How was the first-in-human dose set for approved oligonucleotides?

“In addition, on the basis of these non-clinical studies the applicant estimated an acceptable safe starting dose for humans based on the results observed.”

“In a chronic monkey study, multi-focal intimal hyperplasia with mixed inflammatory infiltrates was evident in vascular beds in 2 of 6 monkeys treated for 12 months with 30 mg/kg/week with a no-observed-adverse-effect-level (NOAEL) of 10 mg/kg/week”

“The FDA placed protocol ION373-CS1 on hold for IT doses of ION373 exceeding 25 mg, which is approximately 1/10th the NOAELs in mouse and monkey”

“The NOAEL in the 9-month ITL study in juvenile monkey was 25 mg.”

“Due to the observation of degeneration and necrosis in renal tubular epithelium in a significant number of HD animals, the NOAEL for this study was the MD of 300 mg/kg”

“The no observed adverse effect levels (NOAELs) in the chronic studies were the high doses of 150 and 300 mg/kg/month in rat and monkey, respectively.”

“The NOAEL for donidalorsen was determined to be 6 mg/kg/week in monkeys, based on PLT reductions”

“As shown in the table below, safety margins based on AUCs at the NOAELs in the pivotal toxicity studies in monkey and juvenile rat are 20-fold and 6-fold, respectively, compared to the mean AUC observed in DMD patients”

“No adverse findings were associated with chronic, weekly administration of givosiran to rats and monkeys at doses that achieved exposure multiples of 3.5- and 26.3 fold, respectively when compared to exposures achieved in patients receiving the maximum recommended human dose.”

“In the rabbit, based on the retinal vacuolation, the NOEL for avacincaptad pegol is 0.5 mg/eye for single and repeated IVT injections (0.66X the recommended clinical dose).”

“Since none of the findings were considered adverse, the NOAEL was 300 mg/kg/28 days and provides a 19-fold exposure multiple to clinical exposure based on body”

“In the peer-review, additional injection-related, but no drug-related findings were observed and a NOAEL of 3 mg/eye was confirmed.”

“The liver is the primary site of patisiran-LNP uptake and accumulation, and hepatotoxicity determined the NOAELS in all non-clinical species.”

“The no observed adverse effect levels (NOAELs) in the chronic repeat-dose toxicity studies with once monthly dosing were the highest doses tested, 200 and 300 mg/kg for rats and monkeys, respectively.”

“Based on neurological signs in the 9-month study, the NOAEL for IT administration of tofersen in cynomolgus monkey was 12 mg every 2 weeks, resulting in plasma Cmax and AUC0-24h of 4840 ng/mL and 30,000 µg·h/mL, respectively.”

“The no observed adverse effect level (NOAEL) was the high dose (HD) of 1 mg/kg/week in females, based on the absence of toxicity, and the MD of 0.5 mg/kg/week in males, based on severe clotting.”

“The NOAEL was considered 180 mg/kg/Q4W (140-fold MRHD, BSA), the highest dose tested, based on the absence of significant toxicity.”

“The NOAEL for nedosiran in the most sensitive and relevant species, the juvenile monkey, is 100 mg/kg, with a corresponding AUC0-48h 400 µg·h/mL, which is approximately 29-fold higher”

“No NOAEL could be determined. Instead, a highest non-severely toxic dose (HNSTD) of 15 mg/kg was established, as no mortalities or life-threatening were observed at this dose.”

“The no-effect dose (0.3 mg) for neurotoxicity in the 53-week monkey study was associated with csf levels (12 ng/mL) generally less than that in SMA patients (7-35 ng/mL); therefore, there is no safety margin based on csf levels.”

“The NOAEL was 6 mg/kg/week, based on the severe thrombocytopenia observed at 10 and 20 mg/kg/week.”

“Drug-related effects consistent with the expected toxicities of an ASO with a phosphorothioate backbone were evident in the liver, kidney, and spleen.”

“Based on the 39-week study, the NOAEL for IV administration of vitolarsen in male cynomolgus monkeys was 60 mg/kg (Cmax = 613.9 µg/mL; AUC0-24h = 261.1 µg*h/mL).”

“The NOAEL for this study was the LD of 100 mg/kg. The AUC0-t at this dose was 239,000 ng•hr/mL. This dose provides a safety margin of approximately 2.6X over the recommended human dose of 30 mg/kg, based on plasma exposure.”

“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.”

“Cynomolgus monkey: 7 or 9/s/g 0-3-6-12-20 39 wk 3”