Paradigm Biopharmaceuticals Ltd. announces Successful Primary Endpoint in Phase 2 Trial. Paradigm is assessing a number of key secondary and exploratory endpoints in the PARA_OA_008 phase 2 clinical trial, including: correlation between synovial fluid biomarker changes and clinical outcomes; changes in one or more synovial fluid biomarkers from baseline to 6 months; changes in WOMAC pain, function, stiffness, and patient global impression of change (PGIC) from baseline at designated timepoints; and MRI changes in the bone and joint. Participants in the study were asked to provide baseline pain scores using the WOMAC osteoarthritis index.

After patients had initiated treatment, their pain scores are measured at predetermined timepoints from day 11 out to 12 months, with day 56 the predetermined endpoint for WOMAC assessment. In Para_OA_008, the mean percentage change from baseline in WOMAC pain is 50% compared to 30%, p=0.05 for twice weekly iPPS and placebo, respectively. The mean percentage change from baseline in WOMAC function is 50% compared to 25%, p=0.017 for twice weekly iPPS compared to placebo, respectively.

Interim analysis of the effects of iPPS treatment on dogs with naturally occurring OA has identified positive trends. This ongoing study consists of 21 client-owned dogs of varying breeds that presented at the U-Vet Werribee Animal Hospital, Victoria, Australia, for lameness assessment. Dogs of both genders with either radiologically and/or clinically defined OA of the knee/stifle (hind limb) or elbow (front limb) are progressively screened and randomised in a 2:1 ratio to either treatment with iPPS or saline (placebo) groups to attain a total of 14 iPPS treated and 7 control dogs.

The canine OA study aims to confirm the in vivo mechanism of action of iPPS and to define potential disease modification outcomes. The key data sought from this study are changes from baseline at week 8 and week 26, in: i) Joint function as measured by percentage body weight distribution (BWD%) in the affected limb as measured by the TPI%. ii) Biomarkers of joint degeneration within the synovial fluid and in serum; and iii) Structural changes determined by OA clinical scores as assessed by X-ray and MRI.

Early interim observations in nine osteoarthritic dogs who had received subcutaneous iPPS at a dose of 3 mg/kg (human equivalent dose of 1.7 mg/kg) weekly for 6 weeks demonstrated the following: i) Seven of nine dogs treated with iPPS had a clinically meaningful improvement in the affected limb as measured by TPI% at week 8 compared to baseline. ii) A mean percentage change (improvement) from baseline in TPI% of 10.08% was observed for the affected hind limb (n=5) and 5.6% for the affected front limb (n=4). A mean increase of 5% in TPI% is considered to be a clinically meaningful improvement (16,17).

iii) Dogs demonstrated a response to iPPS treatment with changes in cartilage degradation biomarkers in the synovial fluid. Aggrecan degradation neoepitope (ARG) the canine equivalent of human ARGS, levels were reduced in the synovial joint of 3/4 iPPS-treated dogs. These results support the in vivo MoA since iPPS inhibits ADAMTS-5 enzyme, which degrades aggrecan in cartilage to produce ARG (18).

Furthermore, it is known that degrading cartilage matrix releases hyaluronic acid (HA) into the synovial fluid in OA (19). In this study, 4/4 dogs had reduced levels of HA following iPPS treatment. iv) Analysis of serum biomarkers demonstrated that 3/6 dogs showed a reduction in serum ARG, and 5/9 dogs had reduced serum HA, supporting the effect of iPPS on these biomarkers observed in the synovial fluid.

Additionally, in the serum, it was demonstrated that 7/9 iPPS-treated dogs responded to treatment with reduced levels of C3M (a degradation fragment of type III collagen), 6/9 dogs had lower levels of CTX-I (a degradation fragment of type I collagen), and 4/9 dogs had reduced levels of CTX-II (a degradation product of type II collagen) (20).