What safety margins were accepted for approved oligonucleotides?

“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 (clinical exposures anticipated from a 200 mg/wk dose based on body surface area comparisons across species).”

“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”

“In monkeys with normal coagulation at baseline, fitusiran administration at up to 0.5 mg/kg/week (representing a dose below the MRHD based on BSA comparisons) for 39 weeks decreased AT protein and activity up to 74% and 71%, respectively, and all doses were well-tolerated.”

“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 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 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 is considered to be 1.0 mg/eye (0.66X the recommended clinical dose) even though optic tract vacuolation at 3.0 mg/eye was not associated with any adverse histopathology or significant ERG findings.”

“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).”

“The NOAEL from the 9-month NHP toxicology study was determined to be 12 mg, which converts to a HED of 120 mg (based on the monkey-to-human CSF volume scaling) thus providing safety margins of 1.2-fold, based on CSF volumetric scaling (10x), relative to the human dose of 100 mg.”

“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.”

“Safety margins based on AUCs at the no observed adverse effect levels (NOAELs) for severe thrombocytopenia in monkeys and kidney toxicity in rats were ≤ ~2-fold.”

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

“In these studies, the no observed adverse effect level (NOAEL) in mice and highest non severely toxic dose (HNSTD) in monkeys were identified as the highest doses administered, which produced exposures that were up to 2.4 and 28.1 times, respectively, the human exposure at the recommended clinical dose.”

“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 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.”

“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.”

“Safety margins based on plasma (AVI-4225 or eteplirsen) exposures at the NOAELs in adult animals are low (<1 in mdx mouse, 3.4 in monkey); however, plasma exposures at the highest doses tested, which were associated with minimal-to-slight toxicity (except for moderate dilatation of lateral ventricles), were 17 and 20 times the anticipated human exposure.”

“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.”

“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.”

“At the overall no-effect dose (300 mg/kg), plasma exposure (AUC) was 4 times that in humans at the recommended human dose of 30 mg/kg/week.”

“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”

“Based on doses normalized to CSF volume, the NOAELs in mouse and monkey provide safety margins of 34 and 10, respectively, compared to the (b) (4) human dose of 25 mg, but of 17 and 5, respectively, compared to the proposed human dose of 50 mg.”

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

“This NOAEL of 6 mg/kg/wk gives a 6x safety margin based on BSA relative to maximum recommended human dose of 80 mg/month.”

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

“It should be noted that other systemic manifestations of TLR9 immunostimulation were seen in monkeys (i.e. spleen hyperplasia from 2.5 mg/kg/w and lymph node hyperplasia and liver inflammation at 12.5 mg/kg/w). Of importance, a NOAEL of 0.5 mg/kg 1018 ISS (>10-fold the clinical dose on mg/kg basis) for systemic immunostimulatory effects was identified in this study.”

“It should be noted that other systemic manifestations of TLR9 immunostimulation were seen in monkeys (i.e. spleen hyperplasia from 2.5 mg/kg/w and lymph node hyperplasia and liver inflammation at 12.5 mg/kg/w). Of importance, a NOAEL of 0.5 mg/kg 1018 ISS (>10-fold the clinical dose on mg/kg basis) for systemic immunostimulatory effects was identified in this study.”

“The NOAEL in this study was 6 mg/kg/wk and the exposure at this dose level provided an exposure-based safety margin to the proposed clinical regimen of ~29 fold (monthly) and ~58-fold (every-8- week).”

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

“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”

“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”

“25-week rat 200 378 44 X 36-week monkey 300 1290 150 X”

“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.”

“They are 99-fold and 101-fold based on Cmax and 48.9-fold and 99.6-fold based on AUC in rats and monkeys, respectively, compared to the 300 mg human 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”

“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.”

“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.”

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

“The pegaptanib plasma concentration (30 minutes postdose on Day 91) at the NOAEL was approximately 240-fold higher than human maximum pegaptanib plasma concentrations following 3 mg/eye IVT doses.”

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

“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. Plasma exposures (AUC) at the NOAELs were ~600 and ~4400 times, respectively, those expected in humans at the proposed clinical dose of 25 mg once every 3 months, after adjusting for the 3-fold difference in dosing frequency.”

“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 necrosis and granulomatous inflammation at the injection sites were considered adverse reactions and were expected to resolve over time.”

“Target organs of toxicity were identified in a 13-week rat toxicology study, which included adverse findings in the kidneys, liver and lymphoid tissues. Defibrotide also prolonged prothrombin time (PT) in rats, in addition to activated partial thromboplastin time (APTT) in rats and dogs.”

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

“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).”

“Group 2 (115 ug of fomivirsen + triamcinolone) or in control animals had no ocular alterations. A transient decrease in IOP was identified in 3/6 Group 2 animals.”

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