Otarmeni
lunsotogene parvec
Species
MonkeyMouse
Longest study
27 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Conducted Stated
Speciesopen answer page →
Species
Mouse (Otof-Q828X hom disease model) and cynomolgus monkey
“Single-dose toxicology studies were conducted in Otof-Q828X hom mice and cynomolgus monkeys.”
Why that species
Otof-Q828X mice recapitulate human deafness phenotype; monkey inner ear anatomy similar to human, clinical surgical approach
“This study provides the most clinically relevant procedural safety data, as it utilized the same RWM surgical approach intended for clinical use and was performed in monkeys with inner ear anatomy similar to humans.”
Surrogate molecule
No surrogate; clinical-process DB-OTO (non-GMP lot B564TOXP1) used in all GLP studies
“The same non-GMP lot (B564TOXP1) was used across all three GLP studies to ensure consistency in the pivotal safety and activity studies.”
Study lengthopen answer page →
Longest pivotal study
27 weeks
“A 7- and 27-Week Toxicity and Biodistribution Study Following a Single Intracochlear Injection of DB-OTO in Cynomolgus Monkeys”
Pivotal GLP studies
GLP single-dose: 2-month adult mouse (RWM), 3-month juvenile mouse (PSCC), 7/27-week cynomolgus (bilateral RWM)
“The 2-month Good Laboratory Practice (GLP) study in adult mice, and the 3-month GLP study in juvenile mice, at dose levels up to 1.3 x 1011 vg/ear showed no DB-OTO-related adverse findings, with a no observed adverse effect level (NOAEL) of 1.3 x 1011 vg/ear.”
Route in tox
Intracochlear via round window membrane; posterior semicircular canal in juvenile mice (worst-case systemic exposure)
“The intended clinical route of administration, IC injection via the round window membrane (RWM), was used in adult mice and monkeys, while a posterior semicircular canal (PSCC) injection was used in juvenile mice to assess a worst-case scenario for systemic exposure.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (low AAV insertional mutagenesis risk; limited distribution beyond inner ear)
“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”
Carcinogenicity
Not conducted (local distribution, no clinical AAV carcinogenesis evidence)
“No carcinogenicity studies have been conducted with DB-OTO.”
Reproductive & developmental
Not conducted; gonadal biodistribution/expression assessed in tox studies (negligible, no findings)
“Across these nonclinical studies, there was negligible biodistribution of DB-OTO vector to the gonads, no expression of hOTOF mRNA in the gonads, and no gross or microscopic findings in the gonads, suggesting a low reproductive and germline integration risk.”
Safety pharmacology
No standalone studies; endpoints (Irwin/FOB, neuro exams) incorporated into toxicology studies
“No standalone safety pharmacology studies were conducted with DB-OTO. However, the toxicology studies included some safety pharmacology endpoints and are reviewed in the ‘Toxicology Studies’ section.”
First doseopen answer page →
First-in-human starting dose
PD Emax modeling of mouse ABR data: plateau >2e13 vg/mL; clinical 3e13 vg/mL (1.5x), concentration-scaled NOAEL margins 2.2-2.4x
“The selection of the proposed clinical dose concentration of 3 x 1013 vg/mL is supported by the pharmacodynamic modeling (OTOF-10116) of ABR improvements in the Otof-Q828X hom mouse model as well as the safety profile established in the GLP toxicology studies.”
NOAEL / key findings
NOAEL = highest dose (1.3e11 vg/ear mouse; 4.4e12 vg/ear monkey); adverse findings procedure-related (facial paralysis, cochlear damage)
“The 6-month GLP study in monkeys at dose levels up to 4.4 × 1012 vg/ear demonstrated no DB-OTO-related toxicity, with a NOAEL of 4.4 × 1012 vg/ear.”
Risksopen answer page →
Immune & cytokine safety
All monkeys anti-AAV1 NAb positive by week 27, no anti-otoferlin antibodies; NAbs not associated with safety signal; minimal cochlear infiltrates
“There were no serum or CSF samples positive for anti-otoferlin antibodies at any time point.”
Biodistribution & persistence
Cochlear retention through 27 weeks; transient plasma/CSF; low neural off-target expression; none in gonads; shedding only Day 2
“Viral shedding was detected in multiple samples (buccal swabs, nasal swabs, feces, and urine) on Day 2 post-administration in monkeys but was absent by 7 weeks, indicating clearance from excretory pathways.”
Modality-specific risk
Intracochlear surgical procedure risk (facial paralysis, permanent cochlear damage); off-target neural transgene expression
“However, the long-term consequences of low-level transgene expression in non-target neural tissues (brain, DRG, spinal cord) remain unknown and warrant continued monitoring in human subjects.”