What flexibility did FDA and EMA accept for approved oligonucleotides?

“Carcinogenicity 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.”

“An embryofetal development study in rabbit will be needed but may be conducted as a postmarketing requirement.”

“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, due to unexplained deaths in female mice in the 9- week ICV toxicity study.”

“5053-5: Conduct a 13-week intrathecal toxicity study for detected leachables with local CNS toxicity concerns including butylated hydroxytoluene (BHT) (0.65 µg/day), boron (6.6 µg/day),”

“The Applicant previously sought CHMP Scientific Advice on the necessity for studies in rabbits and it was agreed that studies may not be required on the basis that neither donidalorsen nor the unconjugated PS-only compound, ISIS 546254, were pharmacologically active in the rabbit.”

“At the pre-NDA meeting, the Division agreed that it would be acceptable to submit the report of the 6-month carcinogenicity study in Tg.rasH2 mice and a summary of the in-life data for the 2-year carcinogenicity study in rats at the time of the NDA submission and to submit the final report as a PMR (Refer to IND 142564 pre-NDA Meeting Preliminary Comments dated 04/10/2024).”

“While this may provide an explanation for the observations, there was an absence of plasma exposure data in this study to allow a direct derivation of safety to the clinical exposure.”

“No AUC data was available for the juvenile mouse study. The lack of AUC data from the juvenile mouse study prevents a quantitative assessment of potential increased sensitivity in younger subjects.”

“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.”

“Because the patient population is primarily male, standard reproductive and developmental studies were not required. To assess male fertility, the sponsor conducted a histopathological evaluation of male reproductive organs in the pivotal toxicity studies,”

“For mdx mouse, the pharmacological activity of the human product cannot be tested because of differences in the dystrophin gene mutation, requiring use of a mouse-specific PMO, exon 23 skipping AON and, therefore, resulting in a different truncated dystrophin.”

“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.”

“A less-than standard battery of nonclinical studies (no chronic toxicity study in rodent [to assess systemic exposure], pre- and postnatal development (PPND) study in rodent, or carcinogenicity studies in mouse and rat) was conducted to support approval of nusinersen.”

“Carcinogenicity studies were not conducted. The sponsor has requested a waiver based on the infeasibility of conducting lifetime studies in rodents by the IT route, but given the significant systemic exposure documented in clinical studies, it is recommended that a parenteral study in one species be conducted postmarketing.”

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

“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 ocular studies were conducted in rabbit and dogs, which, as the Applicant indicated, are species in which ARC1905 is expected to have very low activity.”

“The Applicant justification to omit the conduct of nonclinical carcinogenicity studies is based on avacincaptad pegol mechanism of action, route of administration, a supportive literature review, an analysis of pharmacological class effects, and nonclinical and clinical data collected to date.”

“Nonclinical recommendations for (1) submission for a waiver request for FEED (fertility and early embryonic developmental) and PPND (pre-and postnatal developmental), along with the justification and supporting data, (2) conduct of embryofetal development studies in relevant species”

“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.”

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

“At the recommended human dose of 30 mg/kg, plasma exposure (AUC of ∼90 µg*hr/mL) is only 2.6-fold lower than that at the no-adverse-effect-level in the most sensitive species (juvenile rat).”

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

“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.”

“In conclusion, based on the available data from volanesorsen, no additional juvenile toxicity studies for olezarsen are warranted at this time.”

“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.”

“Based on the negative outcome of this investigation in Tg.rasH2 mice, the lack of genotoxicity, immunosuppressive or proliferative findings in other toxicity studies, as well as the similarity of eplontersen and inotersen, which was not carcinogenic in rats, the lack of a 2 years rat carcinogenicity study is acceptable”

“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.”

“Carcinogenicity studies were not submitted in the NDA but are to be conducted post-approval (as PMRs), as agreed to by the division (DN1), if vutrisiran is approved.”

“Target-mediated effects on reproductive function and development were not evaluated in rat or rabbit because of the lack of sequence homology;”

“Species-specific differences in the nucleotide sequence of apoB mRNA caused a reduction (monkey) or complete loss (mouse, rat, dog and rabbit) of the intended pharmacological activity of mipomersen in these species.”

“The CHMP noted that monkeys instead of dogs were used in the cardiovascular safety study. However, taking into account the suitability of the monkey model showed for the preclinical development it is considered acceptable.”

“In accordance with EMA advice, a juvenile toxicology study was not conducted since it was unlikely to generate additional information from what is already available [CHMP Scientific Advice 2017]”

“The limit for the single largest individual unspecified impurity of % exceeds the ICH Q3A threshold of 0.2% based on a 300 mg dose.”

“Reproductive toxicology studies are typically not conducted for the DMD indication. Therefore, detailed examination of male reproductive organs and sperm evaluations were conducted as part of the chronic toxicity studies.”

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

“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.”

“With respect to intraocular toxicity, the safety margins are 2-3 fold. However, taking into account the larger human eye as compared to dogs and rabbits, the ratio to clinical local exposure is further increased and thus considered acceptable.”

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

“Considering that tofersen is not pharmacologically active in mice and rabbits, these studies do not provide data regarding the pharmacological activity of tofersen in terms of its potential effects on reproduction or development. This limits the predictive value of these studies in terms of human safety.”

“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.”

“The antisense strand of plozasiran is fully complementary to monkey and human ApoC-III mRNAs, whereas plozasiran has seven sequence mismatches to the rodent ApoC-III mRNA transcript. Moderate pharmacodynamic activity was observed in rats only at toxic doses; however, the lack of full rat mRNA sequence homology makes this species suitable only for assessing off-target toxicity.”

“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.”

“Not performed, given the physiochemical property of lumasiran and targeted liver delivery, this was determined to be acceptable.”

“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.”

“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.”

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

“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”

“Dedicated studies were not conducted in juvenile animals. In the chronic monkey GLP toxicology study, givosiran was administered once weekly at dose levels between 10 and 100 mg/kg for 39 weeks, followed by a 13-week recovery phase.”

“A 2-year carcinogenicity study in rat has not been submitted. A study protocol was submitted on October 27, 2015, for Special Protocol Assessment and was reviewed by the division and the Executive CAC committee (Minutes dated December 2, 2015).”

“A waiver from performing carcinogenicity studies was requested by the sponsor. The sponsor stated that "lack of meaningful systemic exposure, additional systemic toxicity studies are neither relevant nor useful for assessing the safety profile of this compound".”

“However, given the high mortality due to toxicity of volanesorsen, the value of these studies is limited.”