Tegsedi
inotersen
Species
MonkeyRatMouse
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, rat and cynomolgus monkey; monkey the only pharmacologically relevant species
“Inotersen is pharmacologically active in cynomolgus monkey but not rodent or rabbit.”
Why that species
Target sequence conserved in monkey; 8 mismatches in rodents and 4 in rabbit
“The target sequence of inotersen is conserved between monkeys and humans, but contains 8 mismatches in rodents and 4 mismatches in rabbits.”
Surrogate molecule
Yes: mouse (ISIS 401724) and rat (ISIS 594799) TTR-specific surrogate ASOs in tox, repro and carcinogenicity studies
“For this reason, mouse- and rat-specific analogues of inotersen were included in the toxicology evaluations in order to distinguish toxicity associated with reduction of the target (TTR) from toxicities related to the chemistry of the oligonucleotide”
Species: general tox
Mouse, rat (up to 26 weeks) and cynomolgus monkey (up to 39 weeks)
“The toxicity of repeated s.c. injections of inotersen was investigated for up to 26 weeks in mice and rats and for up to 39 weeks in monkeys using comparable drug substance as tested in the clinical program.”
Species: DART
Mouse (CD-1) and rabbit (New Zealand White)
“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”
Species: carcinogenicity
Transgenic rasH2 mouse (short-term); 2-year rat study ongoing, results post approval
“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.”
Surrogate used in
Yes: mouse- and rat-specific inotersen analogues included in the toxicology evaluations
“For this reason, mouse- and rat-specific analogues of inotersen were included in the toxicology evaluations in order to distinguish toxicity associated with reduction of the target (TTR) from toxicities related to the chemistry of the oligonucleotide”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“In the 39-week study, inotersen was administered at doses of 0, 3, 6, 10, and 20 mg/kg once weekly.”
Pivotal GLP studies
SC: mouse 13- and 26-week; rat 26-week; cynomolgus monkey 13-week and 39-week, with recovery
“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).”
Route in tox
Subcutaneous (clinical route) in all species
“In all species, inotersen was administered by subcutaneous injection.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
“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.”
Carcinogenicity
26-week rasH2 mouse (inotersen + surrogate) negative; 2-year rat study as postmarketing requirement
“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.”
Reproductive & developmental
Full battery in mouse (FEED/EFD, PPND, with surrogate) and rabbit EFD; only reduced fetal weight at rabbit high dose
“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”
Safety pharmacology
Standalone core battery: mouse CNS, telemetered monkey CV/respiratory, hERG; no adverse effects
“No adverse effects of inotersen were observed on a core battery of safety pharmacology parameters in CNS in CD-1 mouse (CNS) or cynomolgus monkey (cardiovascular and respiratory) following acute SC doses of up to 300 or 40 mg/kg, respectively.”
Genotox: Ames
Negative (Ames)
“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.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster lung cells: negative
“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.”
Genotox: in vivo
CD-1 mouse micronucleus (single SC doses up to 2000 mg/kg): negative
“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.”
Carcinogenicity model
26-week TgRasH2 mouse with inotersen and mouse surrogate ISIS 401724: no drug-related tumors
“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.”
Carcinogenicity timing
rasH2 mouse study completed; 2-year rat study ongoing at approval, results submitted post approval
“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.”
hERG / QT
No hERG inhibition up to 300 µM; no CV/respiratory effects in telemetered monkeys up to 40 mg/kg SC
“In safety pharmacology studies, inotersen did not inhibit hERG currents in vitro up to 300 µM and did not affect cardiovascular or respiratory function of telemetered monkeys following s.c. injections up to 40 mg/kg.”
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 Tegsedi 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 39-wk NOAEL 6 mg/kg/wk (severe thrombocytopenia); rat NOAEL 5 mg/kg (glomerulopathy); margins <=~2-fold (FDA pharmacology/toxicology review, p. 70)
NOAEL / key findings
Monkey 39-wk NOAEL 6 mg/kg/wk (severe thrombocytopenia); rat NOAEL 5 mg/kg (glomerulopathy); margins <=~2-fold
“The NOAEL was 6 mg/kg/week, based on the severe thrombocytopenia observed at 10 and 20 mg/kg/week.”
Risksopen answer page →
Immune & cytokine safety
Monkey perivascular inflammation with ADA, CRP, IL-6, TNFa, IgG/IgM rises; complement Bb activation; ADA in some monkeys
“In the same study, five other animals across the three lowest dose groups showed perivascular mixed cell infiltration in multiple organs, associated with increases in anti-drug antibody, CRP, IL-6, MIP-1β, TNFα, and serum IgG and IgM”
Biodistribution & persistence
Rapid plasma-to-tissue distribution; high levels in kidney, liver, lymph nodes, injection site, bone marrow
“High concentrations of inotersen were detected in kidneys, liver, mesenteric lymph nodes, injection site and bone marrow.”
Modality-specific risk
Thrombocytopenia (monkey, clinically translated) and renal glomerular toxicity; PS-ASO class pro-inflammatory effects
“In the 39-week monkey study, severe thrombocytopenia associated with petechiae, bruising, and internal hemorrhages was observed within the first 11-14 weeks of dosing in two animals (one in each of the two highest dose groups), necessitating early euthanasia.”
Anti-drug antibodies: animals
ADA in some monkeys of the 39-week study; median trough levels ~2- to 12-fold higher than ADA-negative animals
“However, anti-inotersen antibodies (ADAs) developed in some monkeys of the 39 weeks toxicity study, which increased the median plasma trough concentrations of inotersen at approximately 3 months or beyond from ~2- to 12-fold compared to those monkeys that did not develop antibodies (see section 3.2.3 below).”
Anti-drug antibodies: patients
30.4% (34 of 112 patients in study CS2)
“In study CS2 34 out of 112 patients (30.4%) developed anti-drug antibodies following chronic treatment with inotersen.”
Label warnings
Boxed warning: Thrombocytopenia and glomerulonephritis
- Thrombocytopenia
- Glomerulonephritis and Renal Toxicity
- TEGSEDI REMS Program
- Stroke and Cervicocephalic Arterial Dissection
- Inflammatory and Immune Effects
- Liver Injury
- Hypersensitivity Reactions/Antibody Formation
- Uninterpretable Platelet Counts: Reaction between Antiplatelet Antibodies and ethylenediaminetetra-acetic acid (EDTA)
- Reduced Serum Vitamin A Levels and Recommended Supplementation
NephrotoxicityThrombocytopeniaCardiovascularImmune-mediated reactionsHepatotoxicityHypersensitivity & infusion reactionsMetabolic & endocrine
US prescribing information, Boxed Warning and 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 Tegsedi 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 39-wk NOAEL 6 mg/kg/wk (severe thrombocytopenia); rat NOAEL 5 mg/kg (glomerulopathy); margins <=~2-fold (FDA pharmacology/toxicology review, p. 70)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (SC) with 26-week recovery
“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”
Pivotal GLP studies
SC: mouse 13- and 26-week; rat 26-week; cynomolgus monkey 13-week and 39-week, with recovery
“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).”
DART package
Species: DART
Mouse (CD-1) and rabbit (New Zealand White)
“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”
Reproductive & developmental
Full battery in mouse (FEED/EFD, PPND, with surrogate) and rabbit EFD; only reduced fetal weight at rabbit high dose
“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”
PPND / ePPND: when
PPND in mouse completed before the marketing application
“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.”
Carcinogenicity
Species: carcinogenicity
Transgenic rasH2 mouse (short-term); 2-year rat study ongoing, results post approval
“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.”
Carcinogenicity model
26-week TgRasH2 mouse with inotersen and mouse surrogate ISIS 401724: no drug-related tumors
“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.”
Carcinogenicity timing
rasH2 mouse study completed; 2-year rat study ongoing at approval, results submitted post approval
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
AUC margins at NOAELs for monkey thrombocytopenia and rat kidney toxicity ≤ ~2-fold
“Safety margins based on AUCs at the no observed adverse effect levels (NOAELs) for severe thrombocytopenia in monkeys and kidney toxicity in rats were ≤ ~2-fold.”
NOAEL / key findings
Monkey 39-wk NOAEL 6 mg/kg/wk (severe thrombocytopenia); rat NOAEL 5 mg/kg (glomerulopathy); margins <=~2-fold
“The NOAEL was 6 mg/kg/week, based on the severe thrombocytopenia observed at 10 and 20 mg/kg/week.”
Efficacy evidenceopen answer page →
Efficacy evidence
Transgenic mouse expressing human TTR Ile84Ser mutation and cynomolgus monkey (TTR mRNA/protein lowering)
“In vitro (human and monkey hepatocytes) and in vivo (monkey and transgenic mouse expressing the human TTR Ile84Ser mutation) studies documented decreases in TTR mRNA and protein levels following repeat-dose subcutaneous (SC) administration of inotersen.”
Why that model
Target sequence conserved in monkey; 8 mismatches in rodents and 4 in rabbits
“The target sequence of inotersen is conserved between monkeys and humans, but contains 8 mismatches in rodents and 4 mismatches in rabbits.”
Reviewer's view of the efficacy data
EMA: proof of concept adequately demonstrated in human/monkey hepatic cells, monkeys and mutant human TTR transgenic mice
““Proof-of-concept” of the pharmacodynamic activity of inotersen was adequately demonstrated by the inhibition of TTR mRNA translation in hepatic cells of humans and monkeys in vitro as well as in monkeys and in transgenic mice overexpressing a mutated human TTR variant in vivo.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
2-year rat carcinogenicity study not submitted before approval; required post-marketing
“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).”
“The nonclinical data submitted for inotersen are adequate to support approval of the NDA, with a PMR for a 2-year carcinogenicity study in rat.”
Safety marginVerdict not stated
NOAEL AUC margins for severe thrombocytopenia (monkey) and kidney toxicity (rat) about 2-fold or less
“Safety margins based on AUCs at the no observed adverse effect levels (NOAELs) for severe thrombocytopenia in monkeys and kidney toxicity in rats were ≤ ~2-fold.”
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