Successful Integration of Nonclinical and Clinical Findings in Interpreting the Clinical Relevance of Rodent Neoplasia with a New Chemical Entity. (January 2015)

• Record Type: Journal Article
• Authors: Ways, Kirk; Johnson, Mark D.; Mamidi, Rao N. V. S.; Proctor, James; De Jonghe, Sandra; Louden, Calvert
• Is Part Of: Toxicologic pathology. Volume 43:Number 1(2015)
• Page Start: 48
• Page End: 56
• Publication Date: 2015-01
• Subjects: SGLT2 inhibitor -- canagliflozin -- rat carcinogenicity -- pheochromocytomas -- renal tubular tumors -- Leydig cell tumors -- carbohydrate malabsorption.; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623314557179
• Languages: English
• ISSNs: 0192-6233

Abstract

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been developed for the treatment of adults with type 2 diabetes mellitus (T2DM). During the phase 3 program, treatment-related pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. Treatment-related tumors were not seen in the 2-year mouse study. A cross-functional, mechanism-based approach was undertaken to determine whether the mechanisms responsible for tumorigenesis in the rat were of relevance to humans. Based on findings from nonclinical and clinical studies, the treatment-related tumors observed in rats were not deemed to be of clinical relevance. Here, we describe the scientific and regulatory journey from learning of the 2-year rat study findings to the approval of canagliflozin for the treatment of T2DM.