Which nonclinical studies did approved oligonucleotides skip?

“Casimersen was tested in a standard battery of in vitro (bacterial reverse mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) genetic toxicology assays. The studies were adequately conducted and negative.”

“Carcinogenicity assessments are deferred to post-marketing for the DMD indication.”

“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval”

“A standard battery of genetic toxicology assays was conducted for vutrisiran (in vitro bacterial mutagenicity, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo rat (bone marrow) micronucleus assay. All assays were adequate and negative.”

“Per prior agreement, 2-year carcinogenicity studies of vutrisiran in rat and mouse are to be conducted as post-marketing requirements.”

“The LD was the NOAEL for maternal and developmental toxicity.”

“Donidalorsen was evaluated for genotoxicity potential both in vitro and in vivo.”

“its tumorigenic potential has been evaluated in a 27-week carcinogenicity study in Tg.rasH2 mice, and a 2-yr carcinogenicity study in Sprague Dawley (SD) rats, which is ongoing”

“Reproductive and developmental toxicity studies were conducted in one species only, namely CD-1 mice”

“Eteplirsen was negative in a standard battery of genetic toxicology (Ames, in vitro chromosomal aberration in CHO, in vivo mouse micronucleus) assays.”

“Carcinogenicity studies have not been conducted for eteplirsen. As agreed to by the division, carcinogenicity studies in two species would be conducted post approval as PMRs.”

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

“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”

“A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.”

“Givosiran showed marked maternal toxicity in rabbits (including mean maternal body weight loss) and resulted in increased post-implantation loss as a result of increased early resorptions and a low incidence of skeletal variations.”

“Avacincaptad pegol was negative for genotoxicity based on a standard battery of studies including the bacterial reverse mutation assay, chromosomal aberration in mammalian cells and in vivo mouse bone marrow micronucleus assays.”

“Carcinogenicity No studies were conducted. The Applicant submitted a justification to support a waiver request not to conduct the carcinogenicity studies”

“In the embryofetal development (EFD) toxicity studies in rats and rabbits, there was no avacincaptad pegol-related adverse effects on any measured maternal or fetal parameter at doses up to 1.2 mg/kg/day (NOAEL).”

“Mipomersen sodium did not exhibit genotoxic potential in a battery of studies, including the in vitro Bacterial Reverse Mutation (Ames) assay, an in vitro cytogenetics assay using a mouse lymphoma cell line, and an in vivo micronucleus assay in mice.”

“The Committee concluded that hepatocellular adenomas and combined hepatocellular adenomas or carcinomas were drug-related in female mice administered 60 mg/kg/week mipomersen.”

“Mipomersen was not teratogenic in mice or rabbits at doses providing modest margins of exposure (2 to 5 times) compared to humans.”

“Inclisiran was negative in an adequate panel of mutagenicity assays.”

“Inclisiran lacked tumorigenic potential in these studies.”

“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).”

“Therefore, the carcinogenicity potential for pegaptanib sodium is considered low, based on the negative in vitro and in vivo genotoxicity assays for pegaptanib sodium and its component modified nucleotides.”

“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.”

“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.”

“It can be concluded that patisiran-LNP was not genotoxic in either the in vitro or in vivo assays.”

“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study.”

“No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”

“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”

“Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”

“Reproductive toxicology studies did not reveal any serious fertility or teratogenic effects of lumasiran.”

“Tofersen was negative in a complete battery of genetic toxicology studies.”

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

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

“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies”

“In a 2-year carcinogenicity study in Sprague Dawley rats, fitusiran was not carcinogenic up to the highest dose tested”

“Fitusiran was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”

“Plozasiran was not genotoxic when tested in the in vitro bacterial mutation (Ames) assay, in vitro chromosomal aberration assay in cultured TK6 lymphoblastoid cells, and in vivo micronucleus assay in mice.”

“In the 26-week study in Tg.rasH2 mice, administration of plozasiran by the SC route Q8W up to 120 mg/kg (~50-fold clinical dose, based on AUC) did not increase the incidence of tumors in male or female mice.”

“The NOAEL for male and female fertility was 50 mg/kg (19-fold the human dose, based on BSA).”

“Nedosiran was negative in the bacterial reverse mutation assay and did not induce micronuclei in mammalian cells in vitro or in vivo (Table 48).”

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

“Higher postimplantation loss and lower numbers of live fetuses were observed at doses of ≥6 mg/kg/dose (0.7x the MRHD, based on body surface area), and fetal cardiovascular and skeletal malformations were observed at a dose of 20 mg/kg/dose (2x the MRHD).”

“In genetic toxicity studies, imetelstat was not mutagenic in the in vitro bacterial reverse mutation assay.”

“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.”

“Increased rates of post-implantation loss and early resorptions that resulted in a decreased number of viable fetuses and litter size per animal, and decreased uterine weight were observed at”

“ISIS 396443 was negative in an adequately conducted standard battery of in vitro (Ames and chromosomal aberration in CHO) and in vivo (mouse micronucleus) assays.”

“Carcinogenicity studies have not been conducted with nusinersen at this time. The Division has recommended that a carcinogenicity study be conducted after approval.”

“No clear evidence of reproductive or developmental toxicity was seen in mouse and rabbit studies, and ISIS 396443 was negative for genotoxicity in a standard battery of in vitro and in vivo assays.”

“Inotersen was negative in an adequate standard battery of in vitro (Ames, chromosomal aberration in Chinese hamster lung cells) and in vivo (CD-1 mouse micronucleus at single doses up to 2000 mg/kg SC) assays.”

“In transgenic (TgRasH2) mice, subcutaneous administration of inotersen (0, 10, 30, or 80 mg/kg) or a species-specific surrogate (ISIS 401724; 30 mg/kg) weekly for 26 weeks resulted in no drug-related increase in tumors.”

“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”

“Olezarsen was not mutagenic in vitro or in vivo.”

“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”

“The Agency agreed that embryofetal development and pre-/postnatal development evaluations conducted with the unconjugated active ASO component of olezarsen in mice and/or rabbits were adequate to support a marketing application.”

“Viltolarsen was negative in a standard battery of in vitro (Ames, chromosomal aberration in CHL cells) and in vivo (mouse micronucleus) assays.”

“Carcinogenicity studies of viltolarsen were not submitted to the NDA, as agreed to by the Division.”

“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.”

“Golodirsen was negative in an adequately conducted standard battery of in vitro (Ames, chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”

“No carcinogenicity studies have been conducted. The sponsor has conducted dose-ranging (DR) studies (reviewed below) to support planned carcinogenicity studies.”

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

“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.”

“Taking into account the lack of a genotoxic effect of volanesorsen”

“The carcinogenic potential of volanesorsen was assessed in 2-yr repeated dose studies in mice (Study No. 304801-AS15) and rats (Study No. 304801-AS16).”

“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”

“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”

“No new studies were provided. The Division agreed these studies can be completed as post-marketing requirements (PMRs) given the benefit:risk and unmet medical need.”

“No adverse fertility or embryofetal developmental effects were observed in mouse administered zilganersen subcutaneously at doses of 0, 10, 30, or 60 mg/kg once every 2 weeks.”