Wainua

“Eplontersen is pharmacologically active in monkey but not mouse.”

“The target sequence of eplontersen and inotersen is 100 % complementary to human and Cynomolgus monkey TTR mRNA, whereas 8 mismatches in mice and rats preclude effective hybridisation and, hence, pharmacological activity in these animals.”

“A parallel group administered 10 mg/kg SC ION-1184986, the mouse-specific ASO, showed reduction of ~82% in hepatic TTR mRNA, compared to controls; no adverse effects were observed.”

“In a 39-week study in cynomolgus monkeys, eplontersen (0, 5, 10, or 25 mg/kg SC Q4W) resulted in an increase in complement Bb in HDM, basophilic granules in liver Kupffer cells and kidney tubular cells at the HD, and granular macrophages in the lymph nodes at all doses.”

“The nonclinical studies of eplontersen submitted to the NDA included general toxicology studies of up to 26 weeks (mouse) and 9 months (monkey) in duration”

“The toxicity of eplontersen was investigated with different s.c. administration regimen (weekly, biweekly, monthly) for up to 26 weeks in mice, 14 weeks in rats and up to 39 weeks in monkeys.”

“Eplontersen was negative in adequately conducted in vitro (Ames, chromosomal aberration) and in vivo (mouse bone marrow micronucleus) assays.”

“In a 26-week carcinogenicity study in male and female Tg.rasH2 mice, subcutaneous administration of eplontersen (0, 250, 500, or 1500 mg/kg) monthly for 26 weeks resulted in no increase in neoplasms.”

“Potential effect of eplontersen on embryo-foetal development in a second species, pre- and post-natal development or juvenile toxicity were not investigated.”

“Safety pharmacology studies did not indicate any adverse effects on CNS, cardiovascular, or respiratory endpoints in male cynomolgus monkeys administered a single ascending dose of eplontersen of up to 24 mg/kg by SC injection.”

“Based on plasma exposure, the NOAEL in monkey will provide safety margins of 134 (AUC0-24h) and 112 (Cmax) compared to the proposed human dose of 45 mg.”

“Thus, these ADAs represent binding antibodies without neutralising capacity.”

“In SD rats administered [3H]ASO-eplontersen, radioactivity levels peaked in plasma at 0.5 h postdose, then distributed into tissues, primarily liver and kidney, with the highest levels observed in the liver at 8 h and kidney at 2 days; radioactivity was undetectable in brain and spinal cord.”

“Potential safety concerns for eplontersen based on the route of administration and therapeutic class (including information from the previously approved hATTR drug inotersen) were thrombocytopenia, glomerulonephritis, renal impairment, abnormal liver function, injection site reactions, flu-like symptoms, central nervous system disorders, hemorrhages, and coagulation abnormalities.”