The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Cisplatin-Induced Hearing Loss.

The otoprotective effects of OTO-104 were investigated following both acute and chronic administration of cisplatin. The acute administration of cisplatin to guinea pigs resulted in profound hearing loss (70-80 dB SPL) across all frequencies tested. A single intratympanic injection of 6% OTO-104, but not of lower doses, almost completely protected against cisplatin ototoxicity. In contrast, a dexamethasone solution administered under the same experimental conditions offered no otoprotection. OTO-104 was also very effective in protecting against the progressive hearing loss observed with the chronic administration of cisplatin (3 injections at a weekly interval). The otoprotection was found to be dependent upon the activation of dexamethasone-dependent classical nuclear receptor pathways.

The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Noise-Induced Hearing Loss.

The otoprotective effects of OTO-104 were investigated both prior to and following acute acoustic trauma. Guinea pigs received a single intratympanic injection of OTO-104 and were assessed in a model of acute acoustic trauma. Doses of at least 2.0% OTO-104 offered significant protection against hearing loss induced by noise exposure when administered 1 day prior to trauma and up to 3 days thereafter. Otoprotection remained effective even with higher degrees of trauma. In contrast, the administration of a dexamethasone sodium phosphate solution did not protect against noise-induced hearing loss. Activation of the classical nuclear glucocorticoid and mineralocorticoid receptor pathways was required for otoprotection by OTO-104. The sustained exposure properties of OTO-104 were also superior to a steroid solution.

Randomized Clinical Trial of a Sustained-Exposure Ciprofloxacin for Intratympanic Injection During Tympanostomy Tube Surgery.

OBJECTIVE: This exploratory clinical trial evaluated the safety and clinical activity of a novel, sustained-exposure formulation of ciprofloxacin microparticulates in poloxamer (OTO-201) administered during tympanostomy tube placement in children. METHODS: Double-blind, randomized, prospective, placebo- and sham-controlled, multicenter Phase 1b trial in children (6 months to 12 years) with bilateral middle ear effusion requiring tympanostomy tube placement. Patients were randomized to intraoperative OTO-201 (4 mg or 12 mg), placebo, or sham (2:1:1 ratio). RESULTS: Eighty-three patients (52 male/31 female; mean age, 2.80 years) were followed for safety (otoscopic exams, cultures, audiometry, and tympanometry) and clinical activity, defined as treatment failure (physician-documented otorrhea and/or otic or systemic antibiotic use ≥3 days post surgery). At baseline, 14.3% to 36.8% of children showed positive cultures of middle ear effusion samples in at least 1 ear. Through day 15, treatment failures accounted for 14.3%, 15.8%, 45.5%, and 42.9% of patients (OTO-201 4 mg, OTO-201 12 mg, placebo, and sham, respectively); treatment failure reductions for OTO-201 doses were significant compared to pooled control (P values = .023 and .043, respectively). Observed OTO-201 safety profile was indistinguishable from placebo or sham. CONCLUSIONS: Results of this first clinical trial suggest that OTO-201 was well tolerated and shows preliminary clinical activity in treating tympanostomy tube otorrhea.

Myoblasts derived from normal hESCs and dystrophic hiPSCs efficiently fuse with existing muscle fibers following transplantation.

Human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) have an endless self-renewal capacity and can theoretically differentiate into all types of lineages. They thus represent an unlimited source of cells for therapies of regenerative diseases, such as Duchenne muscular dystrophy (DMD), and for tissue repair in specific medical fields. However, at the moment, the low number of efficient specific lineage differentiation protocols compromises their use in regenerative medicine. We developed a two-step procedure to differentiate hESCs and dystrophic hiPSCs in myogenic cells. The first step was a culture in a myogenic medium and the second step an infection with an adenovirus expressing the myogenic master gene MyoD. Following infection, the cells expressed several myogenic markers and formed abundant multinucleated myotubes in vitro. When transplanted in the muscle of Rag/mdx mice, these cells participated in muscle regeneration by fusing very well with existing muscle fibers. Our findings provide an effective method that will permit to use hESCs or hiPSCs for preclinical studies in muscle repair.

Distribution of dexamethasone and preservation of inner ear function following intratympanic delivery of a gel-based formulation.

Intratympanic (IT) delivery of drugs to the ear is increasingly used for both clinical and research purposes. One limitation of IT delivery is that drugs are rapidly lost from the middle ear by a number of processes, so that prolonged delivery of drug is technically difficult. In the present study, the delivery characteristics of a poloxamer hydrogel formulation containing dexamethasone (dex) were evaluated. The gel is liquid at room temperature, allowing IT injection, but transitions to a gel at body temperature, providing a prolonged residence time in the middle ear. A 50-µl volume of control or dex-containing gel (dex-gel) was injected through the tympanic membrane of guinea pigs. Cochlear function was assessed with cochlear action potential and acoustic emission thresholds measured immediately, 6 or 24 h after IT gel injection. After 6- or 24-hour treatment with dex-gel, perilymph drug gradients along the cochlea were assessed by taking samples sequentially from the apex, and endolymph was sampled from the basal turn. Control gel injections caused small changes in sound field calibrations and functional measures for low-frequency stimuli, consistent with an induced conductive loss. Within 24 h, responses returned to normal. Twenty-four hours after dex-gel injection, low-frequency changes remained as the dex-gel was retained better in the middle ear, but there was no indication of high-frequency loss. While perilymph sample data showed that dex gradients were substantially lower than after single injections of dex solution, quantitative analysis of this result suggests that some dex may have entered the perilymph through the thin bone in the apical region of the cochlea. Endolymph levels of dex remained lower than those in the perilymph. This study confirms that a poloxamer hydrogel-based dex formulation provides an effective method for a prolonged delivery, providing a more uniform distribution of drug in the inner ear.

Pharmacokinetics of dexamethasone solution following intratympanic injection in guinea pig and sheep.

Information on inner ear pharmacokinetics is limited in the literature, especially in large animals and in humans. A preliminary study was designed to explore the differences in inner ear exposure between guinea pigs and sheep following a single intratympanic injection of a 2% dexamethasone sodium phosphate solution. In both species, significant levels of dexamethasone were observed in the perilymph within 1 h, and decreasing by 50- to 100-fold within 12 h. Overall, the exposure to dexamethasone in the inner ear was significantly lower in sheep by 17- to 27-fold than in guinea pigs. Systemic and CNS exposure were minimal in both species as indicated by the low drug levels observed in plasma and CSF. Altogether, the preliminary evidence presented herein suggests the sheep as a practical and acceptable animal model to study the inner ear pharmacokinetics of drug candidates in large mammals and its potential towards extrapolation to human exposure.

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study.

OBJECTIVES: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. STUDY DESIGNS: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. SETTING: Three private otolaryngology practices in the US. PATIENTS: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. INTERVENTIONS: Intratympanic FX-322. MAIN OUTCOME MEASURES: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. RESULTS: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). CONCLUSIONS: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Dose-dependent sustained release of dexamethasone in inner ear cochlear fluids using a novel local delivery approach.

The thermo-reversible triblock copolymer poloxamer 407 was investigated as a drug delivery vehicle for micronized dexamethasone into the middle and inner ears of guinea pigs. The study characterized the gelation and in vitro release kinetics of poloxamer formulations. In vivo, the pharmacokinetic profile of formulations containing varying concentrations of poloxamer and dexamethasone was examined following intratympanic administration. Significant drug levels within the perilymph were observed for at least 10 days, while systemic exposure was minimal. The sustained-release kinetics profile could be significantly modulated by varying the concentrations of both poloxamer and dexamethasone. Assessment of auditory function revealed a small transient shift in hearing threshold, most probably of conductive nature, which resolved itself within a week. No significant histological changes of the round window membrane or cochlea could be noted. Poloxamer 407 thus represents an effective and safe delivery system to achieve sustained release of dexamethasone to the inner ear.

OTO-201 for the Treatment of Acute Otitis Externa: Results from a Phase 3 Randomized Clinical Study.

OBJECTIVES: OTO-201 is a ciprofloxacin otic suspension previously approved by the US Food and Drug Administration to treat children with bilateral otitis media with effusion requiring tympanostomy tube placement. In this phase 3, double-blind, randomized, prospective, sham-controlled, multicenter study, a single dose of OTO-201 was administered to the external auditory canal in subjects with unilateral or bilateral acute otitis externa. METHODS: Two hundred sixty-two subjects, 3 to 83 years of age, were randomized, and 260 subjects were included in the intent-to-treat analysis population: OTO-201 (0.2 mL, 12 mg, n = 130) or sham (air injection, n = 130). The primary efficacy measure was clinical cure (CC) on day 8, judged by blinded assessor for erythema, edema, otorrhea, and tenderness. Subjects were monitored over 28 days for efficacy and safety. RESULTS: OTO-201 demonstrated a significant increase in CC compared with sham at day 8 (69.2% vs 46.1%, P < .001). Higher CC was also noted on day 4 ( P = .028), day 15 ( P < .001), and day 29 ( P < .001). A similar effect was observed in the pathogen-positive population. Single OTO-201 administration in the office setting was well tolerated by subjects. CONCLUSIONS: In this study in subjects with acute otitis externa, a single administration of 12 mg OTO-201 to the external auditory canal demonstrated a significantly higher proportion of subjects with CC and bacterial eradication compared with sham starting on day 4 and on all other observation days through day 29, with no safety or tolerability concerns identified. OTO-201 is the first agent in a randomized phase 3 study to demonstrate the efficacy and safety of a single-dose, health care professional-administered topical antibiotic for the treatment of acute otitis externa.

Intratympanic Sustained-Exposure Dexamethasone Thermosensitive Gel for Symptoms of Ménière's Disease: Randomized Phase 2b Safety and Efficacy Trial.

OBJECTIVE: To evaluate safety and efficacy of a single intratympanic injection of OTO-104, sustained-exposure dexamethasone, in patients with unilateral Ménière's disease. STUDY DESIGN: Randomized, double-blind, placebo-controlled, Phase 2b study over 5 months. SETTING: Fifty-two academic and community otolaryngology centers. PATIENTS: One hundred fifty four patients (77 per group) aged 18 to 85 years inclusive. INTERVENTION: Single intratympanic injection of OTO-104 (12 mg dexamethasone) or placebo. MAIN OUTCOME MEASURES: Efficacy (vertigo) and safety (adverse events, otoscopy, audiometry, tympanometry). RESULTS: Primary endpoint (change from baseline in vertigo rate at Month 3) was not statistically significant (placebo [-43%], OTO-104 [-61%], P = 0.067). Improvements with OTO-104 were observed in prospectively defined secondary endpoints number of days with definitive vertigo, (Month 2 [P = 0.035], Month 3 [P = 0.030]), vertigo severity (Months 2-3, P = 0.046) and daily vertigo counts (Month 2, P = 0.042), and in some Short Form-36 (SF-36) subscales (Month 2 bodily pain P = 0.039, vitality P = 0.045, social functioning P = 0.025). No difference in tinnitus loudness or tinnitus handicap inventory (THI-25) was observed. OTO-104 was well tolerated; no negative impact on safety compared with placebo. Persistent tympanic membrane perforation was observed in two OTO-104 treated patients at study end. CONCLUSION: OTO-104 was well-tolerated, did not significantly affect change from baseline in vertigo rate, but did reduce number definitive vertigo days, vertigo severity, and average daily vertigo count compared with placebo during Month 3. Results provide insight into analyzing for a vertigo treatment effect and support advancing OTO-104 into Phase 3 clinical trials for the treatment of Ménière's disease symptoms.

Safety and Efficacy of Intratympanic Ciprofloxacin Otic Suspension in Children With Middle Ear Effusion Undergoing Tympanostomy Tube Placement: Two Randomized Clinical Trials.

IMPORTANCE: Otorrhea after tympanostomy tube placement (TTP) in children is common. Although not approved by the US Food and Drug Administration, antibiotic ear drops are routinely used intraoperatively and prescribed for multidose, multiday postoperative administration by caregivers. OBJECTIVE: To investigate the safety and efficacy of a single-dose intratympanic, intraoperative, thermosensitive, otic suspension of ciprofloxacin (OTO-201) in children requiring TTP. DESIGN, SETTING, AND PARTICIPANTS: Two identically designed, prospective, double-blind, sham-controlled, multicenter phase 3 randomized clinical trials included 532 patients aged 6 months to 17 years with middle ear effusions. Patients with confirmed bilateral effusions on the day of TTP were randomized to TTP alone or to TTP with OTO-201 injection. Children underwent a 28-day observation period. Data were collected from November 14, 2013, to June 3, 2014. Final follow-up was completed on June 16, 2014, and intent-to-treat data were analyzed from June 10 to August 27, 2014. MAIN OUTCOMES AND MEASURES: Efficacy was assessed as treatment failure, including the presence of otorrhea, use of otic or systemic antibiotics, loss to follow-up, or missed visits. Safety was assessed for serious adverse events and treatment-emergent adverse events using audiometry, otoscopy, and tympanometry. RESULTS: Among the 532 patients included in the trials, 175 were randomized to TTP only and 357 to OTO-201 treatment (304 boys [57.1%]; 228 girls [42.9%]; mean [SD] age, 2.4 [2.1]). At day 15, the cumulative proportion of treatment failures (primary end point) was 24.6% (44 of 179 patients) in trial 1 and 21.3% (38 of 178 patients) in trial 2 in the OTO-201 groups vs 44.8% (39 of 87 patients) in trial 1 and 45.5% (40 of 88 patients) in trial 2 in the TTP-alone groups. At day 15 otorrhea-only treatment failures in trial 1 included 21 of 179 (11.7%) in the OTO-201 group vs 22 of 87 (25.3%) in the TTP-only group; in trial 2, 17 of 178 (9.6%) in the OTO-201 group vs 29 of 88 (33.0%) in the TTP-only group. The odds of otorrhea-only failure were significantly reduced in the OTO-201 groups compared with the TTP-only groups in both trials (age-adjusted odds ratios, 0.38 [95% CI, 0.19-0.75] and 0.19 [95% CI, 0.09-0.38]; P < .001 for both trials, post hoc analysis). No drug-related serious adverse events were seen, and most adverse events were mild or moderate. No evidence of increased tube occlusion and no negative effect on results of audiometry, tympanometry, or otoscopy were noted with OTO-201 administration. CONCLUSIONS AND RELEVANCE: Two large phase 3 randomized clinical trials demonstrate the safety and efficacy of a single intraoperative administration of OTO-201 for middle ear effusion at the time of TTP. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01949142 and NCT01949155.

Phase 3 Trials of Thermosensitive Ciprofloxacin Gel for Middle Ear Effusion in Children with Tubes.

OBJECTIVE: To investigate the efficacy, safety, and microbiology of a thermosensitive otic suspension of ciprofloxacin (OTO-201) in children with bilateral middle ear effusion undergoing tympanostomy tube placement. STUDY DESIGN: Two randomized, double-blind, sham-controlled phase 3 trials. Patients were randomized to intratympanic OTO-201 or sham. SETTING: Children with bilateral middle ear effusion undergoing tympanostomy tube placement. SUBJECTS/METHODS: Studies evaluated 532 patients (6 months to 17 years old) in a combined analysis of efficacy (treatment failure: presence of otorrhea, otic or systemic antibiotic use, lost to follow-up, missed visits), safety (audiometry, otoscopy, tympanometry), and microbiology. RESULTS: There was a lower cumulative proportion of treatment failures in patients receiving OTO-201 vs tympanostomy tubes alone (1) on days 4, 8, 15, and 29; (2) on day 15, primary end point (23.0% vs 45.1%; age-adjusted odds ratio, 0.341; P < .001; reduction in relative risk, 49%); and (3) on day 15, blinded-assessor otorrhea treatment failure (7.0% vs 19.4%; age-adjusted odds ratio, 0.303; P < .001; reduction in relative risk, 64%). Per-protocol and subgroup analyses (baseline demographics, pathogen type, culture status, effusion type, microbiologic response) supported these findings. There were no drug-related serious adverse events; the most frequent treatment-emergent adverse events in both groups were pyrexia, postoperative pain, nasopharyngitis, cough, and upper respiratory tract infection. OTO-201 administration had no evidence of increased tube occlusion and no negative effect on audiometry, tympanometry, or otoscopy. CONCLUSIONS: Combined analysis of 2 phase 3 trials demonstrated a lower cumulative proportion of treatment failures through day 15 compared with TT alone when OTO-201 was administered intratympanically for otitis media with bilateral middle ear effusion at time of tympanostomy tube placement.

Glial cell line-derived neurotrophic factor alters axon schwann cell units and promotes myelination in unmyelinated nerve fibers.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the development and maintenance of a subset of dorsal root ganglion sensory neurons. We administered high-dose exogenous recombinant human GDNF (rhGDNF) daily to adult rats to examine its effect on unmyelinated axon-Schwann cell units in intact peripheral nerves. In rhGDNF-treated animals, there was a dramatic proliferation in the Schwann cells of unmyelinated fibers, which resulted in the segregation of many unmyelinated axons into a 1:1 relationship with Schwann cells and myelination of normally unmyelinated small axons. This study demonstrates that the administration of high doses of a growth factor to adult rats can change the phenotype of nerve fibers from unmyelinated to myelinated.

Leptin: from animals to humans.

Leptin has been shown to have a wide repertoire of peripheral effects, some of which are mediated through the central nervous system and others that are induced through a direct action on target tissues. There is now evidence showing that leptin exerts some of its metabolic effects acting directly on peripheral tissues. The role of leptin has expanded from a narrow position in obesity to effects on biological processes, such as diabetes, appetite, thermogenesis, the immune system and reproduction. Here in a first part, we review preclinical evidence for direct effects on specific tissues (neurons, liver and muscle) and metabolic pathways. In a second part we review clinical evidence for leptin effects. In particular we review the effects of recombinant human leptin in lean, obese, diabetic subjects and in patients with congenital leptin deficiency or lipoatrophic diabetes. Additionally, while clinic leptin has not shown dramatic effects in obese/diabetic subjects with measurable serum leptin, in states of leptin deficiency treatment with leptin has been shown to have profound effects on body weight and appetite and insulin resistance.

Effects of continuous lumbar intrathecal infusion of leptin in rats on weight regulation.

Intracranial leptin alters food consumption and body weight. To systematically characterize the effects of extended continuous spinal intrathecal delivery on such regulation, female rats received continuous lumbar spinal infusion (14 days) through catheters connected to osmotic minipumps of a vehicle or one of several doses of recombinant murine leptin (0.03-10 microg/day). The following observations were made. (1) Leptin resulted in a dose-dependent suppression in body weight and food consumption at doses above 0.3 microg/day. (2) Food consumption was initially reduced. Weight fell for 7 days and then plateaued at a level proportional to dose. (3) The ratio of food consumed to body weight was constant for control animals across the study. Leptin-infused rats slowed the initial fall in weight by increasing food consumption, such that the food to body weight ratio returned to that of control values. Rats were thus regulating food consumption to sustain body weight as defined by leptin dose. (4) On day 14, cisternal cerebrospinal fluid was obtained and leptin measured. Concentrations covaried in a log linear fashion with infusion dose. Body weight and food consumption covaried similarly with cisternal leptin concentrations across dose groups. Our data suggest that steady state infusions of leptin induce a degree of appetite suppression that leads to a steady state level of body weight loss and not simply to a simple block of consumatory behavior. The unexpected potency of the observed effects of intrathecal leptin relative to doses that are required after i.c.v. delivery suggests that at least a portion of the effects of intrathecal leptin may reflect a medullary action. The observed correlation of cisternal leptin levels with the behavioral effects is also consistent with a reliable distribution of the infused leptin to target supraspinal sites.

Strategies for the delivery of leptin to the CNS.

Leptin is the major regulator of body fat. It is a 16 kD protein released by fat cells into the blood and crosses the blood-brain barrier (BBB) to interact with its receptors at the arcuate nucleus to affect feeding, thermogenesis, and other functions. Within normal and obese body weight ranges, serum and cerebrospinal fluid (CSF) levels of leptin directly correlate with body mass index and adiposity. In animals, leptin at high levels exerts effects on appetite and at low levels informs the brain when fat reserves are adequate to switch behavioral, endocrine, and immune functions from starvation mode. Leptin offers a unique therapeutic opportunity for conditions related to body weight control, such as reversal of obesity and anorexia, and as an indirect treatment for diseases related to being over- or under-weight, such as insulin resistant diabetes and the endocrine changes accompanying starvation. In humans and in many rodent models, obesity may be a consequence of leptin resistance. More specifically, resistance likely results from an impaired transport of leptin across the BBB. Peripheral administration of native leptin results in weight reduction in moderately obese individuals and weight loss and reversal of insulin resistance and dyslipidemia in individuals with low leptin levels. The peripheral pharmacokinetic and BBB transport characteristics of native leptin suggests strategies for improving the therapeutic profile of leptin. These strategies include the development of longer lasting and more permeable analogs, development of antagonists, enhancing the activity of the leptin transporter, and delivering leptin by intrathecal administration.

OTO-201: nonclinical assessment of a sustained-release ciprofloxacin hydrogel for the treatment of otitis media.

HYPOTHESIS: OTO-201 can provide sustained release to the middle ear and effectively treat otitis media, when compared with FDA-approved ciprofloxacin otic drop formulations. BACKGROUND: There is an unmet medical need for antibiotic therapy that can provide a full course of treatment from a single administration by an otolaryngologist at the time of tympanostomy tube placement, obviating the need for twice daily multiday treatment with short-acting otic drops. METHODS: Studies in guinea pigs and chinchillas were conducted. OTO-201 was administered as a single intratympanic injection and compared with the twice daily multi-day treatment with Ciprodex or Cetraxal otic drops. RESULTS: OTO-201 demonstrated sustained release of ciprofloxacin in the middle ear compartment for days to approximately 2 weeks depending on the dose. The substantial C(max) values and steady drug exposure yielded by OTO-201 were in contrast to the pulsatile short lasting exposure seen with Ciprodex and Cetraxal. OTO-201 was also effective in a preclinical chinchilla model of Streptococcus pneumoniae-induced otitis media. The degree of cure was comparable to that afforded by Ciprodex and Cetraxal. There was no evidence of middle or inner ear pathology in guinea pigs treated with OTO-201, unlike Ciprodex and Cetraxal, which both demonstrated mild cochlear ototoxicity. No adverse effects of the poloxamer 407 vehicle were noted. CONCLUSION: Intratympanic injection of OTO-201 constitutes an attractive treatment option to twice daily multiday dosing with ciprofloxacin ear drops for the treatment of otitis media, as evidenced by superior middle ear drug exposure, efficacy in an acute otitis media model, safety of administration, and convenience of a single dose regimen.

A randomized, double-blind, placebo-controlled clinical study to assess safety and clinical activity of OTO-104 given as a single intratympanic injection in patients with unilateral Ménière's disease.

OBJECTIVE: To evaluate the safety, tolerability, and clinical activity of a single intratympanic injection of OTO-104, sustained-release dexamethasone formulation, in patients with unilateral Ménière's disease. STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled, dose-escalation study of 16 weeks' (4-wk lead-in before dosing; 12-wk follow-up after dosing) duration for each patient. SETTING: Fifteen centers (physician offices and academic or tertiary referral centers). PATIENTS: Forty-four patients aged 22 to 75 years. INTERVENTION: Single intratympanic injection of OTO-104 (3 or 12 mg) or placebo. MAIN OUTCOME MEASURES: Safety and tolerability were assessed via adverse event reports, otoscopy, audiometry, and tympanometry. Clinical activity was assessed primarily as changes in vertigo frequency. RESULTS: OTO-104 was well tolerated, with no impact on hearing function. Plasma levels were observed in a few patients and were barely quantifiable. The most frequently reported adverse event considered related to investigational product was tympanic membrane perforation; no clinical sequelae were associated with these perforations and all were graded mild or moderate. At Month 3, the observed mean ± standard deviation (SD) change from baseline in vertigo frequency was -0.124 ± 0.153, -0.147 ± 0.166, and -0.211 ± 0.153 for the placebo, 3-mg OTO-104, and 12-mg OTO-104 groups, respectively; corresponding to 42%, 56% and 73% reductions in vertigo frequency, respectively. Similar results were observed for tinnitus, measured by the Tinnitus Handicap Inventory (THI-25). CONCLUSION: OTO-104 was safe and well tolerated. Although the sample size was small, the data suggest 12 mg of OTO-104 was associated with a clinically meaningful reduction in vertigo frequency compared to placebo 3 months after treatment.

Principles of inner ear sustained release following intratympanic administration.

OBJECTIVE/HYPOTHESIS: Previous studies revealed that intratympanic administration of the steroid dexamethasone in poloxamer 407 hydrogel, a class of thermoreversible polymers, resulted in significant and durable exposure in the inner ear. Interestingly, varying the concentrations of the poloxamer vehicle and of the steroid impacted the pharmacokinetic profile of dexamethasone in the perilymphatic compartment. Here, the respective contributions of different vehicles (aqueous solution, poloxamer hydrogel) and steroid drugs (dexamethasone, methylprednisolone) were investigated. In particular, various forms of the steroids, discriminated by their aqueous solubility, were compared. STUDY DESIGN: In vitro studies characterized the gelation profile and drug release kinetics of the various formulations. The inner ear pharmacokinetic profile of the different formulations was investigated in guinea pigs. RESULTS: Drugs formulated in poloxamer 407 shared significantly more prolonged exposure than those formulated in aqueous solutions both in vitro and in vivo in the inner ear. Furthermore, drugs with low aqueous solubility yielded increased degree and duration of exposure in the inner ear relative to water-soluble drugs. CONCLUSIONS: The inner ear pharmacokinetic profile of drugs administered intratympanically is not only highly dependent upon the nature of the vehicle but also upon the physicochemical properties of the drug delivered.

OTO-104: a sustained-release dexamethasone hydrogel for the treatment of otic disorders.

HYPOTHESIS: To investigate whether OTO-104, a poloxamer-based hydrogel containing micronized dexamethasone for intratympanic delivery, can provide long-lasting inner ear exposure and be well tolerated. METHODS: OTO-104 was administered intratympanically to guinea pigs and sheep, and its pharmacokinetic and toxicity profiles were examined. RESULTS: After a single intratympanic injection of OTO-104 (from 0.6% to 20%, w/w), significant and prolonged exposure to dexamethasone in the inner ear was observed. Increasing the concentration of OTO-104 resulted in higher perilymph drug levels as well as a more prolonged duration of exposure. At the highest dose, therapeutic perilymph levels of dexamethasone could be sustained over 3 months in guinea pigs and more than 1 month in sheep. A toxicologic evaluation was conducted, including assessments of middle and inner ear function and physiology, as well as appraisal of local and systemic toxicity. A small and transient shift in hearing threshold was observed, most probably conductive in nature. No significant histologic changes in middle or inner ear tissues were noted. Although macroscopically mild erythema/inflammation was documented in a subset of guinea pigs treated with 20% OTO-104, the nature and the severity of these changes were not different between the poloxamer vehicle, saline, and 20% OTO-104 groups. No evidence of acute dermal toxicity, delayed hypersensitivity, or systemic adverse effects was found. CONCLUSION: OTO-104 is a novel proprietary therapeutic delivery system that can achieve prolonged, sustained release of dexamethasone within the inner ear fluids. The administration of this clinical candidate formulation via intratympanic injection is expected to be well tolerated both locally and systemically.