OTARMENI Solution for injection Ref.[116655] Active ingredients: Lunsotogene parvec

There are no pharmacodynamics data for OTARMENI.

Biodistribution (within the body) and Vector Shedding (excretion/secretion)

OTARMENI vector DNA levels in various matrices and nonclinical tissues were determined using a qualified quantitative polymerase chain reaction (qPCR) assay. Expression of human OTOF mRNA was determined in selected nonclinical tissues.

Nonclinical data

Systemic distribution of vector DNA was evaluated in cynomolgus monkeys at weeks 7 and 27 after a single bilateral intracochlear infusion of dose levels up to 4.4 × 10¹² vg/ear (7.3 × 10¹³ vg/mL), and in juvenile mice at days 30 and 90 and in adult mice at days 30 and 60 after a single unilateral inner ear infusion of dose levels up to 1.3 × 10¹¹ vg/ear (6.5 × 10¹³ vg/mL).

The highest levels of vector DNA were detected in the cochleae. Human OTOF mRNA expression in the cochleae was sustained over the study durations (27 weeks in monkeys, 60-90 days in mice), with peak expression at 6 weeks in monkeys and 4 weeks in mice, then plateauing through the final time points.

Vector DNA distribution to non-otic tissues was limited, with levels at least 10-fold lower than cochlear levels in monkeys and at least 3-fold lower in mice. The highest levels of OTARMENI vector DNA were detected in the parotid lymph node, cervical dorsal root ganglion, cervical spinal cord, and brain, while sporadic or low levels were detected in other non-otic tissues. No measurable vector DNA was detected in ovaries, and only minimal levels were detected in testes (1 of 4 mouse samples near detection limit).

Human OTOF mRNA expression in non-otic tissues was restricted to neural tissues at substantially lower levels than in the cochlea. In monkeys, human OTOF mRNA was detected only in cervical and lumbar dorsal root ganglia of one monkey at Week 7 (no detection at Week 27). In mice, human OTOF mRNA was detected in brain, cervical dorsal root ganglia, and cervical spinal cord at levels 4.9- to 96.4-fold lower than cochlear expression. No human OTOF mRNA was detected in reproductive tissues or other non-neural tissues in either species.

Clinical data

Systemic distribution of vector DNA in plasma and vector DNA shedding in urine, saliva, and stool were evaluated in 15 patients administered OTARMENI at the dose of 7.2 × 10¹² vg/ear in Study DB-OTO-001. Samples were collected at baseline, at Day 1, and Week 2, 4, 6, 12, 24, and 36 following OTARMENI administration. Vector DNA was detectable in plasma, urine, and saliva at Day 1 after OTARMENI administration and was undetectable by Week 2 (the next sampling timepoint). In stool, vector DNA was detectable through Week 6 and became undetectable by Week 12. Peak concentration was observed at Day 1 after OTARMENI administration and declined substantially thereafter.

No animal studies have been performed to evaluate the effects of OTARMENI on carcinogenicity, mutagenesis, or impairment of fertility.

In a 6-month study, cynomolgus monkeys (22 to 63 months old) received bilateral intracochlear administration of OTARMENI at dose levels up to 4.4 × 10¹² vg per ear. Vehicle control animals underwent the same surgical procedure, which was designed to closely mimic the intended clinical procedure.

Procedure-related complications were observed across all treatment groups, including vehicle controls. Facial nerve paralysis occurred in 6 of 36 animals (3 of 12 control animals and 3 of 24 OTARMENI-administered animals). Of the OTARMENI-administered animals that developed facial paralysis, 2 showed complete recovery by Day 3, while 1 required euthanasia on Day 3 due to severe facial paralysis and associated corneal complications. The 3 control animals with facial paralysis did not recover by their Week 7 euthanasia time point. Permanent auditory damage was documented, including spiral ganglion cell degeneration and hair cell loss in the cochlea observed in 2 of 6 control animals and 7 of 13 OTARMENI-administered animals at Week 27. Damage was primarily limited to the injection site area in the basal turn of the cochlea, though one animal experienced more extensive cochlear damage. Hearing threshold elevations affected 55-84% of ears at high frequencies (8-16 kHz) and 21-33% of ears at low frequencies (1-4 kHz), with no recovery observed over the 6-month study duration. Additional post-operative adverse reactions included vestibular symptoms (lasting through Day 5) such as ataxia, head tilt, and coordination problems.

The efficacy of OTARMENI was evaluated in an ongoing, multi-center, single-arm study (Study DB-OTO-001; NCT05788536). The study enrolled pediatric patients with molecularly confirmed OTOF gene associated profound sensorineural hearing loss (defined as >90 dB HL on pure tone audiometry averaged across 0.5, 1, 2, and 4 kHz and auditory brainstem response), evidence of outer hair cell activity by otoacoustic emissions testing, and who were considered candidates for cochlear implant. Patients with cochlear implants in the same ear to be treated with OTARMENI were excluded from the study.

A total of 24 patients (10 patients received unilateral treatment and 14 patients received bilateral treatment) received a single dose of OTARMENI at a dose of 7.2 × 10¹² vector genomes (vg) in 0.24 mL per ear.

The demographic characteristics of the population (N=24): The median age was 2 years (range 10 months to 16 years), 16 patients (67%) were female, 17 patients (71%) were White, 4 patients (17%) were Asian, and 3 patients (13%) had race not reported. Eleven patients (46%) were Hispanic.

Of the 24 patients, 20 had completed efficacy assessments at 24 weeks. Among these 20 patients, five had a contralateral cochlear implant in place prior to enrollment, and two received a cochlear implant in the contralateral ear during the same surgical session for OTARMENI administration. Two patients had bilateral hearing aids before OTARMENI treatment.

The primary efficacy endpoint was the achievement of a hearing sensitivity threshold ≤70 dB HL assessed by average pure tone audiometry (i.e., average of PTA thresholds at 0.5, 1.0, 2.0, and 4.0 kHz) at Week 24 after product administration. The key secondary efficacy endpoint was the presence of auditory brainstem response (ABR) to a click (broadband sound) stimulus of ≤90 dB nHL at Week 24 after product administration.

Efficacy results for Study DB-OTO-001 are presented in Table 2 below.

Table 2. Efficacy Results for Study DB-OTO-001:

ABR: Auditory Brainstem Response; CI: Confidence Interval; PTA: Pure Tone Audiometry
^* For patients who were treated bilaterally, the data reflect the treated ear with better average PTA/better ABR to click at Week 24.
^† Patient without available Week 24 data (n=1) was imputed as a non-responder.

At Week 24, a total of 9/20 (45%) patients achieved an average PTA threshold ≤45 dB HL (ability to hear soft conversational speech level) and 3/20 (15%) achieved ≤25 dB HL (normal hearing level i.e., ability to hear whispers).

One patient received a cochlear implant as rescue treatment approximately 8 months after OTARMENI administration in the same ear following determination of treatment failure.

Among the 20 patients, 12 patients were evaluated at Week 48 after product administration. Of these, all 9 patients who previously had a response at Week 24 and who were evaluated at Week 48 maintained their response. One additional patient who had not initially achieved response at Week 24, achieved an average PTA threshold ≤70 dB HL by Week 48, resulting in a total of 10/12 (83%) patients who achieved an average PTA threshold ≤70 dB HL by Week 48. Eight of the 12 (67%) patients achieved an average PTA threshold ≤45 dB HL and 5 of the 12 patients (42%) achieved ≤25 dB HL by Week 48. Additionally, 9 of the 12 patients (75%) demonstrated presence of auditory brainstem response (ABR) to a click (broadband sound) stimulus of ≤90 dB nHL by Week 48.