TPX-100 is a 23-amino acid peptide derived from Matrix Extracellular Phosphoglycoprotein (MEPE), a small integrin-binding ligand N-linked glycoprotein (SIBLING) family member. MEPE is highly expressed by osteocytes, is downregulated in osteoarthritis, and may play a role in osteoarthritic bone remodeling . TPX-100 acts selectively on cells committed to hard tissue lineage, viz. bone, cartilage or dentin. In animal models, the actions of TPX-100 are limited to bone and cartilage formation and repair . Based on preliminary in vitro data, the putative mechanism of action of TPX100 is via integrin binding with formation of TGF-β receptor complexes and activation of its effector, Smad3. Smad3 can regulate cartilage matrix synthesis via induction of type II collagen in chondrocyte lineage cells and play a role in homeostasis of knee joint bone .
TPX-100 has been shown to induce articular cartilage formation 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 (25, 125 or 250 mg/injection) vs. vehicle in a dose-dependent manner. After 6 months, histopathological staining in TPX-100-treated joints demonstrated robust articular (hyaline) cartilage formation and increased Type II collagen compared with vehicle-treated controls . In a standardized rat model of ACL transection and partial medial meniscectomy, IA TPX-100 dose dependently reduced joint damage and improved osteoarthritis scores in actively treated animals compared with controls.
In humans, a Phase II randomized, double-blind, placebo-controlled, 12-month trial of TPX-100 (NCT01925261) has been completed to evaluate safety, tolerability and efficacy of IA TPX-100 in subjects with bilateral, mild-moderate (ICRS grades 2–3) patellofemoral cartilage defects, with or without tibiofemoral cartilage defects . Each subject’s contralateral placebo-treated knee served as a paired internal control, intended to control for effects of age, sex, weight, genetic factors, and activity levels on outcome measures. The pre-selected primary efficacy outcome measure in this trial was the 6-month change in patellar cartilage thickness as measured using standardized magnetic resonance imaging (MRI) in TPX-100-treated knees compared with placebo-exposed knees (See Fig. 1; CONSORT diagram). Subjects were screened clinically and with MRI. Synovitis and meniscal damage were among the exclusion criteria for enrollment. Briefly, Part A of the study evaluated safety of four, once-weekly IA doses of TPX-100 in sequential dose cohorts (25, 50, 100 and 200 mg/injection) of 6–9 subjects, with progression to the next dose following Safety Review Committee approval. All doses were reasonably safe and well tolerated, and the highest dose, 200 mg/injection, was selected for Part B of the study for evaluation of efficacy and safety. Of the 118 subjects enrolled for Parts A and B, 93 subjects received 4 injections of 200 mg TPX-100 and had baseline MRIs with at least one follow-up scan. Per the statistical analysis plan, these subjects made up the primary analysis population. Efficacy outcome measures included MRI cartilage measures (6 and 12 months) and patient-reported outcomes (WOMAC, KOOS, NRS for pain at 3, 6 and 12 months). Semi-quantitative MRI analysis by central readers blind to clinical data and treatment assignment demonstrated that only 14% of knees had measurable patellar cartilage thickness changes, with no significant treatment differences at 6 or 12 months. MRIbased MOAKS evaluation, including cartilage defects, meniscal pathology and Hoffa's synovitis, did not show differences at baseline or follow up between TPX-100-treated knees and placebo-exposed knees, and there were no significant within-knee changes in bone marrow lesions at 6 or 12 months. In contrast, patient benefit, measured by WOMAC and KOOS scores, was statistically significant and clinically meaningful in favor of TPX-100-treated knees at 6 months compared with placebo, with robust functional benefits sustained through the end of the study at 12 months . Posthoc analyses revealed that 68 (73%) of subjects had, in addition to bilateral patellofemoral cartilage defects, moderate to severe (ICRS 2–4) bilateral tibiofemoral cartilage defects. In these subjects, sustained, statistically significant and clinically meaningful clinical benefits in favor of TPX-100-treated knees were observed, nearly identical to those in the whole population .
The present study (TPX-100-5) was designed as a retrospective MRI study to investigate femoral boneshape change at 6 and 12 months after TPX100 or placebo administration and to analyze relationships between cartilage thickness and femoral bone shape change at 6 and 12 months after TPX100 or placebo administration.
Bone shape change, measured by MRI, has been shown to predict radiographic onset of OA , is associated with radiographic structural progression , discriminates people with knee OA from those without knee OA  and is more responsive to change over time than is radiographic assessment . In each of these studies, the femur (defined as the whole of the lateral and medial femoral condyles) had greater discrimination and responsiveness to change than did the tibia or patella. The femoral bone shape (“B-score”) metric is a form of statistical z-score that represents the position of a femoral bone shape along a shape vector from a non-OA knee shape (origin) towards an OA knee shape (positive direction). Non-OA and OA knees used to define this 3-dimensional (3D) shape vector were categorized using centrally-read and adjudicated Kellgren-Lawrence grading .
Bowes et al demonstrated that in a large observational cohort of over 4,500 subjects’ knees from the Osteoarthritis initiative (OAI), MRI-measured B-score produced logistic regression models for clinically important outcomes that were very similar in terms of predictive validity to those using categorical Kellgren-Lawrence grading (KLG), which is the conventional radiographic standard for OA diagnosis.
These data provide construct validity for this new, continuous scalar measurement. In addition, Bowes et al showed that bone shape is directly associated with the risk of clinical outcome measures such as knee pain, functional deficit and joint failure, as indicated by total joint replacement, with only small effect sizes from adjusting models for potential covariates such as age, sex, ethnicity, body mass index (BMI), alignment, previous knee surgery, non-steroidal anti-inflammatory drugs (NSAIDs) use and smoking status [10
]. These findings support femoral B-score as a structural endpoint in clinical trials of disease-modifying osteoarthritis drugs (DMOADs).