Waylivra
volanesorsen
Sources:EMA assessment report ↗
Species
MonkeyRatMouseRabbit
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 (rabbit for embryo-fetal); monkey most relevant
“Monkey is considered the most relevant species to humans based on the general pharmacokinetic behavior of 2’-MOE ASOs (plasma AUC, Cmax, and clearance).”
Why that species
Monkey shares the ASO binding site (100% homology with human); rodents lack sequence homology so species-specific ASOs were used
“While monkeys share the same sequence at this site, due to a lack of sequence homology in other species, different 2′-MOE ASOs”
Surrogate molecule
Yes: species-specific murine 2'-MOE apoC-III ASO (ISIS 440670) used in mouse pharmacology and reproductive studies alongside volanesorsen
“Because of the divergence between the mouse, hamster and human apoC-III sequences, species-specific ASOs were employed in their respective in vivo evaluations.”
Species: general tox
Mouse, rat and monkey
“Formal studies evaluating local tolerance were not conducted however the injection sites were evaluated as part of the repeat-dose studies in mice, rats and monkeys which did not reveal any evidence of substantive irritation.”
Species: DART
Mouse (fertility/EFD and pre/postnatal, Segment I/II/III) and rabbit (EFD, Segment II)
“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”
Species: carcinogenicity
Mouse and rat (2-year)
“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).”
Surrogate used in
Yes: murine-specific apoC-III ASO (ISIS 440670) alongside volanesorsen in the mouse pre/postnatal study
“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.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Cynomolgus monkey: 7 or 9/s/g 0-3-6-12-20 39 wk 3”
Pivotal GLP studies
GLP SC repeat-dose: monkey 13- and 39-week, rat 26-week, mouse 13- and 26-week studies; 2-year mouse and rat carcinogenicity
“Volanesorsen plasma PK following SC administration in male and female monkeys were further studied in the 39-week toxicity study (study 304801-AS11).”
Route in tox
SC (IV loading doses in the 13-week monkey study)
“0-4-8-12-40 (loading IV, subsequent SC, SC only @40)”
Skipped studiesopen answer page →
Genotoxicity
Conducted: bacterial reverse mutation, mouse lymphoma TK, mouse bone-marrow micronucleus; all negative
“Taking into account the lack of a genotoxic effect of volanesorsen”
Carcinogenicity
Conducted: 2-year SC studies in mouse and rat; tumours above historical controls, considered secondary to chronic inflammation
“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 & developmental
Conducted: mouse fertility/EFD (Seg I/II) and peri-postnatal, rabbit EFD (Seg II); no untoward effects attributed to apoC-III reduction
“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”
Safety pharmacology
Dedicated: hERG assay, monkey ECG/BP (IV and SC), mouse Irwin CNS and respiratory studies; no relevant effects at tested doses
“There was no significant inhibition of the hERG current by ISIS 304801 at the concentrations tested (89.5 and 251 µM) and therefore an IC50 value could not be determined.”
Genotox: Ames
Negative (Salmonella)
“304801-IS02/Gene mutations in bacteria/GLP Salmonella strains 1.5-5000µg/plate, - S9 Negative”
Genotox: in vitro mammalian
Mouse lymphoma L5178Y/TK+/- assay: negative
“L5178Y/TK+/- 100-500µg/ml +/- S9 Negative”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Mouse, micronuclei in bone marrow 1000-2000 mg/kg Negative”
Carcinogenicity model
2-year mouse and rat
“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).”
Carcinogenicity timing
2-year mouse and rat studies completed before the marketing application
“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.”
hERG / QT
Negative: no significant hERG inhibition at 89.5 and 251 µM (IC50 not determinable)
“There was no significant inhibition of the hERG current by ISIS 304801 at the concentrations tested (89.5 and 251 µM) and therefore an IC50 value could not be determined.”
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 Waylivra 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-week NOAEL 3 mg/kg (per EMA table); thrombocytopenia, kidney/liver basophilic granules, inflammatory cytokines, injection-site findings (EMA assessment report, p. 35)
NOAEL / key findings
Monkey 39-week NOAEL 3 mg/kg (per EMA table); thrombocytopenia, kidney/liver basophilic granules, inflammatory cytokines, injection-site findings
“Cynomolgus monkey: 7 or 9/s/g 0-3-6-12-20 39 wk 3”
Risksopen answer page →
Immune & cytokine safety
Complement activation in monkeys (class effect, species-specific); cytokine/chemokine increases (MCP-1, MIP-1b); anti-volanesorsen antibodies in 50-72% of monkeys
“Complement activation is seen in monkeys, a known effect of antisense oligonucleotides and considered species specific.”
Biodistribution & persistence
Liver and kidney accumulation, tissue concentrations hundreds-thousands-fold above plasma; tissue t1/2 12.5-32 days
“For all evaluated dose levels, volanesorsen concentrations 48 hours after the last dose (Day 93) were several hundred-to several thousand-fold higher in kidney cortex and liver than in plasma.”
Modality-specific risk
Thrombocytopenia (platelet reduction in all species), ASO class effects in liver, kidney, lymph nodes, skin; complement activation
“The main hazard identified in animals is a reduction in platelet count leading to thrombocytopenia, which has also been observed in humans in the clinical trials.”
Anti-drug antibodies: animals
Monkeys: ADA increased median plasma trough concentrations ~1.2- to 14-fold from ~3 months of dosing
“The presence of anti-volanesorsen antibodies resulted in an increase in the median plasma trough concentrations of approximately 1.2- to 14-fold in the samples collected approximately 3 months or later after initiation of dosing in all dose groups.”
Anti-drug antibodies: patients
30% in FCS patients (CS6); 16% to 40% in other studies
“Antibodies to volanesorsen were formed in 30% of the patients with familial chylomicronemia syndrome treated with volanesorsen (study CS6). In the other studies, the formation of anti-drug antibodies ranged from 16% to 40% (studies CS2, CS4, and CS16).”
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 Waylivra 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-week NOAEL 3 mg/kg (per EMA table); thrombocytopenia, kidney/liver basophilic granules, inflammatory cytokines, injection-site findings (EMA assessment report, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (SC); recovery duration not stated
“Volanesorsen plasma PK following SC administration in male and female monkeys were further studied in the 39-week toxicity study (study 304801-AS11).”
Pivotal GLP studies
GLP SC repeat-dose: monkey 13- and 39-week, rat 26-week, mouse 13- and 26-week studies; 2-year mouse and rat carcinogenicity
“Volanesorsen plasma PK following SC administration in male and female monkeys were further studied in the 39-week toxicity study (study 304801-AS11).”
DART package
Species: DART
Mouse (fertility/EFD and pre/postnatal, Segment I/II/III) and rabbit (EFD, Segment II)
“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”
Reproductive & developmental
Conducted: mouse fertility/EFD (Seg I/II) and peri-postnatal, rabbit EFD (Seg II); no untoward effects attributed to apoC-III reduction
“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”
PPND / ePPND: when
PPND in mouse (volanesorsen and murine apoC-III surrogate) completed before the marketing application
“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.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (2-year)
“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).”
Carcinogenicity model
2-year mouse and rat
“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).”
Carcinogenicity timing
2-year mouse and rat studies completed before the marketing application
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
Monkey 39-week NOAEL 3 mg/kg (per EMA table); thrombocytopenia, kidney/liver basophilic granules, inflammatory cytokines, injection-site findings
“Cynomolgus monkey: 7 or 9/s/g 0-3-6-12-20 39 wk 3”
Efficacy evidenceopen answer page →
Efficacy evidence
Fructose-fed hypertriglyceridemic rhesus monkeys dosed with volanesorsen (binding site 100% homologous)
“Because the binding site for volanesorsen is 100% homologous between rhesus monkey and human apoC-III mRNAs and lipid metabolism in nonhuman primates resembles that observed in humans, the effects of volanesorsen in rhesus monkeys that were made hypertriglyceridemic via administration of a high-fructose supplement were evaluated.”
Why that model
Mouse and hamster apoC-III sequences diverge from human, so species-specific ASOs were used in rodent models
“Because of the divergence between the mouse, hamster and human apoC-III sequences, species-specific ASOs were employed in their respective in vivo evaluations.”
Reviewer's view of the efficacy data
EMA: monkey PD study supportive of therapeutic benefit at the 300 mg dose and at reduced doses
“The PD study conducted in the monkey is supportive for a potential therapeutic benefit at 300 mg/kg as well as at a reduced dose level in case of thrombocytopenia.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityCriticised but acceptedBeyond the letter
Mouse and rat carcinogenicity studies of limited value: high toxicity-related mortality and early termination of study groups
Why: No genotoxicity; tumours most likely secondary to chronic inflammation · Weight of evidence
“However, given the high mortality due to toxicity of volanesorsen, the value of these studies is limited.”
“Taking into account the lack of a genotoxic effect of volanesorsen and the likelihood that most tumours were secondary to chronic inflammation, volanesorsen has little carcinogenic risk for patients, despite the early termination of study groups in the mouse and rat study.”
DARTVerdict not stated
Mouse pre/postnatal study run with both volanesorsen and a murine-specific apoC-III ASO surrogate (ISIS 440670)
“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.”
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