Deciphering the Impact of M2951 on RA and SLE: Insights from BTK Occupancy and Efficacy Analysis

The text discusses the development and evaluation of M2951, a new and highly selective Bruton's tyrosine kinase (BTK) inhibitor. BTK is a significant target in treating hematological conditions and is also implicated in autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) due to its influence on B cell and innate immune cell activation. The study aimed to characterize M2951's efficacy in vitro and in disease models for RA and SLE. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to link BTK inhibition with disease severity reduction.

M2951 was tested in various biochemical and cellular assays to confirm its potency and specificity. It was then evaluated in NZB/W F1 mice infected with an adenovirus expressing IFN-alpha to synchronize disease onset, with efficacy measured through proteinuria and kidney damage assessment. In a collagen-induced arthritis (CIA) model, paw scores were used to gauge M2951's effectiveness.

A biochemical assay was created to quantify BTK occupancy in blood cells and splenocytes, which was instrumental in building a PKPD model that connected target occupancy with efficacy. M2951 showed potent inhibition of BCR- and FcR-mediated signaling, leading to reduced activation and function of B cells and certain myeloid cells. It demonstrated significant efficacy in mouse models of RA and SLE, with a notable decrease in disease severity. The NZB/W F1 IFN-α-accelerated SLE model showed that efficacy was associated with B cell inhibition, a reduction in autoantibodies, and a decrease in circulating memory B and T cells. RA-like symptoms were also mitigated in the CIA model.

To translate preclinical efficacious doses to humans, the necessary target occupancy for disease reduction was determined. The pharmacodynamic model indicated that BTK occupancy of 60% and 80% corresponded to 80% and nearly complete disease inhibition, respectively, in both RA and SLE models. The study concludes that M2951 has potential in treating autoimmune diseases and could guide informed dose decisions for its development in rheumatologic diseases.

The authors disclosed their affiliations with Merck KGaA and EMD Serono, indicating a potential conflict of interest.