Background/Purpose: CC-292 is a small molecule inhibitor of Bruton’s tyrosine kinase (Btk), which is a component of the B cell receptor signaling complex found in B lymphocytes and myeloid cells. Btk plays a crucial role in B cell development, maturation, and function. CC-292 inhibits Btk activity by irreversible covalent binding with high affinity to the adenosine triphosphate (ATP) binding site of Btk. Inhibition of Btk could regulate inflammation in RA by two different mechanisms; by blocking B cell receptor–dependent B cell proliferation and the reduction of autoantibody levels, and by inhibiting Fc gamma receptor (FcγR)-induced TNFα, IL-1β and IL-6 production in macrophages. CC-292 was evaluated over a 4 week treatment period in female subjects with active RA on background methotrexate (MTX) (NCT01975610).

Methods:  47 adult female RA subjects were randomized 1:1 CC-292 375 mg PO daily or placebo (PBO). Subjects were required to have a diagnosis of sero-positive RA for at least 6 months, meeting the 2010 ACR/EULAR Classification Criteria for RA. The RA must have been active despite at least 3 months of treatment with MTX and on a stable dose (7.5 to 25 mg/week oral or parenteral) for at least 4 weeks prior to randomization. Permitted concomitant RA medications included sulfasalazine, antimalarials, and low dose corticosteroids (prednisone or equivalent ≤ 10 mg/day).

Results: CC-292 showed ACR20 (primary endpoint) improvement in 10 (42%) of 24 RA subjects vs. 5 (22%) of 23 RA subjects on placebo. ACR20 improvement separated from placebo as early as week 1, and progressed through week 4. This positive trend was not considered statistically significant (p=0.25). The magnitude of ACR20 difference of 20% between treatment groups at 4 weeks, although not statistically significant, is on par with the effect seen in RA with other DMARDs. There were numerical trends for ACR50 and ACR70 favoring CC-292. No trends for improvement were observed for the exploratory endpoints of DAS28, HAQ-DI, or swollen and tender joint counts. Pharmacodynamic measurement of Btk occupancy showed no free Btk in the peripheral blood mononuclear cells as early as week 1. CC-292 reduced osteoclast activity, reduced B-cell lymph node trafficking, reduced class switched and activated memory B-cell, and increased mature naive B-cells. Treatment emergent adverse events (TEAEs) were comparable across both treatment arms. The most frequently reported TEAEs (≥ 5% subjects) in the CC-292 arm were nausea, back pain, diarrhea, cough, and migraine. There were no deaths in the study. There were no serious TEAEs and one severe TEAE of stomatitis.

Conclusion: The study did not meet its primary endpoint of improvement in ACR20 at 4 weeks, nor the secondary endpoints of ACR50 and ACR70 at 4 weeks, although there were numerical trends combined with a responder sub-group analysis suggest potential efficacy of CC-292 in this female subject RA population. In this study, CC-292 was well tolerated and had a favorable safety profile over 4 weeks of treatment. CC292 BTK inhibition impacts RA with a different MOA and profile than current therapies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-phase-2a-4-week-double-blind-proof-of-concept-efficacy-and-safety-study-of-cc-292-versus-placebo-as-co-therapy-with-methotrexate-in-active-rheumatoid-arthritis-ra/