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Thymic Lymphomas in a 6-Month rasH2-Tg Mouse Carcinogenicity Study With the RORγt Inverse Agonist, BMS-986251
Helen G Haggerty1, Jean G Sathish1, Carol R Gleason2
1Nonclinical Research and Development, Bristol Myers Squibb, New Brunswick, New Jersey 08903, USA.
Abstract:
BMS-986251 is a retinoid-related orphan receptor γt (RORγt) inverse agonist that was in development for the treatment of autoimmune diseases. RORγt is a nuclear hormone receptor and transcription factor that is involved in the differentiation and function of T helper 17 cells. RORγt-deficient (constitutive or conditional) mice develop thymic lymphomas with >50% mortality at 4 months, whereas heterozygous mice are normal. A 6-month study was conducted in rasH2-Tg hemizygous mice to assess the potential carcinogenicity of BMS-986251. BMS-986251 was administered once daily by oral gavage to groups of 27 mice/sex at doses of 0 (water control), 0 (vehicle control), 5, 25, or 75 mg/kg. The positive control, N-methyl-N-nitrosourea, was administered by a single intraperitoneal injection to 15 mice/sex at a dose of 75 mg/kg. There were no tumors attributed to BMS-986251 except for thymic lymphomas. Thymic lymphoma was observed in 1 male (3.7%) and 3 females (11.1%) at the mid dose, and 6 females (22.2%) at the high dose. No lymphomas were observed in the negative control groups whereas the incidence of lymphomas in the positive control group was 47-60%. The incidence of thymic lymphomas in the BMS-986251-treated groups was higher than published literature and test facility historical control data. Furthermore, increased thymic lymphoid cellularity (lymphoid hyperplasia) was observed at the mid dose in males and at all doses in females. Since lymphoid hyperplasia may represent a preneoplastic change, a no-effect dose for potential tumor induction was not identified in this study. These results led to the discontinuation of BMS-986251 and underscore the challenges in targeting RORγt for drug development.
Insights
BMS-986251, a drug targeting retinoid-related orphan receptor gamma t (RORγt) for autoimmune diseases, caused thymic lymphomas in mice. This led to the drug's discontinuation due to safety concerns.
Area of Science:
- Pharmacology and Toxicology
- Immunology
- Oncology
Background:
- Retinoid-related orphan receptor gamma t (RORγt) is a key transcription factor in T helper 17 cell differentiation, implicated in autoimmune diseases.
- RORγt inhibition is a therapeutic strategy for autoimmune conditions, but potential safety risks, including carcinogenicity, require thorough investigation.
- Previous studies indicate RORγt deficiency can lead to thymic lymphomas in mice, highlighting the importance of evaluating RORγt-targeting agents for oncogenic potential.
Purpose of the Study:
- To assess the potential carcinogenicity of BMS-986251, a novel RORγt inverse agonist, in a relevant animal model.
- To determine if BMS-986251 administration leads to an increased incidence of tumors, particularly thymic lymphomas.
- To identify a no-effect dose for potential tumor induction by BMS-986251.
Main Methods:
- A 6-month carcinogenicity study was conducted in rasH2-Tg hemizygous mice.
- BMS-986251 was administered orally at doses of 0, 5, 25, or 75 mg/kg/day; N-methyl-N-nitrosourea served as a positive control.
- Tumor incidence, specifically thymic lymphomas, and lymphoid cellularity were evaluated.
Main Results:
- BMS-986251 treatment resulted in an increased incidence of thymic lymphomas, particularly in female mice at mid and high doses.
- Lymphoid hyperplasia in the thymus was observed in BMS-986251-treated groups, suggesting a preneoplastic change.
- The incidence of thymic lymphomas exceeded historical control data, and a no-effect dose for tumor induction was not identified.
Conclusions:
- BMS-986251 demonstrated potential carcinogenicity, specifically inducing thymic lymphomas and lymphoid hyperplasia in a rasH2-Tg mouse model.
- The observed safety concerns led to the discontinuation of BMS-986251 development for autoimmune diseases.
- Targeting RORγt for therapeutic purposes presents significant challenges due to potential oncogenic risks, necessitating careful risk-benefit assessments.
