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.”
Species: general tox
Otof-Q828X homozygous mouse and cynomolgus monkey (single-dose studies)
“Single-dose toxicology studies were conducted in Otof-Q828X hom mice and cynomolgus monkeys.”
Species: DART
Not conducted (intracochlear route, limited systemic exposure, target population, no toxicology concerns)
“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted with DB-OTO.”
Surrogate used in
No surrogate used; clinical-process DB-OTO lot used across 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.”
Instead of carcinogenicity
Review of animal toxicology and local biodistribution data, and lack of clinical evidence of AAV carcinogenesis
“These were considered not warranted based on a review of the animal toxicology studies, data from biodistribution studies showing limited DB-OTO vector distribution beyond the local compartment of the inner ear, and a lack of clinical evidence of carcinogenesis attributable to recombinant AAV vectors.”
DRG histopathology
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.
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.”
Genotox: Ames
Not conducted (AAV insertional mutagenesis risk considered low)
“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”
Genotox: in vitro mammalian
Not conducted (AAV insertional mutagenesis risk considered low)
“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”
Genotox: in vivo
Not conducted (AAV insertional mutagenesis risk considered low)
“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”
Carcinogenicity model
Not conducted (limited vector distribution beyond inner ear; no clinical evidence of AAV carcinogenesis)
“No carcinogenicity studies have been conducted with DB-OTO. These were considered not warranted based on a review of the animal toxicology studies, data from biodistribution studies showing limited DB-OTO vector distribution beyond the local compartment of the inner ear, and a lack of clinical evidence of carcinogenesis attributable to recombinant AAV vectors.”
Carcinogenicity timing
Not warranted (intracochlear route, limited systemic exposure)
“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”
hERG / QT
Not conducted; no standalone safety pharmacology (endpoints in 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.”
Anti-drug antibodies: animals
Monkeys: no anti-otoferlin antibodies; anti-AAV1 NAb titers (pre-existing or induced) not associated with any safety signal
“There were no serum or CSF samples positive for anti-otoferlin antibodies at any time point. Preexisting or post-DB-OTO administration positive serum or CSF anti-AAV1 NAb titers were not associated with any safety signal.”
Anti-drug antibodies: patients
All patients developed anti-AAV1 NAbs through Week 12 (10/15 titer >10000); 7/15 (46.7%) developed anti-OTOF antibodies
“All patients developed anti-AAV1 neutralizing antibody responses through Week 12, with 10/15 (66.7%) having titer >10000, 3/15 (20.0%) having titer 1000 to 10000, and the rest having titer <1000. A total of 7/15 (46.7%) patients developed anti-OTOF antibody responses through Week 12,”
Label warnings
- Procedure-Related Risks
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
United States and unnamed ex-US sites: DB-OTO-001 (7 US, 4 ex-US sites), the only clinical study
“Study DB-OTO-001 was conducted in 7 US and 4 ex-US sites.”
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
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.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (single intracochlear administration); single-dose mouse and cynomolgus monkey studies
“Single-dose toxicology studies were conducted in Otof-Q828X hom mice and 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.”
DART package
Species: DART
Not conducted (intracochlear route, limited systemic exposure, target population, no toxicology concerns)
“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”
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.”
PPND / ePPND: when
Not conducted; not warranted (intracochlear route, limited systemic exposure, target population, no toxicology concerns)
“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted with DB-OTO.”
Carcinogenicity model
Not conducted (limited vector distribution beyond inner ear; no clinical evidence of AAV carcinogenesis)
“No carcinogenicity studies have been conducted with DB-OTO. These were considered not warranted based on a review of the animal toxicology studies, data from biodistribution studies showing limited DB-OTO vector distribution beyond the local compartment of the inner ear, and a lack of clinical evidence of carcinogenesis attributable to recombinant AAV vectors.”
Carcinogenicity timing
Not warranted (intracochlear route, limited systemic exposure)
“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL concentrations ~2.2x (mouse) and ~2.4x (monkey) the clinical dose concentration (vg/mL)
“In the toxicology studies, the NOAELs were identified as the highest concentrations evaluated (6.5 x 1013 vg/mL in mice and 7.3 x 1013 vg/mL in monkeys), which provides safety margins of approximately 2.2-fold and 2.4-fold, respectively.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Otof-Q828X homozygous deafness mouse: dose-dependent ABR threshold recovery with otoferlin expression in IHCs
“Nonclinical pharmacology studies were conducted in Otof-Q828X hom (homozygous) mice, a model of OTOF-related deafness that recapitulates the human phenotype with profound hearing loss and absent auditory brainstem responses (ABRs).”
Why that model
Otof-Q828X mouse recapitulates human OTOF deafness (profound hearing loss, absent ABRs)
“Nonclinical pharmacology studies were conducted in Otof-Q828X hom (homozygous) mice, a model of OTOF-related deafness that recapitulates the human phenotype with profound hearing loss and absent auditory brainstem responses (ABRs).”
Reviewer's view of the efficacy data
Supportive: sustained otoferlin expression and durable ABR improvement for at least 30 weeks support long-term benefit
“This study demonstrated that a single IC administration of DB-OTO resulted in sustained otoferlin protein expression in IHCs and durable ABR threshold improvements that were maintained for at least 30 weeks post-administration.”
Test articleopen answer page →
Test article vs clinical lot
Non-GMP DB-OTO lot B564TOXP1 used in all three GLP studies; clinical product manufactured under GMP. Bridging: Nonclinical material judged comparable to the clinical investigational product based on process consistency
“The nonclinical studies used non-GMP (Good Manufacturing Practice) material, while the clinical product is manufactured under GMP conditions. However, the nonclinical material was determined to be comparable to the clinical investigational drug product based on the process consistency. The same non-GMP lot (B564TOXP1) was used across all three GLP studies to ensure consistency in the pivotal safety and activity studies.”
Vector and route
Dual AAV1 vector system (hOTOF split into 5' and 3' halves), single intracochlear infusion
“The therapy utilizes a dual AAV1 vector system, in which the hOTOF gene is split into a 5' component and a 3' component, with each segment packaged into a separate AAV1 vector.”
First approval
2026 (FDA)
“Summary Basis for Regulatory Action Date: April 22, 2026”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No genotoxicity or carcinogenicity/tumorigenicity studies; tumorigenicity risk to be assessed in a postmarketing study
Why: Limited vector distribution beyond the inner ear; no clinical evidence of carcinogenesis from recombinant AAV vectors · Class precedent · Pharmacology or kinetics · Human data
“No carcinogenicity studies have been conducted with DB-OTO. These were considered not warranted based on a review of the animal toxicology studies, data from biodistribution studies showing limited DB-OTO vector distribution beyond the local compartment of the inner ear, and a lack of clinical evidence of carcinogenesis attributable to recombinant AAV vectors.”
“The potential risk of tumorigenicity will be assessed in a PMC study.”
DARTAcceptedBeyond the letter
No developmental and reproductive toxicity studies
Why: Intracochlear route, limited systemic exposure, target patient population and no safety concerns in toxicology studies · Pharmacology or kinetics
“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the intracochlear route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”
SpeciesVerdict not stated
Single-dose toxicology run in the Otof-Q828X deafness mouse model (plus cynomolgus monkey) rather than healthy rodents
“Single-dose toxicology studies were conducted in Otof-Q828X hom mice and cynomolgus monkeys.”
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