Hearing Research 426 (2022) 108637

Contents lists available at ScienceDirect

Hearing Research
journal homepage: www.elsevier.com/locate/heares

Therapeutics for hearing preservation and improvement of patient

outcomes in cochlear implantation—Progress and possibilities
Robert D. Gay∗, Ya Lang Enke, Jonathon R. Kirk, Denise R. Goldman
Cochlear Limited, 1 University Avenue, Macquarie University, NSW 2109 Australia

a r t i c l e i n f o a b s t r a c t

Article history: The emergence of therapeutics targeted at hearing loss holds great promise in the development of novel
Received 9 December 2021 treatments for this heterogenous condition. Whilst such therapeutics are largely designed to be effica-
Revised 11 October 2022
cious in and of themselves, the possibility of combination with devices, namely cochlear implants, could
Accepted 18 October 2022
result in much more effective treatment options. Here, we review the otoprotective molecules currently in
Available online 19 October 2022
clinical development, as well as generic steroids, discussing mechanisms of action and mode of delivery
Keywords: to the perilymph of the cochlea. Presenting both preclinical and clinical data, we explore the challenges
Otoprotection these molecules face in reaching the inner ear. Furthermore, we consider the role of the cochlear im-
Inner ear therapeutics plant as a drug delivery platform along with the ability of these drugs to preserve residual hearing and
Inner ear drug delivery improve outcomes in implant recipients.
Inner ear pharmacokinetics © 2022 The Authors. Published by Elsevier B.V.
Inner ear steroids
This is an open access article under the CC BY-NC-ND license
Cochlear implant
Hearing preservation
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

1. Introduction Despite the improvements in the intervention and the preser-

At its clinical inception in the 1970s, the goal of cochlear im-
plantation was to help restore the sensation of hearing to the pro-
foundly deaf; a goal it has unequivocally achieved (Clark, 1996).
Over time, significant changes in surgical approach and electrode
design endeavoured to further refine the intervention, particularly
focusing on preserving residual hearing where present in a recipi-
ent. Today, cochlear implant (CI) candidacy has evolved to include
individuals with moderate to severe hearing loss, or some level of
residual hearing at lower frequencies. These recipients can access
the benefits of improved hearing outcomes, via electrical stimula-
tion from a CI alone or in combination with an acoustic ‘hybrid’
component (Roland et al., 2016).
Following CI surgery many recipients with preoperative, func-
tionally relevant low-frequency acoustic hearing can experience
hearing preservation (Gantz et al., 2016; Jurawitz et al., 2014;
Lenarz et al., 2006; Roland et al., 2018). Where hearing has been
preserved in the immediate postoperative period, at least partially
according to HEARRING criteria (Skarzynski et al., 2013), multi-
ple authors have reported combined complete and partial hearing
preservation rates above 60% at 1 year follow-up (Mamelle et al.,
2020; Moran et al., 2017; Snels et al., 2020; Thompson et al., 2020).
∗
Corresponding author.
E-mail address: rgay@cochlear.com (R.D. Gay).
vation of residual hearing, significant loss of functionally relevant
low-frequency acoustic hearing can occur immediately following
surgery and, in the months, following. Whilst the causes of this
loss are not well understood, it appears to be triggered indepen-
dently of the electrode selection or the surgical approach adopted
(Rowe et al., 2016). As has been described elsewhere in this issue
(Kirk and Smyth, 2022; Lopez, 2022; Rahman et al., 2022) there is
increasing evidence of the role of electrode insertion trauma, in-
flammation, and the implant-associated foreign body response im-
pacting the consistency of acoustic hearing preservation both im-
mediately following surgery and long term. It is hypothesised that
modulating these impacts with drug therapies delivered before,
during and following cochlear implantation may prove beneficial.
This paper reviews existing therapeutic approaches and new
drugs in development which may be applicable as protective and
preventative treatments in CI patients with aidable levels of low-
frequency hearing post-implantation. These treatments may also
result in augmented CI performance and improved patient out-
comes. Recent progress in the use of steroids as well as other oto-
protective approaches are discussed. The challenges of drug deliv-
ery to the inner ear as well as the applicability to CI recipients of
treatments in development for sudden sensorineural hearing loss
(SSHL), noise-induced hearing loss (NIHL) and age-related hearing
loss (ARHL) are also considered.

https://doi.org/10.1016/j.heares.2022.108637
0378-5955/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
2. Steroids in cochlear implantation
Despite being unapproved for the treatment of hearing loss,
steroids remain the “go-to” pharmacotherapeutic treatment. They
are utilised in an unregulated fashion, with administration
route, frequency, and timing varying between clinicians (Santa
Maria et al., 2014). Although reports of efficacy do oscillate, in the
absence of an approved therapeutic option, steroids are currently
broadly used to treat many forms of hearing loss including NIHL,
SSHL, ototoxicity, and Meniere’s disease (Kuthubutheen et al., 2016;
Parys et al., 2022). Due to their ability to reduce the many compli-
cations associated with inflammation (Zoorob and Cender, 1998),
steroids are commonly employed in CI surgery.
Cochlear implant surgery and any trauma associated with elec-
trode insertion can cause inflammation. The ongoing presence
of the CI electrode may also lead to a foreign body response
(Seyyedi and Nadol, 2014). Inflammation and the foreign body re-
sponse associated with the cochlear implant and surgical proce-
dure may play a large role in the post-operative loss of preserved
residual acoustic hearing. Treatment with systemic steroids prior
to or during recovery, and/or local steroids perioperatively, may
support its preservation (Cho et al., 2016; Kuthubutheen et al.,
2018, 2016; Skarzynska et al., 2021, 2018). Local administration of
steroids may be given during cochlear implant surgery once the
round window niche has been identified. Injection onto the round
window membrane is possible via a posterior tympanotomy di-
rectly into the middle ear (Cho et al., 2016).
The application of steroids onto the round window membrane
relies on diffusion across the membrane into the cochlea. Subse-
quent distribution through the scala tympani depends on passive
diffusion and leads to a concentration gradient from the base to
the apex of the cochlea being established (Plontke et al., 2007a).
Since the round window membrane is usually opened during CI
surgery to facilitate electrode insertion, approaches for more di-
rect and deeper intracochlear delivery have been proposed. For
example, the use of an intracochlear catheter to deliver steroids
deep into the scala tympani during surgery prior to CI electrode
insertion (Prenzler et al., 2020, 2018). Other approaches include
a modified electrode with a polyamide canula running from the
tip of the electrode to an osmotic pump for longer term delivery
(Scheper et al., 2017).
Local steroid administration is expected to provide higher
perilymph concentrations when compared to systemic dosing
(Bird et al., 2011, 2007; O’Leary et al., 2021). However, it should
be noted that clearance of the steroid from perilymph may still be
rapid and any therapeutic effects limited as a result (Salt et al.,
2018, 2012). Because of this, research has focused on sustained in-
tracochlear steroid delivery to ensure that therapeutic concentra-
tions are maintained despite drug clearance.
The CI electrode itself has been evaluated in preclinical and
clinical studies as a sustained-release delivery option with steroids
incorporated either into a coating applied to the electrode, or more
commonly into the silicone carrier of the electrode array. These
studies vary widely on key experimental details including method,
metrics, model, and duration which make comparison challeng-
ing. For example, some earlier studies included dexamethasone in
acetate form (Stathopoulos et al., 2014), while later studies ap-
ply dexamethasone base which has more favourable pharmacoki-
netics when administered via intracochlear route (Ahmadi et al.,
2019; Astolfi et al., 2016; Bas et al., 2016; Briggs et al., 2020;
Eshraghi et al., 2019; Manrique-Huarte et al., 2020; Needham et al.,
2020; Wilk et al., 2016). While the guinea pig is most often the an-
imal model of choice, published studies exploring long-term dex-
amethasone eluting electrode arrays to-date have utilised rat, ger-
bil, or macaque.
2
Hearing Research 426 (2022) 108637
The efficacy of long-term dexamethasone elution for hearing
preservation, as far as suppressing a post-op threshold shift ap-
pears mixed across these studies (Chen et al., 2021; Wilk et al.,
2016). However, there is more support and agreement amongst
other endpoints that have implications for overall cochlear health,
where measured. This is particularly the case when considering
preclinical studies of dexamethasone-eluting devices with dura-
tions beyond 1-month post-op. These studies have found that a
dexamethasone-eluting electrode, whilst not protecting the cochlea
from mechanical damage during insertion, more consistently re-
duced markers of inflammation in terms of gene expression and
key cellular mediators, reduced tissue formation and new bone
growth, and better-preserved key structures of the peripheral
neural substrate spiral gangleon neurons (SGN), inner and outer
hair cells, support cells) when compared to control conditions
(Ahmadi et al., 2019; Bas et al., 2016; Chen et al., 2021; Manrique-
Huarte et al., 2020; Simoni et al., 2020; Toulemonde et al.,
2021).In humans, where such histological assessments are not eth-
ically possible, a dexamethasone-eluting electrode study in ten im-
planted adults demonstrated significant lower electrode impedance
measures in the basal and mid regions of the cochlea com-
pared to standard controls for up to 24 months (clinicaltrials.gov:
NCT02905305) (Briggs et al., 2020). This agrees with most preclini-
cal studies, which present a resounding consensus on the effective-
ness of long-term dexamethasone elution for reducing electrical
impedances. Despite this, the link between changes in impedances
and changes in the real-time local environment is still somewhat
elusive, but more recent studies analysing complex impedances are
shedding some light on the matter. Total electrode impedance rep-
resents both an access component, the resistance in the current
path between the recording electrodes, and a polarisation com-
ponent which represents the resistive and capacitive properties at
the electrode-tissue interface (Tejani et al., 2021). Based on correla-
tions in animal studies, lower impedance which can be attributed
to general suppression of the inflammatory response may be in-
dicative of changes at the electrode interface as well as reduced
tissue within the bulk current path (Wilk et al., 2016). Applications
of impedance as a biomarker are explored further in an article by
Leblans in this issue (Leblans, 2022).
Several additional clinical trials are currently underway explor-
ing steroid elution from a cochlear implant. These include a sin-
gle arm 10-patient study (Clinicaltrials.gov NCT04450290), and a
larger pivotal randomized controlled trial with up to 120 patients.
A key objective of this latter study is to show the efficacy of the
dexamethasone-eluting electrode through reduction in electrode
impedances as compared to an approved standard electrode. In ad-
dition, the improvement of speech recognition from preoperative
baseline will be assessed along with assessment of the benefit-
risk balance of a dexamethasone-eluting electrode, as compared to
a standard electrode through examination of adverse events and
speech recognition outcomes with each device (Clinicaltrials.gov:
NCT04750642). These data, when available will determine whether
extended-release intracochlear delivery of dexamethasone provides
meaningful benefits for CI recipients. These benefits will need to
be carefully weighed up against the risks of introducing a thera-
peutic into the inner ear. Should the benefits prove to be clinically
relevant, for example significantly improving word recognition in
quiet and/or noise, this has the potential to set a new benchmark
for future therapeutics for hearing preservation and improvement
of patient outcomes in CI. These are explored below.
Whilst dexamethasone has been the steroid of focus for eluting
electrodes, other steroids may also be considered. As presented in
Table 1, common corticosteroids differ by a multitude of proper-
ties including potency, mode of action, and pharmacokinetic pro-
file. Many of these steroids exhibit high glucocorticoid activity with
R.D. Gay, Y.L. Enke, J.R. Kirk et al. Hearing Research 426 (2022) 108637

Table 1
Comparison of the properties of common glucocorticoids relative to hydrocortisone and their route of administration in preclinical and clinical inner ear
therapy (Table adapted from Liu et al., 2013).

Relative glucocorticoid Relative mineralocorticoid

Compound activity activity Preclinical Clinical References

Hydrocortisone 1 1 S (Takeda et al., 2021)

Prednisone 4 0.8 S (Skarzynska et al., 2021; Woodson
et al., 2021)
Prednisolone 4 0.8 S S (Plontke, 2018)
Methylprednisolone 5 Minimal S (Dahm et al., 2021, 2019; Woodson
et al., 2021)
Triamcinolone 5 0 IT, IC IC (Dhanasingh and Hochmair, 2021;
Prenzler et al., 2018; Salt et al., 2019;
Salt and Plontke, 2018)
∗
Triamcinolone Acetonide 60–90 Negligible IT IT (Dahm et al., 2021, 2019; Honeder
et al., 2019; Salt et al., 2019)
Dexamethasone 30 Minimal S, IT, IC S, IT, IC (Bas et al., 2016; Briggs et al., 2020;
Cho et al., 2016;
Manrique-Huarte et al., 2020;
Skarzynska et al., 2018)
Betamethasone 30 Negligible IT S (Abdullah et al., 2021;
Skarzynska, 2019)
∗∗
Fluticasone Propionate >1200 Negligible IT, IC (Pierstorff et al., 2019, 2018)

S: Systemic: oral, intravenous, intraperitoneal or intramuscular, IT: intratympanic, IC: intracochlear.

∗
Estimate based on relative IC50 and EC50 determined in cell line receptor binding affinity assays (Nehmé et al., 2009).
∗∗
Estimate based on steroid receptor cell line testing relative to dexamethasone (Wilkinson et al., 2008).

minimal-to-no mineralocorticoid activity. This may be preferable
due to the potential action of mineralocorticoids on intracochlear
ion and fluid balance. Especially as disruption of this is tightly con-
trolled environment is the cause of many forms of hearing loss
(Wangemann, 2006).
An alternative inner ear steroid delivery approach has been
pioneered for fluticasone propionate (FP), a potent glucocorti-
coid with lower solubility than dexamethasone. Whilst used pre-
dominantly in inhaled applications, FP has been described as
demonstrating long term intracochlear release for up to 180 days
when eluted from a polymer-coated particle loaded with the drug
(Pierstorff et al., 2018).
3. Other drugs for otoprotection
Opportunistically, drugs in development for otoprotection may
prove efficacious in preservation of preoperative low-frequency
acoustic hearing from the trauma of cochlear implant surgery. In CI
surgery, the time of trauma is better known and can be planned so
that a therapy can be administered during the appropriate thera-
peutic window, whilst in SSHL, the patient may seek medical treat-
ment from hours to days following the onset of symptoms. Addi-
tionally, many of the inflammatory, oxidative stress and apoptotic
pathways triggered in SSHL are similarly expressed in cochlear im-
plantation (Wang et al., 2020; Zhang et al., 2015).
Current candidates in clinical development for treatment of
SSHL which target these causal pathways and may have application
in preserving residual hearing and improving outcomes in cochlear
implantation are discussed below.
3.1. Peroxisome proliferator-activated receptor gamma (PPARɣ)
agonist
The diabetes drug pioglitazone is a peroxisome proliferator-
activated receptor gamma (PPARɣ) agonist, which exhibits anti-
inflammatory and anti-apoptotic effects and regulates redox
balance. Pioglitazone has been shown to prevent drug induced
hair cell damage in mouse organ of Corti explants and noise
induced cochlear damage in rats (Paciello et al., 2018; Sekulic-
Jablanovic et al., 2017). Clinical development by Strekin AG led
to a placebo-controlled, proof-of-concept Phase II clinical trial to
evaluate the safety and efficacy of pioglitazone to preserve residual
hearing in adults undergoing CI surgery. Formulated into a 1.2%
thermosensitive gel, the investigational product named STR-001
was delivered via intratympanic injection. A group of 110 cochlear
implant candidates with moderate to severe hearing loss were en-
roled into the trial and changes in their residual hearing thresholds
were assessed 6 weeks after surgery. Administration of STR-001
was found to be well tolerated but did not show any significant
hearing preservation benefit. The mean of pure tone audiome-
try assessments at 125, 250, 500 and 750 Hz was found to be
25±16 dB for 53 patients in the treated group and 27±16 dB for 54
patients in the placebo group. As the nominal difference between
the two groups was not statistically significant, the primary study
objective was not met (Clinicaltrialsregister.eu: 2015–002672–25).
A subsequent Phase III clinical trial evaluated the safety and
tolerability of intratympanic administration of the STR-001 ther-
mosensitive gel followed by oral treatment with STR-001 tablets
in 165 patients with SSHL. Following confirmation of the diag-
nosis of severe or profound sudden sensorineural hearing loss by
audiogram, patients received a single intra-tympanic injection fol-
lowed by oral tablets once a day for three months. Patients were
randomised into three groups to receive either STR-001 in both
the intratympanic injection and the tablets, STR-001 in the in-
tratympanic injection and placebo tablets or placebo in both the
intratympanic injection and the tablets. Treatment was again found
to be well tolerated although there was an increase in the occur-
rence of the non-serious adverse events of dizziness and tinnitus
in patients who received the STR-001 intratympanic injection and
placebo tablets (12.5%) compared to the other two groups (3.7%
and 3.85% respectively for dizziness and 5.56% and 1.92% respec-
tively for tinnitus). Assessment of the primary endpoint of absolute
hearing improvement using average pure tone audiogram thresh-
olds after 12 weeks of treatment was inconclusive as were the sec-
ondary endpoints of improvements in speech recognition at both
60 dB and 80 dB (Clinicaltrialsregister.eu: 2017–0 0 0242-22).
3.2. MAPK/JNK pathway inhibition
In 2003, Wang et al. proposed inhibition of the MAPK /
JNK pathway as a potential treatment for SSHL (Wang et al.,
2003). This pathway was previously identified as responsible for
cochlear cell death after trauma and in particular noise exposure
(Forge, 1985; Hu et al., 2002) as well as in the initiation of apopto-

3
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
sis (Dhanasekaran and Reddy, 2008; Hibi et al., 1993). A chemically
synthesized cell permeable JNK ligand named D-JNKI-1, which in-
hibits JNK mediated activation of c-Jun (Bonny et al., 2001) was
evaluated in a guinea pig noise trauma model.
Results from these in vivo studies showed that direct applica-
tion of D-JNKI-1 via a minipump into the scala tympani of the
guinea pig cochlea prevented acoustic trauma-induced permanent
hearing loss in a dose-dependent manner. In this study the D-JNKI-
1 inhibitor was delivered 2-days pre-trauma as well as during and
5-days post-trauma (Wang et al., 2003).
D-JNKI-1 was licenced by Auris Medical AG and known subse-
quently as the investigational product AM-111. Further preclinical
testing demonstrated protection from noise trauma, reduced hair
cell loss, and reduced the number of inflammatory cells present
at 21 days after treatment (Barkdull et al., 2007; Coleman et al.,
2007).
Initial clinical development of AM-111 entailed a Phase I/II clin-
ical trial of 11 patients suffering from acute acoustic trauma after
exposure to firecrackers. The study reported that intratympanic ad-
ministration of a 250 μl gel of either 0.4 or 2.0 g/ml of AM-111
within 24 h of the trauma was well tolerated albeit with an in-
crease in reports of tinnitus in most patients. Following removal of
data points from patients experiencing persistent tinnitus, the per
protocol improvement of the remaining 7 patients 30 days after
treatment was 14±16 dB (Suckfuell et al., 2007).
Clinical development progressed through a 210 patient Phase II
clinical trial and two Phase III clinical trials of 256 and 300 pa-
tients respectively. The Phase II study evaluated the same 2 doses
of AM-111 and a placebo treatment in patients suffering noise in-
duced or idiopathic sudden sensorineural hearing loss (ISSHL). In-
tratympanic injection of 250μls of a gel formulation of AM-111 or
placebo was required to be administered within 48 h of the onset
of the hearing loss. The study failed to demonstrate a treatment
benefit for the entire study population because mild-to-moderate
SSHL cases showed unexpectedly strong spontaneous recovery.
However, in severe-to-profound SSHL patients (threshold >60 dB),
AM-111 0.4 mg/ml showed statistically significant, clinically rel-
evant, and persistent improvements in hearing and speech dis-
crimination and higher tinnitus remission compared with placebo
(Suckfuell et al., 2014).
The first Phase III study enroled 256 patients, aged 18 to 65
years, presenting within 72 h following ISSHL onset with mean
hearing loss ≥ 40 dB and mean threshold > 60 dB at the 3 worst
affected contiguous test frequencies. Patients received a single in-
tratympanic dose of either 0.4 mg/ml AM-111, 0.8 mg/ml AM-111
or placebo. Assessment of hearing improvement at 28 days post
treatment failed to show significance in the overall study popula-
tion. Despite this, a post-hoc analysis showed a clinically relevant
and nominally significant treatment effect for AM-111 0.4 mg/ml
in patients with profound ISSHL (Staecker et al., 2019). The second
Phase III study was prematurely terminated after the enrolment of
only 56 of the planned 300 patients, attributed to the failure of
the first Phase III study to meet its primary endpoint (clinicatri-
als.gov: NCT02809118).
3.3. Calcineurin inhibitor & 5HT3 receptor antagonist
The antiemetic Serotone®, a racemic mixture of azasetron has
been marketed in Japan following approval in the mid-1990s
(https://www.torii.co.jp/en/release/20 09/20 090113.html). Azasetron
is both a calcineurin inhibitor and a 5HT3 receptor antagonist. Cal-
cineurin, which is activated by increased Ca2+ levels immediately
following severe noise trauma, has been shown to activate cell
death pathways in guinea pig cochlear hair cells (Minami et al.,
2004). 5HT3 receptors, named for their ligand serotonin (5-
hydroxytryptamine or 5HT), are gated ion channels which con-
4
Hearing Research 426 (2022) 108637
trol the cellular influx of Ca2+ ions following trauma, disrupting
homoeostasis, causing excitotoxicity and neuroinflammation. Dis-
covery of their expression in mouse and rat cochleae (Oh et al.,
1999) and the ability of the 5HT3 receptor antagonist ondansetron
to reduce functional impairment and reduce vestibular deficit in
humans and animals (Dyhrfjeld-Johnsen et al., 2013; Venail et al.,
2012), led to the investigation of azasetron as a treatment for SSHL.
Ultimately, the (R) enantiomer of azasetron, which was found to
be more highly distributed to the inner ear than the (S) enan-
tiomer following oral dosing in rats, was progressed by Sensorion
SA into preclinical and clinical development for hearing loss indi-
cations.
Under the development name SENS-401 (R-azasetron besylate),
efficacy has been demonstrated in a range of animal models. For
example, protection from cisplatin chemotherapy induced hear-
ing loss by SENS-401 was demonstrated in rats, whilst the tox-
icity of cisplatin against 4-tumour cell lines in vitro was found
to be maintained in the presence of SENS-401 (Petremann et al.,
2017). In a rat noise induced hearing loss model, twice daily doses
of SENS-401 demonstrated a dose-response protective relationship
with significant improvements in ABR measures after 28 days of
oral treatment. These improvements were achieved with up to a
96-hour delay between administering the trauma and starting to
dose SENS-401. Similarly, a significant increase in surviving outer
hair cells, particularly at the basal turn of the cochlea, was re-
ported with delayed dosing (Petremann et al., 2019).
A Phase I study evaluated safety and tolerability of oral SENS-
401 in healthy volunteers. Across three cohorts, test subjects re-
ceived either one 29 mg oral dose of SENS-401 daily for 7 days or
one 29 mg or 43.5 mg oral dose of SENS-401 twice daily for 6 days
plus once on the 7th morning. The study also included placebo
treatment in each cohort at a 2:1 ratio. Whilst the primary out-
come measure was safety, pharmacokinetics and interconversion of
the (R) enantiomer to the (S) enantiomer in human plasma were
also evaluated (Clinicaltrials.gov: NCT03071003).
Results of the clinical trial have not been published, however it
is thought to have been successfully completed (Fakhfouri et al.,
2019). Sensorion have progressed the clinical development of
SENS-401 with a Phase II clinical trial in 115 patients suffering
from SSHL (Clinicaltrials.gov: NCT03603314).
As in the Phase II trial, 2 different doses of SENS-401 were eval-
uated against a placebo with all patients receiving 2 oral doses
of SENS-401 tablets per day for 4 weeks. The trial inclusion cri-
teria required participants to have started treatment within 96 h
of the onset of their SSHL. The primary endpoint of the study was
a 15 dB improvement in pure tone audiometry in the affected ear
from baseline in comparison to placebo at the end of the 4 week
treatment period
Results reported by the company in early 2022 showed that al-
though the drug was safe and well tolerated the primary end point
was not met (https://s27.q4cdn.com/232015521/files/doc_news/
Sensorion- Updates- on- SENS- 401- Phase- 2- trial- in- Sudden- Sensor-
ineural- Hearing- Loss- 2022.pdf). A subsequent analysis of ex-
ploratory endpoints found that a statistically significant and
clinically meaningful treatment effect of at least 10 dB vs placebo
was observed with the high dose at Day 84 in the per protocol
idiopathic SSNHL population (81 patients) treated with corticos-
teroids (https://s27.q4cdn.com/232015521/files/doc_news/2022/03/
03_17_22_SENS_SENS_401_Secondaryendpoints_ENG_Q4.pdf). Why
an effect was seen 8 weeks after the end of dosing is unclear and
remains to be explained. Additionally, in a sub-group of idiopathic
patients suffering from profound hearing loss (PTA at screening
≥ 80 dB) treated with corticosteroids, a significant response was
observed at Day 28 and at Day 84, demonstrating a 19 to 26 dB
significant improvement from baseline compared to placebo for
the low and high doses respectively.
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
Sensorion are also entering the clinic to investigate the ability
of SENS-401 to reach the perilymph following oral dosing (Clin-
icaltrials.gov: NCT05258773). This study will be undertaken in CI
patients and will allow for the evaluation of the protection and
preservation of their pre-operative residual hearing. A further clin-
ical study is also being planned to evaluate SENS-401 for the pre-
vention of cisplatin induced hearing loss.
3.4. Glutathione peroxidase-like antioxidant
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) a synthetic
seleno-organic drug molecule with anti-inflammatory and antiox-
idant activities has been investigated as a possible treatment for
a range of indications including hearing loss and tinnitus. With
a glutathione peroxidase-like activity (Müller et al., 1984), ebselen
treatment of rat organ of Corti explants in vitro resulted in protec-
tion of hair cells from damage (Kopke et al., 1997). Oral treatment
for 7 days post intratympanic injection of gentamicin protected
guinea pig organ of Corti from ototoxic effects (Takumida et al.,
1999). Later work identified oral dosing of ebselen as protecting
against noise induced permanent threshold shifts and outer hair
cell loss in guinea pigs and rats (Lynch et al., 2004; Pourbakht and
Yamasoba, 2003). Further preclinical studies found that ebselen can
protect against cisplatin and tobramycin aminoglycoside induced
hearing loss in rat and mice models respectively (Gu et al., 2021;
Lynch et al., 2005)
Renamed SPI-1005, clinical development of ebselen was com-
menced by Sound Pharmaceuticals Inc. in 2006 with a Phase I
in 32 healthy volunteers evaluating the safety, tolerability and
pharmacokinetics of single oral SPI-1005 doses from 200 mg to
1600 mg (clinicatrials.gov: NCT01452607) (Lynch and Kil, 2009).
Additional clinical trials have followed in Meniere’s Disease, to-
bramycin induced ototoxicity in cystic fibrosis patients, as well as
cisplatin induced, and noise induced hearing loss. For Meniere’s
Disease, a 40 patients Phase I/II study (Kil et al., 2018), and a
subsequent completed 149 patient Phase II study (clinicatrials.gov:
NCT03325790), both reported statistically significant and clinically
relevant improvements in hearing loss, word recognition, and tin-
nitus loudness compared to placebo (Kil et al., 2022). An ongoing
200 patient Phase III study is due to be completed in April 2023
(Clinicaltrials.gov: NCT04677972).
An 80 patient Phase II clinical trial is underway to evaluate SPI-
1005 s ability to protect patients’ hearing against tobramycin in-
duced ototoxicity, when given orally, twice daily for 21 days (clin-
icatrials.gov: NCT02819856). A further 80 patient Phase II clinical
trial evaluating the SPI-1005 s otoprotective potential in patients
receiving cisplatin chemotherapy is also on-going (clinicatrials.gov:
NCT01451853).
Finally, and most relevant to the impacts of cochlear implanta-
tion, Sound Pharmaceuticals Inc. completed an 83 patient Phase II
clinical trial to assess the ability of SPI-1005 to prevent noise in-
duced hearing loss following a calibrated sound challenge. Three
dose levels of SPI-1005 or placebo were administered twice daily
for 4 days starting 2 days before the noise challenge. Measured
15 min after the end of the calibrated sound challenge, a signif-
icant and clinically meaningful 68% reduction in the temporary
threshold shift was detected in the group taking 400 mg SPI-1005
versus the placebo group. The groups dosed with 200 mg and
600 mg of SPI-1005 experienced a 21% and a 7% reduction respec-
tively in the temporary threshold shift, which was not significant
(Clinicaltrials.gov: NCT01444846) (Kil et al., 2017).
As a result of the highest dose group (600 mg) experiencing
the poorest reduction in the temporary threshold shift, a further
dose range finding Phase II study has been undertaken treating 180
patients with prior noise induced hearing loss. In this study pa-
tients were dosed orally with 200 mg SPI-1005, 400 mg SPI-1005
5
Hearing Research 426 (2022) 108637
or placebo one day before a calibrated sound challenge and for 6
days after the challenge. Pure tone audiometry and word recog-
nition assessments will be performed before dosing and after the
sound challenge, and adverse events tracked. At the time of writ-
ing results for this study are yet to be reported (Clinicaltrials.gov:
NCT02779192).
3.5. Other molecules
The latest company to enter the clinic with an otoprotective
molecule is Audiocure GmbH who are developing AC102. Claim-
ing a mechanism of action that reduces apoptosis of outer hair cell
after acute trauma as well as triggering regeneration of inner and
outer hair cells and neurons, the molecule entered a Phase I clin-
ical trial in 2020 (https://www.audiocure.com/pr_20190129- 3- 2/).
Whilst the composition of AC102 and its precise mechanism of ac-
tion has not been disclosed, patents filed by the company indicate
that it is likely to be a 9-methyl-ß-carboline which has been found
to have stimulative, protective, regenerative and anti-inflammatory
effects on dopaminergic neurons (Polanski et al., 2010). The com-
pany intends to explore the utility of AC102 in hearing loss, tinni-
tus and cochlear implant electrode insertion trauma.
A range of other therapeutic molecules which target the inflam-
matory, oxidative stress and apoptotic pathways via varying mech-
anisms of action are currently under development by several dif-
ferent companies. These are summarised in Table 2 along with
their latest status as at time of writing.
Additional therapeutic molecules which target other causes of
hearing loss are also in development. These include approaches
to regrow spiral ganglion neurons, regenerate hair cells and re-
connect their synapses as well as replacing mutated genes with
adeno-associated virus gene therapy approaches. Whilst these ther-
apies may also improve CI outcomes they are not designed to pre-
serve or protect the candidate’s existing residual hearing. As such
we have not explored these approaches in this paper, but they are
covered in other reviews (Isherwood et al., 2022; Schilder et al.,
2019).
4. Supportive therapies and their delivery
Despite the significant surgical and implant design improve-
ments that aim to support the preservation of residual hearing
during and after cochlear implantation, CI patients may still lose
their residual hearing in the weeks or months after surgery. Ther-
apeutics could provide a solution, working in a synergistic fashion
with CIs. Presented here is the latest status of several therapeutics
in development for a range of otologic indications. Based on their
mechanisms of action, these therapeutics may have application in
preserving or enhancing residual hearing and thus improving out-
comes in cochlear implant patients. We review and discuss these
otoprotective interventions through the lens of achieving success-
ful drug delivery. Should inner ear drug delivery be achievable,
we consider the potential impact the therapeutics could have on
cochlear implant patients based on their mechanism of action.
Where inner ear drug delivery is a challenge, we explore the op-
portunities that the CI’s inner ear access could provide.
5. Systemic drug delivery
A key challenge for inner ear therapeutics, as with many drugs,
lies in delivery. That is, reaching the desired location, at an effica-
cious concentration and over the necessary time course to bind to
the target and elicit a response (Morgan et al., 2012). The inner ear
is a privileged environment within the body, isolated and protected
from the extended circulatory systems, much like the eye and the
brain. Indeed, the cochlea is found deep within the temporal bone,
R.D. Gay, Y.L. Enke, J.R. Kirk et al. Hearing Research 426 (2022) 108637

Table 2
Compounds under preclinical and clinical development for the treatment of a range of hearing loss indications.

Mechanism of Route of Target

Company Molecule Action Administration Indications Status Reference

Acousia ACOU082 KCNQ4 receptor Transdermal patch ARHL Preclinical www.acousia.com

Therapeutics agonist NIHL (Rim et al., 2021)
GmbH
Acousia ACOU085 KCNQ4 receptor Intratympanic DIHL Preclinical www.acousia.com
Therapeutics agonist injection NIHL (Rim et al., 2021)
GmbH SSHL
CI
Nordmark Ancrod Fibrinogenase Intravenous SSHL Phase II www.nordmark-pharma.de
Arzneimittel GmbH reduces levels of infusion and Cinicaltrials.gov: NCT01621256
& Co. KG fibrinogen subcutaneous
injection
Anida Pharma Inc AP-001 Prevents ROS Intratympanic DIHL Preclinical www.anida.com
Neuroprotectin formation injection NIHL
D1 SSHL
CI
Audiocure Pharma AC-102 Stimulative, Intratympanic NIHL Phase I www.audiocure.com
GmbH protective, injection ARHL
regenerative and CI
anti-inflammatory
effects on
dopaminergic
neurons
Auris Medical AM-111 Inhibition of the Intratympanic SSHL Phase III www.aurismedical.com
Holdings Ltd D-JNKI-1 JNK stress kinase injection Clinicaltrials.gov: NCT02561091
Decibel DB-020 Prevents ROS Intratympanic DIHL Phase I www.decibeltx.com
Therapeutics Inc Sodium formation injection Clinicaltrials.gov: NCT04262336
Thiosulphate
Decibel DB-041 Blocks outer hair Oral DIHL Phase I www.decibeltx.com
Therapeutics Inc (ORC-13661) cell www.oricularx.com
(Licenced from mechanoelectrical
Oricular transducer channel
Therapeutics Inc) and prevents
uptake of
aminoglycosides
Fennec PedmarkTM Prevents ROS Intravenous DIHL Registration www.fennecpharma.com
Pharmaceuticals Sodium formation infusion (Brock et al., 2018; Freyer et al., 2017)
Inc Thiosulphate
Gateway GW-HP1 Calcium channel Oral NIHL Phase II www.gatewaybiotechnology.com
Biotechnology Inc Zonisamide blocker Clinicaltrials.gov: NCT04768569
Gateway GW-HLT2 Calcium channel TBA TBA Preclinical www.gatewaybiotechnology.com
Biotechnology Inc Tetrandrine blocker (Yu et al., 2018)
Hoba Therapeutics HB-097 Neurotrophin/ TBA TBA Preclinical www.hobatherapeutics.com
Recombinant Neuroprotectant (Jørgensen et al., 2012)
human
cometin
Moderna Inc mRNA-1647 mRNA vaccine Subcutaneous CMV in Phase II www.modernatx.com
injection pregnancy Clinicaltrials.gov: NCT04232280
Novear TBA TRVP1 inhibition TBA NIHL Preclinical www.noveartherapeutics.com
Therapeutics and anti-TNFα (Dhukhwa et al., 2019)
Oblato Inc NHPN-1010 Prevents ROS Oral NIHL Phase I Clinicaltrials.gov: NCT02259595
(Licenced from (HPN-07 and formation (Choi, 2012)
Otologic NAC)
Pharmaceuticals
Inc)
Otonomy OTO-510 Not disclosed Intratympanic DIHL Preclinical www.otonomy.com
injection
Pragma TBA Metabotropic TBA ARHL Preclinical www.pragmatherapeutics.com
Therapeutics glutamate receptor SSHL
subtype 7
modulation
PTC Therapeutics EPI-743 NADPH quinone Oral NIHL Phase II www.ptcbio.com
(formerly VincerinoneTM oxidoreductase 1 clinicaltrials.gov: NCT02257983
Bioelectron/Edison (NQO1) reduces
Pharmaceuticals) oxidative stress
Sensorion SA SENS-401 5HT3 receptor Oral SSHL Phase II www.sensorion.com
Azasetron antagonist and Clinicaltrials.gov: NCT03603314
calcineurin
inhibitor
(continued on next page)

6
R.D. Gay, Y.L. Enke, J.R. Kirk et al. Hearing Research 426 (2022) 108637

Table 2 (continued)

Company Molecule Mechanism of Route of Target Status Reference

Action Administration Indications

Sensorion SA SENS-401 5HT3 receptor Oral DIHL Preclinical www.sensorion.com

Azasetron antagonist and (Petremann et al., 2017)
calcineurin
inhibitor
Sensorion SA SENS-401 5HT3 receptor Oral CI Preclinical www.sensorion.com
Azasetron antagonist and
calcineurin
inhibitor
Sound SPI-1005 Glutathione Oral NIHL Phase II www.soundpharma.com
Pharmaceuticals Ebselen peroxidase-like Clinicaltrials.gov: NCT02779192
activity
Sound SPI-1005 Glutathione Oral DIHL Phase II www.soundpharma.com
Pharmaceuticals Ebselen peroxidase-like Clinicaltrials.gov:
activity NCT02819856 and NCT01451853
Spiral Therapeutics LPT99 Apoptotic Protease Intratympanic NIHL Phase I www.spiraltx.com
Activating Factor 1 injection DIHL ANZCTR.org.au: 12,618,001,461,280
(APAF1) inhibitor
Strekin AG STR-001 Peroxisome Intratympanic SSHL Phase III www.strekin.com
Pioglitazone Proliferator- injection + oral CI Clinicaltrialsregister.eu:
Activated Receptor 2017–000,242–22
gamma (PPARɣ)
Ting Therapeutics TT001 Cyclin-Dependent TBA NIHL Preclinical www.tingtherapeutics.com
(AZD5438) kinase 2 (CDK2) DIHL (Hazlitt et al., 2018)
inhibitor
13Therapeutics, P13 Modulation of Eardrop NIHL Preclinical www.13therapeutics.com
Inc. Toll-like Receptor ARHL
signalling
KEY: ARHL: Age Related Hearing Loss. NIHL: Noise Induced Hearing Loss. DIHL: Drug Induced hearing Loss. SSHL: Sudden Sensorineural Hearing Loss. CI: Cochlear Implant.
TBA: To Be Announced.

making direct access highly invasive. Furthermore, it is surrounded

by a blood-labyrinth-barrier (BLB) which is comprised of non-
fenestrated capillaries with tight junctions (Jahnke, 1980). The BLB
is considered to be comparable to the well characterised blood-
brain-barrier (BBB) (Inamura and Salt, 1992; Pardridge, 2005). Like
the BBB, the BLB regulates the entry and exit of compounds based
on their molecular weight and lipophilicity (Jahnke, 1980). The BLB
acts as a biological gatekeeper to the cochlear perilymph, whose
homoeostasis is critical for functional hearing.
Systemic drug administration targeted to the inner ear may
struggle to reach the cochlear perilymph at sufficient concentra-
tions, if at all, whilst exposing the rest of the patient’s body to the
drug and the risk of off-target side effects. This challenge is ex-
emplified in attempts at otoprotection in patients undergoing cis-
platin chemotherapy. In addition to neutralising the ototoxic effects
of the chemotherapy in the inner ear, otoprotective drugs deliv-
ered systemically may work off-site and compromise the activity Fig. 1. BOILED-Egg plot of otoprotective drugs in development for hearing loss
of the chemotherapeutic in cancerous tissues (Li et al., 2001). It which are delivered systemically.
is unlikely the patient or oncologist would risk the effectiveness
of potentially life-saving treatments to protect hearing. It is these
challenges that Fennec’s PedmarkTM (sodium thiosulfate) faces as it A useful tool to assess the characteristics of a therapeutic small
is administered systemically via IV infusion. Treatment is indicated molecule and its potential ability to cross the BBB and by inference
to commence 6 h after the infusion of the chemotherapy to avoid the BLB is the Brain Or IntestinaL EstimateD permeation method
any impact on its efficacy (Brock et al., 2018; Freyer et al., 2019). (BOILED-Egg) (Daina and Zoete, 2016). Based on an assessment
Where the therapeutic is targeted to the inner ear, with lim- of the topological polar surface area (TPSA) and a measure of
ited or acceptable off-site effects, and can cross the BLB, systemic lipophilicity (WLOGP), each molecule is displayed on a graph with
dosing may be a feasible option. areas predefined for absorbence from the intestines into the circu-
Oral administration is being trialled for Sensorion’s SENS-401, lation (shown as the white of a boiled egg) and from the circula-
Strekin’s STR-001 and Sound Pharmaceuticals’ SPI-1005. SENS-401 tion into the brain, across the BBB (shown as the yolk of a boiled
(azasetron) has a molecular weight of 349.81 Da whilst the molec- egg). Assuming that the behaviour of the BBB and BLB are compa-
ular weight of SPI-1005 (ebselen) and STR-001 (pioglitazone) are rable, compounds falling within, or close to, the yolk of the egg are
274.20 Da and 356.44 Da respectively. All are therefore poten- also predicted to reach the perilymph of the cochlea from systemic
tially small enough to cross the BLB, which has a molecular weight administration.
threshold of less than 400 – 500 Da (Pardridge, 2003). However, By way of example, utilising the characteristics of dexametha-
other factors such as high lipid solubility (lipophilicity), also need sone within the BOILED-Egg modelling results in its plotting within
to be considered. the white of the boiled egg (Fig. 1). This would suggest that, as the

7
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
molecule is not able to cross the BLB, systemic dosing is unlikely
to be efficacious in the inner ear. This may also explain why a sin-
gle dose of dexamethasone delivered via intratympanic injection or
applied to the round window during CI surgery is less efficacious
than the sustained exposure provided by a drug eluting electrode.
The former may not be able to cross into the scala tympani effec-
tively and the later may not be able to leave.
As shown in Fig. 1, SENS-401 sits on the cusp of the border be-
tween the egg white and yolk, whilst SPI-1005 is plotted within
the yolk indicating likely transfer across the BLB into the peri-
lymph for both molecules following systemic administration. STR-
001, however, is entirely outside of the egg yolk which is a poten-
tial indication of it not being able to transfer from the circulation
into the perilymph. As such, whilst STR-001 was initially delivered
via local intratympanic injection, the addition of the systemic oral
dosing arms to the Phase III study, with the goal of increasing the
exposure of the inner ear to the therapy, may not have provided
any further benefit.
Further concerns regarding the ability of STR-001 to enter the
cochlea from oral dosing are also raised by the finding that pi-
oglitazone complexes with human serum albumin (Faridbod et al.,
2011). Association with an 86.5 KDa protein in the systemic cir-
culation would impede any uptake across the BLB unless this was
mediated by a receptor, which is still to be demonstrated.
Interestingly, ebselen is also associated with human serum al-
bumin in vivo. In contrast to STR-001 however, transfer to proteins
containing reactive thiols appears to allow transport of ebselen
across membranes such as the BLB (Schewe, 1995; Wagner et al.,
1994). Thus, according to analysis via the BOILED-Egg method, but
dependant on off-target side effect safety profiles, both SPI-1005
and SENS-401 appear to be promising orally dosed systemic thera-
peutics for the treatment of SSHL.
There are currently four other drugs in clinical development for
hearing loss indication with oral routes of administration (Table 2).
These are Decibel Therapeutics’ DB-041, Oblato Inc’s NHPN-1010
(HPN-07 + NAC), PTC Therapeutics’ EPI-743 and Gateway Biotech-
nology Inc’s GW-HP1. As shown in Fig. 1, assessment of each drug
with the BOILED-Egg tool finds that they are either unable to cross
from the intestine into the systemic circulation (HPN-07 and EPI-
743) or unable to travel from the systemic circulation across the
BBB or BLB (DB-041, NAC and GW-HP1). Whilst mechanisms of ac-
tion may provide otoprotection, it remains to be reported whether
any of these compounds are indeed efficacious in human clinical
trials when dosed orally.
The SwissADME version of the BOILED-Egg method also pro-
vides visualisation of whether or not a molecule is a sub-
strate of the ATP-dependant drug transport protein P-Glycoprotein
(Daina et al., 2017). P-Glycoprotein functions to back-transport
molecules from the brain and the inner ear to the blood across
the BBB and BLB respectively (Saito et al., 1997; Schinkel, 1999). As
such, any molecules that are a substrate of P-Glycoprotein which
are predicted to be transported out of the perilymph are plotted
in blue on the BOILED-Egg (Figs. 1 and 2). Molecules which are
not substrates of P-Glycoprotein and are predicted to remain in the
perilymph are plotted in red (Figs. 1 and 2).
As shown in Figs. 1 and 2, dexamethasone is plotted blue as
it is a substrate of P-Glycoprotein. As such dexamethasone will be
continually removed from the cochlea and constant replenishment
will be required for efficacy. Thus, sustained intra-cochlea deliver
would appear to be required for dexamethasone to be efficacious,
and limited or no efficacy would be expected from systemic or sin-
gle middle ear dosing.
In this analysis ebselen, which appears able to cross into the in-
ner ear following oral dosing, is not removed by P-Glycoprotein
mediated transport. This does not appear to be the case for aza-
setron which, if able to enter the inner ear, is predicted to be re-
8
Hearing Research 426 (2022) 108637
Fig. 2. BOILED-Egg plot of otoprotective drugs in development for hearing loss
which are delivered locally.
Plots generated at the Swiss Institute of Bioinformatics SwissADME website (http://
swissadme.ch/index) using canonical Simplified Molecular-Input Line-Entry System
(SMILES) data obtained for each molecule from the National Library of Medicine’s
PubChem website (https://pubchem.ncbi.nlm.nih.gov/).
X-axis plots Topological Polar Surface Area (TPSA) whilst the Y-axis plots a predic-
tive model of lipophilicity (WLOGP) (Daina et al., 2017). Blue dots are substrates of
P-Glycoprotein whist red dots are not. The boundary of the egg white represents
the intestinal-blood interface whilst the boundary of the egg yolk represents the
blood-brain and blood-labyrinth barriers.
moved. These findings should influence the development of each
drug’s systemic dosing regimen to establish a sufficient steady
state plasma concentration to maintain the desired therapeutic
concentration in the cochlea.
Whilst models are useful for evaluating and predicting the per-
formance of a therapeutic in vivo, ultimately, clinical data is the
true test of efficacy. Results to date from Sensorion’s clinical devel-
opment of SENS-401 demonstrate a protection and restoration of
hearing of up to 15 dB for patients entering the trial with SSNHL
greater than 80 dB. Data from Sound Pharmaceuticals’ on-going
clinical trials with ebselen are keenly awaited.
Should clinical efficacy not be demonstrated by any of the sys-
temically dosed compounds discussed, it will be important to con-
sider whether other routes of administration would be more effica-
cious. As each has a proven mechanism of action, at least preclin-
ically, intratympanic and even intracochlear administration could
be considered to validate their therapeutic potential.
Based on their mechanisms of action, each of the molecules
in development presented in Table 2 should also be considered
for the reduction of the body’s response to electrode insertion in
cochlear implantation and the protection of low-frequency residual
hearing in CI recipients. As detailed by Kirk and Smyth in this is-
sue (Kirk and Smyth, 2022), cochlear implantation triggers a cas-
cade of reactions in the cochlea including inflammation, fibrosis
and apoptosis with each contributing in an additive way to the
resulting additional hearing loss. Inhibiting any of these reactions
is likely to be beneficial in reducing the body’s response to the
trauma and improving patient outcomes by protecting their low-
frequency residual hearing from damage by the body’s defensive
responses.
To date none of the systemically dosed otoprotectants listed
in Table 2 have been tested in a CI patient population, although
their anti-inflammatory and anti-apoptotic properties may indeed
prove beneficial (STR-001, SENS-401 and SPI-1005). Calcium chan-
nel blockers (GW-HP1, GW-HLT2), antioxidants and anti-reactive
oxygen species therapies also feature prominently (PedmarkTM ,
NHPN-1010, and EPI-743) and similarly block the initiation of
apoptosis. Evaluating these treatments in preclinical animal CI
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
models and the CI patient population may demonstrate significant
efficacy in improving CI outcomes whilst also potentially harness-
ing the CI to improve sustained drug delivery to the inner ear.
6. Local drug delivery
Where systemic delivery to the inner ear is not possible or not
well tolerated, a more local drug delivery approach must be con-
sidered. Intratympanic injection, where the therapeutic is injected
through the tympanic membrane and into the middle ear, has been
widely used. The success of this approach relies on two key factors.
Firstly, the injected therapeutic must have contact with either the
round or oval window membranes of the cochlea and secondly, the
therapeutic must be able to diffuse across these membranes into
the perilymph. Whilst simple in theory, in practice intratympanic
injection is not straight forward and some therapeutics in develop-
ment may indeed have failed to progress in the clinic because of
issues utilising this mode of administration.
The middle ear space connects to the nasopharynx via the Eu-
stachian tube. With a primary role of equalising middle ear and
atmospheric pressure, the Eustachian tube also drains fluid which
may accumulate in the middle ear, especially during infection. As
a result, injecting a liquid therapeutic into the middle ear will lead
to rapid clearance to the stomach via the Eustachian tube and the
oesophagus. From there, some systemic exposure may even occur,
if the drug can be absorbed from the stomach, with the potential
for off-site side effects, as discussed above.
In general, it is the off-label use of liquid steroid solutions
which exploit this route of administration. Intratympanic injection
is relatively rapid and when performed in adults can be under-
taken in the doctor’s office rather than the operating theatre. The
patient will lie on their side during the treatment and for 20 to
30 min post injection to reduce loss to the stomach and allow the
liquid to bathe the cochlear window membranes. The patient will
also be instructed to not swallow during this time to reduce clear-
ance.
A more reliable approach developed for intratympanic injection
is the use of thermosensitive gels to deliver therapeutics into the
middle ear. These polymer compounds are liquid at room temper-
ature and a gel at body temperature. They allow for the injection
of a therapeutic liquid into the middle ear which then increases
in viscosity to improve middle ear residence and reduce clearance.
Many of the molecules in development discussed above utilise this
approach, with the Poloxamer 407 compound being the most fre-
quently used carrier. Whilst clearance to the stomach may still oc-
cur, the gel provides a greater opportunity for the therapeutic to
be in contact with the oval and round window membranes. Chal-
lenges remain as the oval window is covered by the stapes foot-
plate and the round window sits within a niche making it less
accessible, often obstructed by the bony round window promon-
tory. These human anatomical factors, which may prevent the gel
therapeutic contacting the window membranes, may be different
to those in animal models used to preclinically evaluate the per-
formance of such gels in vivo. The round window membrane itself,
whilst of similar construction across species, is thicker in larger an-
imals (Goycoolea et al., 1988). Furthermore, the thickness of the
bone of the cochleae may also differ between animals and humans
such that drug uptake into the cochlea may not only be via these
window membranes but across the bone itself (Salt et al., 2011).
As a result, translation of preclinical result to human clinical out-
comes may not always be assured.
Furthermore, in around 33% of patients the round window is
obstructed by either fat or fibrous plugs or extraneous round win-
dow ‘false’ membranes (Alzamil and Linthicum, 20 0 0). These ob-
structions may interfere with the exposure of the round window
9
Hearing Research 426 (2022) 108637
membrane to the therapeutic gel, resulting in variable dosing and
clinical outcomes.
The failed development of Otividex® by Otonomy Inc., may
exemplify the challenges and variability of intratympanic dosing.
Also known as OTO-104, 12% dexamethasone was formulated into
a Poloxamer 407 gel for intratympanic injection. Clinical develop-
ment for the treatment of unilateral Meniere’s Disease progressed
through to three Phase III clinical studies of 165, 176 and 149 pa-
tients respectively. Only one of these three Phase III clinical stud-
ies met their primary endpoint and after over 10 years of clinical
trials the company recently ceased development (Clinicaltrials.gov:
NCT02612337, NCT02717442 and NCT03664674).
Once the therapeutic molecule is successfully presented to the
round window membrane, it must travel into the perilymph of the
scala tympani. The round window is a semi-permeable membrane
made up of three layers. The outer and inner epithelial layers are
continuations of the middle ear mucous membrane and scala tym-
pani mesothelial cell lining respectively. Between sits fibroblasts,
collagen and elastic fibre connective tissue infused with blood and
lymph vessels (Goycoolea, 2001). Animal studies have shown that a
wide range of molecules can travel across the round window mem-
brane; as small as a sodium ion (22.8 Da) and as large as the pro-
tein albumin (66.5 KDa) or the monoclonal antibody golimumab
(∼150 KDa) (Ghossaini et al., 2013). This ability is based on a range
of factors including the molecule’s size, concentration, lipid solu-
bility, electrical charge, the presence of facilitating agents and the
thickness and condition of the membrane. Membrane thickness is
the key difference between species used in pre-clinical studies and
humans, with transfer mechanisms of diffusion, pinocytosis and
phagocytosis identified (Goycoolea et al., 1988).
There is evidence that different molecules cross the round
window membrane at different rates which appears to correlate
with each molecule’s lipid solubility and polar surface area prop-
erties. In one study the uptake of two similar molecules from
the middle ear into the scala tympani and scala vestibuli in
guinea pigs was compared. In this study, a less polar molecule
(dexamethasone) was transferred across the round and oval win-
dows far quicker that a more polar one (dexamethasone phos-
phate) (Salt et al., 2018). Comparing these two molecules with
the BOILED-Egg method indicates that dexamethasone is plotted
within the white of the egg, whilst dexamethasone phosphate, be-
ing more polar and having a higher topological polar surface area
(TPSA), is plotted outside of the egg white (Fig. 2). These differ-
ing membrane permeability characteristics present numerous chal-
lenges and considerations around the inner ear delivery approach
chosen and the compound’s retention. Different membrane per-
meability characteristics have also been reported for triamcinolone
(poorer permeability) and triamcinolone acetonide (better perme-
ability) as well as for methylprednisolone succinate (poorer per-
meability) and methylprednisolone (better permeability) (Salt and
Plontke, 2018). As a result, the BOILED-Egg model assessment of
other molecules in development is important to define their abil-
ity to readily cross membranous boundaries. This is an additional
key factor that must be considered when developing an inner ear
drug for intratympanic administration.
Once inside the scala tympani a molecule will either be pas-
sively lost to the systemic circulation across the BLB if its proper-
ties plot it within the egg yolk, or it may be pumped out if it is a
substrate of the P-Glycoprotein membrane transporter.
Should the molecule remain in the scala tympani it will need
to diffuse from the basal turn of the cochlea towards the apex to
reach regions corresponding to lower frequencies of sound. Diffu-
sion will be incredibly slow (Plontke et al., 20 08, 20 07b) and drug
may also be lost to the cerebrospinal fluid (CSF) via the cochlea
aqueduct, if patent. Targeting the apex of the cochlea, and there-
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
fore low frequency hearing, with a therapeutic molecule may re-
quire an alternative delivery approach.
These factors must all be considered when assessing the dos-
ing and target site of therapeutics under development for otopro-
tection which are delivered intratympanically. Below we consider
these factors for the molecules which are currently in clinical de-
velopment as detailed in Table 2.
Intratympanic injection of Strekin’s STR-001 (pioglitazone) ap-
pears to be a sensible approach for delivery of the 356 Da
molecule. As noted above, systemic delivery is unlikely to be suc-
cessful as the molecule is complexed with human serum albumin.
Once inside the scala tympani, the BOILED-Egg model would pre-
dict that STR-001 would not be quickly lost, neither to the systemic
circulation across the BLB nor as a substrate of P-Glycoprotein.
However, translation of the promising preclinical results to the
clinic have failed to demonstrate therapeutic efficacy in both the
Phase II and Phase III clinical trials. We hypothesize that intra-
cochlear drug delivery may be needed to demonstrate efficacy in
humans.
Spiral Therapeutics’ LPT-99 at 628 Da is unable to cross the BLB
according to its size and the BOILED-Egg model (Fig. 2) and may
also be poorly transferred across the round window membrane.
Should LPT-99 successfully reach the scala tympani, clearance is
likely to be rapid as it is a substrate for P-Glycoprotein. Whilst clin-
ical trials for LPT-99 have been completed, no data has yet been
released. Similar challenges may be faced by Decibel Therapeutics’
DB-020 which, although only 158 Da in size, is predicted as un-
able to cross the into the scala tympani by the BOILED-Egg model
(Fig. 2). DB-020 is also a substrate for P-Glycoprotein limiting any
inner ear residence that may be achieved by intra-tympanic in-
jection. Although locally targeted, and therefore less likely to dis-
rupt the chemotherapy treatment than the intravenously dosed
PedmarkTM treatment, DB-020 efficacy will not be known until
the completion of the on-going Phase I/II clinical trial (Clinicaltri-
als.gov: NCT04262336).
Assuming that Audiocure’s AC-102 is indeed a 9-methyl-ß-
carboline, it’s molecular weight would be ∼182 Da which would be
suitable for transport across the round window membrane. How-
ever, according to the BOILED-Egg model, AC-102 is both able to
cross the BLB and is a substrate for P-Glycoprotein (Fig. 2). As a re-
sult, high intracochlear concentrations of AC-102 are not expected
to be maintained following a single intratympanic injection. AC-
102 is still in early clinical development so it may be some time
before it will be known if the predictions of the BOILED-Egg model
are correct.
Auris Medical’s AM-111 is a peptide produced synthetically by
linking the 20 amino acid terminal JNK-inhibitory sequence (JNK
binding domain) of JIP1/IB1 to a ten amino acid HIV-Tat trans-
porter sequence for cell penetration (Bonny et al., 2001). Since
AM-111 is a peptide, it cannot be assessed with the BOILED-Egg
model which has been established for small molecules (Daina and
Zoete, 2016). Clinical data has shown some otoprotective efficacy
of the 0.4 mg/ml intratympanic dose above placebo in both the
Phase II studies (7 and 90 days after treatment), and in the first
Phase III (28 days after treatment). In this Phase III, statistical sig-
nificance was only achieved in a post-hoc analysis of profoundly
hearing-impaired patients. In both studies, higher doses of AM-
111 were not efficacious. It is unfortunate that the company ter-
minated their second Phase III trial and have not continued with
the development of AM-111. Of all the otoprotective molecules in
development discussed in this paper, AM-111 has shown the most
promising clinical efficacy to date. We hypothesise that adopting
a less variable delivery approach, for example, intracochlear drug
delivery, would allow the anti-apoptotic D-JNK-1 inhibition of the
JNK stress kinase pathway to both provide otoprotection after noise
10
Hearing Research 426 (2022) 108637
trauma and to enhance CI patient outcomes by reducing the im-
pacts of electrode insertion trauma.
Amongst the other intratympanically delivered molecules under
development (see Table 2), apoptosis is targeted by CDK2 inhibitors
(TT001), whilst reactive oxygen species are also targeted (AP-001,
DB-020). It remains unclear how efficiently these molecules cross
the round window membrane after intratympanic administration
and therefore how efficacious they are likely to be in the inner ear.
Evaluating all these otoprotective treatments in pre-clinical an-
imal models of CI and subsequently in the CI patient population
may help to overcome the challenges of intratympanic injection.
Combining the drug with a CI also offers the opportunity to im-
prove delivery and extend therapeutic exposure in the inner ear.
Furthermore, based on their mechanisms of action, these treat-
ments also have the potential to improve CI outcomes by protect-
ing and preserving the patients existing residual hearing.
7. Conclusion
After many years of investment, research, and clinical trials
there are still no therapeutics approved for the treatment of hear-
ing loss. Here, we have detailed the status of a wide range of
prospective otoprotective treatments in development which target
a range of hearing loss aetiologies. Hearing loss however is not
a simple pathology, and in most cases a single cause cannot be
identified. As a result, combinations of efficacious therapeutics are
likely to be required in the future to treat the different types of
hearing loss. This adds an additional level of complexity to the al-
ready difficult task of bringing a drug to market.
In contrast, the CI can return some lost hearing function in
most cases regardless of the underlying pathology. This one size
fits all approach is highly effective, but improvement is always pos-
sible. Whilst reviewing the otoprotective therapeutics in develop-
ment we have considered how, based on their mechanisms of ac-
tion, they may contribute to CI outcomes by inhibiting the damag-
ing pathways which may be induced by the CI surgery. Although
there has been little specific progress in combining an otoprotec-
tive drug with a CI to date, there is significant potential. Many of
the drugs in development may benefit CI patients by protecting
their residual hearing and improving outcomes via enhancement
of the biological environment in which the CI functions.
Beyond otoprotection, there are also drugs in development for
hair cell regeneration, spiral ganglion neurite regeneration and
regrowth towards the modiolus as well as neuro-regeneration.
Whilst not explored in this paper, these therapeutic approaches
should also be considered for their potential to improve the out-
comes of CI patients whilst themselves benefiting from CI medi-
ated intracochlear sustained delivery.
The combination of a CI with a therapeutic is a tantalising
prospect helping to better integrate a human-made medical device
into the biology of the body. Whilst bringing a combination device
to the market is also complex and challenging, pairing an inner ear
therapeutic with a device which has been successfully implanted
in the inner ear for over 40 years may bring advantages. These in-
clude potential direct access of the therapeutic to the perilymph
as well as opportunities for sustained release. The CI also offers a
unique potential to provide inner ear monitoring and diagnostics
that could be utilised to objectively measure the responses to and
efficacy of new therapeutics in development
The next phases of otoprotective drug development and the im-
provements that these drugs can bring to cochlear implantation
have great potential to enhance hearing restoration and improve
the lives of the many millions of people who suffer from a dis-
abling hearing loss.
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
Web references
https://www.torii.co.jp/en/release/20 09/20 090113.html. Acces-
sed 16th June 2022.
https://s27.q4cdn.com/232015521/files/doc_news/
Sensorion- Updates- on- SENS- 401- Phase- 2- trial- in- Sudden-
Sensorineural- Hearing- Loss- 2022.pdf. Accessed 16th June 2022.
https://s27.q4cdn.com/232015521/files/doc_news/2022/03/
03_17_22_SENS_SENS_401_Secondaryendpoints_ENG_Q4.pdf. Ac-
cessed 16th June 2022.
https://www.audiocure.com/pr_20190129- 3- 2/. Accessed 16th
June 2022.
http://swissadme.ch/index. Accessed 16th June 2022.
https://pubchem.ncbi.nlm.nih.gov/. Accessed 16th June 2022.
Data Availability
No data was used for the research described in the article.
CRediT authorship contribution statement
Robert D. Gay: Conceptualization, Formal analysis, Writing
– original draft. Ya Lang Enke: Writing – review & editing.
Jonathon R. Kirk: Conceptualization, Writing – review & editing.
Denise R. Goldman: Writing – review & editing.
References
Ahmadi, N., Gausterer, J.C., Honeder, C., Mötz, M., Schöpper, H., Zhu, C., Saidov, N.,
Gabor, F., Arnoldner, C., 2019. Long-term effects and potential limits of intratym-
panic dexamethasone-loaded hydrogels combined with dexamethasone-eluting
cochlear electrodes in a low-insertion trauma Guinea pig model. Hear. Res. 384,
107825. doi:10.1016/j.heares.2019.107825.
Alzamil, K.S., Linthicum, F.H., 20 0 0. Extraneous round window membranes and
plugs: possible effect on intratympanic therapy. Ann. Otol. Rhinol. Laryngol. 109,
30–32. doi:10.1177/0 0 0348940 01090 0105.
Astolfi, L., Simoni, E., Giarbini, N., Giordano, P., Pannella, M., Hatzopoulos, S., Mar-
tini, A., 2016. Cochlear implant and inflammation reaction: safety study of a
new steroid-eluting electrode. Hear. Res. 336, 44–52.
Barkdull, G.C., Hondarrague, Y., Meyer, T., Harris, J.P., Keithley, E.M., 2007. AM-111
reduces hearing loss in a guinea pig model of acute labyrinthitis. Laryngoscope
117, 2174–2182. doi:10.1097/MLG.0b013e3181461f92.
Bas, E., Bohorquez, J., Goncalves, S., Perez, E., Dinh, C.T., Garnham, C., Hessler, R.,
Eshraghi, A.A., van de Water, T.R., 2016. Electrode array-eluted dexamethasone
protects against electrode insertion trauma induced hearing and hair cell losses,
damage to neural elements, increases in impedance and fibrosis: a dose re-
sponse study. Hear. Res. 337, 12–24. doi:10.1016/j.heares.2016.02.003.
Bird, P.A., Begg, E.J., Zhang, M., Keast, A.T., Murray, D.P., Balkany, T.J., 2007. Intratym-
panic versus intravenous delivery of methylprednisolone to cochlear perilymph.
Otol. Neurotol. 28, 1124–1130. doi:10.1097/MAO.0b013e31815aee21.
Bird, P.A., Murray, D.P., Zhang, M., Begg, E.J., 2011. Intratympanic versus intravenous
delivery of dexamethasone and dexamethasone sodium phosphate to cochlear
perilymph. Otol. Neurotol. 32, 933–936. doi:10.1097/MAO.0b013e3182255933.
Bonny, C., Oberson, A., Negri, S., Sauser, C., Schorderet, D.F., 2001. Cell-permeable
peptide inhibitors of JNK. Novel blockers of β -cell death. Diabetes 50, 77–82.
doi:10.2337/diabetes.50.1.77.
Briggs, R., O ’Leary, S., Birman, C., Plant, K., English, R., Dawson, P., Risi, F., Gavrilis, J.,
Needham, K., Cowan, R., 2020. Comparison of electrode impedance measures
between a dexamethasone-eluting and standard CochlearTM Contour Advance®
electrode in adult cochlear implant recipients. Hear. Res. 390. doi:10.1016/j.
heares.2020.107924.
Brock, P.R., Maibach, R., Childs, M., Rajput, K., Roebuck, D., Sullivan, M.J., Laithier, V.,
Ronghe, M., Dall’Igna, P., Hiyama, E., Brichard, B., Skeen, J., Mateos, M.E.,
Capra, M., Rangaswami, A.A., Ansari, M., Rechnitzer, C., Veal, G.J., Covezzoli, A.,
Brugières, L., Perilongo, G., Czauderna, P., Morland, B., Neuwelt, E.A., 2018.
Sodium Thiosulfate for protection from cisplatin-induced hearing loss. N. Engl.
J. Med. 378, 2376–2385. doi:10.1056/nejmoa1801109.
Chen, D., Luo, Y., Pan, J., Chen, A., Ma, D., Xu, M., Tang, J., Zhang, H., 2021. Long-term
release of dexamethasone with a polycaprolactone-coated electrode alleviates
fibrosis in cochlear implantation. Front. Cell Dev. Biol. 9. doi:10.3389/fcell.2021.
740576.
Cho, H.S., Lee, K.Y., Choi, H., Jang, J.H., Lee, S.H., 2016. Dexamethasone is one of the
factors minimizing the inner ear damage from electrode insertion in cochlear
implantation. Audiol. Neurootol. 21, 178–186. doi:10.1159/0 0 0445099.
Clark, G.M., 1996. Electrical stimulation of the auditory nerve: the coding of fre-
quency, the perception of pitch and the development of cochlear implant
11
Hearing Research 426 (2022) 108637
speech processing strategies for profoundly deaf people. Clin. Exp. Pharmacol.
Physiol. doi:10.1111/j.1440-1681.1996.tb01178.x.
Coleman, J.K.M., Littlesunday, C., Jackson, R., Meyer, T., 2007. AM-111 protects against
permanent hearing loss from impulse noise trauma. Hear. Res. 226, 70–78.
doi:10.1016/j.heares.20 06.05.0 06.
Daina, A., Michielin, O., Zoete, V., 2017. SwissADME: a free web tool to evaluate
pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small
molecules. Sci. Rep. 7, 42717. doi:10.1038/srep42717.
Daina, A., Zoete, V., 2016. A BOILED-Egg to predict gastrointestinal absorption and
brain penetration of small molecules. ChemMedChem 11, 1117–1121. doi:10.
10 02/cmdc.20160 0182.
Dhanasekaran, D.N., Reddy, E.P., 2008. JNK signaling in apoptosis. Oncogene 27,
6245–6251. doi:10.1038/onc.2008.301.
Dyhrfjeld-Johnsen, J., Gaboyard-Niay, S., Broussy, A., Saleur, A., Brugeaud, A., Chab-
bert, C., 2013. Ondansetron reduces lasting vestibular deficits in a model of
severe peripheral excitotoxic injury. J. Vestib. Res. 23, 177–186. doi:10.3233/
VES-130483.
Eshraghi, A.A., Wolfovitz, A., Yilmazer, R., Garnham, C., Yilmazer, A.B., Bas, E., Ash-
man, P., Roell, J., Bohorquez, J., Mittal, R., Hessler, R., Sieber, D., Mittal, J., 2019.
Otoprotection to implanted cochlea exposed to noise trauma with dexametha-
sone eluting electrode. Front. Cell Neurosci. 13, 492. doi:10.3389/fncel.2019.
00492.
Fakhfouri, G., Rahimian, R., Dyhrfjeld-Johnsen, J., Zirak, M.R., Beaulieu, J.M., 2019.
5-HT3 receptor antagonists in neurologic and neuropsychiatric disorders: the
iceberg still lies beneath the surface. Pharmacol. Rev. 71, 383–412. doi:10.1124/
pr.118.015487.
Faridbod, F., Ganjali, M.R., Larijani, B., Riahi, S., Saboury, A.A., Hosseini, M.,
Norouzi, P., Pillip, C., 2011. Interaction study of pioglitazone with albumin by
fluorescence spectroscopy and molecular docking. Spectrochim. Acta - Part A:
Mol. Biomol. Spectros. 78, 96–101. doi:10.1016/j.saa.2010.09.001.
Forge, A., 1985. Outer hair cell loss and supporting cell expansion following chronic
gentamicin treatment. Hear. Res. 19, 171–182. doi:10.1016/0378-5955(85)
90121-2.
Freyer, D.R., Brock, P., Knight, K., Reaman, G., Cabral, S., Robinson, P.D., Sung, L., 2019.
Interventions for cisplatin-induced hearing loss in children and adolescents
with cancer. Lancet Child Adolesc. Health doi:10.1016/S2352-4642(19)30115-4.
Gantz, B.J., Dunn, C., Oleson, J., Hansen, M., Parkinson, A., Turner, C., 2016. Multi-
center clinical trial of the Nucleus Hybrid S8 cochlear implant: final outcomes.
Laryngoscope 126, 962–973. doi:10.1002/lary.25572.
Ghossaini, S.N., Liu, J.P., Phillips, B., 2013. Round window membrane permeability to
golimumab in guinea pigs: a pilot study. Laryngoscope 123, 2840–2844. doi:10.
1002/lary.24163.
Goycoolea, M.V., 2001. Clinical aspects of round window membrane permeabil-
ity under normal and pathological conditions. Acta Otolaryngol. doi:10.1080/
0 0 0164801300366552.
Goycoolea, M.V., Muchow, D., Schachern, P., 1988. Experimental studies on round
window structure: function and permeability. Laryngoscope 98, 1–20. doi:10.
1288/0 0 0 05537-1988060 01-0 0 0 02.
Gu, R., Longenecker, R.J., Homan, J., Kil, J., 2021. Ebselen attenuates tobramycin-
induced ototoxicity in mice. J. Cyst. Fibros. 20, 271–277. doi:10.1016/j.jcf.2020.
02.014.
Hibi, M., Lin, A., Smeal, T., Minden, A., Karin, M., 1993. Identification of an
oncoprotein- and UV-responsive protein kinase that binds and potentiates the
c-Jun activation domain. Genes Dev. 7, 2135–2148. doi:10.1101/gad.7.11.2135.
Hu, B.H., Henderson, D., Nicotera, T.M., 2002. Involvement of apoptosis in progres-
sion of cochlear lesion following exposure to intense noise. Hear. Res. 166, 62–
71. doi:10.1016/S0378- 5955(02)00286- 1.
Inamura, N., Salt, A.N., 1992. Permeability changes of the blood-labyrinth barrier
measured in vivo during experimental treatments. Hear. Res. 61, 12–18. doi:10.
1016/0378- 5955(92)90030- Q.
Isherwood, B., Cláudia Gonçalves, A., Cousins, R., Holme, R., 2022. The global hearing
therapeutic pipeline: 2021. Drug Discov. Today 27 (3), 912–922. doi:10.1016/j.
drudis.2021.11.009.
Jahnke, K., 1980. The blood-perilymph barrier. Arch. Otorhinolaryngol. 228, 29–34.
doi:10.10 07/BF0 0455891.
Jurawitz, M.C., Büchner, A., Harpel, T., Schüssler, M., Majdani, O., Lesinski-
Schiedat, A., Lenarz, T., 2014. Hearing preservation outcomes with different
cochlear implant electrodes: Nucleus® hybridTM -L24 and nucleus freedomTM
CI422. Audiol. Neurootol. 19, 293–309. doi:10.1159/0 0 0360601.
Kil, J., Harruff, E.E., Longenecker, R.J., 2022. Development of Ebselen For the Treat-
ment of Sensorineural Hearing Loss and Tinnitus. Hearing Research In Press
doi:10.1016/j.heares.2021.108209.
Kil, J., Huang, M., Nguyen, S., Chandresekhar, S., Lambert, P., 2018. SPI-1005 A novel
investigational drug for the treatment of Meniere’ s Disease. In: 41st Annual
Midwinter Meeting, Association for Researchin Otolaryngology, p. 519.
Kil, J., Lobarinas, E., Spankovich, C., Griffiths, S.K., Antonelli, P.J., Lynch, E.D., Le
Prell, C.G., 2017. Safety and efficacy of ebselen for the prevention of noise-
induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2
trial. Lancet North Am. Ed. 390, 969–979. doi:10.1016/S0140-6736(17)31791-9.
Kirk, J.R., Smyth, D., 2022. New paradigms of hearing loss and preservation: learn-
ings from fundamental studies and clinical research. In this issue.
Kopke, R.D., Liu, W., Gabaizadeh, R., Jacono, A., Feghali, J., Spray, D., Garcia, P., Stein-
man, H., Malgrange, B., Ruben, R.J., Rybak, L., Van De Water, T.R., 1997. Use of
organotypic cultures of Corti’s organ to study the protective effects of antioxi-
dant molecules on cisplatin-induced damage of auditory hair cells. Am. J. Otol.
18, 559–571.
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
Kuthubutheen, J., Joglekar, S., Smith, L., Friesen, L., Smilsky, K., Millman, T., Ng, A.,
Shipp, D., Coates, H., Arnoldner, C., Nedzelski, J., Chen, J., Lin, V., 2018. The role
of preoperative steroids for hearing preservation cochlear implantation: results
of a randomized controlled trial. Audiol. Neurootol. 22, 292–302. doi:10.1159/
0 0 0485310.
Kuthubutheen, J., Smith, L., Hwang, E., Lin, V., 2016. Preoperative steroids for hear-
ing preservation cochlear implantation: a review. Cochlear Implants Int. doi:10.
1080/14670100.2016.1148319.
Leblans, M., 2022. Novel impedance measures as biomarker for intracochlear fibro-
sis. In this issue.
Lenarz, T., Stöver, T., Buechner, A., Paasche, G., Briggs, R., Risi, F., Pesch, J.,
Battmer, R.D., 2006. Temporal bone results and hearing preservation with a new
straight electrode. Audiol. Neurootol. 34–41. doi:10.1159/0 0 0 095612.
Li, G., Frenz, D.A., Brahmblatt, S., Feghali, J.G., Ruben, D.J., Berggren, D.,
Arezzo, J., Van De Water, T.R., 2001. Round window membrane delivery of
L-methionine provides protection from cisplatin ototoxicity without compro-
mising chemotherapeutic efficacy. Neurotoxicology 22, 163–176. doi:10.1016/
S0161-813X(0 0)0 0 010-3.
Lopez, I., 2022. Archival human temporal bone: anatomical and histopathological
studies of cochlear implantation. In this issue.
Lynch, E., Kil, J., 2009. Development of ebselen, a glutathione peroxidase mimic,
for the prevention and treatment of noise-induced hearing loss, in: seminars in
Hearing. pp. 47–55. 10.1055/s-0028-1111106
Lynch, E.D., Gu, R., Pierce, C., Kil, J., 2005. Reduction of acute cisplatin ototoxicity
and nephrotoxicity in rats by oral administration of allopurinol and ebselen.
Hear. Res. 201, 81–89. doi:10.1016/j.heares.20 04.08.0 02.
Lynch, E.D., Gu, R., Pierce, C., Kil, J., 2004. Ebselen-mediated protection from sin-
gle and repeated noise exposure in rat. Laryngoscope 114, 333–337. doi:10.1097/
0 0 0 05537-20 04020 0 0-0 0 029.
Mamelle, E., Granger, B., Sterkers, O., Lahlou, G., Ferrary, E., Nguyen, Y., Mosnier, I.,
2020. Long-term residual hearing in cochlear implanted adult patients who
were candidates for electro-acoustic stimulation. Eur. Arch. Otorhinolaryngol.
277, 705–713. doi:10.10 07/s0 0405- 019- 05745- 6.
Manrique-Huarte, R., Zulueta-Santos, C., Calavia, D., Linera-Alperi, M.Á.de, Gal-
lego, M.A., Jolly, C., Manrique, M., 2020. Cochlear implantation with a
dexamethasone eluting electrode array: functional and anatomical changes
in non-human primates. Otol. Neurotol. 41, e812–e822. doi:10.1097/MAO.
0 0 0 0 0 0 0 0 0 0 0 02686.
Minami, S.B., Yamashita, D., Schacht, J., Miller, J.M., 2004. Calcineurin activation con-
tributes to noise-induced hearing loss. J. Neurosci. Res. 78, 383–392. doi:10.
1002/jnr.20267.
Moran, M., Dowell, R.C., Iseli, C., Briggs, R.J.S., 2017. Hearing preservation outcomes
for 139 cochlear implant recipients using a thin straight electrode array. Otol.
Neurotol. 38, 678–684. doi:10.1097/MAO.0 0 0 0 0 0 0 0 0 0 0 01374.
Morgan, P., Van Der Graaf, P.H., Arrowsmith, J., Feltner, D.E., Drummond, K.S., Weg-
ner, C.D., Street, S.D.A., 2012. Can the flow of medicines be improved? Fun-
damental pharmacokinetic and pharmacological principles toward improving
Phase II survival. Drug Discov. Today 17 (9–10), 419–424. doi:10.1016/j.drudis.
2011.12.020.
Müller, A., Cadenas, E., Graf, P., Sies, H., 1984. A novel biologically active seleno-
organic compound-1. Glutathione peroxidase-like activity in vitro and antioxi-
dant capacity of PZ 51 (Ebselen). Biochem. Pharmacol. 33, 3235–3239. doi:10.
1016/0 0 06-2952(84)90 083-2.
Needham, K., Stathopoulos, D., Newbold, C., Leavens, J., Risi, F., Manouchehri, S.,
Durmo, I., Cowan, R., 2020. Electrode impedance changes after implantation of
a dexamethasone-eluting intracochlear array. Cochlear Implants Int. 21, 98–109.
doi:10.1080/14670100.2019.1680167.
Oh, C.K., Drescher, M.J., Hatfield, J.S., Drescher, D.G., 1999. Selective expression of
serotonin receptor transcripts in the mammalian cochlea and its subdivisions.
Brain Res. Mol. Brain Res. 70, 135–140. doi:10.1016/s0169-328x(99)00110-2.
O’Leary, S.J., Choi, J., Brady, K., Matthews, S., Ozdowska, K.B., Payne, M., McLean, T.,
Rousset, A., Lo, J., Creber, N., Tari, S., Dowell, R., Briggs, R., 2021. Systemic
methylprednisolone for hearing preservation during cochlear implant surgery:
a double blinded placebo-controlled trial. Hear. Res. 404, 108224. doi:10.1016/j.
heares.2021.108224.
Paciello, F., Fetoni, A.R., Rolesi, R., Wright, M.B., Grassi, C., Troiani, D., Paludetti, G.,
2018. Pioglitazone represents an effective therapeutic target in preventing ox-
idative/inflammatory cochlear damage induced by noise exposure. Front. Phar-
macol. 9, 1–15. doi:10.3389/fphar.2018.01103.
Pardridge, W.M., 2005. The blood-brain barrier: bottleneck in brain drug develop-
ment. NeuroRx 2, 3–14. doi:10.1602/neurorx.2.1.3.
Pardridge, W.M., 2003. Blood-brain barrier drug targeting: the future of brain drug
development. Mol Interv 3, 90–105. doi:10.1124/mi.3.2.90, 51.
Parys, Q., van Bulck, P., Loos, E., Verhaert, N., 2022. Inner ear pharmacotherapy for
residual hearing preservation in cochlear implant surgery: a systematic review.
Biomolecules 12, 529. doi:10.3390/biom12040529.
Petremann, M., Romanet, C., Broussy, A., Van Ba, C.T., Poli, S., Dyhrfjeld-Johnsen, J.,
2019. SENS-401 effectively reduces severe acoustic trauma-induced hearing loss
in male rats with twice daily administration delayed up to 96hours. Otol. Neu-
rotol. 40, 254–263. doi:10.1097/MAO.0 0 0 0 0 0 0 0 0 0 0 02088.
Petremann, M., Tran Van Ba, C., Broussy, A., Romanet, C., Dyhrfjeld-Johnsen, J.,
2017. Oral administration of clinical stage drug candidate SENS-401 effectively
reduces cisplatin-induced hearing loss in rats. Otol. Neurotol. 38, 1355–1361.
doi:10.1097/MAO.0 0 0 0 0 0 0 0 0 0 0 01546.
Pierstorff, E., Chen, S., Chaparro, M.P., Cortez, J.M., Chen, Y.J., Ryu, S.Y., Tsai, S.M.,
Baum, M.M., Yang, W.W., Kalinec, F., Smith, T., Ludwig, S., Slattery, W.H., 2018. A
12
Hearing Research 426 (2022) 108637
polymer-based extended release system for stable, long-term intracochlear drug
delivery. Otol. Neurotol. 39, 1195. doi:10.1097/MAO.0 0 0 0 0 0 0 0 0 0 0 01977.
Plontke, S.K., Biegner, T., Kammerer, B., Delabar, U., Salt, A.N., 2008. Dexam-
ethasone concentration gradients along scala tympani after application to
the round window membrane. Otol. Neurotol. 29, 401–406. doi:10.1097/MAO.
0b013e318161aaae.
Plontke, S.K., Mynatt, R., Gill, R.M., Borgmann, S., Salt, A.N., 2007a. Concentra-
tion gradient along the scala tympani after local application of gentamicin to
the round window membrane. Laryngoscope 117, 1191–1198. doi:10.1097/MLG.
0b013e318058a06b.
Plontke, S.K., Mynatt, R., Gill, R.M., Borgmann, S., Salt, A.N., 2007b. Concentra-
tion gradient along the scala tympani after local application of gentamicin to
the round window membrane. Laryngoscope 117, 1191–1198. doi:10.1097/MLG.
0b013e318058a06b.
Polanski, W., Enzensperger, C., Reichmann, H., Gille, G., 2010. The exceptional
properties of 9-methyl-β -carboline: stimulation, protection and regeneration of
dopaminergic neurons coupled with anti-inflammatory effects. J. Neurochem.
113, 1659–1675. doi:10.1111/j.1471-4159.2010.06725.x.
Pourbakht, A., Yamasoba, T., 2003. Ebselen attenuates cochlear damage caused by
acoustic trauma. Hear. Res. 181, 100–108. doi:10.1016/S0378-5955(03)00178-3.
Prenzler, N.K., Salcher, R., Lenarz, T., Gaertner, L., Warnecke, A., 2020. Dose-
dependent transient decrease of impedances by deep intracochlear injection of
triamcinolone with a cochlear catheter prior to cochlear implantation–1 year
data. Front. Neurol. 11, 1–8. doi:10.3389/fneur.2020.00258.
Prenzler, N.K., Salcher, R., Timm, M., Gaertner, L., Lenarz, T., Warnecke, A., 2018. In-
tracochlear administration of steroids with a catheter during human cochlear
implantation: a safety and feasibility study. Drug Delivery Transl. Res. 8, 1191–
1199. doi:10.1007/s13346- 018- 0539- z.
Rahman, M.T., Chari, D., Ishiyama, G., Lopez, I., Quesnel, A.M., Ishiyama, A.,
Nadol, J.B., Hansen, M.R., 2022. Cochlear implants: causes, effects and mitiga-
tion strategies for the foreign body response and inflammation. Hear. Res. 422,
108536. doi:10.1016/J.HEARES.2022.108536.
Roland, J.T., Gantz, B.J., Waltzman, S.B., Parkinson, A.J., 2018. Long-term outcomes
of cochlear implantation in patients with high-frequency hearing loss. Laryngo-
scope 128, 1939–1945. doi:10.1002/lary.27073.
Roland, J.T., Gantz, B.J., Waltzman, S.B., Parkinson, A.J., 2016. United States multicen-
ter clinical trial of the cochlear nucleus hybrid implant system. Laryngoscope
126, 175–181. doi:10.1002/lary.25451.
Rowe, D., Chambers, S., Hampson, A., Eastwood, H., Campbell, L., O’Leary, S., 2016.
Delayed low frequency hearing loss caused by cochlear implantation inter-
ventions via the round window but not cochleostomy. Hear. Res. 333, 49–57.
doi:10.1016/j.heares.2015.12.012.
Saito, T., Zhang, Z.J., Tsuzuki, H., Ohtsubo, T., Yamada, T., Yamamoto, T., Saito, H.,
1997. Expression of P-glycoprotein in inner ear capillary endothelial cells of the
guinea pig with special reference to blood-inner ear barrier. Brain Res. 767, 388–
392. doi:10.1016/S0 0 06-8993(97)0 0821-4.
Salt, A.N., Hartsock, J., Plontke, S., Lebel, C., Piu, F., 2011. Distribution of dexam-
ethasone and preservation of inner ear function following intratympanic de-
livery of a gel-based formulation. Audiol. Neurootol. 16, 323–335. doi:10.1159/
0 0 0322504.
Salt, A.N., Hartsock, J.J., Gill, R.M., Piu, F., Plontke, S.K., 2012. Perilymph pharma-
cokinetics of markers and dexamethasone applied and sampled at the lat-
eral semi-circular canal. J. Assoc. Res. Otolaryngol. 13, 771–783. doi:10.1007/
s10162-012-0347-y.
Salt, A.N., Hartsock, J.J., Piu, F., Hou, J., 2018. Dexamethasone and dexamethasone
phosphate entry into perilymph compared for middle ear applications in Guinea
Pigs. Audiol. Neurootol. 23, 245–257. doi:10.1159/0 0 0493846.
Salt, A.N., Plontke, S.K., 2018. Pharmacokinetic principles in the inner ear: influence
of drug properties on intratympanic applications. Hear. Res. 368, 28–40. doi:10.
1016/j.heares.2018.03.002.
Santa Maria, P.L., Gluth, M.B., Yuan, Y., Atlas, M.D., Blevins, N.H., 2014. Hearing
preservation surgery for cochlear implantation: a meta-analysis. Otol. Neurotol.
35, e256–e269. doi:10.1097/MAO.0 0 0 0 0 0 0 0 0 0 0 0 0561.
Scheper, V., Hessler, R., Hütten, M., Wilk, M., Jolly, C., Lenarz, T., Paasche, G., 2017.
Local inner ear application of dexamethasone in cochlear implant models is safe
for auditory neurons and increases the neuroprotective effect of chronic electri-
cal stimulation. PLoS One 12, 1–22. doi:10.1371/journal.pone.0183820.
Schewe, T., 1995. Molecular actions of Ebselen-an antiinflammatory antioxidant.
Gen. Pharmacol. doi:10.1016/0306-3623(95)0 0 0 03-J.
Schilder, A.G.M., Su, M.P., Blackshaw, H., Lustig, L., Staecker, H., Lenarz, T., Safied-
dine, S., Gomes-Santos, C.S., Holme, R., Warnecke, A., 2019. Hearing protection,
restoration, and regeneration: an overview of emerging therapeutics for inner
ear and central hearing disorders. Otol. Neurotol. 40, 559–570. doi:10.1097/
MAO.0 0 0 0 0 0 0 0 0 0 0 02194.
Schinkel, A.H., 1999. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv.
Drug. Deliv. Rev. doi:10.1016/S0169-409X(98)0 0 085-4.
Sekulic-Jablanovic, M., Petkovic, V., Wright, M.B., Kucharava, K., Huerzeler, N., Lev-
ano, S., Brand, Y., Leitmeyer, K., Glutz, A., Bausch, A., Bodmer, D., 2017. Ef-
fects of peroxisome proliferator activated receptors (PPAR)-γ and -α agonists
on cochlear protection from oxidative stress. PLoS One 12. doi:10.1371/journal.
pone.0188596.
Seyyedi, M., Nadol, J.B., 2014. Intracochlear inflammatory response to cochlear im-
plant electrodes in humans. Otol. Neurotol. 35, 1545–1551. doi:10.1097/MAO.
0 0 0 0 0 0 0 0 0 0 0 0 0540.
Simoni, E., Gentilin, E., Candito, M., Borile, G., Romanato, F., Chicca, M., Nordio, S.,
Aspidistria, M., Martini, A., Cazzador, D., Astolfi, L., 2020. Immune response
R.D. Gay, Y.L. Enke, J.R. Kirk et al.
after cochlear implantation. Front. Neurol. 11, 341. doi:10.3389/fneur.2020.
00341.
Skarzynska, M.B., Kolodziejak, A., Gos, E., Skarzynski, P.H., 2021. The clinical ef-
fects of steroids therapy in the preserving residual hearing after cochlear im-
plantation with the OTICON neuro Zti EVO. J. Clin. Med. 10, 2868. doi:10.3390/
jcm10132868.
Skarzynska, M.B., Skarzynski, P.H., Krol, B., Kozieł, M., Osińska, K., Gos, E., Skarzyn-
ski, H., 2018. Preservation of hearing following cochlear implantation using dif-
ferent steroid therapy regimens: a prospective clinical study. Med. Sci. Monit.
24, 2437–2445. doi:10.12659/MSM.906210.
Skarzynski, H., de Heyning, P., Agrawal, S., Arauz, S.L., Atlas, M., Baumgart-
ner, W., Caversaccio, M., de Bodt, M., Gavilan, J., Godey, B., van de Heyn-
ing, P., Agrawal, S., Arauz, S.L., Atlas, M., Baumgartner, W., Caversaccio, M., de
Bodt, M., Gavilan, J., Godey, B., Green, K., Gstoettner, W., Hagen, R., Han, D.M.,
Kameswaran, M., Karltorp, E., Kompis, M., Kuzovkov, V., Lassaletta, L., Lev-
evre, F., Li, Y., Manikoth, M., Martin, J., Mlynski, R., Mueller, J., O’Driscoll, M.,
Parnes, L., Prentiss, S., Pulibalathingal, S., Raine, C.H., Rajan, G., Rajeswaran, R.,
Rivas, J.A., Rivas, A., Skarzynski, P.H., Sprinzl, G., Staecker, H., Stephan, K., Us-
ami, S., Yanov, Y., Zernotti, M.E., Zimmermann, K., Lorens, A., Mertens, G., 2013.
Towards a consensus on a hearing preservation classification system. Acta Oto-
laryngol. 133, 3–13. doi:10.3109/0 0 016489.2013.869059.
Snels, C.W.M., Huinck, W.J., Swinnen, F.K.R., Dhooge, I., Mylanus, E.A.M., 2020. Short
and long term preservation of hearing thresholds corrected for natural hearing
loss in cochlear implant recipients using a straight electrode. Cochlear Implants
Int. 21, 110–116. doi:10.1080/14670100.2019.1680168.
Staecker, H., Jokovic, G., Karpishchenko, S., Kienle-Gogolok, A., Krzyzaniak, A.,
Lin, C.Der, Navratil, P., Tzvetkov, V., Wright, N., Meyer, T., 2019. Efficacy and
safety of AM-111 in the treatment of acute unilateral sudden deafness—A
double-blind, randomized, placebo-controlled phase 3 study. Otol. Neurotol. 40,
584–594. doi:10.1097/MAO.0 0 0 0 0 0 0 0 0 0 0 02229.
Stathopoulos, D., Chambers, S., Enke, Y.L., Timbol, G., Risi, F., Miller, C., Cowan,
R., Newbold, C., Stathopoulos, D., Chambers, S., Enke, Y.L., Timbol, G., Risi, F.,
Miller, C., Cowan, R., Newbold, C., 2014. Development of a safe dexamethasone-
eluting electrode array for cochlear implantation Development of a safe
dexamethasone- eluting electrode array for cochlear implantation 0100. doi:10.
1179/1754762813Y.0 0 0 0 0 0 0 054
Suckfuell, M., Canis, M., Strieth, S., Scherer, H., Haisch, A., 2007. Intratympanic treat-
ment of acute acoustic trauma with a cell-permeable JNK ligand: a prospec-
tive randomized phase I/II study. Acta Otolaryngol. 127, 938–942. doi:10.1080/
0 0 016480601110212.
Suckfuell, M., Lisowska, G., Domka, W., Kabacinska, A., Morawski, K., Bodlaj, R.,
Klimak, P., Kostrica, R., Meyer, T., 2014. Efficacy and safety of AM-111 in the
treatment of acute sensorineural hearing loss: a double-blind, randomized,
placebo-controlled phase II study. Otol. Neurotol. 35, 1317–1326. doi:10.1097/
MAO.0 0 0 0 0 0 0 0 0 0 0 0 0466.
13
Hearing Research 426 (2022) 108637
Takumida, M., Popa, R., Anniko, M., 1999. Free radicals in the guinea pig inner ear
following gentamicin exposure. ORL J. Otorhinolaryngol. Relat. Spec. 61, 63–70.
doi:10.1159/0 0 0 027643.
Tejani, V.D., Yang, H., Kim, J.-.S., Hernandez, H., Oleson, J.J., Hansen, M.R., Gantz, B.J.,
Abbas, P.J., Brown, C.J., 2021. Access and polarization electrode impedance
changes in electric-acoustic stimulation cochlear implant users with de-
layed loss of acoustic hearing. J. Assoc. Res. Otolaryngol. 1–24. doi:10.1007/
S10162- 021- 00809- Z.
Thompson, N.J., Dillon, M.T., Buss, E., Park, L.R., Pillsbury, H.C., O’Connell, B.P.,
Brown, K.D., 2020. Electrode array type and its impact on impedance fluctua-
tions and loss of residual hearing in cochlear implantation. Otol. Neurotol. 41,
186–191. doi:10.1097/MAO.0 0 0 0 0 0 0 0 0 0 0 02457.
Toulemonde, P., Risoud, M., Lemesre, P.E., Beck, C., Wattelet, J., Tardivel, M., Siep-
mann, J., Vincent, C., 2021. Evaluation of the efficacy of dexamethasone-
eluting electrode array on the post-implant cochlear fibrotic reaction by three-
dimensional immunofluorescence analysis in mongolian gerbil cochlea. J. Clin.
Med. 10. doi:10.3390/jcm10153315.
Venail, F., Biboulet, R., Mondain, M., Uziel, A., 2012. A protective effect of 5-HT3
antagonist against vestibular deficit? Metoclopramide versus ondansetron at the
early stage of vestibular neuritis: a pilot study. Eur. Ann. Otorhinolaryngol. Head
Neck Dis. 129, 65–68. 10.1016/j.anorl.2011.10.006
Wagner, G., Schuch, G., Akerboom, T.P.M., Sies, H., 1994. Transport of ebselen in
plasma and its transfer to binding sites in the hepatocyte. Biochem. Pharma-
col. 48, 1137–1144. doi:10.1016/0 0 06- 2952(94)90150- 3.
Wang, J., Van De Water, T.R., Bonny, C., De Ribaupierre, F., Puel, J.L., Zine, A., 2003.
A peptide inhibitor of c-Jun N-terminal kinase protects against both aminogly-
coside and acoustic trauma-induced auditory hair cell death and hearing loss. J.
Neurosci. 23, 8596–8607. doi:10.1523/jneurosci.23- 24- 08596.2003.
Wang, Q., Shen, Y., Hu, H., Fan, C., Zhang, A., Ding, R., Ye, B., Xiang, M., 2020. Sys-
tematic transcriptome analysis of noise-induced hearing loss pathogenesis sug-
gests inflammatory activities and multiple susceptible molecules and pathways.
Front. Genet. 11, 1–11. doi:10.3389/fgene.2020.00968.
Wangemann, P., 2006. Supporting sensory transduction: cochlear fluid homeostasis
and the endocochlear potential. J. Physiol. 576, 11–21. doi:10.1113/jphysiol.2006.
112888.
Wilk, M., Hessler, R., Mugridge, K., Jolly, C., Fehr, M., Lenarz, T., Scheper, V., 2016.
Impedance changes and fibrous tissue growth after cochlear implantation are
correlated and can be reduced using a dexamethasone eluting electrode. PLoS
ONE 11, e0147552. doi:10.1371/journal.pone.0147552.
Zhang, H., Stark, G., Reiss, L., 2015. Changes in gene expression and hearing thresh-
olds after cochlear implantation. Otol. Neurotol. 36, 1157–1165. doi:10.1097/
MAO.0 0 0 0 0 0 0 0 0 0 0 0 0787.
Zoorob, R., Cender, D., 1998. A different look at corticosteroids. Am. Fam. Phys. 58,
443.