CRx-102

A dissociated steroid with a novel mechanism providing the immuno-inflammatory benefits of glucocorticoid steroids without associated steroid side effects.

• Description: Synergistic combination of prednisolone, a glucocorticoid steroid, and dipyridamole, a cardiovascular drug. We believe CRx-102 works through a novel mechanism that selectively amplifies the glucocorticoid steroid's desirable activities without replicating associated side effects.
• Data: Positive phase 2 clinical results in hand osteoarthritis (OA), rheumatoid arthritis (RA) and an inflammatory biomarker study.
• Formulation: Developing a modified-release, once-daily capsule potentially providing greater synergy through co-exposure and an improved tolerability profile.
• Commercial opportunity: NSAID/COXIB replacement in OA. Replacement of, or add-on to, some NSAIDS, steroids and DMARDs in RA.

OA represents a market of 33 million patients in the U.S., and RA has another 2 million patients in the U.S.

About Rheumatoid Arthritis

Rheumatoid arthritis is a chronic disease, mainly characterized by inflammation of the lining, or synovium, of the joints. According to the Arthritis Foundation, rheumatoid arthritis affects 1% of the United States population, or 2.1 million Americans. Rheumatoid arthritis can lead to long-term joint damage, resulting in chronic pain, loss of function and disability. Because it is a chronic disease, rheumatoid arthritis continues indefinitely and frequent flares in disease activity can occur. Rheumatoid arthritis is also a systemic disease, which means it can affect other organs in the body. Studies have shown that early aggressive treatment of rheumatoid arthritis can limit joint damage, which in turn limits loss of movement, decreased ability to work, higher medical costs and potential surgery.

About Osteoarthritis

Osteoarthritis is one of the most common degenerative joint diseases and a frequent cause of physical disability among older adults. In the United States more than 33 million people suffer from osteoarthritis. Osteoarthritis affects the hands, lower back, neck, and weight bearing joints such as the knees, hips, and foot joints. Symptoms of osteoarthritis range from stiffness and intermittent mild pain to severe joint pain and impaired biomechanical function. Although there is no cure for most forms of osteoarthritis, various therapies can help patients manage symptoms such as non-steroidal anti-inflammatory drugs, COX-2 inhibitors, local analgesics, opioids, intra articular corticosteroid injection and surgery.

Status: In Phase 2b studies in both OA and RA.

Clinical Results:

Phase 2a Rheumatoid Arthritis

We studied CRx-102 in a multi-center randomized, blinded, placebo-controlled phase 2a clinical trial of 59 patients with rheumatoid arthritis (Full News Release). The clinical trial compared CRx-102 plus a disease-modifying, anti-rheumatic drug (DMARD) to placebo plus DMARD in subjects with rheumatoid arthritis.

CRx-102 demonstrated statistically significant* improvements:

• ACR20 - 63% ACR20 response at day 42 compared to 30% with placebo (p=0.025)
• DAS28 - 1.6 mean change from baseline to day 42 compared to 0.7 with control (p=0.016).
• CRP - 50% median reduction in C Reactive Protein (CRP) from baseline to day 42 compared to 19% with control (p=0.024).
• CRx-102 was generally well tolerated, and there were no serious adverse events reported for subjects treated with CRx-102. The most common adverse events observed with CRx-102 that occurred with a frequency of greater than 5% were headache, gastro-intestinal symptoms and dizziness, known side effects of dipyridamole.

ACR20 is a standard measure developed by the American College of Rheumatology to rate RA disease improvement and DAS 28, a composite disease activity score using 28 joint counts that is used to monitor disease activity in RA patients. Patients are classified as ACR20 responders if they demonstrate at least a 20% improvement from baseline in tender and swollen joint count and at least 3 of 5 other symptom-related criteria.

*Data provided are per protocol. Statistical significance remains with intent-to-treat analysis.

Phase 2a Hand Osteoarthritis

We studied CRx-102 in a randomized, blinded, placebo controlled phase 2a clinical trial in 83 patients with moderate to severe osteoarthritis of the hand in Norway (Full News Release). The study met its primary endpoint of improvement in joint pain using the AUSCAN index. The AUSCAN Osteoarthritis Index is a composite patient-reported outcome tool developed specifically for hand osteoarthritis, similar to the WOMAC index which is used for knee and joint osteoarthritis.

• CRx-102 demonstrated a 31% improvement in pain compared to 7% improvement for placebo (p=0.007).
• CRx-102 demonstrated improvements in clinical secondary endpoints including stiffness, the AUSCAN physical function subscale, joint pain and patient global assessment scores.
• In addition, tender joint counts of the 18 joints of the hand were significantly improved in the CRx-102 group compared to placebo in the per-protocol population.
• A similar result was seen for soft tissue swelling although it did not reach statistical significance (p = 0.058) in the per-protocol analyses.
• Patients were enrolled in the clinical trial that had moderate to severe hand osteoarthritis as determined by ACR criteria and a minimum score on the pain dimension of the AUSCAN scale. CRx-102 was dosed in this trial using 3mg of prednisolone and two different doses of dipyridamole. Patients received the lower ratio for the first week of treatment and the higher ratio for the following five weeks.
• CRx-102 was generally well tolerated, and there were no serious adverse events reported from patients taking CRx-102. The most common adverse events observed with CRx-102 that occurred with a frequency of greater than 5% were headache and nausea, known side effects of dipyridamole, one of the two components of CRx-102.