Background/Purpose: Rheumatoid Arthritis (RA) involves a complex interaction of multiple cell systems, cytokines and mediators. We recently developed a predictive software-based mathematical model that emulates RA pathophysiology at cellular level by incorporating the interaction of known cell systems and associated signaling and metabolic pathways. For this study, this model was used to design a novel therapy for RA by screening more than one million in-vivo equivalent studies.  CWG952 is an oral small molecule novel multi-targeted therapy, rationally designed to reduce signs, symptoms and radiologic progression of RA. It combines 3 FDA-approved drugs, repurposed from different indications, in a computer-generated specific ratio of individually sub-therapeutic dosages. We present results of this therapy on the murine collagen-induced arthritis (mCIA) model in an early therapeutic RA setting.

Methods: mCIA was induced in male DBA-1 mice by subcutaneously injecting 0.05 ml/mouse of Bovine Collagen in complete Freund’s adjuvant (CFA) emulsion on day 0. A booster dose of collagen in incomplete Freund’s adjuvant (IFA) emulsion was given via the same route three weeks later (day 21). On day 21, mice without clinical signs of RA were randomly assigned to 2 groups of 9 and subsequently orally gavaged with CWG952 or vehicle. Front and hind paws were evaluated every other day for clinical disease using a 0-4 scale with a maximum score of 16 per animal. After obtaining a terminal serum sample, mice were sacrificed on day 42. Hind paws were collected, processed and evaluated by a histopathologist blinded to group assignments.  Scores (0 to 5), for synovitis, panus formation, cartilage destruction and bone erosion were assigned to each hind paw and mean scores for each mouse were calculated.

Results:

Compared to the vehicle control, CWG952 treatment regimen significantly slowed disease progression and decreased the median total clinical disease by 72% and histological disease by 43% respectively. Liver enzyme and lipid assays conducted on the terminal serum samples showed no difference between the Vehicle and CWG952 treatment arms. Key efficacy results are summarized below.

	Vehicle control (n=9), Mean ± SEM	CWG952 (n=9), Mean ± SEM	P values (2-tailed t-test)
Day 39 Paw Scores	10.89±1.01	6.89±1.42	0.044
Paw Scores (mean day 25-41)	7.57±1.07	4.14±1.20	0.060
Synovitis Score	4.22±0.35	3.06±0.39	0.041
Cartilage Destruction	3.72±0.51	2.22±0.46	0.043
Bone Erosion	3.83±0.49	2.28±0.48	0.038

Conclusion: CWG952, an oral combination of 3 FDA-approved drugs, repurposed from other indications, and combined at sub-therapeutic dosages, shows profound impact on disease progression. These results suggest that CWG952 can be an effective therapeutic agent for treating RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-combination-therapy-of-existing-repurposed-therapies-designed-by-predictive-software-modeling-shows-profound-impact-on-disease-progression-in-a-murine-collagen-induced-arthritis-model/