Contributions
Abstract: P1610
Type: LB Poster
Abstract Category: Late Breaking News
Background: RORγt is a key transcription factor and master regulator of human Th17 cells, a unique subset of CD4+T cells. RORγt controls cellular differentiation, function and IL-17 producing T-helper lymphocyte release by Th17 cells and help in mediating the immunopathology of human autoimmune Multiple Sclerosis (MS). ARN-6039 is an inverse agonist of the RORγt of IL-17-TH17 pathway. Early pharmacology studies demonstrated that ARN 6039 is both orally bioavailable and highly CNS penetrant.
Design/methods: ARN-6039 was tested in vitro for RORγt inverse agonist activity, inhibition of the activation of CD4+T lymphocytes to Th17 cell differentiation and IL-17, primary B cell direct IL-17 production, effect of differentiation of OPCs and its brain penetrant activity. Cytokine-IL-17 production and EAE efficacy studies were also conducted in BALB/c and C57BL/6 mouse models for ARN-6039 effects in vivo. A Phase 1, single-center, randomized, double-blind, placebo-controlled, safety, tolerability, and pharmacokinetic study of single ascending oral doses of ARN‑6039 in healthy adult subjects has been initiated.
Results: The preclinical investigations for ARN 6039 demonstrated reductions in IL17 expression, therapeutic effects in EAE models after disease onset, and evidence of remyelination. The selectivity, on target mechanism, brain-uptake, PK, correlative PK/PD, drug-like, and ADME profiles of ARN-6039 results will be presented. Detailed 28-day toxicology, safety pharmacology results of ARN-6039 and its genotoxicity results will also be presented. Based on the preclinical data including non-clinical GLP safety, tolerability and MTD, a Phase 1 trial has been initiated. Two cohorts of 10 normal subjects each were enrolled and completed the dosing. Initial safety, tolerability, and pharmacokinetics are favorable. Complete safety, PK for this Phase 1 trial will be discussed.
Conclusions: Preclinical data strongly support ARN 6039 as a new agent which is both orally available and highly brain penetrant, with efficacy in EAE models. Additional evaluations support potential beneficial effects including remyelination and neuroprotection. From further testing in animals ARN 6039 demonstrates an excellent safety and tolerability profile. The initial results of the Phase 1 trial in normal subjects demonstrate an excellent safety and tolerability profile. Further Phase 1 testing and preparations for potential Phase 2 clinical trials in relapsing and remitting MS patients are underway.
Disclosure: Study supported by: Arrien Pharmaceuticals
Disclosure: J.W.R, member Scientific Advisory Board for Arrien Pharmaceuticals, N.G.C, None, V.Y, Arrien Pharmaceuticals, R.P.A, Arrien Pharmaceuticals, J.A.H, None, R.R.K, Arrien Pharmaceuticals, G.A, None, and H.V, Arrien Pharmaceuticals
Abstract: P1610
Type: LB Poster
Abstract Category: Late Breaking News
Background: RORγt is a key transcription factor and master regulator of human Th17 cells, a unique subset of CD4+T cells. RORγt controls cellular differentiation, function and IL-17 producing T-helper lymphocyte release by Th17 cells and help in mediating the immunopathology of human autoimmune Multiple Sclerosis (MS). ARN-6039 is an inverse agonist of the RORγt of IL-17-TH17 pathway. Early pharmacology studies demonstrated that ARN 6039 is both orally bioavailable and highly CNS penetrant.
Design/methods: ARN-6039 was tested in vitro for RORγt inverse agonist activity, inhibition of the activation of CD4+T lymphocytes to Th17 cell differentiation and IL-17, primary B cell direct IL-17 production, effect of differentiation of OPCs and its brain penetrant activity. Cytokine-IL-17 production and EAE efficacy studies were also conducted in BALB/c and C57BL/6 mouse models for ARN-6039 effects in vivo. A Phase 1, single-center, randomized, double-blind, placebo-controlled, safety, tolerability, and pharmacokinetic study of single ascending oral doses of ARN‑6039 in healthy adult subjects has been initiated.
Results: The preclinical investigations for ARN 6039 demonstrated reductions in IL17 expression, therapeutic effects in EAE models after disease onset, and evidence of remyelination. The selectivity, on target mechanism, brain-uptake, PK, correlative PK/PD, drug-like, and ADME profiles of ARN-6039 results will be presented. Detailed 28-day toxicology, safety pharmacology results of ARN-6039 and its genotoxicity results will also be presented. Based on the preclinical data including non-clinical GLP safety, tolerability and MTD, a Phase 1 trial has been initiated. Two cohorts of 10 normal subjects each were enrolled and completed the dosing. Initial safety, tolerability, and pharmacokinetics are favorable. Complete safety, PK for this Phase 1 trial will be discussed.
Conclusions: Preclinical data strongly support ARN 6039 as a new agent which is both orally available and highly brain penetrant, with efficacy in EAE models. Additional evaluations support potential beneficial effects including remyelination and neuroprotection. From further testing in animals ARN 6039 demonstrates an excellent safety and tolerability profile. The initial results of the Phase 1 trial in normal subjects demonstrate an excellent safety and tolerability profile. Further Phase 1 testing and preparations for potential Phase 2 clinical trials in relapsing and remitting MS patients are underway.
Disclosure: Study supported by: Arrien Pharmaceuticals
Disclosure: J.W.R, member Scientific Advisory Board for Arrien Pharmaceuticals, N.G.C, None, V.Y, Arrien Pharmaceuticals, R.P.A, Arrien Pharmaceuticals, J.A.H, None, R.R.K, Arrien Pharmaceuticals, G.A, None, and H.V, Arrien Pharmaceuticals