Background/Purpose: TPX-100, a peptide derived from Matrix Extracellular Phosphoglycoprotein (MEPE), has been shown to induce articular cartilage regeneration after cartilage injury in animal models. A previously-reported Phase 2 double-blind, randomized, 12-month clinical trial in subjects with bilateral mild-to-moderate patellofemoral (PF) OA showed knees treated with TPX-100 (one IA injection/week for 4 weeks) had statistically significant and clinically meaningful improvements in knee function at 6 and 12 months compared with placebo-exposed knees. No between-knee differences in patellar cartilage morphology were seen; however, only 14% of knees had PF cartilage changes within limits of detection on follow-up MRIs, limiting comparative power. We now report a post-hoc clinical “responder” analysis, using pre-specified criteria for functional improvement (Roos 2003). Because nearly ¾ of subjects had bilateral tibiofemoral (TF) OA as well as PF OA, we analyzed TF cartilage thickness/volume changes in responders versus non-responders.

Methods: Adult men and women with MRI-confirmed bilateral (ICRS 2-3) PF OA were enrolled at 18 U.S. sites. Among subjects enrolled (n=118), one knee was randomly assigned to receive IA TPX-100 via 4 weekly injections (20-200 mg/injection), while the contralateral knee received identical placebo injections. The use of the contralateral knee as an internal control was designed to lessen bias due to inter-subject variation (e.g. age, sex, BMI, genetic factors, and activity levels). Knee-specific patient-reported outcomes (PROs) included the Knee Osteoarthritis Outcome Scores (KOOS) and WOMAC scores for each knee. Baseline, 6- and 12-month MRIs were read centrally, blind to treatment assignment. This analysis, while post hoc, was conducted based on pre-defined criteria for clinically-important differences derived from the literature. The database was locked prior to the present analysis.

Results: As reported previously, TPX-100 was safe and well tolerated. Overall analgesic use, including NSAIDs, declined by 68%. Efficacy analyses were based, per protocol, on subjects who received 4 weekly IA injections of 200 mg TPX-100 or placebo in each knee and who had at least one MRI after baseline (n=93 subjects/186 knees). Among TPX-100-treated knees, 61/93 (66%) met pre-defined responder criteria, with significantly more TPX-100-treated knees than placebo-exposed knees showing functional improvement at 6 or 12 months or both (p≤ 0.02). Among these subjects, 68 (73%) also had MRI-confirmed bilateral TF OA (ICRS 2-4), and 44/68 (65%) of TPX-100-treated knees met responder criteria at 6 or 12 months or both. TPX-100 responder knees also had significant increases in TF cartilage thickness compared with baseline (p≤ 0.003).

Conclusion: In clinical trials of disease-modifying OA drug (DMOAD) candidates, a frustrating discordance has been noted between structural (cartilage) change and measures of patient benefit, reflected in the FDA’s new draft guidance document (August 2018). The present analysis represents, to our knowledge, the first time that clinically meaningful functional benefit has been linked with MRI-confirmed knee cartilage thickness increases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intra-articular-tpx-100-in-knee-osteoarthritis-robust-functional-response-at-6-and-12-months-is-associated-with-increased-tibiofemoral-cartilage-thickness/