VYNE Therapeutics Inc. announced positive preclinical data in a rheumatoid arthritis (“RA”) model from its VYN201 program. The data demonstrated that VYNE's pan-BET inhibitor VYN201 used as an intra-articular injection resulted in significant inhibition of inflammation in a validated animal model of RA. The data supports the potential to develop VYN201 as a locally-administered intra-articular treatment for an autoimmune joint disease.

RA is a chronic autoimmune and inflammatory disease with an average prevalence of 0.5–1.0% in the population worldwide. RA is characterized by inflammation of the synovial membrane, resulting in progressive cartilage damage and bone erosion. Symptoms of RA most commonly include pain, swelling, redness and stiffness in the affected joints, limiting the range of motion.

In this validated preclinical model for RA, inflammatory arthritis was induced in BALB/c mice by systemically injecting a mixture of four arthritogenic monoclonal antibodies against collagen II at day 1. In addition, the mice received a lipopolysaccharide injection systemically at day 4 to stimulate an acute systemic inflammatory response. Each treatment group (n=7 per group) was injected with either an intra-articular dose of VYN201 vehicle, an intra-articular dose of VYN201, an intra-articular dose of dexamethasone (1mg/kg) or a systemic dose of dexamethasone (1mg/kg, via intraperitoneal injection). The intra-articular doses were administered on days 0, 3, 6 and 9 while the dexamethasone systemic injections were given daily beginning at day 0 through 11.

For the VYN201 treatment groups, four doses of VYN201 were evaluated (at concentrations ranging from 0.01 to 10mg/kg). Each animal treated with the intra-articular injections received the injection in the ankle of one rear paw. The untreated rear paw was assessed to evaluate any potential anti-inflammatory systemic effect.

Treatment response was evaluated based on an assessment of paw thickening or swelling (in millimeters) and arthritis scoring based on a five-point composite severity scale of redness, swelling of the ankles and wrists, and paw thickness. Scoring in this model ranges from 0 (normal) to 4 (extensive signs and symptoms of arthritis). BET proteins play a key role in regulating gene transcription via epigenetic interactions (“reading”), and recent research has determined a key role for these BET proteins in regulating B cell and T cell activation and subsequent inflammatory processes.

As epigenetic readers, BET proteins regulate the recruitment of transcriptional factors that are key to the production of several pro-inflammatory cytokines. Inhibiting BET proteins blocks cytokine transcription and therefore may have significant therapeutic potential across a wide variety of immuno-inflammatory/fibrotic and myeloproliferative neoplastic disorders. A locally administered pan-BET inhibitor has the possibility to positively impact diseases involving multiple, diverse inflammatory cell signaling pathways that are active in many immune-inflammatory diseases.