RORgamma, a hot target for treatment of Th17 cell-mediated immune diseases, but also for immune therapy of cancer

STUTTGART, Germany I February 4, 2016 I Targeting the proinflammatory cytokine interleukin-17 (IL-17) produced by T helper cells has become a clinically validated strategy of successfully treating psoriasis, psoriatic arthritis and ankylosing spondylitis. The first approved and marketed antibody secukinumab from Novartis also shows great commercial promise as evidenced by sales of US$ 261 mln in the first year of market launch. The success is due to superior efficacy of anti-IL17 over established psoriasis antibodies targeting TNFα and interleukin-12/23 with a multi-billion dollar market only for psoriasis. However, neutralizing IL-17 with antibodies has proved ineffective and possibly deleterious in patients with inflammatory bowel disease. Given that T helper 17 (T_H17) cells express IL-17 together with many other proinflammatory cytokines (IL-17F, IL-22, IL-26, and granulocyte-macrophage colony-stimulating factor), targeting the Th17 cell lineage may be superior to blocking a single effector cytokine.

Th17 cells specifically express the DNA-binding transcription factor retinoic-acid-receptor-related orphan receptor gamma T (RORγT). The activity of RORγT is required for the proliferation and functionality of immune Th17 cells.. Active RORgammaT is a prerequisite for the differentiation of T cells into Th17 cells. Small-molecule inhibition of RORγT has therefore emerged as a novel strategy for the treatment of autoimmune diseases while stimulation of RORγT by agonists holds promise in immune-oncology. Orally bioavailable RORgamma agonists have demonstrated single agent therapeutic activity in multiple in vivo animal models of cancer. Ex vivo treatment with RORgamma agonist compounds has been shown to enhance the therapeutic benefit of adoptive T-cell therapy by improving both immune cell persistence and activation.

In a new report released by La Merie Publishing, the landscape of drug discovery and development of novel small molecule antagonists (inverse agonists) and agonists of RORγ is described and analyzed. Nuclear receptors are „difficult-to-drug“ targets, and, thus, represent a high entry barrier, which requires specific expertise in structure-based drug discovery.

The report entitled “RORgamma Modulators 2016: A comparative analysis of the landscape of RORgamma antagonists and agonists“ outlines the scientific rationale for discovering antagonists of RORgamma for treatment of autoimmune and inflammatory diseases, but also of agonists of RORgamma for treatment of cancer. Clinical as well as non-clinical data for validation of RORgamma as target are provided and lead and up-side indications for development including the key product profile are discussed. Potential safety concers for novel RORgamma modulators were identified. Drug discovery approaches of more than 30 technology and pharmaceutical companies are shown regarding strategies in partnering as well as in applied technologies.

Based on the experience in the past, estimates of the required time from start of a discovery program of RORgamma modulators until entry into human studies are calculated. The competitive landscape of RORgamma modulator development and discovery projects is analyzed and the profiles of companies are presented, separately for unpartnered technology or pharmaceutical companies and for partnerships between technology and pharmaceutical companies.

About La Merie

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SOURCE: La Merie Publishing