How long were the pivotal tox studies for approved oligonucleotides?

“A one year (53 weeks) repeat dose toxicity study in juvenile cynomolgus monkeys with a 26-week recovery phase”

“The toxicity and pharmacokinetics (PK) of ISIS 396443 were evaluated following single IT bolus doses (up to 7 mg) in adult monkeys or following repeated IT bolus doses (weekly or every other week) for 14 (0.3, 1, or 3 mg/dose) and 53 (0.3, 1, or 4 mg/dose) weeks in juvenile monkeys.”

“Repeat-dose toxicity studies with mipomersen were performed using a subcutaneous injection for time intervals of 3 and 6 months in mice, 13 weeks and 5 months in rats, and 5 weeks, 13 weeks, and 12 months in cynomolgus monkeys.”

“Repeat-dose toxicity studies with mipomersen were performed using a subcutaneous injection for time intervals of 3 and 6 months in mice, 13 weeks and 5 months in rats, and 5 weeks, 13 weeks, and 12 months in cynomolgus monkeys.”

“In the pivotal general toxicology studies of SC vutrisiran in rat (13- and 26-week) and cynomolgus monkey (13- and 40-week), non-adverse findings were observed in the liver (both species), kidneys (rat), and lymph nodes (monkey).”

“Frequency of dosing: Every 4 weeks, Day 1 to Day 281 Route of administration: SC injection to the dorsal region”

“Inclisiran was also well-tolerated in repeat dose studies up to 29-weeks of duration in rats and 40-weeks of duration in monkeys.”

“Toxicological characterization of inclisiran was performed in studies of 29 weeks in rats and 40 weeks in NHPs at doses up to 8 times (≤ 250 mg/kg Q4W) and 19 times (300 mg/kg Q4W) the MRHD (based on BSA), respectively.”

“Title: SRP-4045: A 39-week intravenous infusion toxicity study in male cynomolgus monkeys with an 8-week recovery period”

“general toxicology (12-, 22-, and 26-week IV in mouse; 12- and 39-week IV in monkey) studies”

“repeat dose studies in CD-1 mice and cynomolgus monkeys of up to 26- and 39-week duration, respectively”

“plasma TK profile of SC administration of donidalorsen was evaluated in a GLP-compliant 13-week interim/39-week repeat-dose toxicity study in Cynomolgus monkeys with a 26-week treatment-free recovery period”

“39-Week Intravenous Injection Toxicity and Toxicokinetic Study of Eteplirsen in Sexually Mature Male Cynomolgus Monkeys with an 8-Week Recovery”

“Pivotal toxicology studies of eteplirsen were conducted in male monkeys (39-week study) and juvenile male rats (10-week study). A 26-week study was conducted with a mouse-specific surrogate (AVI-4225) in male transgenic mdx mice.”

“In a 39-week monkey study, cynomolgus monkeys were subcutaneously administered vehicle or givosiran (10, 30, or 100 mg/kg) once weekly for 39 weeks followed by a 13-week recovery period.”

“Dawley rats were subcutaneously administered vehicle or givosiran (3, 10, or 30 mg/kg) once weekly for 26 weeks followed by a 13-week recovery period.”

“Study title: A 1-Month (Single-Dose) and 9-Month (Ten-Dose) Toxicity Study of ARC1905 Given by Intravitreal Injections to Rabbits”

“Repeat-dose IVT toxicity studies were conducted in New Zealand White rabbits (0, 0.15, 0.5, and 1.5 mg/eye) and Beagle dogs (0, 0.3, 1, and 3.0 mg/eye).”

“Pivotal long term-studies in up to 9 months with intravitreous injections every 2 weeks did not cause any apparent toxic effects and there was no evidence of increased intra-ocular inflammation during the course of the studies.”

“From the total of studies performed, the 6-month rabbit and 9-month dog studies are considered pivotal.”

“Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or on sperm morphology or count.”

“It is noted that no single cell necrosis or adverse findings are found in the 26-week rat study.”

“Repeat IT dosing with 0, 4, 12, and 35 mg tofersen every 2 weeks for a 9-month period resulted in uncoordinated leg movement and transient impairments of patellar and foot-grip reflexes in HDM and HDF.”

“Nonclinical toxicity studies submitted to the NDA consisted of single dose (rat) and repeat dose (mouse and monkey) general toxicity studies, as well a complete battery of genetic toxicology and reproductive and developmental toxicology studies.”

“Repeat-dose toxicology studies were conducted in healthy rats for up to 26 weeks, healthy monkeys for up to 39 weeks, and in hemophilia mice for up to 26 weeks.”

“A 26-Week Subcutaneous Injection Toxicity, Toxicokinetic, and Fertility and Early Embryonic Development (to Implantation) Study in the Rat Followed By a 13-Week Recovery Period”

“General toxicity studies were conducted for durations up to 26 weeks in juvenile mice and 39 weeks in juvenile and adult monkeys.”

“Repeat dose toxicology studies were conducted in mice for up to 26 weeks and monkeys for up to 39 weeks.”

“Dose and frequency of dosing: 0, 5, 10 or 15 mg/kg for 9 months + 14 weeks recovery; once a week dosing.”

“Additional imetelstat toxicities observed in the chronic pivotal toxicity studies, ie, the 6-month study in mice (003-TOX-2008) and the 9-month study in monkeys, included microscopic findings in the liver and kidney”

“In the 39-week study, inotersen was administered at doses of 0, 3, 6, 10, and 20 mg/kg once weekly.”

“Pivotal toxicity studies were conducted in CD-1 mouse (13-week [30-day interim] + 13-week recovery, 26-week + 13-week recovery), Sprague-Dawley rat (26-week), and cynomolgus monkey (13-week + 13-week recovery, 39-week [26-week interim] + 26-week recovery).”

“In a 39-week monkey toxicity study that included a 26-week recovery period, olezarsen induced a marked reduction in platelet count (>98% decrease) in a single male animal at the 12 mg/kg/wk”

“The nonclinical evaluation of the safety of olezarsen included repeat-dose general toxicology studies of up to 26 and 39-weeks in duration with 13 and 26-week recovery periods in mice and monkeys, respectively”

“Viltolarsen was administered by IV injection for 12 weeks (+4-week recovery) and 39 weeks (+8-week recovery) at doses of 0, 60, 200, and 600 mg/kg QW and 0, 10, 60, and 360 mg/kg QW, respectively.”

“The pivotal IV toxicity studies were conducted in male CD-1 mouse (13 and 26 weeks) and male cynomolgus monkey (12 and 39 weeks).”

“Title: A 39-week intravenous infusion toxicity study in male cynomolgus monkeys with an 8-week recovery period”

“Toxicology: 12- and 26-week studies in mouse; 12- and 39-week studies in monkey; 4- and 10-week toxicity study in juvenile rat.”

“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”

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

“Volanesorsen plasma PK following SC administration in male and female monkeys were further studied in the 39-week toxicity study (study 304801-AS11).”

“The nonclinical package submitted to the NDA included general toxicology studies of up to 26 and 39 weeks' duration in mouse (subcutaneous [SC]) and monkey (intrathecal lumbar [ITL]), respectively”

“In nonclinical toxicology studies, zilganersen was administered via ICV injection in juvenile C57BL/B6Ncrl mouse (13 weeks; 0, 0.05, 0.1, or 0.2 mg every 6 weeks) and via ITL injection in juvenile monkey (9 months; 0, 3, 8, or 25 mg Q4W).”

“Q4W in rats (15, 30, and 120 mg/kg) and monkeys (30, 90, and 180 mg/kg) for durations up to 24- and 37-weeks, respectively”

“Repeat-dose general toxicology studies with plozasiran were conducted with SC administration (consistent with the clinical route) Q4W in rats”

“Chronic administration of lumasiran was assessed in good laboratory practice (GLP) repeat-dose toxicology studies up to 25- and 36-weeks in rats and monkeys, respectively.”

“Dose and frequency of dosing: 30, 100, or 300 mg/kg lumasiran once every 4 weeks for a total of 10 doses Route of administration: SC”