Wainua
eplontersen
Species
MonkeyMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and cynomolgus monkey (monkey the pharmacologically relevant species)
“Eplontersen is pharmacologically active in monkey but not mouse.”
Why that species
Target sequence 100% complementary to human and monkey TTR mRNA; 8 mismatches in rodents
“The target sequence of eplontersen and inotersen is 100 % complementary to human and Cynomolgus monkey TTR mRNA, whereas 8 mismatches in mice and rats preclude effective hybridisation and, hence, pharmacological activity in these animals.”
Surrogate molecule
Yes: mouse-specific GalNAc ASO ION-1184986 in 26-week mouse and fertility/EFD studies
“A parallel group administered 10 mg/kg SC ION-1184986, the mouse-specific ASO, showed reduction of ~82% in hepatic TTR mRNA, compared to controls; no adverse effects were observed.”
Species: general tox
Mouse and cynomolgus monkey
“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”
Species: DART
Mouse (combined fertility and EFD); no second-species EFD or PPND
“The potential for adverse effects on fertility and embryofetal development (EFD) was assessed in a combined fertility and EFD study in mouse”
Species: carcinogenicity
Tg.rasH2 mouse (26-week); no 2-year rat study
“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”
Surrogate used in
Yes: mouse-specific surrogate ASO ION-1184986 in chronic mouse toxicity and fertility/EFD studies
“Nevertheless, a mouse-specific TTR analogue ASO harbouring the same GalNAc conjugate and mixed phosphorothioate and phosphodiester backbone (ION-1184986) like eplontersen was included in the chronic repeat-dose toxicity as well as the combined fertility and embryonic development studies in mice”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“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.”
Pivotal GLP studies
GLP SC studies: mouse 13 and 26 weeks; cynomolgus monkey 13 weeks and 9 months (39 weeks)
“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”
Route in tox
Subcutaneous (weekly, biweekly, monthly regimens)
“The toxicity of eplontersen was investigated with different s.c. administration regimen (weekly, biweekly, monthly) for up to 26 weeks in mice, 14 weeks in rats and up to 39 weeks in monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, chromosomal aberration, mouse micronucleus)
“Eplontersen was negative in adequately conducted in vitro (Ames, chromosomal aberration) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity
26-week Tg.rasH2 mouse study (PMR at FDA approval); no increase in neoplasms
“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.”
Reproductive & developmental
Combined fertility/EFD study in mouse (with surrogate); no adverse effects; no 2nd species, PPND or juvenile
“Potential effect of eplontersen on embryo-foetal development in a second species, pre- and post-natal development or juvenile toxicity were not investigated.”
Safety pharmacology
Single ascending-dose SC study in monkeys (CNS, CV, respiratory) plus in vitro hERG; no effects
“Safety pharmacology studies did not indicate any adverse effects on CNS, cardiovascular, or respiratory endpoints in male cynomolgus monkeys administered a single ascending dose of eplontersen of up to 24 mg/kg by SC injection.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Eplontersen was negative in adequately conducted in vitro (Ames, chromosomal aberration) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster lung cells: negative
“Eplontersen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative (up to 2000 mg/kg SC)
“In vivo, two s.c. injections of up to 2000 mg/kg eplontersen did not induce micronuclei in the bone marrow of mice.”
Carcinogenicity model
26-week Tg.rasH2 mouse, SC up to 1500 mg/kg/month; not tumorigenic
“Eplontersen was not tumorigenic following s.c. injections up to 1500 mg/kg/month in a GLP-compliant 26 weeks carcinogenicity study in transgenic Tg.rasH2 mice.”
Carcinogenicity timing
26-week Tg.rasH2 mouse not assessed at the marketing application; postmarketing requirement
“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.”
hERG / QT
No hERG inhibition up to 300 µM
“Eplontersen concentrations up to 300 µM did not inhibit hERG-currents in vitro.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Wainua don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey NOAEL 25 mg/kg Q4W (39 wk; 134x AUC margin); basophilic granules liver/kidney/lymph nodes; one monkey thrombocytopenia (FDA integrated review, p. 50)
NOAEL / key findings
Monkey NOAEL 25 mg/kg Q4W (39 wk; 134x AUC margin); basophilic granules liver/kidney/lymph nodes; one monkey thrombocytopenia
“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.”
Risksopen answer page →
Immune & cytokine safety
Transient complement Bb increases; non-neutralising ADAs in chronic monkey study; minimal cytokine changes
“Thus, these ADAs represent binding antibodies without neutralising capacity.”
Biodistribution & persistence
Distributes mainly to liver and kidney; undetectable in brain and spinal cord (rat)
“In SD rats administered [3H]ASO-eplontersen, radioactivity levels peaked in plasma at 0.5 h postdose, then distributed into tissues, primarily liver and kidney, with the highest levels observed in the liver at 8 h and kidney at 2 days; radioactivity was undetectable in brain and spinal cord.”
Modality-specific risk
ASO class risks: thrombocytopenia, glomerulonephritis, renal/liver effects (from inotersen); vitamin A deficiency from MoA
“Potential safety concerns for eplontersen based on the route of administration and therapeutic class (including information from the previously approved hATTR drug inotersen) were thrombocytopenia, glomerulonephritis, renal impairment, abnormal liver function, injection site reactions, flu-like symptoms, central nervous system disorders, hemorrhages, and coagulation abnormalities.”
Anti-drug antibodies: animals
ADAs in chronic monkey study: binding, non-neutralising; increased trough concentrations; no impact on efficacy or toxicity
“ADAs were confirmed in the chronic toxicity study in monkeys that were identified as binding antibodies without neutralising capacity. These ADAs increased median plasma trough concentrations of eplontersen”
Anti-drug antibodies: patients
37% (53/144) treatment-emergent ADAs; no effect on Cmax/AUC, increased Ctrough
“53 out of 144 (37%) patients developed treatment-emergent ADAs during treatment with WAINUA. The presence of ADAs did not affect eplontersen plasma C max or AUC, but increased C trough .”
Label warnings
- Reduced Serum Vitamin A Levels and Recommended Supplementation
Metabolic & endocrine
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Wainua don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey NOAEL 25 mg/kg Q4W (39 wk; 134x AUC margin); basophilic granules liver/kidney/lymph nodes; one monkey thrombocytopenia (FDA integrated review, p. 50)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey (SC) with 3-month recovery
“Study 682884-AS05, 9-Month Repeat Dose Toxicity Study of ION-682884 in Cynomolgus Monkeys With a 3-Month Recovery Phase (GLP)”
Pivotal GLP studies
GLP SC studies: mouse 13 and 26 weeks; cynomolgus monkey 13 weeks and 9 months (39 weeks)
“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”
DART package
Species: DART
Mouse (combined fertility and EFD); no second-species EFD or PPND
“The potential for adverse effects on fertility and embryofetal development (EFD) was assessed in a combined fertility and EFD study in mouse”
Reproductive & developmental
Combined fertility/EFD study in mouse (with surrogate); no adverse effects; no 2nd species, PPND or juvenile
“Potential effect of eplontersen on embryo-foetal development in a second species, pre- and post-natal development or juvenile toxicity were not investigated.”
PPND / ePPND: when
No PPND for eplontersen; not required because identical-sequence inotersen was tested in mouse PPND and rabbit EFD
“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
Species: carcinogenicity
Tg.rasH2 mouse (26-week); no 2-year rat study
“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”
Carcinogenicity model
26-week Tg.rasH2 mouse, SC up to 1500 mg/kg/month; not tumorigenic
“Eplontersen was not tumorigenic following s.c. injections up to 1500 mg/kg/month in a GLP-compliant 26 weeks carcinogenicity study in transgenic Tg.rasH2 mice.”
Carcinogenicity timing
26-week Tg.rasH2 mouse not assessed at the marketing application; postmarketing requirement
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 134x human AUC (112x Cmax) at 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.”
NOAEL / key findings
Monkey NOAEL 25 mg/kg Q4W (39 wk; 134x AUC margin); basophilic granules liver/kidney/lymph nodes; one monkey thrombocytopenia
“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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human mutant TTR (I84S) transgenic mice: hepatic hTTR mRNA and plasma TTR reduction
“The pharmacological in vivo activity of eplontersen was investigated in comparison to inotersen in transgenic mice overexpressing a mutant human TTR variant known to cause familial amyloid polyneuropathy in humans (hTTR I84S; Benson et al., 2006).”
Why that model
Sequence fully complementary to human and monkey TTR mRNA; 8 mismatches in mice and rats preclude activity
“The target sequence of eplontersen and inotersen is 100 % complementary to human and Cynomolgus monkey TTR mRNA, whereas 8 mismatches in mice and rats preclude effective hybridisation and, hence, pharmacological activity in these animals.”
Reviewer's view of the efficacy data
EMA: transgenic mice lack disease symptoms, so only hTTR suppression could be evaluated
“As these transgenic mice do not develop the cardiac, neuronal or renal symptoms of the human disease, only the suppression of hTTR mRNA translation could be evaluated.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Carcinogenic potential not assessed at FDA approval; 26-week Tg.rasH2 mouse study made a postmarketing requirement
“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.”
CarcinogenicityAcceptedBeyond the letter
No two-year rat carcinogenicity study; 26-week Tg.rasH2 mouse study plus data from same-sequence inotersen
Why: Negative Tg.rasH2 study, no genotoxic or proliferative findings, and inotersen (same sequence) not carcinogenic in rats · Class precedent · Weight of evidence
“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”
DARTAcceptedBeyond the letter
No rabbit embryo-fetal or pre/postnatal studies; combined mouse fertility/embryo-fetal study only, with inotersen data used instead
Why: Identical sequence to inotersen, which was tested in rabbit embryo-fetal and mouse pre/postnatal studies · Class precedent
“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.”
Similar precedents
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