Targeted Medicines for the Ear - OTO-413 Program Review
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Forward-Looking Statements Safe Harbor Statement These slides and the accompanying oral presentation (the “Presentation”) contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements generally relate to future events or future financial or operating performance of Otonomy, Inc. (“Otonomy”). Forward-lookingstatements in this Presentation include, but are not limited to, the timing of the Phase 1/2 clinical trial for OTO-413, the potential market opportunity for OTO-413, and expectations regarding program advancement. Otonomy’s expectations regarding these matters may not materialize, and actual results in future periods are subject to risks and uncertainties. Actual results may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to: Otonomy’s limited operating history and its expectation that it will incur significant losses for the foreseeable future; Otonomy’s ability to obtain additional financing; Otonomy’s dependence on the regulatory success and advancement of product candidates, such as OTO-413; the uncertainties inherent in the drug development process, including, without limitation, Otonomy’s ability to adequately demonstrate the safety and efficacy of its product candidates, the nonclinical and clinical results for its product candidates, which may not support further development, and challenges related to patient enrollment in clinical trials; the risk of the occurrence of any event; Otonomy’s ability to obtain regulatory approval for its product candidates; side effects or adverse events associated with Otonomy's product candidates; Otonomy’s ability to successfully commercialize its product candidates, if approved; competition in the biopharmaceutical industry; Otonomy’s dependence on third parties to conduct nonclinical studies and clinical trials; Otonomy’s dependence on third parties for the manufacture of its product candidates; Otonomy’s dependence on a small number of suppliers for raw materials; Otonomy’s ability to protect its intellectual property related to its product candidates in the United States and throughout the world; expectations regarding potential market size, opportunity and growth; Otonomy’s ability to manage operating expenses; implementation of Otonomy’s business model and strategic plans for its business, products and technology; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled "Risk Factors" in Otonomy's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the "SEC") on November 5, 2018, and Otonomy’s future reports to be filed with the SEC. This Presentation is dated as of November 5, 2018, and Otonomy undertakes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by applicable law. 2
Hearing Loss: Large and Growing Unmet Need Hearing Loss is 4th Leading Cause of Disability Globally1 1 Lancet, July 2017 NEJM, Dec 2017 Review The n e w e ng l a n d j o u r na l of m e dic i n e Review Article Global hearing health care: new findings and perspectives Allan H. Ropper, M.D., Editor Blake S Wilson, Debara L Tucci, Michael H Merson, Gerard M O’Donoghue Hearing Loss in Adults In 2015, approximately half a billion people had disabling hearing loss, about 6·8% of the world’s population. These Published Online numbers are substantially higher than estimates published before 2013, and point to the growing importance of July 10, 2017 Lisa L. Cunningham, Ph.D., and Debara L. Tucci, M.D., M.B.A. http://dx.doi.org/10.1016/ hearing loss and global hearing health care. In this Review, we describe the burden of hearing loss and offer our and H S0140-6736(17)31073-5 others’ recommendations for halting and then reversing the continuing increases in this burden. Low-cost possibilities exist for prevention of hearing loss, as do unprecedented opportunities to reduce the generally high Division of Head and Neck earing loss in adults is encountered in all medical settings From the Section on Sensory Cell Biology, Surgery and Communication National Institute on Deafness and Other treatment costs. These possibilities and opportunities could and should be exploited. Additionally, a comprehensive Sciences, Department of and frequently influences medical encounters. This disorder constitutes a Communication Disorders, Bethesda, MD worldwide initiative like VISION 2020 but for hearing could provide a focus for support and also enable and facilitate Surgery, Duke University substantial burden on the adult population in the United States, yet (L.L.C.); and the Division of Head and Medical Center, Durham, NC, the increased efforts that are needed to reduce the burden. Success would produce major personal and societal USA (Prof B S Wilson DSc, screening for hearing loss is not routine,1 and treatments are often inaccessible Neck Surgery and Communication Sci- gains, including gains that would help to fulfil the “healthy lives” and “disability inclusive” goals in the UN’s new Prof D L Tucci MD); Duke Global because of the high cost or perceived ineffectiveness. ences, Duke University Medical Center, 2030 Agenda for Sustainable Development. Health Institute Durham, NC (D.L.T.). Address reprint re- (Prof B S Wilson, Prof D L Tucci, quests to Dr. Tucci at the Division of H d dN kS dC i • Most prevalent neurologic health issue: > 360M people have disabling hearing loss2 • High economic burden: medical costs + impact of lower work productivity • Leads to social isolation, lower QoL, and higher rates of dementia and depression • Common causes: aging, noise, ototoxic drugs and genetics • Established clinical outcome measures that are objective patients assessments 2 World Health Organization, Global Estimates on Prevalence of Hearing Loss, 2012. 3
OTO-413 Addresses Significant Population with Cochlear Synaptopathy Speech-in-Noise (SiN) ILLUSTRATIVE Hearing Difficulty • Problem hearing in presence PTA Hearing Deficit of background noise • Hearing loss in standard • U.S. prevalence1 ≈ 9M with test (soundproof booth) SiN only (no PTA changes) • U.S. prevalence2-5 ≈ 42M • Loss/damage to cochlear synapses • Loss/damage to hair cells and/or synapses SIN Difficulty and PTA Deficit Mixed Pathology OTO-413 • Includes patients with age- related and noise-induced Target Patient hearing loss Population • Prevalence ≈ ?? 1 Tremblay et 2 Hoffman al., Ear Hear, 2015 et al., JAMA Otolaryngol HNS, 2017 3 Nash et al., Arch Otolaryngol HNS, 2011 4 Morton et al., N Engl J Med, 2006 5 Brooke et al., JAMA Otolaryngol HNS, 2017 4
Cochlear Synaptopathy and Hearing Loss • In the last decade, research has identified loss or dysfunction of synaptic connections between inner hair cells (IHC) and spiral ganglion neurons (SGN) as playing important role in hearing loss pathology • Synapses can be damaged or lost due to loud noise, aging, and/or exposure to ototoxic chemicals • “Cochlear synaptopathy” contributes to speech-in-noise difficulties as well as age-related and noise-induced hearing loss • Potential to repair synaptopathy using neurotrophic factors Figure from Moser and Starr, Nature Reviews: Neurology (2016) 5
Extensive Support for Synaptopathy and Repair by Neurotrophins Hearing Research xxx (2015) 1e9 Contents lists available at ScienceDirect Hearing Research journal homepage: www.elsevier.com/locate/heares F1000Research 2017, 6(F1000 Faculty Rev):927 Last updated: 16 JUN 2017 Synaptopathy in the noise-exposed and aging cochlea: Primary neural REVIEW Noise-induced degeneration in acquired sensorineural and age-related hearing loss hearing loss: new perspectives Hearing Research xxx (2017) 1e10 and Sharon G. Kujawa a, b, c, M. Charles Liberman potential a, b, * therapies [version 1; referees: 4 approved] Contents lists available at ScienceDirect a Department of Otology and Laryngology, Harvard Medical School, Boston, MA, USA M Charles Liberman b Eaton-Peabody Laboratory, Massachusetts Eye & Ear Infirmary, Boston, MA, USA c Department of Audiology, Massachusetts Eye and Ear, Boston, MA, USA Department of Otolaryngology, Harvard Medical School, Eaton Peabody Laboratories, Massachusetts Eye and Ear, 243 Charles Otology St., Boston, & Neurotology Hearing Research MA, 02114, USA 37:1223–1230 2016, Otology & Neurotology, Inc. a r t i c l e i n f o a b s t r a c t journal homepage: www.elsevier.com/locate/heares Article history: The classic view of sensorineural hearing loss (SNHL) is that the “primary” targets are hair cells, and that cochlear-nerve lossFirst v1 published:to 16 Juncell2017, 6(F1000 Faculty Rev):927 (doi: Open Peer Review Received 2 December 2014 is “secondary” hair degeneration. Our recent Review work in Article mouse and guinea pig Received in revised form has challenged that10.12688/f1000research.11310.1 view. In noise-induced hearing loss, ) exposures causing only reversible threshold 26 January 2015 Accepted 25 February 2015 shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of cochlear-nerve/hair-cell Latest published: 16 Jun 2017, 6(F1000 Faculty Rev):927 (doi: Cochlear synaptopathy in acquired sensorineural hearing loss: Referee Status: Manifestations and mechanismsApplying Neurotrophins to the Round Window Rescues Auditory synapses. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair Available online xxx 10.12688/f1000research.11310.1) cell loss and threshold elevation. This primary neural degeneration has remained hidden for three reasons: 1) the spiral ganglion cells, the cochlear neural elements commonly assessed in studies of SNHL, nerve fibers The Abstract survive for years despite loss of synaptic connection with hair cells, 2) the synaptic terminals of cochleara, b are unmyelinated and difficult to see in the light M. microscope, Charles classic view of sensorineural hearing loss has been that the primary and 3) the Liberman degeneration is , Sharon G. Kujawa a, b, * 1 Invited Referees 2 3 4 Function and Reduces Inner Hair Cell Synaptopathy After ISAAR Special Issue damage targets selective for cochlear-nerve fibersare hair with cells high and thatAlthough thresholds. auditory quiet (e.g. threshold audiometry or auditory brainstem response threshold), nerve not to hair cell degeneration. Recent work has challenged that view. In a b lossforisthreshold required Department typically secondary of Otologydetection these high-threshold Eaton-Peabody in and Laryngology, fibers Harvard Medical School, Boston MA, USA Laboratories, Massachusetts Eye & Ear Infirmary, Boston MA, USA Noise-induced Hearing Loss Trends in Hearing 2016, Vol. 20: 1–9 are critical for hearing in noisy environments. Our research suggests that 1) primary neural degeneration version 1 David J. Sly, Luke Toward a Diagnostic Test for is an importantnoise-induced contributor tohearing loss, exposures the perceptual handicap incausing SNHL, andonly 2) reversible in cases where threshold the hairshifts cells published ! The Author(s) 2016 (and no hair survive, neurotrophin cell loss) therapies nevertheless can elicit cause permanent neurite outgrowth from spiralloss a r t iofc >50% l e iofnthe ganglion neurons and re- f o 16 Jun 2017 a b s t r a c t Campbell, Aaron Uschakov, Saieda Tasfia Saief, Reprints and permissions: establishment synaptic connections of their peripheral between hair cells and the auditory nerve. Similarly, in synapses. This article is part of a Special Issue entitled . Hidden yMatthew Hearing Lam, and Stephen J. Loss O’Leary sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2331216516657466 age-related hearing loss, degeneration of cochlear Article synapses history:precedes both Common causes of hearing loss in humans - exposure to loud noise or ototoxic drugs and aging - often tia.sagepub.com www.nature.com/scientificreports RESEARCH ARTICLE hair cell loss and threshold elevation. This primary neural Received 13 June 2016 degeneration has F1000 Faculty damage Reviews sensoryarehaircommissioned cells, reflected as elevated thresholds on the clinical audiogram. Recent studies in Received in revised form © 2015 Elsevier B.V. All rights reserved. animal models suggest, however, Otolaryngology, that well before Department of Surgery, this overt hearing loss can beUniversity seen, a moreof Melbourne; and yMonash School of Medicine, insidious, remained a “hidden hearing loss” for two reasons: 1) 19 the neuronal 2016 cell bodies survive for years despite loss of synaptic connection December with hair Accepted cells,2017 5 January Available online xxx and 2) the from members of the prestigious F1000 but likely more common, process is taking place that permanently Faculty. In order to make these reviews as between sensory inner hair cells and subsets of cochlear nerve Monash interrupts fibers. The synapticMelbourne, University, silencing of communication affected VIC, 1 neurons Australia 1 Christopher J. Plack , Agnès Léger , Garreth Prendergast , 1 Improved Auditory Nerve Survival with degeneration is selective for auditory nerve fibers with high thresholds. alters auditory information processing, whether accompanied by threshold elevations or 1not, and is a Although not required for threshold detection whenKeywords: quiet, these high-threshold comprehensive and accessible likely contributor as possible, to a variety 1 Karolina Kluk , Hannah Guest , and Kevin J. Munro of perceptual abnormalities, including speech-in-noise difficulties, tinnitus 1 Nanoengineered Supraparticles for fibers are critical peer review andtakes place before hyperacusis. Workpublication; described herethe will review structural and functional manifestations of this orfor hearing in noisy environments. Research Auditory nervesuggests that Hypothesis: and Applying will considerneurotrophins to the rounditswindow appearance and Results: progres- After exposure to 105 dB noise, threshold did not 1. Primary vs. secondary neural degeneration in sensorineural hearing loss grossly primary neural degeneration abnormal brainstem response cochlear is an (ABR). important neural responses, contributor Although the underlying Cochlear such as the auditory Cochlear synaptopathy to neuropathy the perceptual histopathology cochlear synaptopathy referees sion are listed in earsbelow, but their immediately with and reports withoutafter aare possible mechanisms single traditional noiseloss’ ‘hearing exposure underlying willseveral arising from prevent noise-causes inchange, common humans. but the amplitude growth of the auditory brainstem Neurotrophin Delivery into the Deafened handicap in sensorineural hearing loss, is poorly understood, theand it may be dysfunction keyhearing can Hidden to thelossgeneration theoretically of originate not formally published. induced hidden hearing loss. 2017 Elsevier B.V. All rights response © Abstract reserved. was significantly reduced in control ears in Sensorineural hearing loss (SNHL), as a category tinnitus and other of hearing associated anywhere fromperceptual anomalies. hair cell synaptic In cases transmission to where the hair of Noise-induced hearing loss the conduction Background: Loud noise can eliminate neural connections Cochlear synaptopathyresponse to 16hearing (or hidden and 32loss), kHz tones. due toThe amplitude noise growth exposure was Cochlea or aging, has been demonstrated in animal models impairment, includes those etiologies in which the cells survive, neurotrophin underlying therapies action potentials can elicit in auditory neurite nerve fibersoutgrowth (ANFs). One from surviving clearcut eti- between inner hair cells and their afferent neurons (thereby also reduced neurotrophin ears, but to a lesser degree and pathology involves the sensory cells and/or the sensoryauditory neurons neurons of ology 1 Christoph Schreiner , Kavli Institute for using histological techniques. However, diagnosis of the condition in individual humans is problematic because of (a) test andisre-establishment a genetic mutation in otoferlin of their (Santarelli peripheral synapses;et al., 2009), a thus, diminishing sound perception) without causing a detectable the reduction was not significant. Similar results were 1,2,3 3 4 Fundamental Neuroscience, of This phenomenon isreliability and (b) lack of a gold standard validation measure. Wave I of the transient-evoked auditory *, Justin Tan brainstem response , YajunisWang a , Frank Caruso4, Robert K. Shepherd1,2,3 the inner ear. Although primary neural degeneration, i.e. neural loss protein expressed in inner hair cells (IHCs) treatments may be on the horizon. and thought to control Contents change onUniversity audiogram. termed hidden obtained from control ears exposed to 95 dB, but amplitude Andrew K. Wise OPEN Round-window delivery of without hair cell loss, is recognized as a subclass of SNHL, it has vesicle release at the synapses with ANFs (Beurg et al., 2010). noninvasive electrophysiological measureinofneurotrophin-treated auditory nerve function California, USA hearing loss. growth recovered ears, and this has been validated in the animal models. However, in reaching 1 The Bionics Institute, 384–388 Albert Street, East Melbourne, Melbourne, Australia, 2 The Department of been considered rare, comprising mainly cases of congenital and/or In cases of acquired SNHL, far and away 1. the most Overt common vs. ‘hidden’ formloss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .humans, hearing Methods: Guinea pigs were exposed for 2. .hours . . . . . . . .Wave to. . .4. . to . .I . amplitude . . . . . . . . . . . shows 00 statistical high variability significance both between in response to 16 kHzand tones. within There individuals. MedicalThe frequency-following Bionics, University of response, Melbourne, a Australia, 3 Department of Otolaryngology, University Melbourne, hereditary defects (Starr et al., 2000, 1996). As a clinical entity, of SNHL, it has been widely believed 2. thatCochlear the hair cells are the synaptopathy and neurodegeneration in noise-exposed and aging and mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2 Richard Salvi , Center 8 kHz fornoise Hearing at either 95 or 105 dB SPL. sustainedImmediately evoked potential were reflecting significantly morea11111 synchronous neural activity presynaptic ribbons,in postsynaptic the rostral ofbrainstem, Melbourne,isMelbourne, potentially more4robust thanof Excellence in Convergent Bio-Nano Science and neurotrophin 3 regenerates auditory neuropathy, as it is called, is defined by normal hair cell primary targets, and that the degeneration 3. of sensory Glutamate neurons excitotoxicity as an instigating factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Australia, ARC Centre function (as seen in normal otoacoustic emissions) despite absent occurs almost exclusively as a secondary4.consequence Functional effects of theofloss synaptopathy of . . .Deafness, . . . . . . . . . . .University . . . . .at . . . . . .afterward . . Buffalo, . . . . . . .a. . New .4 . . York, . . ml . . . bolus . . . . . . . . .of . . . .neurotrophins . . (brain-derived . . . . . . . . . . . . . .auditory . . . . . . . .brainstem . . . glutamate . . . . . . . . . . . response . . . . . 00Wavereceptors, and colocalized I. However, ribbons after response the frequency-following neurotro- Technology, is a measure andof thecentral activity Department and may of Chemical andbe Biomolecular Engineering, the University of Melbourne, 5. Johnsson, their hair cell targets (Bohne et al., 2000; Cochlear1974). neurodegeneration This view and SR types: neurotrophic factor 1 mg/ml, and neurotrophin-3 USA special vulnerability of low-SR neurons . . . . . . . . . . . . . . . . . . . . . . . . . . .dependent . . . . 1. .mg/ml) . .was . . . . . . on . . . . . . . . phin . .individual . . . treatment. . . differences 00 in central processing. Psychophysical measuresMelbourne, Australia by intersubject variability are also affected cochlear synapses after acoustic 5.1. arises from observing the time course of histopathologySingle unit evidence in the two for low-SR vulnerability . . .delivered. . . . . . . . . . . .to . . . the . . . . . round . . . . . . . . window . . . . . . . . . . .of . . . one . . . . .ear, . . . . and . . . . .saline . . . . . . .to. . .the . . . . . . . . . .Conclusion: . . . . 00 A single dose of neurotrophins delivered to the 5.2. Morphology of synaptic vulnerability . . . . . . . . . . .other. . . . . . . . .Auditory . . . . . . . . . . . .brainstem . . . . . . . . . . . . .responses . . . . . . . . . . . .to . . . in . . . central . . .pure-tone . . . .processing. . . . . .pips . . . . . . . . . . . Differential . were .round . . . . 00window measures may help to reduce intersubject variability due to unrelated factors. A measure reduced synaptopathy and recovered high- * awise@bionicsinstitute.org most common animal models of acquired SNHL i.e. acoustic trauma 3 Tobias Moser , Universitätsmedizin * Corresponding author. Eaton-Peabody Laboratories, Massachusetts Eye and Ear 6. Cochlear synaptopathy and relevance to human SNHL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .can . . . . be . . . .compared, . . . . . . . . . . . . within . . . . . . .an individual, . . 00 between conditions that aredBaffected differently by cochlear synaptopathy. Validation of Infirmary, 243 Charles St., Boston, MA 02114-3096, USA. Tel.: þ1 617 573 3745; and ototoxic antibiotics. Numerous studies over the last 5 decades 6.1. Göttingen, Synaptopathy in human temporal bones . .Germany acquired preoperatively, and at 1 and 2 weeks’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . the postexposure. . . . . .metrics . . . . . . . . .is. . also . . . . . an frequency . . . .issue. . . . . 00 hearing in ears exposed to 95 noise. These Comparisons with animal models, computational modeling, auditory nerve imaging, and human overexposure fax: þ1 617 720 4408. have shown that within 24 h, or less, after a noise exposure or drug 6.2. Cochleae Synaptopathy, low-SR neuropathy and human auditory were function . . . .removed . . . . . . . . . . . and . . . . . whole . . . . . . . . .mounted . . . . . . . . . . .for . . . . . . . . . . . . . . . . . . .findings . . . .immunohis- . . . . 00 suggest that hidden hearing loss may be reduced by recei�e�: 11 �anuar� 2016 E-mail address: Charles_Liberman@meei.harvard.edu (M.C. Liberman). treatment, there can be massive hair cell 6.3. loss, whereas Monitoringthe for first 4 Robert synaptic injury Fettiplace and treatment , Department tochemical efficacy . . .of . . . . . . . . . analysis, . . . . . . . . .with . . . . . . .presynaptic . . . . . temporal . . . . . . . . . . . . . . ribbons . . . . of . . . .bone . . . inner . . . histology . . .hair . . .are . 00all potential . . . . . . . .providing optionstofor trophic support thevalidation, but cochlea after there injury.are Key technical and practical hurdles and difficulties in 7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .cells Neuroscience, University . . . . . . . .and . . . . . . associated . . . . . . . . . . . . . .postsynaptic of Wisconsin . . . . . . . . . . . . . . .glutamatergic. . . . . . . . . . AMPA . . . . . .interpretation. . . . . . . . Words: . . . . . . .Despite . . the . . . 00 BDNF—Glutamate obstacles, a diagnostic Abstract OPENreceptor—Hidden ACCESS test for hidden hearing hearingloss— accepte�: 04 �pri� loss is a worthwhile goal,2016 with important impli- http://dx.doi.org/10.1016/j.heares.2015.02.009 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .receptors . . . . . . . . . . . . .identified . . . . . . . . . . . . . using . . . . . . . .CtBP2 . . . . . . . . and . . . . . .GluA2 . . . . . . . . antibodies 0378-5955/© 2015 Elsevier B.V. All rights reserved. References . . . . . . . . . . . . . . . . . . . . . . . . . Medical . . . . . . . . . School, . . . . . . . . .USA cations. .for . . . . . . . . . . . . . . . .Neurotrophin—Noise—NT-3—Synaptic clinical practice . . . . 00 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 and health surveillance. ribbon. Citation: Wise AK, Tan J, Wang Y, Caruso F, Pu��is�e�: 2� �pri� 2016 Suzuki1,2,3 Junstimulate , Gabriel Corfas4 & M.(SGNs) Charlesin Liberman 1,2 respectively. Otol Neurotol 37:1223–1230, 2016. Cochlear implants electrically spiral ganglion neurons order to provide Shepherd RK (2016) Improved Auditory Nerve Survival with Nanoengineered Supraparticles for speech cues to severe-profoundly deaf In acquired patients. In hearing sensorineural normal loss, hearing suchcochleae the SGNs as that produced by noise or aging, there can be massive Please cite this article in press as: Kujawa, S.G., Liberman, M.C., Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss, Hearing Research (2015), http://dx.doi.org/10.1016/j.heares.2015.02.009 Discuss this article Keywords Neurotrophin Delivery into the Deafened Cochlea. loss of the synaptic depend on endogenous neurotrophins connections secreted between by sensory cells incochlear sensory the organ cells of Corti forand primary sensory neurons, without noise-induced hearing loss, aging, cochlear nerve, auditory brainstem response, frequency-following response PLoS ONE 11(10): e0164867. doi:10.1371/journal. loss of the sensory cells themselves. Because the cell bodies and central projections of these cochlear Comments (0) survival. SGNs gradually degenerate following deafness and consequently there is consid- 1. Overt vs. ‘hidden’ hearing loss (SNHL) has been that cochlear hair cells are among the most damage hair 25 cells, pone.0164867 with excitotoxicity causing neurons survive for months to years, there is a long therapeutic window in which to re-establish The classic view of hearing loss over the last Datefew decades received: 24 November vulnerable elements in the cochlea and that, in the vast majority of 2015; revised: January 2016; accepted: 2 March 2016 a wide- erable interest in developing clinically relevant strategies to provide exogenous neurotro- spread loss of connections between inner University hair cells phins to preserve SGN survival. functional connections and improve hearing ability. Here we show in noise-exposed mice that local A longstanding view of acquired sensorineural hearing has been loss thatcases, aftercochlear exposurenerveof thedegenerate ear to aif,noxious and only long after, the Editor: Olivia Bermingham-McDonogh, The fibers delivery ofpresent study investigated neurotrophin-3 (NT-3) to thethe safety round windowand efficacy niche, 24of a after an exposure that causes an hours stimulus, such loss as excessively loud sound, of their peripheral hair cellthere This view arose,(IHC) is primary targets. funda-and their afferent neurons of Washington, (2). STATES UNITED This ‘‘synaptopathy’’ drug delivery system for theimmediate cochlea using loss ofnanoengineered up to 50% loss ofsilica synapses in the cochlear supraparticles. basal region, can regenerate pre- and post- In the damage to the mentally,sensory hair cellsofofthe because thetemporal inner ear,offsetfollowed results in the loss of both presynaptic ribbons on the IHC between post-insult Received: January 24, 2016 synaptic elements at the hair cell / cochlear nerve overinterface. a period This synaptic regeneration, as documented * Corresponding author. Eaton-Peabody Laboratories, Massachusetts byEye and Ear secondary degeneration ofofhair degeneration Page 1 of 11 cells and auditory connected loss of the spiral ganglion nerves cell and postsynaptic receptors on the afferent nerve. It does not present study we deliveredby Brain-derived confocal neurotrophic microscopy of factor immunostained (BDNF) cochlear sensory of four epithelia, was coupled with a corresponding Infirmary, 243 Charles St., Boston, MA 02114-3096, USA. (1). However, (SGC) E-mail address: Sharon_Kujawa@meei.harvard.edu (S.G. Kujawa). bodies of the primary auditory neurons with which a series of recent studies has changed this theythe detectionAccepted: affect of quiet sounds October (3), but is expected to weeks and evaluated SGN functional 3, 2016 survival as a measure of efficacy. Supraparticles were bilater- recovery, as seen in the suprathreshold amplitude of auditory brainstem response view by showing that after noise exposure, Introduction neural injury make it difficult to Published: differentiate between competing sound ally implanted into the basal turn 1. of cochleaedeliveryin profoundly deafenedinguinea pigs. Oneachievable ear http://dx.doi.org/10.1016/j.heares.2017.01.003 October 27, 2016 neuropathy, cochlear synaptopathy, and Wave popularly Cochlear of neurotrophins humans is likely as an office procedure via 0378-5955/© 2017 Elsevier B.V. All rights reserved. occurs at exposure levels lower than those Hearingrequiredabilityto is sources, usually such assessed as a using speaker among pure-tone background audi- hidden noise. Con- hearing loss (Schaette & McAlpine, transtympanic 2011), because injection, making our received BDNF-loaded supraparticles and the other ear control (unloaded) supraparticles. results highly significant in a translational context. sequently, Copyright: © 2016 Wise ometry (Johnson, 1970), whichthismeasures so-called ‘‘hidden the smallest hearing et al. Thisloss’’ the loss(HHL) is an open is notisthought to be detectable using pure-tone not detected on access article distributed conventional hearing under testing the the After one month of treatment the cochleae were examined histologically. There was signifi- the terms of(i.e., Please cite this article in press as: Liberman, M.C., Kujawa,AddressS.G., Cochlear synaptopathy correspondence andinreprint acquired detectable sensorineural requests to Prof.hearing level Stephenloss: of pure tones at a range J. Manifestations of Commons Creative frequencies.Attribution audiometry. License, which The loss greater cantly seems to affectofselectively survival SGNs in the low that received BDNF supraparticles compared cochleae The resulting audiogram audiogram), is sensitive butto nonetheless dysfunction is anticipated ofuse, thedistribution,to impede com- Recent work on noise-induced and age-related hearing loss shows that the most vulnerable elements in the inner and mechanisms, Hearing Research (2017), http://dx.doi.org/10.1016/j.heares.2017.01.003 O’Leary, M.D., Ph.D., Otolaryngology, Department of Surgery, Uni- spontaneous rate (SR) fibers that have high thresholds munication dailypermits unrestricted Soand ear are not (repeated to the contralateral control cochleae the sensorymeasures cells, but their ANOVA,synapsesp with cochlear = 0.009). SGN nerve terminals1. A noise exposure causing a large, survival versity of Melbourne, 5th Floor, Peter Howson Wing, outerRoyalhair cells. However, Victorian it isinbecoming listening reproduction situations increasingly (4).and in any medium, provided far, are the synapt- thought to be responsible forbut original coding ultimately sound reversible,The elevation of cochlear thresholds, can immediately, and permanently, destroy these syn- Eye and Ear Hospital, 32 Gisborne St, East Melbourne, 3002theVIC,audiogram opathy has been found to occur after noise exposure, drug- was observed over a wide extent ofKujawa, the cochlea. supraparticles were well tolerated clear that is much less author sensitive to inner and source are credited. intensity at moderate-to-high levels (Furman, apses, thereby silencing up to 50% of the fibers in the cochlear nerve, despite no immediate or delayed loss of hair Australia; E-mail: sjoleary@unimelb.edu.au induced hearing loss (ototoxicity) (5,6), and also presby- within the cochlea with a tissue cells response 1,3 . Although that this was localised cochlear to synaptopathy the site does of notimplantation elevate in thethe loss of neural channels likely causes thresholds, This work was funded by the National Health andhair cellResearch Medical (IHC) loss (up to 80% IHC loss may occur acusis in human ears (7). Data It has been Availability found Statement: & Liberman, 2013). This may explain why the loss Allin the mouse relevant data are (2), Council (Australia) and the Garnett Passe and without affecting audiometric Rodney Williams thresholds; Lobarinas, does(7). notThere cochlear base. affectissensitivity Although to quiet sounds. difficulties mild, the tissue understanding responsespeech in noisy or reverberant was significantly greater inenvironments cochleae and may also cause tinnitus , the phan- 2 3,4 Memorial Foundation. guinea pig (8), and within primates including humans the paper. tom sounds commonly brought on by acoustic overexposure. This type of cochlear synaptopathy has been called Salvi, & Ding, 2013)also andcompelling to some clinical types ofevidenceperipheral that tinnitus Themay extent also totreated be which with hidden BDNFhearing loss supraparticlesis a contribu- “hidden compared hearing to5,the loss” controls because the (repeated auditory measures deficits can hide ANOVA, behind a p normal threshold audiogram. The authors disclose no conflicts of interest. Funding: This work was funded by DOI: 10.1097/MAO.0000000000001191 neural dysfunction. aInclinical particular, results manifestation from of rodent synaptopathy torNational (9). Health to hearing difficulties experienced = 0.003). These by humans data support In the the is still adult clinical ear, cochlear potential of nerve fibers often degenerate this technology particularly after as cochlear the insult, including noise damage and oto- models suggest that noise exposureandand Medical Research Council Project Grant aging can supraparticles can be loaded toxicwithantibiotics a variety. This 6 degenerationdrugs. of therapeutic occurs with a variable time course, depending on the nature and severity of APP1005071 and APP1064375, Australian the insult; however, the unmyelinated terminal dendrites within the organ of Corti disappear first (within hours cause permanent 1223 loss of synapses between the IHCs Research Council under the Australian Laureate to days), followed more slowly by the peripheral axons in the osseous spiral lamina (within days to weeks), and, and auditory nerve fibers, without permanently affecting 1 Fellowship scheme (120100030),University and Nationalof Manchester, UK only on a much slower time course, the cell bodies in the spiral ganglion and their central axons that compose sensitivity to quiet sounds (Kujawa & Institutes Liberman,of Health2009, (USA) HHS-N-263-2007- the cochlear nerve (over weeks to months and longer)7–9. Given that cochlear implants can continue to provide Corresponding author: 2015; Sergeyenko, Lall, Liberman, &00053-C. Kujawa, 2013). useful hearing Christopher J. Plack, University of Manchester, Ellen Wilkinson for years after hair cell loss, these long-surviving neurons must remain electrically excitable and Building, The disconnected nerve fibers subsequently degenerate. Manchester M13 9PL, UK. appropriately connected to their central targets10. Thus, in many types of sensorineural hearing loss, there is Copyright © 2016 Otology & NeThis urotolodisorder gy, Inc. Unhas authbeen orized variously reproductioCompeting n of thisInterests: termed acochlear rticle The is pauthors rohEmail: ibhave itedchris.plack@manchester.ac.uk . declared a long therapeutic window wherein a treatment to elicit neurite outgrowth could reconnect silenced cochlear that no competing interests exist. ganglion cells with hair cells, and thereby potentially improve speech in noise performance and reduce tinnitus. Neurotrophin-3 (NT-3) is a member of the neurotrophic factor family that contributes to neuronal differen- Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www. tiation, creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission providedsurvival and axonal outgrowth via its interactions with TrkC receptors11,12. Neurotrophins are necessary the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). for normal development of cochlear innervation13–16, and NT-3 is necessary for the formation and maintenance PLOS ONE | DOI:10.1371/journal.pone.0164867 October 27, 2016 Downloaded from tia.sagepub.com at UCI MEDICAL CENTER on September 12, 2016 1 / 17 1 Department of Oto�o�� an� �ar�n�o�o��� �ar�ar� �e�ica� �c�oo�� �oston �� 0211�� ���. 2Eaton-Peabody �a�oratories� �assac�usetts ��e � �ar In�rmar�� �oston �� 02114� ���. 3Department of Otorhinolaryngology- �ea� an� �ec� �ur�er�� �o�o�u �ni�ersit� �ra�uate �c�oo� of �e�icine� �en�ai� �i�a�i 980�8�74� �apan. 4Kresge �earin� �esearc� Institute an� Department of Oto�ar�n�o�o����ea� an� �ec� �ur�er�� �ni�ersit� of �ic�i�an� �nn �r�or� �I� ���. �orrespon�ence an� re�uests for materia�s s�ou�� �e a��resse� to �.�. �emai�: �un��u�u�i2� meei.�ar�ar�.e�u or ��su�u�i1212�or�.me�.to�o�u.ac.�p� Scientific RepoRts | 6:24907 | DOI: 10.1038/srep24907 1 6
Background on OTO-413 Program • Selected BDNF after extensive evaluation of multiple neurotrophic factors and Trk antibodies - Cochlear explant assay, in vitro testing and in vivo evaluations • OTO-413 comprised of BDNF in thermosensitive polymer (same used for OTIPRIO® and OTIVIDEX™) • IP covers proprietary formulation and manufacturing know-how • Single intratympanic injection of OTO-413 provides sustained- exposure of BDNF to the inner ear • Therapeutic potential of OTO-413 demonstrated in cochlear synaptopathy animal model – presentation selected as “Hot Topic” at 2018 Society for Neuroscience Annual Meeting (November 6) 7
Therapeutic Effects of BDNF in the Cochlea Brain-derived neutrophic factor (BDNF) activates TrkB receptors on SGNs to: • Promote survival of SGNs SGN survival (normalized to 1nM NT-3) 140% 120% 100% 80% BDNF 60% Control hIgG4 40% 20% 0% 0.001 0.01 0.1 1 10 concentration (nM) • Increase neurite outgrowth of SGNs Control 10nM BDNF 35 ** 30 **p
OTO-413 Proof-of-Concept in Synaptopathy Animal Model Recovery of both synapse numbers and auditory function with OTO-413 30 Synapse Counts Visualization of Synapses on Hair Cells Synaptopathy (Punctae/IHC) 25 20 15 10 4 10 20 40 Naïve Frequency (kHz) Noise + Vehicle Noise + OTO-413 1.6 Auditory Function 1.4 Wave 1 amplitude (µV) 1.2 1.0 0.8 0.6 0.4 0.2 0.0 4 10 20 40 Frequency (kHz) 9
OTO-413 Program Status and Plan • Pre-IND meeting completed with FDA • IND enabling activities ongoing • Expect to initiate Phase 1/2 study in hearing loss patients in 1H19 • Initial study population: speech-in-noise hearing difficulty - Common and growing problem not improved by hearing aids - Objective clinical endpoints - Extensive discussions with KOLs about study design • Will outline clinical trial plan and timing in January 10
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