Background/Purpose:
New imaging biomarkers using supervised machine learning offer opportunities to demonstrate effects of potential DMOADs on joint structure in short, small trials based on superior reliability. MIV-711, a cathepsin K inhibitor, demonstrated substantial effects vs placebo on both joint bone area and cartilage thickness following 6 months’ treatment. The Osteoarthritis Initiative (OAI) provides an opportunity to contextualize the short-term interventional trial data against a large prospective cohort.

Methods:
In the MIV-711-201 study (ACR 2017, abstract 14L), patients with ACR knee OA, KL2-3 and pain ≥4 & <10 on 0-10 NRS were enrolled at 6 European sites and randomised to receive MIV-711 100mg or 200mg or matched placebo qd for 6 months. 244 participants were enrolled, 69% women, mean age 62, mean BMI ~32, (evaluable for imaging; 100mg n=72, 200mg n=71, placebo n=68). 3D bone area of the medial femoral condyle (MF) and cartilage thickness in the central medial femur (cMF) were measured using automated segmentation of MR images and active appearance modelling. Rates of change were compared against annual change from all knees with KL grade 0 (normal), 2 or 3 from the OAI cohort using the same method (n =2789, 1870, 918 for KL0,2,3; 3333 patients in total).

Results:
In the MIV-711-201 quantitative MRI data, mean changes in MF bone area (mm²) were 13.4 (7.48, 19.28); 7.54 (-1.19, 16.27); 2.22 (-3.92, 8.37) for the placebo, 100mg and 200mg groups respectively (95% CI, Figure 1a). cMF cartilage thickness (mm) mean changes were -0.042 (0.001, -0.085), -0.008 (0.034,-0.051), -0.007 (0.044,-0.058) for the placebo, 100mg and 200mg respectively (95% CI, Figure 1b). These data are in good agreement with the corresponding published data based on manual segmentation. OAI MF bone area change (mm²) over 12 months was 4.26, 9.177, 20.09 (mm²) for KL0, 2 and 3 respectively (equates to 2.13, 4.59, 10.05 over 6 months assuming linear change, Figure 1c).  OAI cMF cartilage change over 12 months was -0.005, -0.024,-0.060 (mm) for KL0, 2 and 3 respectively (equates to -0.0025, -0.012, -0.03 over 6 months assuming linear change, Figure 1d).The MIV-711 placebo group changes in bone and cartilage were similar to that expected for a group of KL3 knees (OAI). The MF bone area rate of change in the 200mg group was comparable to the rate found in OAI normal (KL 0) knees and both the 100mg and 200mg doses reduced cartilage loss area change by around 80% to a rate comparable to that seen in OAI normal knees.

Conclusion:
This comparison strongly suggests that the 6-month MIV-711 treatment effects found on cartilage and bone measures has structural relevance when compared to the natural progression seen over 12 months in OAI KL3 patients.

Should such beneficial structural effects be maintained over time, the already observed signals on clinical symptoms could become manifest clinical benefits.