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.”
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.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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.”