg) in one knee and saline placebo in the contralateral knee in a triple-blinded fashion. Subjects’ MRIs were analyzed at a single center per published protocols, blind to treatment assignment and clinical data. Femoral bone shape, defined by “B-score”, differentiates pathologic bone shapes associated with OA onset, progression and joint failure from bone shapes of normal, non-OA knees. B-score is based on a vector derived from modelling of 3-D femoral bone shape from >9,000 knee MRIs in the OAI database. Per the statistical analysis plan, finalized prior to study start, subjects with knees whose B-scores were ≥1.5 (n=70), equivalent to KL ≥2 on x ray, made up the study cohort.

Results: Demographics of the study cohort were similar to those of the total study population from TPX-100-1. Knees that received TPX-100versus placebo were well matched in terms of baseline WOMAC function, B-scores and all other clinical measures. TPX-100 treatment was associated with WOMAC scores that demonstrated statistically significant and clinically meaningful improvements compared with controls at 6 and 12 months, and pathological B-score changes that were significantly reduced versus controls. Notably, at 6 months, the trajectory of B-score change in TPX-100-treated knees almost perfectly mirrored that of “non-OA” knees from the OAI, while placebo-treated knees followed a trajectory nearly identical to that of OAI disease progressors. (Figures 1, 2).

Conclusion: The demonstration of concordant drug-associated improvements in WOMAC function and MRI-based bone-shape scores suggest that these measures– independently associated with knee joint failure and TKR—may be useful when appropriately combined in order to advance a viable surrogate marker for DMOAD development. Furthermore, the observed structural and functional benefits demonstrated with TPX-100 treatment, while requiring confirmatory trials, support the potential of TPX-100 as a candidate DMOAD.

Comparative WOMAC Function Scores, IA TPX-100 treatment versus Placebo Controls

Bone-shape (“B”) Scores, IA TPX-100 versus Placebo Controls: Comparison to Historical Controls from the Osteoarthritis Initiative

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/womac-physical-function-and-3d-mri-bone-shape-advancing-a-virtual-total-knee-replacement-endpoint-for-knee-osteoarthritis-clinical-trials/