- Internal research efforts at Reata led to the discovery of a series of highly selective and orally bioavailable allosteric inhibitors of RORγt for the potential treatment of a broad range of autoimmune and inflammatory disorders. RORγt is the master transcription factor that controls the differentiation of naïve CD4+ precursor cells into Th17 cells, which express high levels of pro-inflammatory cytokines, including the key effector cytokine IL-17A.
- RTA 1701 potently suppresses Th17 cell differentiation in vitro, demonstrates strong efficacy in multiple rodent models of autoimmune disease, and significantly suppresses ex-vivo production of IL-17A when dosed orally to non-human primates.
- Reata is evaluating RTA 1701 in a Phase 1 clinical trial with initial safety, pharmacokinetic, and ex vivo IL-17A suppression results expected in the first half of 2019.
- Reata retains all rights to the RORγt inhibitors, which are not subject to any existing commercial collaborations.
RORγt Inhibitors and Therapeutic Potential
RORγt is the master transcription factor that regulates differentiation of naïve CD4+ precursor cells into T-helper 17 (Th17) cells. Naïve CD4+ precursor T cells can differentiate into various lineages of effector T cells, including regulatory T cells (Treg) and Th17 cells1. Treg cells play an essential role in maintaining immune self-tolerance and coordinating immunosuppressive mechanisms to control a broad range of potentially pathogenic innate and adaptive immune responses2. In contrast, Th17 cells express high levels of pro-inflammatory cytokines, including the key effector cytokine IL-17A, and work in opposition to the anti-inflammatory effects of Treg cells to drive pro-inflammatory immune responses. Loss of the balance between Th17 cells and Treg cells, in favor of Th17 cells, disrupts immune homeostasis and can contribute to the chronic pathogenesis of autoimmune diseases.
The clinical significance of aberrant IL-17A signaling has been confirmed by the FDA’s recent approvals of multiple injectable IL-17A targeted therapies. Suppression of IL-17A expression through an orally administered inhibitor RORγt, such as RTA 1701, has the potential for broad activity across multiple chronic inflammatory and autoimmune diseases with high unmet medical need. Autoimmune diseases affect at least 15 million with some estimates as high as 50 million people in the U.S.3 and include conditions such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, and numerous others4.
Reata’s lead molecule from this program, RTA 1701, has a unique, differentiated profile compared to other agents in this space owing to its novel allosteric binding mode and offers the potential to be a best-in-class oral inhibitor of RORγt. In in vitro assays, RTA 1701 demonstrates potent, low nanomolar inhibition of RORγt activity and IL-17A production. Consistent with the in vitro mechanism, oral dosing of RTA 1701 has demonstrated significant efficacy in animal models of autoimmune diseases, including rheumatoid arthritis, and multiple sclerosis5. RTA 1701 also significantly suppresses IL-17A expression after being dosed orally to non-human primates6, which often best reproduce human physiology and immune function. Additional in vitro studies demonstrate that expression of IL-17A is significantly reduced by RTA 1701 treatment in blood cells from patients with rheumatoid arthritis or psoriasis.
- Martinez GJ, Nurieva RI, Yang XO, et al. Regulation and function of proinflammatory Th17 cells. Ann NY Acad Sci 2008;1143:188-211.
- Lei H, Schmidt-Bleek K, Dienelt A, et al. Regulatory T cell-mediated anti-inflammatory effects promote successful tissue repair in both indirect and direct manners. Front Pharmacol 2015;6:184.
- Autoimmune Registry. Estimates of Prevalence for Autoimmune Disease.
- Chen Z, Lin F, Gao Y, et al. FOXP3 and RORγt: transcriptional regulation of Treg and Th17. Int Immunopharmacol 2011;11:536-42.
- Dulubova I, Jian, X, Trevino I, et al. RTA 1701 is an orally-bioavailable, potent, and selective RORγt inhibitor that suppresses Th17 differentiation in vitro and is efficacious in mouse models of autoimmune disease. J Immunol May 1, 2018, 200 (1 Supplement) 121.14.
- Reisman SA, Lee CYI, Proksch JW, et al. RTA 1701 is an oral RORγt inhibitor that suppresses the IL-17A response in non-human primates. J Immunol May 1, 2018, 200 (1 Supplement) 175.22.