What tox package did approved oligonucleotides have, from first-in-human to approval?

“A phase 1 study, Protocol No. ISIS 721744-CS1, was previously conducted in Canada to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS 721744 in healthy volunteers.”

“The 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.”

“This review evaluates the GLP-compliant reproductive and developmental toxicology studies with ISIS 721744 (i.e., combined fertility and developmental toxicity study in mice and PPND study in mice) to support the safety of ISIS 721744 for marketing approval.”

“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”

“6 clinical study centers (4 in US, 1 in UK, 1 in Sweden)”

“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.”

“In a pre- and postnatal development study in rats, givosiran (0, 3, 10, or 30 mg/kg) was administered to pregnant rats approximately every 6 days on GD 7, 13, and 19 and lactation days (LD) 6, 12, and 18 .”

“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”

“Part A: SAD study (001A) in healthy subjects to evaluate safety, tolerability, PK, PD and ADA of lumasiran Country: UK”

“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.”

“A pre- and postnatal development study had a NOAEL of 50 mg/kg with a safety margin of >2X.”

“Two-year rat and 6-month transgenic mouse carcinogenicity studies are underway. The available data do not raise concern for a risk of carcinogenicity that should delay approval given the apparent clinical benefit and unmet need. As such, these studies will be postmarketing requirements.”

“Subjects outside the United States received the IT placebo injection throughout the trial.”

“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”

“5053-4: Conduct a pre- and postnatal development (PPND) study of zilganersen and the mouse surrogate (ISIS 713812) to evaluate maternal and offspring toxicity.”

“5053-1: Conduct a 6-month carcinogenicity study of zilganersen in Tg.rasH2 mice to assess tumorigenic potential. 5053-2: Conduct a 2-year carcinogenicity study of zilganersen in rats to assess tumorigenic potential.”

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

“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females)”

“Carcinogenicity assessments were not conducted. PMRs covering the carcinogenicity assessments are recommended.”

“Given the generally mild effects, recovery periods did not follow the dosing phases of the 6 and 9 months toxicity studies.”

“In a GLP pre- and postnatal development study in rat, SC administration of vutrisiran (0, 5, 10, or 20 mg/kg on GD 7, 13, and 19, and lactation days 6, 12, and 18) resulted in no adverse effects.”

“The potential carcinogenicity of vutrisiran is being assessed in ongoing 2-year studies in rat and mouse; final reports will be submitted post approval per prior agreement with the Division.”

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

“Assessments of the effects of eteplirsen on female fertility, embryofetal development, and early postnatal development were not conducted because the DMD patient population is almost entirely male.”

“The sponsor plans to conduct a 26-week study in transgenic mice and a 2-year study in rats to assess the carcinogenicity of eteplirsen.”

“On Week 37 (after 10 monthly doses), mild retinal vacuolation was observed in the high dose group. The finding did not increase in severity between Doses 1 and 10. The finding was again reversible following a 4-week recovery period (Day 281).”

“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”

“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”

“As it was commented above the primary effects of mipomersen after 12 months of dosing were limited to the 30 mg/kg/week dose group and included decreases in platelet count, a decrease in total complement factor C3, as well as minimal degenerative changes Kynamro Page 26/114 and vacuolation in tubular epithelial cells in the kidney, most of which were recovered to baseline levels during a 6 month recovery period.”

“The NOAEL for pre- and post-natal development in the rat is considered to be 7 mg/kg/week based on reduced bodyweight gain and impaired performance in the visual placing response and grip strength.”

“Two year carcinogenicity studies of mipomersen were conducted in rats and mice. The Executive Carcinogenicity Assessment Committee found the studies adequate.”

“A 40-Week Repeat Subcutaneous Injection Toxicity and Toxicokinetic Study in the Cynomolgus Monkey Followed by a 13-Week Recovery Period (study no.: 5001352) Doses: 0, 30, 100, and 300 mg/kg/every 28 days by SC injection”

“Embryo-fetal assessments in rats and rabbits and a pre and postnatal development study in rats did not demonstrate evidence of reproductive or developmental risk at any dose tested, representing up to 5 and 10 times clinical MRHD (BSA), respectively (≤ 150mg/kg/day in both species).”

“Inclisiran was evaluated in a lifetime (2 year) rat carcinogenicity study at up to 8 times the clinical MRHD (BSA) (≤ 250 mg/kg Q4W) and in a 6-month study in Tg rasH2 mice (≤ 1500 mg/kg Q4W). Inclisiran lacked tumorigenic potential in these studies.”

“Dogs/Beagle 5-7/sex/group. Reversibility 2/sex in control and 3 mg groups. 0, 0.3, 1, 3 in 100µl/eye, IVT 9 months with 6 week recovery”

“The reproductive toxicology program included range-finding embryo-foetal development studies in rabbit and mouse and a final embryo-foetal development study in the mouse.”

“The main argument considered by the CHMP in order to accept the lack of carcinogenicity studies was due to the very low systemic exposure obtained in the clinical population together with the apparent difficulty to perform relevant study obtaining both high systemic and intraocular exposure.”

“In monkeys, IT administration of 0, 4, 12, and 35 mg tofersen in male and female cynomolgus monkeys every other week for 9 months resulted in histologic findings of neuronal vacuolation at all doses; however, vacuolation was not accompanied by neurodegeneration and was not present in recovery groups.”

“There were no effects on embryofetal development in CD1 mouse or NZW rabbit, or on pre- and postnatal development in CD1 mouse.”

“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”

“Monkey (cyno) 37w, 10 monthly doses +4w SC injection GLP SR-00804 Main: 7 M/F Recovery: 2 M/F (control and high dose)”

“FEED and PPND were conducted in rats, EFD in rats and rabbits.”

“The 2-year rat carcinogenicity study is ongoing, and the Agency recommends that completion of this study should be submitted postmarketing (after approval) considering the unmet medical need associated with the FCS clinical indication.”

“At the injection sites, minimal to mild macrophage basophilic hypertrophy was observed in the subcutaneous tissues in the juvenile mice and monkeys, which resolved following an 8-week recovery period, indicating hybridization-independent effects. Findings in Young Adult Monkeys In the young adult cynomolgus monkey study, nedosiran was tested at one dose level of 300 mg/kg once every 4 weeks for 9 months.”

“In a pre- and postnatal study in mice, subcutaneous administration of nedosiran (0, 250, 500, or 1000 mg/kg/dose) or a mouse-specific (pharmacologically active) analog (10 mg/kg/dose) from implantation to weaning did not have adverse effects on the growth, viability, development, and reproductive performance of the offspring.”

“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”

“002-TOX-2008 was a 9-month toxicity study of GRN163L in Cynomolgus Monkeys followed by a 14- week recovery period.”

“No PPND study has been submitted. This was considered acceptable based on the proposed indication which is primarily relevant for older people and that imetelstat has little or no oral bioavailability thereby removing the likelihood of postnatal exposure via lactation.”

“To address the carcinogenicity risk assessment of imetelstat, there will be separate Post Marketing Requirements (PMRs) for carcinogenicity assessments in the mouse and rat species.”

“ISIS 396443: A one year (53 weeks) repeat dose toxicity study in juvenile cynomolgus monkeys with a 26-week recovery phase”

“A pre- and postnatal development study is ongoing; submission of the study should be a post-marketing requirement.”

“the sponsor should conduct a 2-year carcinogenicity study as a post￾marketing requirement.”

“A 39-Week Repeat Subcutaneous Dose Toxicity Study of ISIS 420915 in Cynomolgus Monkeys with a 26-Week Interim Necropsy and a 26-Week Recovery”

“The reproductive and developmental toxicity of inotersen was assessed in a fertility and embryofetal development study in mouse, an embryofetal development study in rabbit, and a pre- and postnatal development study in mouse.”

“No carcinogenic potential was identified in a short-term carcinogenicity study in transgenic rasH2 mice. A 2 year carcinogenicity study in rats is currently ongoing and results will be submitted post approval.”

“In a 39-week monkey toxicity study that included a 26-week recovery period, olezarsen induced a marked reduction in platelet count (>98% decrease)”

“Studies evaluating embryofetal development and pre-/postnatal development were not conducted with olezarsen as there were no effects on parameters evaluated in these studies conducted with the unconjugated ASO volanesorsen.”

“they determined that no additional carcinogenicity studies were required for olezarsen, and that the data from volanesorsen’s carcinogenicity studies were sufficient to support olezarsen.”

“Monkey: Viltolarsen was administered by IV injection for 12 weeks (+4-week recovery) and 39 weeks (+8-week recovery)”

“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”

“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”

“No intact fomivirsen was observed in any of tissues (kidney, liver, ovary, and uterus) following 1, 3, or 8 doses of 10 uM (115 ug) fomivirsen administered every-other-week for three months.”

“fomivirsen is indicated for the local treatment of CMV retinitis in AIDS patients and the dosing schedule stated in the labeling?, the review division would accept the request from the sponsor for a waiver of carcinogenicity studies on fomivirsen.”

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

“No developmental and reproductive toxicity studies were conducted with golodirsen because the patient population is almost entirely male.”

“If the NDA is approved, carcinogenicity studies in two species (26-week in transgenic mouse, 2-year in rat) are to be conducted post-approval, as previously agreed to by the division.”

“Study 682884-AS05, 9-Month Repeat Dose Toxicity Study of ION-682884 in Cynomolgus Monkeys With a 3-Month Recovery Phase (GLP)”

“As eplontersen harbours the identical sequence of inotersen, which had been also tested with respect to embryo-foetal development in rabbits and in a pre-/postnatal development study in mice (see EPAR of “Tegsedi”, the previous CHMP advice is confirmed that further reproduction and developmental toxicity studies are not required for eplontersen.”

“The carcinogenic potential of eplontersen has not been assessed. A 26-week carcinogenicity study in the tg.ratH2 mouse will be a post-marketing requirement.”

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

“An assessment of pre- and postnatal toxicity was performed using subcutaneous administration of volanesorsen or the murine-specific apoC-III inhibitor (ISIS 440670) on alternate days to pregnant female mice at doses up to 87.5 mg/kg/wk from Day 6 of gestation to Day 21 postpartum.”

“Two-year carcinogenicity studies were conducted in mice and rats. Test article-related neoplastic findings were above the historical control ranges, and it is likely that the neoplasms are secondary to chronic inflammation.”