Successful integration of nonclinical and clinical findings in interpreting the clinical relevance of rodent neoplasia with a new chemical entity.
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.
Janssen Research & Development, LLC, Raritan, New Jersey, USA KWays@its.jnj.com.
Kirk
K
Ways
Janssen Research & Development, LLC, Raritan, New Jersey, USA.
Mark D
MD
Johnson
Janssen Research & Development, LLC, Raritan, New Jersey, USA.
Rao N V S
RN
Mamidi
Janssen Research & Development, LLC, Raritan, New Jersey, USA.
James
J
Proctor
Janssen Research & Development, Beerse, Belgium.
Sandra
S
De Jonghe
Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.
Calvert
C
Louden
D000818:Animals; D000068896:Canagliflozin / Q000008:administration & dosage / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D051381:Rats; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013739:Testosterone
D007004:Hypoglycemic Agents; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; D013739:Testosterone
Leydig cell tumors; SGLT2 inhibitor; canagliflozin; carbohydrate malabsorption.; pheochromocytomas; rat carcinogenicity; renal tubular tumors