TPX-100 leads to marked, sustained improvements in subjects with knee osteoarthritis: pre-clinical rationale and results of a controlled clinical trial

Abstract

Purpose: TPX-100 is a 23-amino acid peptide derived from Matrix Extracellular Phosphoglycoprotein (MEPE), a Small Integrin-Binding Ligand, N-linked Glycoprotein (SIBLING) family protein. TPX-100 has been shown to induce articular cartilage proliferation in goats (N = 8/ dose group) after a standardized full-thickness chondral defect and treatment with 4 weekly intra-articular (IA) injections of TPX-100 vs. vehicle (25, 125 or 250 mg/injection). After 6 months, histopathological staining in TPX-100-treated joints indicated robust articular (hyaline) cartilage formation. Additionally, IA TPX-100 reduced joint damage and improved osteoarthritis scores vs. vehicle in rats after standardized ACL transection and partial medial meniscectomy. This Phase 2 study evaluated safety, tolerability and preliminary efficacy of TPX-100 by IA administration in subjects with bilateral patellofemoral osteoarthritis (PFOA). Each subject served as his/her own control, intended to minimize effects of age, sex, genetic factors, and activity levels on outcome measures. Methods: Subjects with ICRS grade 2-3 PFOA, confirmed by centrally-read screening MRI, were enrolled at 15 sites. One knee was randomly assigned to receive 4 weekly injections of TPX-100, while the contralateral knee received placebo injections. Investigator, subject, site and sponsor were blinded to treatment assignment. In Part A of the study, 4 dose cohorts (n = 6–9 subjects/cohort) received 20, 50, 100 or 200 mg/injection. Safety/tolerability of each cohort was evaluated by a Safety Review Committee (SRC). In Part B, all subjects received 200 mg/injection. Quantitative MRIs, obtained at baseline, 6 and 12 months, were read centrally. Validated patient-reported outcomes (PROs) included the Knee Osteoarthritis Outcome Score (KOOS), appropriate for younger, more athletic subjects, and the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Results: All subjects who received 4 weekly 200 mg injections, with at least one follow-up MRI, were analyzed (n = 93 subjects, 186 knees). The study population was typical of the knee OA population in the U.S. (median age, 58.4 years; BMI 30.3), and 68 of 93 subjects (73%) also had ICRS grade 2 – 4 mild to severe bilateral tibio-femoral osteoarthritis (TFOA). Safety: There were no drug-related SAEs and no dose-limiting toxicities across doses. Common adverse events such as knee pain had virtually identical incidences in control and TPX-100-treated knees. Efficacy: Only 14% of knees changed in cartilage thickness/volume over the 12 months of the study. Quantitative MRI revealed no measurable between-knee structural differences in this small sample. However, statistically significant (P<0.05) and clinically meaningful differences in KOOS and WOMAC scores were demonstrated compared with placebo-exposed knees at 6 or 12 months or both, including activities of daily living, sports activities, and knee-related quality of life. Comparing TPX-100 treated knees vs. control knees, at 12 months; there was a significant difference in pain ascending and descending stairs, a chief complaint in PFOA. Overall, use of analgesics, including non-steroidal anti-inflammatory medications, declined markedly (62.5%) during the study. Conclusions: TPX-100, administered in 4 weekly intra-articular injections (200 mg/injection), is safe, well tolerated, and associated with statistically significant and clinically meaningful functional benefits sustained to at least 12 months. Improvement in knee functional status with reduction in disease burden represents a key therapeutic goal in OA therapeutic development. The small sample size of knees with MRI changes in cartilage thickness/volume limited the power of this study to detect differences between knees in these measures. However, pre-clinical large and small animal data indicate the structure-modifying potential of TPX-100, which may be demonstrated with a longer study involving a larger sample size.