Currently, there are no approved medicines available for the treatment of hearing loss. However, research over the past two decades has contributed to a growing understanding of the pathological mechanisms in the cochlea that result in hearing difficulties. The concept that a loss of the synapses connecting inner hair cells with the auditory nerve (cochlear synaptopathy) contributes to hearing loss has gained considerable attention. Both animal and human post-mortem studies support the idea that these synapses (ribbon synapses) are highly vulnerable to noise, ototoxicity, and the aging process. Their degeneration has been suggested as an important factor in the speech-in-noise difficulties commonly experienced by those suffering with hearing loss. Neurotrophins such as brain derived neurotrophic factor (BDNF) have the potential to restore these synapses and provide improved hearing function. OTO-413 is a sustained exposure formulation of BDNF suitable for intratympanic administration that in preclinical models has shown the ability to restore ribbon synapses and provide functional hearing benefit. A phase 1/2 clinical trial with OTO-413 has provided initial proof-of-concept for improved speech-in-noise hearing performance in subjects with hearing loss. Key considerations for the design of this clinical study, including aspects of the speech-in-noise assessments, are discussed.

The high prevalence of hearing loss worldwide and its association with poor outcomes for communication, mental health, and social well-being requires urgent attention (Deal et al., 2019). No effective pharmacological therapies to treat hearing loss are currently available, and their development faces significant hurdles, including understanding the pathological mechanisms of hearing loss and effective means to deliver drugs to the relevant auditory substrates. The idea that degeneration of the cochlear synapses connecting inner hair cells (IHCs) with the auditory nerve (ribbon synapses) after noise trauma and in aging (so-called cochlear synaptopathy) contributes to speech-in-noise (SIN) hearing dysfunction (Kujawa and Liberman, 2009, 2019) has provided impetus for therapies aimed at the inner ear to repair the synaptopathy and restore hearing function. In this review, we will describe the basis of this idea and evidence that connects it to human hearing deficits, provide an overview of a drug discovery program that validated the therapeutic approach in animal studies, outline key considerations for the initial clinical testing protocol in subjects with SIN hearing deficits, and summarize initial proof-of-concept clinical data.

The proposal that degeneration of the synapses and proximal fibers of the type I primary afferents of the spiral ganglion neurons (SGNs) that connect with IHCs (i.e., cochlear synaptopathy) leads to hearing dysfunction was first made by Charles Liberman and Sharon Kujawa based on observations in mice (Kujawa and Liberman, 2009, 2019). For many years, the field had focused on a loss of hair cells as the primary cause of hearing loss, with an understanding that a subsequent degeneration of SGNs also played a role, without appreciating that the ribbon synapses that connect these cochlear cell types are a highly vulnerable component of the system (Liberman and Kujawa, 2017). This was clearly shown in Liberman and Kujawa's seminal studies in mice, where noise insults that caused little or no hair cell loss produced significant cochlear synaptopathy as assessed morphologically by confocal microscopy after immunohistochemical staining of the synaptic components and functionally by measuring the wave 1 component of the auditory brain stem response (ABR). Furthermore, during aging, these synapses were depleted at a much faster rate than outer hair cells (OHCs), IHCs, or SGNs (Sergeyenko et al., 2013). This supported the concept of “hidden hearing loss,” a deficit in hearing function that “hides” behind an otherwise normal audiometric threshold as determined by pure tone averages (PTAs) (Schaette and McAlpine, 2011; Liberman, 2015; Kohrman et al., 2020). The most vulnerable sub-population of synapses are those associated with SGN fibers having a high threshold and low spontaneous rate (Furman et al., 2013), which also have a distinct molecular profile (designated SGN type Ic fibers) (Shrestha et al., 2018). These fibers are activated at higher sound intensities and so do not contribute significantly to the detection of noise in a quiet setting, which explains why their loss does not affect the hearing thresholds. However, the information they carry becomes important for the detection of sounds in the presence of a noisy background (Costalupes et al., 1984). Consequently, Liberman and colleagues proposed that the loss of these fibers may be an important component of the SIN difficulties that are a major complaint of people seeking treatment for hearing loss (Liberman, 2015) as well as a potential cause of tinnitus and hyperacusis (Hickox and Liberman, 2014).

From these initial studies in mice, the vulnerability of ribbon synapses to noise, aging, or ototoxic agents has been expanded and demonstrated in multiple species, including rat, guinea pig, chinchilla, gerbil, and non-human primate (Lin et al., 2011; Gleich et al., 2016; Hickox et al., 2017; Valero et al., 2017; Piu et al., 2018). Most importantly, cochlear synaptopathy has been documented in post-mortem human temporal bone samples, key data that support the general concept that ribbon synapses and their fibers are highly sensitive components of the human cochlea in subjects with substantial noise exposure and during aging (Viana et al., 2015; Wu et al., 2019; Wu et al., 2020, 2021).

Refinement to the concept of cochlear synaptopathy has evolved with emerging data indicating potential differences between species and modalities of noise exposure. In CBA/CaJ mice, a noise insult that produces no permanent audiometric threshold shift results in a permanent loss of ribbon synapses over the lifespan, but in other species, various degrees of synaptic recovery have been observed following noise trauma. In particular, noise-exposed guinea pigs show almost complete recovery of ribbon synapses (Shi et al., 2013; Hickman et al., 2021) as does the C57BL/6 mouse strain (Shi et al., 2015; Kaur et al., 2019). Studies of cochleae from human temporal bones show a consistent loss of auditory nerve fibers associated with aging and noise exposure, suggesting that if recovery from individual noise episodes occurs in human subjects, it is overcome by repeated exposures or some additional ongoing pathological process(es). An important potential difference between the animal and human studies lies in the nature of noise exposure, which in animals is controlled and brief (typically a few hours) but of high intensity, compared to many years of varying intensities of noise exposure in human subjects. This may also be the reason why animal studies consistently show that ribbon synapses are the most vulnerable cochlear components (when compared to IHCs, OHCs, and SGNs), whereas in human subjects with age and noise-related hearing loss, OHCs have a similar vulnerability to auditory nerve fibers (Wu et al., 2021). These factors are important when considering how to evaluate the impact of cochlear synaptopathy in human subjects.

Post-mortem studies of human temporal bones have provided clear evidence for cochlear synaptopathy and confirmed that type I SGN afferent fibers and ribbon synapses are highly vulnerable to noise exposure and age and precede the loss of IHCs and SGN cell bodies (Viana et al., 2015; Wu et al., 2019; Wu et al., 2021). In a recent study, Wu et al. (2021) reported that individuals with a history of noise exposure have a correlated and parallel age-related loss of both OHCs and afferent fibers. Deficits in both cellular components predicted poor word discrimination scores (Wu et al., 2021). This study extends the importance of cochlear synaptopathy beyond subjects with “normal” audiometric thresholds (i.e., hidden hearing loss) to include those with measurable hearing loss. The authors inferred that had SIN measurements been available for this cohort, afferent fiber loss would have been a key contributor to its performance.

Since cochlear synaptopathy cannot be measured directly in living subjects, it has to be inferred from other measures. ABR measurements are conducted in both animal and human studies, and they have the potential to act as a translational bridge, with the wave I component measuring the function of ribbon synapses and the cochlear nerve. Because the deficits in suprathreshold wave I amplitude and loss of ribbon synapses are well correlated in mice after noise trauma (Fernandez et al., 2020), measurements of ABR wave I (including both amplitude and latency) have been investigated in human studies as a surrogate for cochlear synaptopathy. Numerous studies have attempted to correlate this measure with noise history, typically in younger populations that retain relatively normal auditory thresholds (Liberman et al., 2016; Prendergast et al., 2017; Bramhall et al., 2019), but with mixed results. In older populations that have varying degrees of OHC loss and subsequent audiometric threshold elevations, interpretation of wave I ABR changes are compromised by the lack of amplification provided by OHCs, making wave I measurements difficult to interpret in terms of cochlear synaptopathy. The temporal bone studies mentioned above indicate that a greater degree of cochlear synaptopathy is observed with noise and age exposure where audiometric thresholds are elevated (due to OHC loss). Consequently, the impact of lost synapses may be greatest in hearing impaired subjects, a population where wave I ABR measurements cannot be relied on as a measure of cochlear synapses. However, emerging data suggest that ABR measurements from more complex stimuli may be able to tease these components apart (Mepani et al., 2021). Together, these studies indicate that therapies aimed at restoring type I SGN afferent synapses may benefit hearing comprehension in subjects ranging from those with normal audiograms to individuals with audiometric threshold changes indicative of moderate to severe hearing loss.

Despite the uncertainties associated with the interpretation of human functional measurements, a recent study in mice by Resnik and Polley (2021) provided evidence for a direct link between cochlear synaptopathy and hearing dysfunction similar to the SIN deficits in humans (Resnik and Polley, 2021). They observed that in mice with a selective degeneration of SGN type I afferent fibers that reduced wave I ABR amplitudes by 70%, behavioral measurements indicated a significant “tone-in-noise” deficit with no change in “tone-in-quiet.” This effect appeared to be a result of changes in the excitation/inhibition balance in the auditory cortex induced by the loss of peripheral (cochlear) input. Additional studies of this kind may shed further light on the hearing dysfunction that cochlear synaptopathy produces and how this might manifest itself in human subjects.

A therapy that is able to reconnect type I afferent synapses with IHCs in the cochlea may provide considerable therapeutic benefit for people with real-world hearing difficulties. During cochlear development, numerous regulatory mechanisms contribute to the generation of these synapses, the most prominent being the neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) (Fritzsch et al., 2004; Green et al., 2012). Cochlear BDNF and NT-3 expression is elevated during development, being present in support cells and additionally in IHCs and OHCs (Sugawara et al., 2007); postnatally, levels of both neurotrophins decline markedly (Green et al., 2012). Developing central nervous system (CNS) neurons can migrate along a BDNF chemical gradient (Zhou et al., 2007), and in cochleae depleted of hair cells, SGN fibers grow toward a localized exogenous source of BDNF (Wise et al., 2010). Consequently, through the generation of a chemical gradient originating in the organ of Corti, neurotrophins appear to guide afferent fibers to their targets through activating tropomyosin receptor kinases (Trk receptors) present on afferent fibers, thereby establishing appropriate synaptic connections between primary afferent fibers and IHCs. Deletion or disruption of genes encoding the neurotrophins or their receptors, TrkB and TrkC, produces profound disruption of cochlear morphology and function (Fritzsch et al., 2004).

After hearing onset, global cochlear neurotrophin expression is greatly reduced; however, TrkB and TrkC expression in SGNs persists (Green et al., 2012; Ramekers et al., 2012). It follows that neurotrophins, or activation of Trk receptors, would be a promising strategy for restoring cochlear afferent synapses after their disconnection due to noise trauma, aging, or both. Animal studies have shown that cochlear synaptopathy involves disconnection of ribbon synapses and a retraction of type I afferent fibers away from the IHC toward the SGN cell bodies. In the human cochlea, this distance spans a few millimeters (Stakhovskaya et al., 2007), making reconnection feasible. Importantly, the remaining components of these bipolar neurons appear to be intact in subjects with hearing loss, including the SGN cell bodies and the central projections that enter the CNS and connect to brain stem auditory neurons. When the appropriate neuronal tonotopic circuitry established during development is preserved, appropriate auditory function can be restored if the peripheral terminals can be reconnected to the IHCs, which are also relatively intact in subjects with noise- and age-related hearing loss. Therefore, reconnection of the peripheral type I SGN afferent fibers to their IHC targets seems like an attainable therapeutic goal.

Trk receptors, therefore, have become attractive therapeutic targets for restoration of cochlear ribbon synapses, in particular, TrkB and TrkC, which are the cognate receptors for the primary cochlear neurotrophins BDNF and NT-3, respectively. Both TrkB and TrkC are expressed on SGNs and mediate the effects of BDNF and NT-3 to promote neuronal survival, neurite growth, and synapse formation (Green et al., 2012). In addition to the endogenous neurotrophins themselves, several other types of molecules have been considered as Trk receptor agonists, including monoclonal antibodies, small molecule drugs, and modified versions of BDNF and NT-3 (Saragovi et al., 2019; Brahimi et al., 2021). Two additional types of neurotrophin receptors have also been recognized as potential targets due to their ability, once activated, to oppose the effects of TrkB and TrkC. One of these is p75, which has complex interactions with Trk receptors that can lead to neuronal apoptosis, and the other is a truncated form of TrkC that, when activated by NT-3, can produce neuronal death (Brahimi et al., 2021). In both of these cases, antagonist molecules could be of therapeutic interest.

In our studies, we focused on TrkB and TrkC receptor agonists, initially profiling their effects in ex vivo cochlear models to assess their ability to influence SGN survival and fiber outgrowth and their efficacy in a model of excitotoxin-induced cochlear synaptopathy (Fig. 1) (Szobota et al., 2019). Overall, these studies strongly supported the potent neurotrophic benefits of TrkB and TrkC activation on SGNs, with BDNF and a TrkB selective monoclonal antibody agonist (M3) being the most effective. Small molecules that had been reported to activate TrkB receptors and provide neurotrophic effects on SGNs (Yu et al., 2012) were not effective in these models and also provided no evidence of agonist activity in cell based assays where human or rat TrkB was expressed (Szobota et al., 2019), the latter in keeping with more recent reports (Todd et al., 2014; Boltaev et al., 2017).

FIG. 1.

Effects of BDNF and NT-3 in ex vivo and in vivo models of cochlear synaptopathy. (A) Without trophic support, dissociated rat SGNs (left panel) do not survive in culture. Exposure to BNDF or NT-3 (right panel) supports survival (data are presented relative to NT-3 at 1 nM) over a wide concentration range, with BDNF being significantly effective at 10 pM vs NT-3 (***, p < 0.0001, t-test). Human IgG4 was used as a negative control. (B) Neurite outgrowth from explants of rat spiral ganglion shows increased numbers of neurites in response to BDNF and NT-3 over a wide concentration range, with BDNF having the greatest effect. (A) (left) and (B) reproduced from and (A) (right) adapted from Szobota et al., PLoS ONE 14, e0224022 (2019). Copyright 2019 PLOS (Szobota et al., 2019). (C) Effects of a single IT injection of BDNF or NT-3 formulated in P407 in a rat model of cochlear synaptopathy (Piu et al., 2018). BDNF shows a restoration of the wave I component of the ABR and number of IHC synaptic puncta, whereas NT-3 was less effective. In brief, adult Sprague–Dawley rats were exposed to noise (105 dB, 8–16 kHz, 1 h) and 24 h later received a single IT injection of neurotrophin or vehicle in a formulation containing 16% poloxamer 407. At 28 days, ABR recordings were made, and the animals were perfusion-fixed. The functional readout is the amplitude of wave 1 of the ABR, and the morphological readout is the number of synaptic puncta per IHC as determined by immunostaining and quantified using confocal microscopy (Piu, 2020).

FIG. 1.

Effects of BDNF and NT-3 in ex vivo and in vivo models of cochlear synaptopathy. (A) Without trophic support, dissociated rat SGNs (left panel) do not survive in culture. Exposure to BNDF or NT-3 (right panel) supports survival (data are presented relative to NT-3 at 1 nM) over a wide concentration range, with BDNF being significantly effective at 10 pM vs NT-3 (***, p < 0.0001, t-test). Human IgG4 was used as a negative control. (B) Neurite outgrowth from explants of rat spiral ganglion shows increased numbers of neurites in response to BDNF and NT-3 over a wide concentration range, with BDNF having the greatest effect. (A) (left) and (B) reproduced from and (A) (right) adapted from Szobota et al., PLoS ONE 14, e0224022 (2019). Copyright 2019 PLOS (Szobota et al., 2019). (C) Effects of a single IT injection of BDNF or NT-3 formulated in P407 in a rat model of cochlear synaptopathy (Piu et al., 2018). BDNF shows a restoration of the wave I component of the ABR and number of IHC synaptic puncta, whereas NT-3 was less effective. In brief, adult Sprague–Dawley rats were exposed to noise (105 dB, 8–16 kHz, 1 h) and 24 h later received a single IT injection of neurotrophin or vehicle in a formulation containing 16% poloxamer 407. At 28 days, ABR recordings were made, and the animals were perfusion-fixed. The functional readout is the amplitude of wave 1 of the ABR, and the morphological readout is the number of synaptic puncta per IHC as determined by immunostaining and quantified using confocal microscopy (Piu, 2020).

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From these dose-response studies, BDNF emerged as having potent neurotrophic effects toward SGNs, being active over a wide concentration range of 10 pM to 100 nM in SGN survival assays and measures of neurite outgrowth (Fig. 1). This is consistent with reports of BDNF effects on SGNs (Kondo et al., 2013) and other neuronal types (Qian et al., 2006; Todd et al., 2014; Boltaev et al., 2017). In addition, BDNF has been shown to promote SGN survival or fiber growth in a variety of in vivo assays in different species (Wise et al., 2005; Havenith et al., 2011; Zhai et al., 2011; Ramekers et al., 2012); and BDNF in combination with NT-3, or NT-3 alone, has beneficial effects in rodent models of cochlear synaptopathy (Sly et al., 2016; Suzuki et al., 2016).

One of the major challenges for the development of otic therapeutics is how to effectively deliver them to the inner ear compartment. For BDNF, we have evaluated intratympanic (IT) administration in combination with the thermo-reversible polymer, poloxamer P407; this formulation of human recombinant BDNF in P407 was termed OTO-413. In rat pharmacokinetic (PK) studies, IT injections that deposit OTO-413 at the round window membrane (RWM) produced extended therapeutic levels of BDNF in the perilymph and cochlear epithelial tissue for several weeks (Piu et al., 2018). These studies established that a biologic molecule (molecular mass of 27 kDa for the BDNF dimer) can be delivered effectively to the inner ear via the RWM. It was also important to demonstrate that the IT injection of OTO-413 could provide therapeutic benefit in vivo, and for this purpose a rat model of cochlear synaptopathy induced by noise exposure was developed that produces both functional (ABR) and anatomical (ribbon synapse) deficits. In this model, 28 days after an exposure to noise that caused small audiometric threshold shifts, the amplitude of wave I of the ABR was decreased, and IHCs were observed to have fewer synaptic puncta, based on confocal microscopy using antibodies to label presynaptic IHC ribbons (CtBP2) and postsynaptic glutamate receptors (GluA2). A single IT administration of OTO-413 1 day after noise exposure restored both functional and anatomical measures of ribbon synapses when assessed 28 days post-administration over a wide dose range (Piu et al., 2018). In parallel experiments, NT-3 was also evaluated by IT injection in a poloxamer formulation that provided therapeutic levels in the perilymph and cochlear epithelium and similarly showed efficacy in restoring ribbon synapses, but to a lesser degree than BDNF (Piu, 2020 see Fig. 1). These data demonstrate the benefit of IT administration of OTO-413 in restoring SGN afferent fibers and their synapses in a rat model of cochlear synaptopathy, including functional hearing improvement.

In summary, there is compelling evidence that neurotrophins have the ability to restore type I SGN afferent synapses in the cochlea and have the potential to be an effective therapy for SIN hearing difficulties. As a sustained exposure formulation of BDNF for IT administration, OTO-413 has demonstrated an excellent inner ear PK profile and efficacy in a rat model of cochlear synaptopathy, providing morphological and functional evidence for synaptic reconnection. With a very favorable safety profile, OTO-413 has progressed to clinical studies in subjects with SIN hearing impairments.

The ability to hear properly requires sufficient audibility to detect sound under quiet conditions as well as limited distortion to hear spoken words clearly even under challenging conditions with competing background noise (Plomp and Duquesnoy, 1982). Difficulty recognizing speech in background noise is a common complaint of individuals with hearing loss (Wilson, 2003) even after being fitted with hearing aids (Kochkin, 2000). It is estimated that 25 million adults in the United States with normal audiometric thresholds self-report difficulty understanding speech in adverse listening environments (Tremblay et al., 2015), and an even larger number (38 million adults) self-report hearing difficulty with audiometric hearing loss (Edwards, 2020). Difficulty hearing in noise is more common in older compared to younger individuals, with impairment increasing in prevalence beginning in middle age, likely due to aging and cumulative noise exposure, and affecting more men than women (Moore et al., 2014). In many work environments, such as law enforcement, industrial facilities, firefighting, and the military, the ability to hear in noisy and chaotic situations is critical, and any hearing-in-noise deficiencies could lead to serious harm or injury (Tufts et al., 2009). Outside the work environment, accurate speech perception is vital for successful communication, good social participation, and a high quality of life (Cieśla et al., 2016).

Evaluation of SIN hearing is not only important to objectively define any impairment but also to monitor the effects of interventions, including hearing aids, cochlear implants, assistive listening devices, and investigational medications. Even so, SIN testing is often under-utilized in current audiology practice (British Society of Audiology, 2019), which instead almost exclusively relies on pure tone audiometry and word recognition testing in quiet. The latter tests are valuable for assessing sensitivity and audibility in quiet, but not for assessing hearing under more typical and trying listening conditions. Word recognition performance in quiet, which typically correlates well with pure tone thresholds, does not predict performance on SIN testing and is therefore not a substitute for SIN testing (Wilson, 2011).

As reviewed above, cochlear synaptopathy has been hypothesized as the pathological underpinning of hidden hearing loss and is also present in individuals with audiometric threshold shifts (Kujawa and Liberman, 2009; Liberman and Kujawa, 2017; Kujawa and Liberman, 2019; Wu et al., 2021). Loss of cochlear synapses has been demonstrated in human temporal bone samples and may precede hair cell loss as one of the initial manifestations of sensorineural hearing loss. Restoration of the synaptic connections between IHCs and type I SGNs with OTO-413 could help to improve SIN hearing, and the initial clinical study is designed to investigate this further.

A number of factors were considered in designing the study to evaluate the initial clinical efficacy and safety of OTO-413. This included (1) selection of suitable SIN tests to evaluate efficacy, (2) ensuring subjects had an underlying SIN hearing deficit for study eligibility as well as other inclusion and exclusion criteria for enrollment, and (3) including appropriate assessments to monitor the safety and tolerability of OTO-413 administered by IT injection.

A number of SIN tests have been used for clinical and research purposes. Examples include the hearing-in-noise test (HINT) (Nilsson et al., 1994), the quick speech-in-noise test (QuickSIN) (Killion et al., 2004), the words-in-noise test (WIN) (Wilson, 2003), the digits-in-noise test (DIN) (Watson et al., 2012), the American English Matrix test (AEMT) (Kollmeier et al., 2015), the listening in spatialized noise-sentences test (LiSN-S) (Cameron and Dillon, 2008), and the Bamford–Kowal–Bench speech-in-noise test (BKB-SIN; Etymotic Research, Inc., Elk Grove Village, IL). In selecting tests for evaluating OTO-413, we were interested in covering a range of test material modalities (e.g., digits, monosyllable words, and sentences) to determine which tests had sufficient test/re-test reliability and sensitivity for detecting SIN hearing changes. It was also important to utilize tests with minimal practice effects and/or to incorporate pre-testing to enable study subjects to become familiar with the test to limit learning effects. Finally, each test should have sufficient test material to enable repeat testing over an extended follow-up period; using the same speech material within a short time could heighten any learning effects as subjects may remember the word or sentence from prior test sessions.

While digits and monosyllable word tasks may more directly assess peripheral hearing than sentence-based tests, which require more cognitive and linguistic input, sentence-based tests better represent everyday speech than digits or monosyllable words. Trends in performance on digits, words, and words in sentences are generally appreciated with increasing signal-to-noise ratios (SNRs) as the test items become more complex and the range of alternative possibilities increases (Miller et al., 1951). Using a battery of tests that utilize numbers, monosyllable words, and sentences enabled evaluation across various SIN hearing modalities to comprehensively evaluate hearing under noisy conditions.

1. DIN

Digits have been used in SIN testing for clinical diagnostic, screening, and research purposes (Smits et al., 2004; Wilson and Weakley, 2004; van Wieringen and Wouters, 2008). Several different DINs have been developed and evaluated (Van den Borre et al., 2021). Generally, the DIN employs a similar test paradigm with digit triplets (three numbers between 0 and 9) presented in background masking noise (Smits et al., 2013). While the test was initially developed in Dutch, English versions have also been developed and validated (Watson et al., 2012; Smits et al., 2016). The advantage of a digits-based test is that it requires less linguistic or cognitive processing for comprehension compared to a more complex sentence-based test. Use of widely understandable digits enables a more focused assessment of peripheral auditory function. Another advantage is the DIN has limited practice effects, meaning initial test results are typically similar to subsequent results for individual subjects. On the other hand, digits are limited in terms of phoneme distribution representative of daily life speech and do not approximate typical everyday listening conditions in which words are spoken in sentences or phrases.

The DIN we selected in our clinical study uses an adaptive one-up one-down procedure in which the SNR is automatically adjusted based on the previous response to determine the speech reception threshold (SRT; SNR at 50% correct for whole digit triplets). The SRT is calculated based on the average SNR across the last 20 of 23 digit triplets administered. We focused on the 4 kHz low-pass filtered noise version of the DIN, which has been demonstrated to have high sensitivity and specificity as well as a high level of test/re-test reliability (Motlagh Zadeh et al., 2019; Motlagh Zadeh et al., 2021).

2. WIN

The WIN uses monosyllable words presented in multi-talker babble background noise (Wilson, 2003; Wilson and Burks, 2005). One advantage of the WIN is the use of single monosyllable words, which requires less central processing than multi-word sentences (but a greater central requirement than digits). Another key advantage is the use of multi-talker background noise of several speakers talking at the same time, a feature that approximates a real-world hearing environment that people typically encounter in a restaurant or social gathering. None of the background talking is intelligible, and babble may impact speech to a greater degree than standard masking noise and therefore may be more relevant to everyday listening conditions (Wilson, 2003).

The WIN uses the NU 6 monosyllable word materials recorded by a female speaker in the presence of multi-talker babble as the competing background noise. The 35-word version of the test was used in which groups of five words each were presented at seven different, fixed signal-to-babble (S/B) ratios (Wilson and Burks, 2005). We utilized two versions of the test with standard 70 dB HL sound presentation level as well as the more challenging 40 dB HL sound presentation level. The less traditional presentation level of 40 dB HL was chosen to challenge the listener further and potentially to increase the sensitivity for detecting SIN hearing changes. The 50% SRTs were determined using the Spearman–Karber equation as is standard for this test. The WIN has been demonstrated to have high test/re-test reliability following repeat assessments in the same individuals tested 1–3 months apart (Wilson and McArdle, 2007).

3. AEMT

The AEMT is a sentence-based SIN test. The test uses five-word sentences presented in masking background noise. Each sentence is comprised of the same structure, i.e., name, verb, number, adjective, and noun. The sentences are grammatically correct but semantically unpredictable (e.g., “Rachel has four pretty chairs”), thereby making them less likely to be correctly guessed if not heard properly. Another advantage of the AEMT is the large amount of test material available since the words for each sentence are randomly chosen from a base matrix containing 10 names, 10 verbs, 10 numbers, 10 adjectives, and 10 nouns, which can generate thousands of different sentences. The large amount of test material facilitates repeat, longitudinal testing for individual subjects without the risk of subjects remembering a sentence from a prior test session. The matrix test is available in 14 different languages, although test performance differs by language (Kollmeier et al., 2015). The AEMT is administered adaptively, and the SRT is determined by averaging the SNR at 50% correct performance for the 20 sentences of the test. The AEMT has high test/re-test reliability with a limited training effect (Zokoll et al., 2016), assuming practice testing was conducted beforehand.

The ability of OTO-413 to improve SIN hearing is a key objective for clinical testing, so ensuring study subjects have a hearing-in-noise deficit is important for avoiding a ceiling effect. Therefore, to be eligible, subjects must self-report difficulty hearing in noisy environments for the preceding 6 months or longer to ensure the problem is present and persistent. In addition, a SIN deficit is confirmed objectively using a specific SIN test; in our case, we chose the DIN due to its advantages described above (e.g., high sensitivity, good test/re-test reliability, and minimal practice effects). The minimum score for eligibility (≥–12.5 dB SNR) was based on DIN SRT scores in individuals who subjectively complained of SIN hearing difficulty with either normal or mild hearing impairment via pure tone audiometry (Motlagh Zadeh et al., 2021). We also confirmed the high degree of test/re-test reliability in subjects upon repeat testing approximately 1 week after the initial assessment (Fig. 2).

FIG. 2.

DIN SRT scores for 31 individual subjects at testing time 1 (DIN 1) and testing time 2 (DIN 2) approximately 1 week apart. The DIN was administered monaurally using 4 kHz low-pass filtered noise as background noise. SRTs were calculated based on the average SNR across the last 20 of 23 digit triplets administered. Correlation analysis was conducted using Pearson r correlation coefficient (GraphPad Prism 9.0.0 software). DIN SRT scores (dB SNR) were strongly correlated, indicating good test/re-test reliability.

FIG. 2.

DIN SRT scores for 31 individual subjects at testing time 1 (DIN 1) and testing time 2 (DIN 2) approximately 1 week apart. The DIN was administered monaurally using 4 kHz low-pass filtered noise as background noise. SRTs were calculated based on the average SNR across the last 20 of 23 digit triplets administered. Correlation analysis was conducted using Pearson r correlation coefficient (GraphPad Prism 9.0.0 software). DIN SRT scores (dB SNR) were strongly correlated, indicating good test/re-test reliability.

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Additional inclusion criteria for the study were pure tone audiometry thresholds for normal hearing or up to moderately severe hearing loss (≤70 dB of the average at 1, 2, and 4 kHz) in the study ear. We hypothesized that subjects with a range of auditory thresholds could benefit as long as a SIN deficit was present, and as stated previously, OTO-413 through restoration of type I SGN synapses may benefit hearing comprehension in subjects ranging from those with normal audiograms to individuals with audiometric threshold changes indicative of moderate to severe hearing loss. Only native English speakers were included to ensure English fluency did not impact performance on the SIN tests, which were all in English. Subjects had to be without cognitive impairment based on scores on the cognitive screening test, the mini-mental state examination (Folstein et al., 1975). Professional musicians or those with significant formal musical training were excluded since these individuals often perform extremely well on SIN tests. Last, any subjects expected to be exposed to intense noise during the study were excluded.

Appropriate measures to monitor the safety and tolerability of OTO-413 following IT injection focus on standard clinical measures of safety as well as ear-specific measures. Although IT injection is now routine in otolaryngology/neurotology practice, the tympanic membrane and middle ear must be in a healthy state to consider an IT injection; hence, eligibility criteria are included to help ensure this. For example, subjects are excluded with active middle ear disease, abnormal or monomeric tympanic membrane, perforated tympanic membrane, or indwelling myringotomy tubes in the affected ear. Post-administration, otoscopic examinations are conducted to evaluate the appearance of the external ear canal and tympanic membrane as well as to record the presence and size of any tympanic membrane perforations; normal perforations are small in size (“pinhole”) and heal within a week or two after the injection. Tympanometry is performed to assess the function of the tympanic membrane and middle ear post-administration. Typically, perforations of the tympanic membrane are associated with abnormal tympanograms (e.g., type B or C), which revert to normal (type A), once the perforation heals. Last, pure tone audiometry is conducted to determine if there are any changes in hearing across a range of frequencies including extended high frequencies (250–12 500 Hz). In addition to these ear-specific assessments, general safety tests are also conducted, including vital signs, clinical safety labs, and body weight, as well as monitoring for adverse events and any concomitant medications for treatment.

An initial safety and preliminary efficacy study with single IT administration of OTO-413 in subjects with SIN difficulties was completed. This was a randomized, double-blind, placebo controlled study that evaluated four ascending doses of OTO-413 (0.01, 0.03, 0.1, and 0.3 mg OTO-413). Male and female subjects, 21–64 years of age, with pure tone thresholds ranging from normal to moderately severe hearing loss (PTA ≤ 70 dB at 1, 2, and 4 kHz) were enrolled. Self-reported difficulty hearing in noisy environments for at least the prior 6 months, confirmed using the DIN, was required for study eligibility. Dose cohorts of at least eight subjects each received a single IT injection of OTO-413 or placebo to a single ear. Safety assessments (see Sec. V C) and efficacy testing using the SIN tests (DIN, WIN, and AEMT; see Sec. V A) were conducted over a 12-week follow-up period. SIN tests were administered monaurally to each ear at screening and to the study ear that received the IT injection at subsequent visits. SRTs were determined, and clinically meaningful improvement was defined as a change from baseline of ≥–2 dB SNR on the WIN and AEMT and ≥–3 dB SNR on the DIN. The top-line results have been presented (Anderson et al., 2021; Volsky et al., 2021). In a responder analysis from this phase 1/2 study at the highest dose level tested, OTO-413 demonstrated clinically meaningful improvements in one or more SIN tests (DIN, WIN, and AEMT) at both 8 and 12 weeks relative to placebo. OTO-413 also had a favorable safety profile. Improvements in SIN tests were observed in subjects with normal audiometric thresholds as well as those with moderate to severe hearing loss. Details of the findings from this study will be included in a future publication. In addition, an expansion study is under way to further evaluate the effects of OTO-413 in this patient population.

OTO-413 is a promising therapeutic agent that may be useful in treating hearing loss associated with depletion of type I afferent SGN synaptic connections between IHCs and auditory neurons. This cochlear synaptopathy may be an early manifestation of sensorineural hearing loss and underlie SIN hearing difficulties. Preclinical data have demonstrated excellent inner ear PK following IT administration of OTO-413 and efficacy in a rat model of noise-induced cochlear synaptopathy, including morphological and functional evidence for synapse reconnection. Preclinical safety and toxicity studies revealed a very favorable safety profile. A clinical testing program has been designed to evaluate the efficacy and safety of OTO-413 in subjects with SIN hearing impairment and a first-in-human phase 1/2 study completed, with initial evidence of therapeutic benefit based on improvement in SIN tests. Interventional studies of this kind will expand our knowledge of the role played by cochlear synaptopathy in the spectrum of human hearing deficits. From the data gathered to date, it appears that OTO-413 has the potential to improve SIN function in subjects across a range of hearing disabilities, including those with normal audiograms and those with moderate to severe hearing loss.

A.C.F., S.S., F.P., B.E.J., and J.J.A. are Otonomy employees and holders of stock and/or stock options of Otonomy. D. R.M. holds stock in Otonomy and is a consultant to Otonomy, and receives support from the NIHR Manchester Biomedical Research Centre. V.A.S. is a consultant and clinical trial investigator for Otonomy.

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