Otonomy Announces Publication of Phase 1/2 Trial Results Showing Tinnitus Improvement in Patients Receiving OTO-313
Otonomy Announces Publication of Phase 1/2 Trial Results Showing Tinnitus Improvement in Patients Receiving OTO-313
The breakthrough device — based on 20 years of Shore’s research and $14 million in funding — is “nearly market ready,” according to Auricle Inc CEO and Co-Founder, Jon Pearson.
Here is the official product description (Auricle Inc):
Device that combines auditory frequencies and timed somatosensory stimuli to suppress tinnitus-generating neurons that cause ringing in the ears.
Here are the latest details — developing story:
Excerpt from the agreement:
“… a for-profit company called Auricle Inc. (the “Company”). The Company was formed recently to commercialize a device to treat tinnitus…”
Susan Shore, PhD, a Professor in the Department of Otolaryngology-Head and Neck Surgery, and David Martel, Graduate Student Research Assistant in the Department of Otolaryngology-Head and Neck Surgery, are partial owners of a for-profit company called Auricle Inc. (the “Company”). The Company was formed recently to commercialize a device to treat tinnitus and desires to option from the University of Michigan the University’s rights associated with the following technology:
UM OTT File No. 5507, entitled: “Tailored Auditory – Somatosensory Stimulation to Treat Tinnitus” (Inventors: Seth Koehler, David Martel, Susan Shore)
The Office of Technology Transfer selected the Company as a University partner and negotiated the terms of the proposed Agreement in accordance with University policy and its accepted licensing principles.
Here is the Gen 2.0 clinical unit (i.e., the one that was used in the latest Shore clinical trial, it would seem)… which might give us some idea of the Auricle device product hardware (note: no confirmation yet on what the market-ready device will look like).
The unlisted video, “Auricle 2 min 2021 Rosenman Innovator Demo Day AU I0F2VG4”, only has 45 views at the time of this writing (September 7, 2021, 1:29pm EST). Also worth mentioning are the social signals: the video currently has one Like and one comment… both of which can be traced to a mysterious “Michael Sutton” character. Hmmmm…
This is a developing story. Expect more updates soon. Sources below. Remember to subscribe. And please share, if you want to encourage more “exclusive” updates like this one.
More to follow…
Subscribe to the Tinnitus Treatment Report email newsletter to stay informed about the release date for Susan Shore’s Auricle Device for tinnitus. Plus, other promising new tinnitus treatments on the horizon. It’s free, you get one or two emails per week (but only when something interesting is happening). No sneaky third party emails. Privacy respected. Unsubscribe any time with one click.
“These findings suggest that this pharmaceutical treatment may serve as a potential therapeutic in suppressing tinnitus symptoms.”
Reduction of Behavioral Manifestation of Tinnitus Through the Utilization of BK Channel Opener
Manisha Antony & Aarti Patel
Faculty Mentor: Joseph Walton (Department of Communication Sciences and Disorders)
Tinnitus, or “ringing in the ears”, is a prevalent hearing disorder. This study evaluates the effect of the drug candidate, CS0022, on the behavior of male CBA/CaJ mice with acoustic trauma (AT)-induced tinnitus. This compound is known to target the large-conductance calcium and voltage-activated potassium channel, or BK channel. This channel regulates neuronal excitability in the peripheral and central nervous system. Our hypothesis is that positive modulation of BK channel function mitigates changes in central auditory system activity that support the tinnitus percept. Behavioral evidence of tinnitus in mice models can be assessed through the quantification of the acoustic startle reflex and prepulse inhibition.
This study used Gap-Prepulse-Inhibition of the Acoustic Startle Response (GPIAS) to determine the presence and extent of tinnitus in the subjects. The GPIAS assay was first conducted on each mouse for baseline readings prior to AT with a 16 kHz narrowband noise. Post-AT behavioral assessments were conducted 7 to 9 weeks after trauma to select mice that developed tinnitus, while effect was assessed 10 to 11 weeks after trauma. Consecutively, Auditory Brainstem Responses (ABR) were collected to determine hearing thresholds of the subjects and helped evaluate the severity of threshold shifts. The findings suggest that treatment with CS0022 can improve AT-induced tinnitus in mice by modifying BK channels. The GPIAS results were statistically analyzed using a computational approach called Gstar. The ongoing analysis will focus on determining the relationship between the presence of tinnitus and the influence of treatment on permanent hearing loss.
Administration of BK Channel Agonist to Reduce Behavioral and Neural Manifestations of Tinnitus in Mice after Induced Acoustic Trauma
Kristie Labib & Malak Ibrahim
Faculty Mentor: Joseph Walton (Department of Communication Sciences and Disorders)
Tinnitus is a hearing disorder affecting approximately one third of all adults, and unfortunately has no FDA approved curative treatments. The deafferentation of central auditory structures as a result of ARHL or acoustic trauma (AT) causes a reduction in auditory sensory input. This then causes compensatory shifts in the balance of excitation and inhibition of the firing rate of the neurons within the CAS, which most often translates to hyperactivity. One particular BK channel modulator, known as CS0022, has been studied for its effect on hyper-excitability and inhibition in animal models. As a result, this study seeks to investigate this BK channel modulator therapy further and examine its effects on tinnitus in order to support its advancement and clinical usage. Auditory Steady State Responses (ASSRs) are electrophysiologic responses that display hearing sensitivity by evoking periodic amplitude-modulated tones (AM tones). They elicit steady state responses through neural phase-locking, which demonstrates auditory perceptive abilities. The study’s first objective is to examine the effects of AT on ASSR responses, as it is hypothesized that AT suppresses neural phase locking abilities. The study’s second objective is to examine the effect of CS0022 on the ASSRs of animals with AT-induced tinnitus, as it is hypothesized that CS0022 would enhance neural phase locking abilities. The data demonstrated that animals with tinnitus generally exhibited decreases in ASSR peak amplitudes following AT and increases in ASSR amplitudes following CS0022 administration. These findings suggest that this pharmaceutical treatment may serve as a potential therapeutic in suppressing tinnitus symptoms.
This is from a June 2021 news article on the USFRI website’s newsroom:
Research: Developing a novel therapeutic for treating tinnitus
Faculty Advisor: Professor Joseph Walton
Industry Partner: Cognosetta
Manisha Anthony recently graduated from USF with a degree in biomedical science and plans on attending medical school. She has been doing research at USF Professor Joseph Walton’s auditory neuroscience lab in the Department of Communication Science and Disorders for nearly two years. The lab focuses on studying tinnitus, a hearing disorder caused by age-related hearing loss or noise-induced trauma, and for which there are few effective treatments to lessen symptoms and no cure. She joined a project in Dr. Walton’s startup, Cognosetta, in 2020 that is working to develop a new drug to address tinnitus.
“Through my experience at Cognosetta, I was able to gain substantial knowledge that will help me with my future endeavors. I was able to be involved in various aspects of the research and the challenges I faced in this research has helped me be more independent and develop critical thinking skills. The most rewarding part for this experience was the wonderful opportunities for our team to present our accomplishments at the Undergraduate Research Conference and Association for Research in Otolaryngology. I am grateful to be a part of this research lab as it has opened an interest in neuroscience for me, which I hope to continue to study in the future. Most importantly I would like to thank my mentors Dr. Joseph Walton, Dr. Luisa Scott and Dr. Collin Park for guiding me and helping me achieve this honor.”
Research: Developing a novel therapeutic for treating tinnitus
Faculty Advisor: Professor Joseph Walton
Industry Partner: Cognosetta
Kristie Labib recently graduated with a Bachelor of Science degree in biomedical sciences and will be starting at the USF Morsani College of Medicine in the fall of 2021. She also worked as an undergraduate in Dr. Walton’s lab on research projects on pharmaceutical and therapeutic methods at alleviating symptoms of tinnitus.
“My most valued experience in this research was my involvement in a project that examined the effectiveness of a new drug at suppressing symptoms of tinnitus. I was fortunate to work diligently on it with the support of my mentors Dr. Joseph Walton, Dr. Luisa Scott, and Dr. Collin Park. We observed successful results, which then drove me to write a USF Honors thesis on the neurological benefits of the drug on tinnitus symptoms. Additionally, we had the data presented on posters at both the Undergraduate Research Conference and the Association for Research in Otolaryngology. As part of the Cognosetta, Inc., team our work allowed us to be selected as one of the 21 Fibonacci Finalists in the Cade Prize research competition for Florida’s most innovative startups. Being able to share these achievements with my colleagues allowed us to grasp the impact we have on medicine through this project.
“I will forever be indebted to USF and my mentors, as this journey in tinnitus research fueled my desire to pursue a career in medicine. Although my experiences were unforgettable, I wish that this would only be the beginning of my journey, as I would like to pursue a career as an otolaryngologist after medical school.”
Research: Developing a novel therapeutic for treating tinnitus
Faculty Advisor: Professor Joseph Walton
Industry Partner: Cognosetta
Malak Ibrahim recently graduated from USF with a major in biomedical sciences and a minor in psychology. She will start at the Florida International University Herbert Wertheim College of Medicine in the fall. She conducted her undergraduate research on a potential pharmaceutical to treat tinnitus at USF’s Global Center for Hearing and Speech Research under Dr. Walton with the additional mentorship of Dr. Collin Park and Dr. Luisa Scott.
Malak conducted her USF Honors thesis work on the neurological testing used to evaluate a novel therapeutic theorized to alleviate the symptoms of tinnitus, as well as presented this research at USF’s 2021 Undergraduate Research Symposium. She hopes to continue conducting promising research as a future medical student and physician in order to advance medicine and healthcare.
“My years conducting research under Dr. Walton have proved to be an invaluable experience. I learned how to innovate and adapt in a professional, collaborative manner, skills that I am sure will aid me in my next step as a medical student. I also gained an appreciation for the medical applications of scientific exploration and how transformative they can be in healthcare.”
Get CS0022 updates through the Tinnitus Treatment Report email newsletter. It’s free and you get early access to “impossible”-to-find updates.
New research project will investigate the therapeutic effects of a short exposure to prisms on hearing deficits of tinnitus.
Could special glasses offer relief to people with tinnitus? According to the science, it’s not such a crazy question…
And a research project (led by Carine Michel) dedicated to finding out the answer has received a grant worth 213,408 euros (around $250,000 USD) from the ANR (France’s Agence Nationale De La Reserche).
Yes, the glasses may seem gimmicky, at first. But the science is fascinating…
From the official project description (emphasis ours):
Glasses to ear differently – GLAD
Our project aims at better understanding the link between visuo-motor plasticity (by using a short exposure to glasses shifting the visual field) and auditory perception to propose an innovative therapeutic method to reduce hearing loss. There are many evidences showing the therapeutic effects of prism adaptation on lateralized impairments, while our recent innovative result shows the effect of prism adaptation on auditory perception in healthy individuals (Michel et al., 2019; Bonnet et al., submitted).
Our project has two main objectives:
1) from a fundamental point of view, we will deepen our understanding of the effects of prism adaptation on auditory processes in healthy participants, and
2) from a clinical point of view, we will investigate the therapeutic effects of a short exposure to prisms on hearing deficits of tinnitus and presbycusis.
Importantly, this avenue of research builds on recent studies related to “visuo-motor plasticity” and something called “cross-modal enhancement”.
In short, the idea that tinkering with one sense (such as vision) can have an effect on another sense (such as hearing). And, hopefully, in a predictable way… that will allow such tinkering to perhaps someday serve as a volume knob for tinnitus. Or augment auditory perception by using the auditory’s connections to eyesight and visual areas of the brain (becoming well-established).
Some background and related research:
Modifying auditory perception with prisms? Aftereffects of prism adaptation on a wide auditory spectrum in musicians and nonmusicians
Prism adaptation consists of pointing to visual targets while wearing prisms that shift the visual field laterally. The aftereffects are not restricted to sensorimotor level but extend to spatial cognition. There is a link between spatial representation and auditory frequency, with an association of low frequencies on the left side and high frequencies on the right side of space.
Influence of Visual Prism Adaptation on Auditory Space Representation
We here show that there is indeed a slight influence of visual adaptation on the perceived direction of acoustic sources.
The research dollars appear to be attracted as well…
The Swiss National Science Foundation also recently funded a project related to audio-visual cross-modal effects: “Cross-modal interaction after brain lesion – the influence of auditory stimulation on visual neglect”. The project began earlier this year and will continue until February 2025.
From the project description (emphasis ours):
The relevance of our project is twofold. First, the project will shed light on the neuronal mechanisms underlying audio-visual cross-modal effects. Second, by clarifying how and to which degree audio-visual cross-modal effects may improve visuospatial attention in neglect patients, the project will potentially allow to develop new therapeutic approaches.
And if the connection to tinnitus still seems like a stretch… consider this paper from last year, “Increased risk of tinnitus in patients with early-onset cataracts: a nationwide population-based case-control study”, which concluded that “patients with early-onset cataract are at an increased risk of developing tinnitus in subsequent years”.
Note: that particular paper points to ROS (reactive oxygen species) as the main contributing factor… but it’s hard to ignore the eye-ear connection given the other emerging research and ongoing projects on the topic.
It gets the noggin’ joggin’:
Could a change in eyesight create a mismatch in auditory perception, and influence the central gain cause of tinnitus?
It’s certainly a fair question.
Which might explain why some other big, familiar institutions are also investigating this vision-tinnitus axis.
For instance, this Johns Hopkins University project that began last July. Titled, “Cross-modal enhancement of auditory plasticity and performance in adults”, the project has received nearly $1 million USD in funding so far and will continue until June 2025, if everything goes as planned.
The project aims to discover the “mechanisms that can recover adult cortical plasticity is of essence to benefit recovery of hearing or for treating abnormal auditory processing as occurs with tinnitus.”
Here is the full project description — certainly worth a read (formatting and emphasis ours):
Cross-modal enhancement of auditory plasticity and performance in adults
It is well documented that the ability of the brain to undergo plasticity becomes limited in adults. In particular, sensory experience-dependent plasticity of cortical circuits is rather confined to a limited time during development, termed the critical period. Recovery and refinement of sensory processing is therefore difficult in adults. For example, the success rate of speech recognition in artificial cochlear implant patients becomes quite low, if the surgery is done later in life.
Hence discovery of mechanisms that can recover adult cortical plasticity is of essence to benefit recovery of hearing or for treating abnormal auditory processing as occurs with tinnitus.
We found that temporary visual deprivation is quite effective at producing large-scale plasticity in the adult primary auditory cortex (A1) of mice. Such changes occurred as potentiation of feedforward excitatory synapses from the primary auditory thalamus (MGBv) to layer 4 (L4) as well as L4 to L2/3. This was accompanied by weakening of synapses arising from lateral intracortical sources to L2/3 of A1. In parallel, we also observed refinement of cortical circuits of A1 L4 and L2/3. Collectively, these changes suggest that A1 circuit adapts to allow better processing of bottom-up auditory inputs, which is consistent with our published observation of refinement of A1 L4 neuronal receptive field and lowering of detection threshold in visually deprived mice. In this application, we aim to determine the mechanisms involved in driving adult A1 plasticity with visual deprivation, and whether visual deprivation improves auditory behavior in adults. Based on our observation that visual deprivation induced potentiation of thalamocortical (TC) inputs to A1 L4 requires audition, but no due to changes in the auditory environment, we surmise that there is central adaptation in circuits mediating auditory signals going through the thalamus and the cortex.
In particular, we hypothesize that short-term visual deprivation promotes A1 plasticity in adults by regulating inhibitory circuits at the level of thalamus and cortex (Aim 1). The circuit and synaptic adaptation seen in A1 following vision loss accompanied refinement of A1 L4 neural function, and is predicted to enhance auditory function.
We will examine how short- term visual deprivation alters auditory behavioral tasks in adults, and investigate whether this is due to changes in A1 neuronal responses and population encoding during auditory tasks using in vivo 2-photon imaging (Aim 2).
Results from our proposed study will provide mechanistic understanding on how short-term visual deprivation enables plasticity of adult A1 via regulation of thalamic and cortical circuits, and will provide means to enhance auditory processing in the adult brain that could benefit development of treatment options for enhancing or recovering auditory function as would be needed for better prognosis of artificial cochlear implants. Furthermore, our results can be generalized to provide insights into how cortical circuits adapt to losing major inputs as it may happen during injury, stroke, and neuronal degeneration.
Public Health Relevance
Discovering mechanisms to enhance adult brain function is of utmost importance when devising therapeutics to recover and refine normal brain function later in life. We found that temporarily depriving vision leads to recovery of plasticity in the adult auditory cortex, which can benefit auditory function. In this proposal, we aim to determine the mechanisms that allow recovery of adult brain plasticity, and whether temporary visual deprivation improves auditory performance in adults.
And perhaps even substantial enough to give those “gimmicky” glasses — which could potentially increase auditory perception (via multiple mechanisms)… and possibly alter or diminish tinnitus perception (to be determined) — some legitimacy. And in the context of all this research, perhaps this anti-tinnitus glasses project happening in France does not seem so “wacky” anymore…
But first, a quick rant:
Speaking of “wacky”, I have noticed an influx of Hope Police commenting on my articles and notes. “Hope Police” is the label I assign to people who feel the need to protect others from False Hope. They can be found commenting on articles like this one in Facebook groups or Reddit posts. They are easy to spot because they are Very Serious about making it clear that “THIS IS NOT THE TINNITUS CURE EVERYONE HAS BEEN WAITING FOR” and other variations of “NOTHING TO SEE HERE, KEEP IT MOVING.” In reality, what they really spread is False Nope. The opposite of False Hope and… a much bigger villain. Often these Hope Police and Protectors of Truth do not even bother reading the article. And so their criticisms are limited to the atmosphere of the article… what the article implied, apparently… or, get this… they explain how the problem with the article is that it could potentially be perceived by someone as suggesting the treatment in question is a cure. In other words, these Hope Police protect imaginary people from imaginary scenarios involving imaginary problems. Anyway, if you can’t already tell… it bugs me. But after giving it some more thought, I have decided to take the high road and… instead of publicly shaming these straw-treatment “debunkers”… I have decided to offer them a very special meme that will hopefully clear things up:
That’s a peace offering.
As for everyone else…
I offer an invitation to join the newsletter (email updates)… that gives you “early access” to tinnitus treatment-related news and updates (that you won’t find anywhere else) — mostly pertaining to experimental not-yet-available tinnitus therapies. I send 1-2 issues per week. But only when something good is happening. See link below:
If you would like updates on the development of these “anti-tinnitus prism adaptation glasses” (as well as other experimental tinnitus-related treatments and not-yet-released drugs), subscribe to the email newsletter.
Last but not least, references for this [draft] article.
DRAFT COPY — you are seeing an “early access” version of this article. This report is sent to email newsletter subscribers, who receive it up to a week early.
Researchers at the Southern Illinois University School of Medicine have successfully tested a drug (sazetidine-A) related to the smoking cessation drug Chantix, in a sound-exposure animal model of tinnitus. Human clinical trials could begin as early as 2022…
This information is unclassified and from an Annual Progress Report prepared for the U.S. Army Medical Research and Development Command. From the report:
Tinnitus is the perception of sound in the absence of an environmental stimulus. This phantom sound in the head, is most commonly caused by noise exposure, resulting in damage to the inner ear. Within the veteran population seeking VA care, 16-27% suffer from serious hearing loss and tinnitus. Unfortunately, those most affected are bound to the sounds in their heads have difficulty concentrating, suffer from depression and may even contemplate suicide. We posit that breaking the bond between attention and tinnitus will ameliorate the impact of tinnitus. Drugs acting at receptors that bind the brain chemical acetylcholine (nAChRs), a substance involved in brain circuits that control attention could ameliorate tinnitus. We have successfully tested the drug (sazetidine-A), in an established sound-exposure animal model of tinnitus.
Preliminary studies are now starting to support their hypothesis: drugs that act at specific receptors that bind the brain chemical acetylcholine (nAChRs), a substance released by brain circuits that control attention, could alleviate tinnitus.
And these drugs, which include sazetidine-A (related to smoking cessation drug Chantix) and varenicline, could allow tinnitus sufferers with “habituation-proof” tinnitus to finally find relief thanks to a pill that — hypothetically — works to “disconnect” the looped circuit that may be preventing habituation (or extinguishment) from taking its normal course.
The result? Hopefully a way for people with severe disabling tinnitus to “get used to it” and have their tinnitus diminish, on its own, like most people… thanks to a drug involving the chemical substance involved in brain circuits that control attention. By addressing that chemically-based “habituation-proof” circuit, it could unlock the normalizing process.
Whether these drugs can do that remains to be proven. But the evidence from preliminary studies suggests it might be possible. That’s what this project is exploring.
From the progress report (which is dated August 2020 but only released publicly more recently):
4. Impact The results form SA1, delineated above, are the first of their kind to show significant tinnitus-related attentional abnormalities in principal AI output neurons. First they show significant abnormalities in the number and size of the presynaptic excitatory messages arriving at these neurons. Secondly they show significant tinnitus-related differences in nAChR sensitivity at different doses of acetylcholine. Since we will be pharmacologically targeting these receptors in attempts to normalize their tinnitus pathology, understanding these tinnitus-related differences is critical. The ability of sazetidine-A to effect disproportional changes in resting membrane potential and action potential threshold in animals with behavioral evidence of tinnitus suggests a unique receptor target. Finally, preliminary data suggests that sazetidine-A was able to normalize a tinnitus-related increased sensitivity to acetylcholine. Collectively, we feel these are exciting and highly publishable findings when matured. They also support the proposed SA2&3 studies.
The SA1, SA2, SA3 refer to “Specific Aims”, which are like goals/stages of the project. Right now, the researchers are in the final “stage” of this project. Human clinical trials would be a separate project that follows the completion of this one. I’m speculating, and I don’t know the future. But that’s where this is headed, as of now.
These findings and the theory behind these exciting hypotheses will continue to be studied and tested as part of this ongoing research project, “Nicotinic Receptor Pathology in Tinnitus: Auditory Cortex and Selective Desensitizing Nicotinic Agents” — which is supported by a grant of nearly $1.8 million, courtesy of the Department of Defense and the Congressionally Directed Medical Research Program.
Importantly, the research is aimed at treating the most severe cases of tinnitus: tinnitus that cannot be ignored or simply tuned out. Their goal is to develop new drugs capable of ameliorating tinnitus in “those most affected”, the people who are “bound to the sounds in their heads” and who “cannot do regular work”, “have great difficulty concentrating”, and “may even contemplate suicide”.
This is described in the project abstract (see below) along with more details about what is being studied and the hypothesis behind this new area of exploration in the realm of chronic tinnitus treatments.
As for the project itself… it is scheduled to complete in July 14, 2022 and… barring any surprises… it looks like human clinical trials could follow shortly after. Why so soon? Because the “new” drugs in question are closely related to already-approved smoking cessation drugs (such as Chantix)… in fact, Chantix might be a viable candidate, though we will have to wait and see to know for sure. In any case, the clinical trial process would likely be faster and less complex, as the safety profile of the drug is already well established in humans.
So it’s got that goin’ for it, which is nice.
Here are the details, including both abstracts (the second one is heavier on the science):
Nicotinic Receptor Pathology in Tinnitus: Auditory Cortex and Selective Desensitizing Nicotinic Agents
Principal Investigator: CASPARY, DONALD M
Institution Receiving Award: SOUTHERN ILLINOIS UNIVERSITY SCHOOL OF MEDICINE
Tinnitus is the perception of sound in the absence of an external environmental stimulus. This phantom sound in the head, sometimes referred to as “ringing in the ears,” is a Fiscal Year 2018 Peer Reviewed Medical Research Program topic area. It is most commonly caused by noise exposure, resulting in damage to the inner ear containing the hair cells and nerve fibers that carry sound to the brain. The military working environment presents many high noise situations with noise levels often so intense that standard hearing protection is not adequate. A recent study found that Soldiers deployed to battle zones were ~52 times more likely to suffer auditory damage than non-deployed Soldiers. The American Tinnitus Association reports that within the Veteran population seeking Department of Veterans Affairs (VA) care, 16%-27% suffer from serious hearing loss and tinnitus. The VA awarded disability compensation for serious hearing loss tinnitus to approximately 972,000 Veterans with an annual aggregate cost of nearly $1.5 billion. The U.S. Centers for Disease Control and Prevention estimates that more than 50 million Americans – nearly 15% of the population – experience some form of tinnitus, with 10%-15% of this total suffering extreme and debilitating tinnitus. Conversely, the majority of chronic tinnitus sufferers are able to ignore their tinnitus, tuning out the din while going about their daily lives. Unfortunately, those most affected are bound to the sounds in their heads; they have great difficulty concentrating, suffer from depression, cannot do regular work and may even contemplate suicide. Studies proposed here are focused on developing a treatment for those individuals most impacted by tinnitus. Our hypothesis postulates that breaking the bond between attention and tinnitus will ameliorate the impact of tinnitus, allowing patients to return to a more normal life. We propose that drugs that act at specific receptors that bind the brain chemical acetylcholine (nAChRs), a substance released by brain circuits that control attention could ameliorate tinnitus. Our preliminary studies have successfully tested a drug (sazetidine-A) related to the smoking cessation drug Chantix, in a sound-exposure animal model of tinnitus. All proposed studies will be carried out in our well-established rat tinnitus model, and our laboratories have significant experience in all proposed methods. Proposed studies will test the ability of Chantix to ameliorate tinnitus. Similar to what is seen in human tinnitus patients, our recent studies in a rat tinnitus model finds tinnitus-related deficits in selective attention. We will test if both these drugs related to nicotine can normalize selective attention in our animal model. Proposed basic science studies will test if these agents can normalize aberrant brain cell response properties recorded in structures located at the highest level of the central auditory system, the auditory cortex. Preliminary receptor binding studies suggest that nicotinic acetylcholine receptors are altered in animals with evidence of tinnitus. Proposed studies will map the markers for the different receptor subtypes that make up these acetylcholine receptors in animals with and without tinnitus. Using brain slices from auditory cortex of animals with and without tinnitus, proposed studies will examine the function and the pharmacology of these receptors and the impact of Chantix and similar nicotinic drugs on the response properties of these brain cells. Collectively, these studies will provide new pharmacologic information on possible novel treatments for tinnitus while improving our understanding of the relationship between attention and tinnitus suffering and the cellular mechanisms that underpin this hypothesis.
Tinnitus is defined as a phantom sound (ringing in the ears) that can significantly affect the quality of life for those who suffer its effects. Noise exposure, with its consequent acoustic damage, is the most common cause of tinnitus. The military working environment presents many situational high noise levels, frequently so intense that standard hearing protection is inadequate. There is a growing awareness that maladaptive attentional mechanisms are involved in the pathology of tinnitus. Individuals most disturbed by their tinnitus have their attention bound to the percept while showing significantly impaired selective attention. Basal forebrain neurons involved in attentional circuits can increase release of the neuromodulator acetylcholine (ACh), where it acts at nicotinic cholinergic receptors (nAChRs), located on terminals and neurons in the primary auditory cortex (AI). This forebrain cholinergic system is a component of a perceptual network that may enhance attention to tinnitus as well as generating emotional reactions to tinnitus. The proposed basic science and translational studies will use a novel pharmacologic approach to treat individuals whose attention is inextricably bound to phantom sounds in their head. Our preliminary data indicate that the nAChR-Beta2 selective partial agonist and desensitizer sazetidine-A reduced the impact of tinnitus in our animal model. The focus of the present proposal is to examine the therapeutic potential of two nAChR partial agonists, sazetidine-A and the smoking cessation drug varenicline. Preliminary binding and subunit expression studies suggest that nAChR subunits are altered in AI of animals with behavioral evidence of tinnitus. All specific aims (SAs) will use an established sound-exposure rat model of tinnitus. SA1A will use immunoprecipitation and florescent in situ hybridization (FISH) to characterize tinnitus-related changes in heteromeric and homomeric nAChRs in AI neurons from animals with and without behavioral evidence of tinnitus. nAChRs comprising different combinations of subunits are present on presynaptic terminals/inputs that innervate neurons across layers of AI. Our preliminary studies show altered numbers and affinity of nAChRs in AI layers IV and VI. SA1B will characterize functional pharmacology of tinnitus-related changes in acetylcholine (ACh) evoked synaptic currents from AI layers IV and VI neurons in an AI slice preparation. SA1C will examine the pharmacologic responses of bath applied sazetidine-A and varenicline on ACh evoked synaptic currents from AI layer IV and VI neurons as in SA1B. SA2A will catalog and compare tinnitus-related changes in AI single-unit responses from awake animals with and without behavioral evidence of tinnitus, while attempting to normalize tinnitus-related aberrant unit responses with systemic injections of sazetidine-A and varenicline. SA3A will test whether varenicline, similar to sazetidine-A, can ameliorate tinnitus in our animal model. SA3B is based on findings that animals with behavioral evidence of tinnitus, similar to human tinnitus sufferers, show impaired selective auditory attention. Others have shown that sazetidine-A can normalize impaired visual attention. SA3B will examine the ability of sazetidine-A and varenicline to normalize impaired selective attention in animals with behavioral evidence of tinnitus. Collectively, results from these proposed studies will directly test the hypothesis that tinnitus can be ameliorated using attention-altering drugs while examining basic science mechanisms underpinning this hypothesis at the level of the auditory cortex.
That’s all for now.
This article is a DRAFT and you are receiving early access because you are subscribed to email updates (or the link was shared by someone who is subscribed). How to get updates:
I will be releasing more updates and progress reports on this project, as they become available, leading up to July 14, 2022. Sign up for the TinnitusTreatmentReport.com newsletter to get these articles (it’s free and I send updates that do not appear on the front page of this website). I am not involved in the study and I do not have any information about human trials!
An important update on the development status of sulodexide, an anticoagulant drug that significantly reduced tinnitus severity scores in a phase 2 clinical trial in patients with chronic subjective tinnitus.
Sulodexide is a “highly purified mixture of glycosaminoglycans composed of low molecular weight heparin (80%) and dermatan sulfate (20%).”
It successfully completed a phase 2 study, “Randomized Double Blind Controlled Trial on Sulodexide Efficacy in Chronic Idiopathic Subjective Tinnitus”, and the results have already been published.
These phase 2 results were first published a little over three years ago, on May 1, 2018, in a paper titled, “Sulodexide Monotherapy in Chronic Idiopathic Subjective Tinnitus: A Randomized Controlled Trial” and… the results were so impressive, the American Tinnitus Association wrote glowingly about sulodexide in that year’s Summer issue of Tinnitus Today, their flagship publication. From the article, “Anticoagulant Sulodexide Therapy for Tinnitus”:
After the 40-day administration of placebo or sulodexide, a significantly lower THI score was found in the group that had taken sulodexide, compared to those taking placebo (THI score of 30.1 and 40.5, respectively). Scores on the Mini-TQ also demonstrated a greater decrease for those taking sulodexide (average of 9.7 vs. 12.5). Further analysis showed that those taking sulodexide demonstrated decreased scores on the THI and Mini-TQ, regardless of their beginning score. The mechanisms by which sulodexide may improve tinnitus are not yet understood. However, this study demonstrated that this drug has potential to reduce the severity of tinnitus and holds promise for further study in this area.
Since then, sulodexide continues to be mentioned in a growing number of scientific papers. Most recently, the study of sulodexide was cited in a paper from April 16, 2021, titled, “Methodological Aspects of Randomized Controlled Trials for Tinnitus: A Systematic Review and How a Decision Support System Could Overcome Barriers”, published in the Journal of Clinical Medicine.
Another paper, also published within the last 12 months, titled “Auditory Neural Plasticity in Tinnitus Mechanisms and Management”, described how certain mechanisms behind sulodexide are connected to tinnitus:
There are also reports of drugs that can improve the microcirculation of the cochlea by improving the blood flow and thus increasing the clearance of ROS through the bloodstream […] and sulodexide has antithrombotic and anticoagulant activities, both of which have been shown to have positive effects in tinnitus patients […] mainly by improving the subjective perception and emotional response to tinnitus. However, the changes of inner ear microcirculation in tinnitus are not completely clear yet, and various antioxidants still need to pass through the blood-labyrinth barrier; thus, the therapeutic effect is not very precise.
Meanwhile, further recognition of its therapeutic potential (emphasis: potential) can be found in other credible sources, too. For example, in a 28-page clinical policy bulletin from health care giant, Aetna, on the topic of tinnitus treatments. Within that document, sulodexide — “a natural glycosaminoglycan with anti-thrombotic, profibrinolytic and vascular anti-inflammatory properties” — is categorized as an experimental and investigational tinnitus treatment option and the bulletin mentions how researchers believe sulodexide holds promise.
Sulodexide is currently “stuck” between phase 2 and phase 3 clinical trials.
And nothing has happened for the last three years. Its advancement toward a potential approval for use in chronic tinnitus has been frozen.
But unlike other promising treatments that seem to mysteriously “vanish”… and which receive a lot of attention and fanfare… only to “ghost” the tinnitus community without explanation…
The reason sulodexide “ghosted” actually has nothing to do with a clinical trial failure, retraction of results, some scary side effect that was later discovered, patent issues, lawsuits… nor does it have anything to do with some Big Pharma conspiracy to withhold a possible tinnitus treatment because it’s not profitable enough.
The reality of the situation is much more complex. But also simple to explain:
The geopolitical situation in the country where sulodexide was being studied and where the clinical trials took place (and conceivably, would have continued to take place) is not able to support its further advancement into phase 3 at this time.
I am going to respect the privacy of the individuals I contacted while investigating the situation here…
But that’s the situation.
To reiterate: there exists, at this very moment, a phase 3-worthy tinnitus treatment (a drug) that seems to hold great promise… and it is NOT moving forwarad — at all.
It is “stranded” in between phase 2 and phase 3.
It has been so for years. Nothing has happened, with respect to its advancement toward phase 3 and perhaps some day an approval, since the end of the last phase 2.
I know that might be sad to read for some people.
But the good news is, there is no “expiry date” and it can be unfrozen, unstuck, unpaused, and…
The only danger is for the community and research community to “forget” about sulodexide (or any other promising candidate, for that matter).
That appears to be what has happened. Consider this: big budget marketing campaigns and savvy PR departments exist to make sure you don’t forget about FX-322, Lenire, etc. But there is nobody actively working to make sure sulodexide receives your attention and driving its advancement and funding.
Whether that changes will ultimately be up to you — the community — and the organizations and people who are in a position that allows them to make the necessary arrangements required to give sulodexide (and the people who study it) a chance at continuing the next leg of this valuable work.
My hope is that this article can get the process started and put sulodexide back on the radar. (Side note: A few people on TinnitusTalk did notice, back in 2018. But that, sadly, was not enough. The thread, for whatever reason, did not grab the attention of the rest of the community at the time, and became inactive.)
The community — which means YOU — can decide whether it is worth discussing. Worth emailing organizations asking them for their position on this treatment. Talking about it on reddit, TinnitusTalk, Facebook, wherever else.
See what happens.
How to get updates on this situation:
Please remember to sign up for the TinnitusTreatmentReport.com email newsletter for ongoing updates about sulodexide and other promising tinnitus drug candidates.
The Neuroscience and the Treatment of Tinnitus
Henton, Amanda; Tzounopoulos, Thanos Ph
Brian Fargo, inXile founder, gives $1 million to advance UCI research for tinnitus treatment
Funding will support development of innovative implantable electronic stimulation device
Researchers in Brazil are studying the effects of donepezil in patients with chronic tinnitus.
Some quick details on donepezil and the new phase 2 trial:
Donepezil is a drug that is similar to memantine, rivastigmine, and galantamine.
Donepezil was approved for medical use in the United States in 1996. It is available as a generic medication. In 2018, it was the 128th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
It is a cholinesterase inhibitor that “inhibits voltage-activated sodium currents reversibly and delays rectifier potassium currents and fast transient potassium currents.” More detailed information available here: https://www.ncbi.nlm.nih.gov/books/NBK513257/
It is already approved and used to treat other conditions (such as Alzheimer’s disease) – though its effects are apparently small and its mechanism still not fully understood.
And now it is being investigated as part of a phase 2 trial to determine whether or not it can help people with chronic tinnitus caused by sensorineural hearing loss.
The study was registered about 6 months ago on November 3, 2020.
It will enroll up to 50 participants.
According to the study record, the date of first enrollment = January 29, 2021.
But according to that same study record, the study status = Not yet recruiting.
Which means there was probably either a delay in starting the trial or a delay in updating parts of the study record. (Probably the latter.)
This information is current as of May 17, 2021. However, it is based on records that are only current as of February 23, 2021. So, the current status might actually be recruiting. We just can’t tell from the current study record.
But it does tell us about outcomes and the hypothesis:
Improvement is expected from patients with tinnitus who will use the medication comparing to placebo group. The methods Student’s t test and ANOVA analysis will be used, before and after placebo and active drug therapy, for quantitative variables. Statistical significance level of 0.05 or 5% will be adopted for two-tailed samples and study power of 95%. The qualitative variables will be described by their frequency of presentation.
The memory improvement is expected from patients who will use the medication comparing to placebo group. The methods Student’s t test and ANOVA analysis will be used, before and after placebo and active drug therapy, for quantitative variables. Statistical significance level of 0.05 or 5% will be adopted for two-tailed samples and study power of 95%. The qualitative variables will be described by their frequency of presentation.
That’s all for now.
This article is a PREVIEW COPY [draft]. As a subscriber to TinnitusTreatmentReport.com email updates, you get access to it a few days early – before it is posted to the front page.
Not signed up? Subscribe here. It’s free and you can expect between 1-3 emails per week (but only if something is happening). No spam, no promotional emails, privacy respected.
Professor Dirk De Ridder, a world-leading expert in tinnitus, is investigating the combined effect of ketamine and brain stimulation on tinnitus loudness and distress, as part of a new phase 1/2 clinical trial.
The aim of the study is to determine if low dose ketamine, through its effects on brain plasticity, is able to catalyze transcranial electrical stimulation, and reduce tinnitus severity as a result.
A total of 24 participants with chronic tinnitus will get a chance to receive treatment with the experimental drug/device combination therapy, at the University of Otago Dunedin School of Medicine, in New Zealand. The treatment will be delivered twice, 10 days apart.
Inclusion criteria: Adults aged between 18-70 years with constant subjective tinnitus and a grade of 3 or higher (considered “moderate to severe”) on the tinnitus questionnaire.
The trial (Registration number: ACTRN12621000119897p), titled “Effect of ketamine and concomitant multi-target high definition transcranial electrical stimulation on tinnitus loudness and distress in adults- A feasibility and safety study”, is registered prospectively on the Australia New Zealand Clinical Trials Registry.
As of May 12, 2021, it is unclear whether or not anyone has been enrolled (yet) or if the coordinators have begun recruiting participants.
The anticipated date of first enrollment is listed as February 15, 2021. However, according to the provisional study record, the trial’s ethics application is still awaiting approval.
Here is some more information, taken directly from the provisional study record (emphasis/formatting ours):
Ketamine and High Definition, Trancranial Infraslow Pink Noise Stimulation (HD-tIPNS)
The intervention arm will receive a low dose of subcutaneous ketamine (0.5mg/kg) as a bolus, from a clinician experienced in administration. This will be followed by HD-tIPNS administered for a single session of 30 minutes duration, beginning ~25 minutes after ketamine delivery, by a researcher experienced in administering neuromodulation techniques.
A battery-driven wireless 32 channel transcranial current stimulator (Starstim32 TCS®, Neuroelectrics) will be used to deliver stimulation while the participants are comfortably and quietly seated. Simulation [sic] is delivered by AgCl electrodes placed in the international 10-20 arrangement, secured in a neoprene cap (see Neuroelectrics website for headset image). For the active treatment group, the stimulation will be delivered at a current strength of maximum of 2mA for 30min, with 60s ramp up and ramp down at the beginning and end of each stimulation session, with continuous stimulation in between. For sham stimulation, to create an identical skin sensation to the active stimulation, the current will be applied for a 60s ramp up (0-2mA) and 60s ramp down (2-0mA) at the beginning and the end of each stimulation session, without any current for the remainder of the stimulation period.
This Intervention will be delivered twice, spaced 10 days apart. Intervention duration will be a total of 2 hours in length to allow for safety monitoring. After a 20 day washout, both groups will transition to the intervention, delivered twice again, 10 days apart.
The delayed start occurs as follows: Participants can be allocated to start with Ketamine + Active Stimulation or Ketamine + Sham Stimulation. Both the sham stimulation and the active stimulation groups will receive active stimulation after the 20 day washout (the Ketamine + Sham stimulation is the active control). Therefore the Ketamine + Sham stimulation (Active control) receives a delay to the start of active intervention.
Participants will undergo treatment at the Department of Psychological medicine laboratory at the Dunedin School of Medicine, University of Otago.
- Intervention  Treatment: Drugs
- Intervention  Treatment: Devices
Comparator / control treatment: Participants in the control arm will receive a low dose of subcutaneous ketamine (0.5mg/kg) as a bolus, from a clinician experienced in administration. This will be followed by Sham stimulation, designed to create identical skin sensations to active stimulation. Participants will use identical equipment to that of the active group, and will receive a short dose of the treatment protocol, mimicking the initial tingling/prickling commonly experienced with Transcranial electrical stimulation.
Tinnitus Functional Index (TFI). The TFI has eight subscales that address the intrusiveness of tinnitus, the sense of control the patient has, cognitive interference, sleep disturbance, auditory issues, relaxation issues, quality of life, and emotional distress. This provides an overall measure of how much of a problem tinnitus is for participants (severity).
- Adults aged between 18-70 years with constant subjective tinnitus and a grade of 3 or above on the tinnitus questionnaire.
- Minimum age 18 Years
- Maximum age 70 Years
- Gender Both males and females
This article will be updated as more information is added to the study record.
For additional updates related to this ketamine/brain stimulation combination therapy (and other experimental not-yet-available tinnitus treatments), subscribe to the Tinnitus Treatment Report newsletter (email updates). It’s free, there’s no spam or sneaky promotional emails, and your information is kept private.
Questions? Comments? Feedback? Send an email to email@example.com and say hello.
Studying tinnitus linked to different disorders can lead to the identification of molecular mechanisms, early diagnosis, and the application of new drugs for treating tinnitus.
University of Granada researchers identify genes linked to tinnitus
Added value of this study
We have found a significant enrichment of missense rare variants in synaptic genes including ANK2, TSC2 and AKAP9 in patients with tinnitus extreme phenotype in Meniere disease patients. We also replicated these findings in an independent cohort of tinnitus patients from Sweden. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, the top GO terms being membrane trafficking and cytoskeletal protein binding in neurons.
This is the first study reporting the association of rare variation in ANK2, TSC2 and, AKAP9 genes with severe tinnitus and supports the involvement of membrane trafficking and cytoskeletal protein binding in the pathophysiology of severe tinnitus.
A new phase 3 clinical trial for tinnitus has begun recruiting at Mazandaran University of Medical Sciences, a top medical university in Iran.
Researchers will investigate whether or not a combination of bitter almond oil and cinnarizine can reduce tinnitus severity in patients with chronic tinnitus.
The title of the study is “The Efficacy of bitter almond oil on the severity of chronic tinnitus.”
Participants in the treatment group will receive a combination of bitter almond ear drops and cinnarizine tablets, twice daily (every 12 hours), for one month.
Tinnitus severity will be measured
thrice three times: 1) immediately before treatment begins, 2) after two weeks of treatment, and 3) after 4 weeks of treatment, using VAS and THI scores.
This trial was registered on February 16, 2021 and will enroll up to 70 patients with doctor-confirmed chronic tinnitus, between the ages of 17 and 75, male and/or female.
As of March 1, 2021, recruiting for this study was set to begin on March 5, 2021. No reason to assume that date has changed. But we will update this post as we get more information.
As for the treatment itself – a unique combination of ear drops and tablets – here is some very basic background information:
More information on bitter almond oil will follow. For now, an important warning:
WARNING: “bitter almond oil” might sound like a harmless natural ingredient, but in reality it is associated with some extremely serious chemical compounds (i.e. cyanide). Needless to say, there is NO safe (or legal) do-it-yourself approach to copying this trial. Or any trial, for that matter… but especially this trial.
Some interesting information on the cinnarizine component, from the Meniere’s Society UK:
Cinnarizine has two pharmacological actions. It is a calcium antagonist, though not a powerful one. This acts mainly on the blood vessels and prevents constriction on these vessels. In theory it therefore improves the micro circulation of the ear. At the same time it has a mild antihistaminic effect.
Remember to subscribe to the email newsletter for updates related to this cinnarizine/bitter almond combination therapy (and news about other experimental tinnitus treatments in development).
Otonomy’s recently announced OTO-313 clinical trial was posted to ClinicalTrials.gov on April 2 and will enroll an estimated 140 participants.
Here is a link to the official study record (NCT03918109): A Randomized, Double-blind, Placebo-controlled Phase 2 Study of OTO-313 Given as a Single Intratympanic Injection in Subjects With Unilateral Subjective Tinnitus
April 11 Update: As we predicted, the OTO-313 study has now expanded its study locations and is currently recruiting in seven states: California, Colorado, Florida, Louisiana, North Carolina, South Carolina, and Utah. (We expected all these locations, with the one surprise being South Carolina.)
The new OTO-313 study is currently recruiting in two locations: Florida and North Carolina. However, we expect to see more recruitment sites added across the United States in the coming weeks. Here are some likely states the trial will expand to (based on the previous OTO-313 study locations): California, Colorado, Illinois, Kentucky, Louisiana, New Jersey, New York, North Carolina, Texas, Utah, West Virginia.
It is unknown whether this phase of the trial will expand to other countries.
More updates to follow…
Remember to subscribe to the email newsletter for upcoming OTO-313 updates (and news about other experimental tinnitus treatments in development).
Otonomy Initiates Phase 2 Clinical Trial of OTO-313 in Tinnitus
March 25, 2021 at 7:30 AM EDT
Phase 2 study design based on successful Phase 1/2 trial including use of Tinnitus Functional Index (TFI) responder analysis for primary efficacy endpoint
Patient enrollment criteria refined to enrich study population
Top-line results expected in mid-2022
Notably absent from the recent FX-322 data readout: partial data on measures of FX-322 on tinnitus.
In fact, there is no mention of “tinnitus” at all.
What’s going on?
Dear Frequency Therapeutics,
We understand that the timing and completeness of data readouts is subject to change. Such is the nature of forward looking statements.
But when things do change – things such as the availability of FX-322 day-90 tinnitus-related data – you ought to mention it.
Your clinical trials include tinnitus-related outcomes as a secondary outcome measure…
Your previous press releases mention tinnitus…
Your corporate presentations and event slides mention tinnitus.
In January, you listed “partial data on measures of FX-322 on tinnitus” as part of the anticipated phase 2a readout (planned for late Q1 2021)…
And yet, two days ago, on March 23, you released an update that did not even include the word “tinnitus” in the text.
Not even in the tiny text at the bottom. (We looked everywhere.)
Until Frequency Therapeutics releases a statement or formal update on tinnitus study results, it is reasonable to assume there is no good news. There seems to be no other explanation as to why the word tinnitus was “scrubbed” from the ongoing list of talking points.
Prove us wrong, Frequency Therapeutics.
Because we hope we’re wrong. We hope there’s promising tinnitus data somewhere that someone forgot to publish or mention. But, sadly, that seems unlikely.
To our readers: as soon as we have more information about FX-322 and tinnitus… we will be sending it out via the email newsletter. But it’s important to remember that FX-322 is NOT the only “horse in the race” toward effective tinnitus treatments. Others exist. And we will be posting information about them next week. (Note: these treatments have received far less mainstream attention and PR than “famous” upcoming drugs such as FX-322… yet some are surprisingly further along in their development than you might expect.)
American Tinnitus Association Seeking Tinnitus Research Proposals
A new clinical trial from Otolith Labs, a U.S. Defense Department-backed startup developing a device that could potentially extinguish the debilitating symptoms of vertigo, motion sickness, and now… lower tinnitus volume?
The study, titled Evaluation of the OtoBand as a Treatment to Reduce the Perceived Loudness of Tinnitus (NCT04787653) was posted to ClinicalTrials.gov on March 8, 2021 (a few hours ago, as of this writing).
Unlike the Neuromod (Lenire) clinical trials, this OtoBand study involves a placebo device and group. (We here at Tinnitus Treatment Report applaud this decision.)
Here is a brief summary of how the study – which is an at-home study (conducted remotely and does not require travel to/from the clinic) – will work:
This proposed study is a blinded study in which the participant will wear the OtoBand when their tinnitus is present to determine if the OtoBand reduces the perceived loudness of their tinnitus. The Study will be placebo controlled with each participant using an effective device for half of the enrollment period and a placebo device for half of the enrollment period. The order of placebo and effective usage will be randomized, and the researchers will be blinded to which device a participant is using. Study participants will be instructed in an online telehealth conference on how to operate the OtoBand and how to wear the OtoBand. Participants will be enrolled for approximately 30 days from Informed Consent to Wrap-up call.
Great, but what does this “OtoBand device” look like?
Here is a photo from Otolith Labs company website:
We are unsure if this is the *exact* same model of the Otoband device that is being studied for its potential in reducing tinnitus loudness. The above photo might be an earlier version, a prototype. Plus, we do not know what design changes might be made during development. (It is not uncommon to see the design of novel devices like this evolve over time.)
As for the effectiveness of the device… we do not know anything yet. That’s what this clinical trial will hopefully tell us, in time…
Otoband clinical trial results… available when?
Not sure yet. The study was literally only added to the ClinicalTrials.gov database today. Too early to even guess. But here’s a good way to stay current with what’s happening:
For updates on the progress of OtoBand, I invite you to sign up for the Tinnitus Treatment Report email newsletter. It’s an easy way to get the very latest in tinnitus treatment development news and updates. For devices such as OtoBand, as well as pharmacological updates (e.g., FX-322, OTO-313, CS0022, and more). The email updates are 100% free and – importantly – your information is never shared with third parties, and you an unsubscribe with one click. Simple.
The first issue will begin sending soon (perhaps an exclusive update related to FX-322’s upcoming tinnitus study results)…
Got feedback? Send an email to firstname.lastname@example.org and speak your mind. Request an update!
Frequency Therapeutics Announces Publication of Phase 1/2 Data Showing Hearing Improvements in Acquired Sensorineural Hearing Loss Patients Receiving FX-322
A pre-clinical tinnitus drug candidate from Cognosetta has shown promising results (and could soon be ready for human trials), according to new research.
CS0022 (formerly called BMS-191011) is a next generation BK channel opener designed to lower tinnitus volume by regulating the abnormal neural excitability in the central auditory system (CAS)… thereby restoring the proper “balance of excitation and inhibition” necessary for silence.
The small company behind CS0022 is Cognosetta, Inc. If you have been following our updates here at Tinnitus Treatment Report, that company name might sound familiar.
Just over a year ago, on January 14, 2020, we posted this: Cognosetta, Inc receives funding from NIH to test a novel therapeutic for treating tinnitus…
Today, we finally have a follow-up about what is happening with that “novel therapeutic” and its development.
First, a quick primer on the company behind the drug. From the Cognosetta website:
Cognosetta is developing a first-in-market, brain targeted pharmaceutical solution for treating tinnitus […] Our priority is developing a first-in-market medication […] for those with moderate to severe tinnitus […] Our scientists have identified a drug target and drug candidates for improving neurophysiological and behavioral measures of tinnitus and age-related hearing loss. To support the clinical success of these drug candidates our scientists are also advancing quantitative methods for evaluating the efficacy of new drug candidates that can be shared across the preclinical and clinical development stages.
Here is a snapshot of their current pipeline, with CS0022 approaching human trials.
How close to human testing and safety trials is CS0022?
Too early to give an exact date.
But, according to a poster presentation from the upcoming 44th Annual ARO MidWinter Virtual Meeting, the drug continues to impress with promising results in preclinical (animal) studies.
Here is a “sneak preview” copy of the upcoming poster presentation – scheduled for Sunday, February 21, 2021:
The BK Channel Opener CS0022 Mitigates Chronic Tinnitus Following Acoustic Trauma
Background: Subjective tinnitus is an audiological and neurological condition that gives rise to a phantom perception of sound. The condition disproportionately impacts individuals with risky occupational or avocational noise exposure. Patients and animal models of tinnitus exhibit altered central auditory system (CAS) neural activity that is presumed to support the tinnitus percept. Broadly, these changes can be characterized by a dysregulation in the balance of excitation and inhibition that leads to neuronal hyperexcitability and synchrony. The large conductance calcium-activated potassium (BK) channel regulates neural excitability in the CAS and other brain regions. Our recent work suggests that systemic administration of a class of BK channel openers reduces salicylate-induced tinnitus in mice through action in the CAS. The main objective of the current study is to determine whether a similar low-exposure treatment also reduces behavioral and neural manifestations of tinnitus in a chronic tinnitus model induced by noise exposure.
Methods: Auditory brainstem response (ABR) thresholds and acoustic startle behavior were assessed in young adult CBA mice before and after acoustic trauma. For acoustic trauma, awake mice were placed in a small, sound transparent cage, and then exposed for 1 hour via free field to a 113 dB SPL, 1 kHz wide band noise centered at 16 kHz. Ten weeks after damaging noise exposure, mice began systemic treatment with a BK channel opener, CS0022. Gap-prepulse inhibition of the acoustic startle reflex (GPIAS) tracked the development of tinnitus and subsequent effects of treatment. A novel machine learning algorithm and computational analysis method was used to determine which mice displayed tinnitus from the GPIAS protocol.
Results: The acoustic trauma procedure caused limited permanent ABR threshold shifts, ranging from none to moderate (~50 dB) in the high frequencies above 16 kHz. Mice were selected for preliminary analysis if they exhibited minimal permanent hearing loss (< 10 dB) and GPIAS evidence of tinnitus at 16 or 32 kHz after acoustic trauma. Six out of the six selected mice showed less suppressed pre-pulse inhibition for the selected tinnitus frequencies following systemic treatment with a BK channel opener. In contrast, treatment did not influence acoustic startle amplitude functions. Pharmacokinetics studies confirmed low exposure in brain. As expected, improved startle selection via machine learning-enhanced computational analysis increased the power and accuracy for identifying tinnitus and treatment effects.
Conclusions: Ongoing neurophysiological and alternate behavioral measures continue to probe treatment outcomes in this model of acoustic trauma-induced chronic tinnitus. Thus far, preliminary outcomes support the idea that treatment with BK channel openers such as the one used in the current study may reduce evidence of tinnitus. There is currently no effective cure for chronic tinnitus, increasing the urgency for studies exploring the utility of promising drug candidates.
Credit to lead author Luisa Scott of Cognosetta Inc and her co-authors at the University of South Florida.
Thanks to their hard work, it looks like we now have another viable first-in-market tinnitus drug candidate to follow…
Plus, a shiny new meme to help spread the word:
If you want to keep up with promising new tinnitus treatments that are currently in development (including CS0022)… I encourage you to sign up for Tinnitus Treatment Report email updates.
It’s an email newsletter with fresh links and updates (never junk), and… I believe there is no faster way to consistently stay on top of the very latest tinnitus treatment options and scientific breakthroughs.
(It is 100% free, no spam or advertorials, and your information is kept secure and private. Promise.)
Got questions? comments? requests?
Send an email to email@example.com and introduce yourself, say hello.
References and further reading:
February 4, 2021
Discovery of a New Type of Neuron Holds Clues About Tinnitus
Hough Ear Institute tinnitus treatment update:
New research suggests that NAC/HPN-07 treatment (development code name: NHPN-1010) could potentially “reduce, or perhaps reverse, both primary neurodegeneration and excitotoxic trauma in cochleae and prevent or attenuate maladaptive neural plasticity in central auditory pathways.”
In other words, this drug could possibly reduce or even REVERSE tinnitus. At least, that’s what this study is suggesting.
Some more context: this was studied in a blast-induced model of tinnitus. However, the results are no less remarkable… and seem to have broader implications…
Here is a link to the study (which was published moments ago, on January 7, 2021):
NAC/HPN-07 is also known by its code name, NHPN-1010 (the much anticipated Hough Ear treatment). The lead author of this paper is Dr. Richard Kopke, CEO of Hough Ear Institute.
More information about this study and the drug (NHPN-1010) will follow soon. Including some answers about when the treatment mentioned in this paper could be offered in human clinical trials. Hmmm…
A strong start to tinnitus science in 2021. Lots happening 🙂
P.S. Keep an eye on this reddit thread for some discussion, opinion, and unfiltered speculation.
P.P.S. For more NAC/HPN-07 updates and breaking tinnitus treatment and science-related developments… please remember to sign up for email updates (it’s free and first issue will be sent out soon). Even better, share TinnitusTreatmentReport.com with others who might find this information helpful, too…
What can biobanks bring to hearing, and in particular to tinnitus?
British Tinnitus Association awards £125k grant for research that could predict who will develop tinnitus
Otonomy expects to start Phase 2 trial of OTO-313 in tinnitus in first quarter of 2021
Here’s Why the Jury’s Still Out on Lenire
October 19, 2020
Researchers Develop New Technology to Objectively Measure Tinnitus
Technology lets clinicians objectively detect tinnitus for first time
The role of prediction and gain in tinnitus
Frequency Therapeutics Announces Expanded FX-322 Clinical Development Program and Upcoming Day-90 Phase 2a Analysis
Company Will Report Data from Phase 2a Sensorineural Hearing Loss (SNHL) Study in Late Q1 2021
First Patient Dosed in Phase 1b Study of Age-Related Hearing Loss; Additional Phase 1b Study for Severe SNHL Patients to Start This Quarter
Neuromod Successfully Closes €10.5 Million Series B Financing for Tinnitus Treatment Device Lenire®
Auckland University researchers trialing MDMA as tinnitus cure
Quick research update…
New paper outlines how elevated levels of manganese, cadmium, chromium, and selenium could potentially be the cause of subjective tinnitus.
Authors conclude that supplementation or reduction of these heavy metal elements “could be considered as novel therapeutic goals” for treating tinnitus.
Further studies are necessary. For now, here is the abstract for the study, The Role of Manganese, Cadmium, Chromium and Selenium on Subjective Tinnitus, published October 9, 2020:
Elevated levels of heavy metals like cadmium (Cd) and manganese (Mn) are known to lead to oxidative damage-related oto-toxicity and decreased levels of chromium (Cr) and selenium (Se) are known to lead to oto-toxicity due to reduced anti-oxidant activity. The aim of the present study was to evaluate serum levels of Cd, Mn, Cr, and Se and their relationship with tinnitus. A total of 48 patients with tinnitus (Group 1) and 40 healthy controls (Group 2) were included in the study. All participants were applied audiology tests. Severity of tinnitus was measured with Tinnitus Severity Index Questionnaire (TSIQ) in group 1. Serum Mn, Cd, Cr, and Se measurements were done by using The Agilent ICP-MS system consisted of a 7700 coupled plasma mass spectrometry (ICP-MS). Serum Cd, Mn, and Cr levels were higher in group 1 and Se level was lower in group 1 than that of group 2. We may conclude that Cd, Mn, Cr, and Se levels could play an important role in etio-pathogenesis of tinnitus, and thereby supplementation or reduction of these elements could be considered as novel therapeutic goals.
Get email alerts:
Remember to sign up for the free once-weekly email newsletter for tinnitus treatment updates and the very latest research…
Questions? Comments? Feedback? Email firstname.lastname@example.org and say hello.
New Tinnitus Treatment Alleviates Annoying Ringing in the Ears
A noninvasive device designed to rewire brain circuits reduced symptoms of tinnitus in a large, exploratory clinical trial
Is tinnitus all in the genes?
How much will FX-322 cost? David Lucchino, Frequency Therapeutics CEO, talks pricing and value…
Frequency Therapeutics Completes Enrollment of FX-322 Phase 2a Study for Sensorineural Hearing Loss
Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies.
The Neural Bases of Tinnitus: Lessons from Deafness and Cochlear Implants
Journal of Neuroscience 16 September 2020, 40 (38) 7190-7202; DOI: https://doi.org/10.1523/JNEUROSCI.1314-19.2020
The new study identifies candidate genes that could reveal the underlying causes and molecular mechanisms involved in tinnitus and ultimately lead to new targeted treatments.
“Our study has identified a number of interesting candidate genes for further investigation, most notably RCOR1,” write the study authors.
The preprint, which was posted to medRxiv on September 13, 2020,
has not yet been certified by peer review but it was supported by funding from some big names such as Action on Hearing Loss and NIHR UCLH BRC (Deafness and Hearing Problems).
March 21, 2021 update: This research has now been peer-reviewed and was recently published in Scientific Reports (Nature). https://www.nature.com/articles/s41598-021-85871-6
Researchers performed a genome-wide association study of tinnitus involving 172,608 volunteers.
Identification of the genetic variants involved in tinnitus would help reveal the nature of the mechanisms involved in generating tinnitus after hearing loss, a requisite for development of treatments. Previous pilot genome-wide association studies and candidate gene studies for tinnitus have lacked sufficient power to establish specific genetic risk factors but the relatively high heritability demonstrates there is potential to use such approaches to reveal the underlying mechanisms.
“Three variants in close proximity to the RCOR1 gene reached genome wide significance,” according to the study.
Worth a read.
Link to peer-reviewed paper (full text):
Link to preprint abstract: https://doi.org/10.1101/2020.09.11.20192583 Link to preprint [PDF]: https://www.medrxiv.org/content/10.1101/2020.09.11.20192583v1.full.pdf
The authors responsible for this fascinating paper (preprint) now at the forefront of the genetics of tinnitus: Helena Rose Rees Wells, Fatin N Zainul Abidin, Maxim Freydin, Frances MK Williams, Sally J Dawson.
It is therefore possible that the association of MYO3B, ARID5B and ZNF318 with tinnitus is secondary to their role in hearing since tinnitus is usually manifested when there is a hearing loss present. However, it may be that the nature of the hearing loss caused by these genes variants creates a deficit which particularly potentiates the generation of tinnitus.
More “tinnitus gene” coverage to follow…
How to follow this research (and get news about upcoming treatments such as FX-322, GW-201, and the Susan Shore device)? Keep checking the front page – OR – subscribe to the free email newsletter for treatment updates, including a once-weekly summary of new links that were added to this site.
Wells, H.R.R., Abidin, F.N.Z., Freidin, M.B. et al. Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank. Sci Rep 11, 6470 (2021). https://doi.org/10.1038/s41598-021-85871-6
Comments? Corrections? Questions? Email email@example.com (admin) and say hello.
From a case report that was published earlier this summer. The use of a spinal cord stimulator provided a patient with “near total relief of otalgia, total relief of tinnitus, and mild improvement in sensorineural hearing loss.”
How did it work? Will it work for you? What type of tinnitus does this work for?
Way too soon to even speculate.
If you want a good discussion topic, look at the last sentence in the abstract (quoted below):
Neuromodulation continues to grow in its scope and application in the relief of chronic and debilitating disorders. Both otalgia and tinnitus can be multifactorial in etiology, with diagnostic and treatment challenges. This is a case of spinal cord stimulator placement providing a patient with near total relief of otalgia, total relief of tinnitus, and mild improvement in sensorineural hearing loss. We believe that this is the first report showing benefit of high spinal cord stimulation in tinnitus, and we consider whether there are neuronal connections between upper cervical nerve roots and the auditory pathways.
Do neuronal connections between the upper cervical nerve roots and the auditory pathways exist?
For all tinnitus patients or just some (i.e. is it common or rare)?
Would people with this subtype of tinnitus be treatable with high spinal cord stimulation?
Could they expect the same “total relief” as the patient in the case study?
We don’t know yet.
But it sure is exciting to think about.
Wouldn’t it be nice if answering these research questions helped uncover a treatable “cervical nerve root” tinnitus subtype?
… all thanks to a case report that could have just as easily been forgotten?
Case reports are like tiny seeds.
If planted and watered enough, they can sometimes sprout into new research.
Your attention is the water.
Whenever you discuss a case report or ANY OTHER research topic or paper online… whenever you share it with others in the tinnitus community… whenever you post about it online…
You are watering that seed of an idea, helping it grow.
Then it can start to take root.
Other people notice.
They start to water it.
It becomes bigger, now with branches of its own… it becomes a ‘thing’ within the tinnitus community.
Researchers and the people who control the funding dollars [you know who you are, hi] begin to take notice. And while they might not comment*, they see it on their radar. The attention of the community is important. They monitor it. It is a factor they must consider.
* too busy reading My Posting Place?
The “voice of the patient” is an increasingly-important element of publicly funded projects and grant decisions.
You influence policy by sharing links to research and ideas with the community. I’m talking about places like Reddit (r/tinnitus and r/tinnitusresearch) and, of course, TinnitusTalk.
These forums are effectively a “public record” of research topics and things like views, comments, posts… are quietly becoming metrics that influence decisions and literally help researchers get grant money more easily.
Meanwhile, ideas and papers and topics that are NOT discussed by the community… certainly not helpful. Without a public record or the support of the “voice of the patient”, a paper or research topic could be totally ignored. Simply because it did not have enough people to vouch for it and those responsible for deciding what to fund understandably had no idea it was important to anyone.
So remember to pay attention and join the discussion somewhere because your share, your comment, your post… is a lot like a vote, and that will continue to become more and more relevant in the future.
One more thing…
Remember to subscribe to email updates so that you never miss exciting case reports like this spinal cord stimulation one… plus, some other exclusive tinnitus treatment-related updates that are ignored everywhere else. (COMMENT: the weekly newsletter digest is ALMOST READY and if you have submitted your email address you will get the first issue as soon as it is sent. Totally free, one email per week, no spam, privacy respected.)
Feedback? Comments? Requests? Send an email to firstname.lastname@example.org and say hello.
Dr. Will Sedley discusses role of “predictive brain processing” in tinnitus in latest interview – via Tinnitus Talk [PDF]
Did you mean: tinnitus talk podcast will sedley
Tinnitus and the Power of Prediction — Dr. Will Sedley
ANNOUNCEMENT – Tinnitus Treatment Report now includes tinnitus preprints. You can find these “preprints” (early not-yet-published research papers) in the Research section of the home page. Just look for the word [Preprint] next to the article title!
What is a preprint?
In academic publishing, a preprint is a version of a scholarly or scientific paper that precedes formal peer review and publication in a peer-reviewed scholarly or scientific journal. The preprint may be available, often as a non-typeset version available free, before and/or after a paper is published in a journal. Source: Wikipedia
Where can you find tinnitus preprint papers?
You could run custom searches for tinnitus at bioRxiv, medRxiv, Preprints.org, PMC, Research Square, EuropePMC, and other preprint servers – or – you can skip all the digging and simply visit the front page of TinnitusTreatmentReport.com, which uses a system that automatically monitors those same sources… automatically identifies, filters, and retrieves the newest tinnitus-related preprints… and automatically adds them to its great (and convenient) wall of tinnitus research.
Your only job? Just keep an eye on the #research section and look for the [Preprint] label!
Here are two recent tinnitus preprints from this month (August 2020):
Preprints will also be included in the weekly newsletter when it is ready (very soon). So remember to join the email updates list while it is still open if you want to get email updates.
Questions, comments, suggestions? Send an email to email@example.com and say hello.
Frequency Therapeutics Provides Business Updates and Reports Second Quarter 2020 Financial Results
Expects to Complete Enrollment of FX-322 Phase 2a Study for Sensorineural Hearing Loss by Early Q4 2020; Study Readout Anticipated in Q2 2021
Recently Announced Clinical Data Show FX-322 Delivery to the Cochlea and Preliminary Evidence of a Durable Clinical Benefit; Plans New Studies in Additional Patient Populations
Raised $42.3 Million Private Placement, Providing Company Runway into 2023
August 12, 2020 07:30 AM Eastern Daylight Time
WOBURN, Mass.–(BUSINESS WIRE)–Frequency Therapeutics, Inc. (Nasdaq: FREQ), a clinical-stage biotechnology company focused on harnessing the body’s innate biology to repair or reverse damage caused by a broad range of degenerative diseases, today announced business updates and financial results for the second quarter ended June 30, 2020.
“We are pleased with the steady progress in our Phase 2a study, despite the challenges of the pandemic, and we anticipate completing enrollment early in the fourth quarter of 2020 and sharing data from the study in the second quarter of 2021,” said Frequency Therapeutics Chief Executive Officer David L. Lucchino. “In the last quarter, we generated compelling cochlear drug delivery data for FX-322, as well as important durability data suggesting that some patients who were given a single injection of FX-322 in our original Phase 1/2 study maintained statistically significant improvements in word recognition between 12 and 21 months following administration. We believe that these clinical advances are important building blocks as we work to further our understanding of FX-322 drug activity and the patient populations we hope to treat.
The name of the leading tinnitus drug candidate is tetrandrine (TET) and researchers believe it could prevent and treat tinnitus by targeting both inflammatory and calcium signaling pathways.
Recent media coverage of Bao’s efforts to develop the first human treatment for tinnitus left many people itching to know more about the mysterious new drug.
The articles teased at the possibility of a cure… but did not provide specific details or even hint at how it might work.
The website for Bao’s company, Gateway Biotechnology, appeared to be equally secretive. The only reference to an upcoming tinnitus treatment in their pipeline was a code name: GW-201.
Sadly, a search for GW-201 on Google did not fill in the blanks.
But today, we have finally tracked down those elusive details concerning Bao’s tinnitus research and GW-201 – including a copy of the official project abstract.
The information was found by searching through a U.S. Department of Health & Human Services (HHS) grant-award program database for new entries with “Gateway Biotechnology Inc” as the recipient name.
TARGETING MULTIPLE SIGNALING PATHWAYS FOR TINNITUS PREVENTION AND TREATMENT
Award Number: R44DC018759
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH
Subjective tinnitus is the perception of a phantom sound, which negatively impacts the quality of life for millions of people worldwide. Despite the great demand for remedy, there are no FDA-approved drugs to prevent or treat tinnitus. Possible causes of tinnitus are complicated. The current view is that hyperactivity in the central auditory nervous system contributes to the majority of tinnitus cases. This abnormal electrical activity, including an increase in delta-band activity, may be the direct result of an increase in T-type calcium channel activity. Other studies suggest that inflammatory responses within the brain may be involved in the development and persistence of tinnitus; therefore, drug candidates targeting both inflammatory and calcium signaling pathways may act synergistically to prevent and treat tinnitus. Tetrandrine (TET), an approved drug used in China, exhibits both anti-inflammatory and calcium channel-blocking properties. Using a new tinnitus detection method in mice, we have shown that both salicylate-induced and noise-induced tinnitus can be effectively treated by TET in a dose-dependent manner. Our hypothesis is that TET or its chemical analogs can be developed as drugs to prevent and treat tinnitus. In our proposed experiments, we have two parallel goals: (1) obtain investigational new drug (IND)-enabling toxicity and pharmacokinetics data for TET (Aim 1) and (2) optimize second-generation products with structure-activity relationship studies of TET and its chemical analogs (Aim 2). Successful accomplishment of Aim 1 will enable TET to advance into clinical development. In addition, the studies of Aim 2 will enable us to identify additional candidates in case TET fails at clinical stages. By targeting multiple cellular signaling pathways that impinge upon tinnitus, our study will open new areas for the treatment and prevention of tinnitus. The extensive body of data publicly available for TET and its analogs will help us significantly reduce development time and costs.
SOURCE: HHS Tracking Accountability in Government Grants System (TAGGS)
From a U.S. patent assigned to Gateway Biotechnology…
In some cases, the therapeutically effective amount of TET or salt thereof is in a supplement product. In some cases, the therapeutically effective amount of TET or salt thereof is comprised in an herb extract. In some cases, the herb is Stephania tetrandra. In some cases, the herb is Stephania tetrandra S Moore. In some cases, the therapeutically effective amount of TET or salt thereof is isolated and purified. In some cases, the therapeutically effective amount of TET or salt thereof is a diastereoisomer having a diastereomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or from at least about 50% to about 100%.
Gateway Biotechnology, Inc., a biotechnology company that repurposes drugs with established safety records to prevent and treat hearing disorders, today announced that is has been assigned U.S. patent number 10,434,097 to develop a compound isolated from a Chinese medicinal plant for the prevention and treatment of noise-induced hearing loss.
Developing story… more information about GW-201, tetrandrine (TET), and Stephania tetrandra will be added to this post…
This exclusive update is brought to you by Tinnitus Treatment Report. If you have a question, comment, or correction for this article, send an email to firstname.lastname@example.org and say hello. For email updates about GW-201, tetrandrine (TET), and other promising new treatments in the pipeline for tinnitus, subscribe.
DISCLAIMER: This website does not offer medical advice. The information, media, and content featured on this website is for information, educational, and entertainment purposes only. Do not use this information instead of consulting with a doctor or qualified professional healthcare provider responsible for your care. This website does not endorse, recommend, suggest, or offer any advice related to healthcare decisions, symptoms, nutrition, wellbeing, or choice of medical interventions. Do not use any of the information on this website to guide your treatment plan or make decisions regarding your personal health. Always talk to your doctor or a qualified healthcare professional before making a decision affects your health. In case of a medical emergency, contact your local emergency services provider or the appropriate authorities.
NEOMED researcher receives federal grant for first human tinnitus treatment
NIH FUNDS NEOMED TINNITUS RESEARCHER
Categories: Innovation & Research | Tags: Anatomy & Neurobiology, Hearing Research
Tinnitus affects millions in the United States, and yet as of today, there is no treatment for this uncomfortable and disruptive hearing impairment. Northeast Ohio Medical University researcher Jianxin Bao, Ph.D., a professor in the Department of Anatomy and Neurobiology and a member of the Hearing Research focus area, has spent his 20-year career looking for a treatment. Now, as the Principal Investigator on a research proposal for Gateway Biotechnology, Inc., a company he co-founded, Dr. Bao has received a major boost from the federal government.
Otonomy Reports Positive Top-Line Results from Phase 1/2 Clinical Trial of OTO-313 in Patients with Tinnitus
Otonomy Provides Update on Clinical Trials and Development Programs
June 15, 2020 16:05 ET | Source: Otonomy, Inc.
SAN DIEGO, June 15, 2020 (GLOBE NEWSWIRE) — Otonomy, Inc. (Nasdaq: OTIC), a biopharmaceutical company dedicated to the development of innovative therapeutics for neurotology, today provided an update on its product pipeline and the timeline to results for the company’s three ongoing clinical trials, including the Phase 3 trial of OTIVIDEX in Ménière’s disease. The company will host a conference call and webcast today at 4:30 p.m. ET to review these updates.
Congressman Tim Ryan Announces National Institute on Deafness and Other Communications Disorders Grant for Tinnitus Prevention and Treatment
Frequency Therapeutics Shares Clinical Data From Exploratory Study Confirming Delivery of FX-322 to the Cochlea – Top-Line Results Show Consistent Drug Entry in All Patients
Causes of tinnitus
FAU team of researchers uses computer-based model to explain chronic ringing in the ears
This new paper titled, The Stochastic Resonance model of auditory perception: A unified explanation of tinnitus development, Zwicker tone illusion, and residual inhibition, is a must-read for anyone interested in a fascinating “big picture” explanation of tinnitus.
The 25-page PDF document (see link below) is a pre-print that is dated March 27, 2020. A “pre-print” is a paper that has not yet been published and has not yet gone through the peer review process. Think of it like an “unofficial” copy of a paper that is waiting to be published and must still be verified.
Here is the link to the PDF of the paper:
Despite the pre-print status, it is worth sharing because it offers insight into the fundamental nature of tinnitus, including its various causes, why it’s hard to tell why tinnitus gets worse for some people but not for others, and… best of all… as the title mentions, this paper includes a a “unified explanation” of tinnitus development. A “big picture” model that could explain all the other models, and bring them together.
Here are some of the “big picture” visuals you will find inside:
The authors outline many of the current and widely-studied tinnitus models and theories. They describe how these models are similar, how they are different, and point out the apparent contradictions. And then they explain how all these models may fit within an even bigger model: a “big picture” theory and explanation of tinnitus – in many of its various forms – that is based on something called stochastic resonance (SR). (For more background on SR: see this post from May 14, 2019, which describes the SR model of tinnitus.)
As the authors mention, the study does have its limitations. The theory does not literally explain everything. But it lays some solid groundwork and provides new direction for researchers to continue their search for an “everything” model of tinnitus that has both explanatory and predictive power. Solid progress!
It appears that a serious amount of research and consideration went into creating this work, which draws from 122 relevant papers, many of which are quite recent. (In other words, this is NOT simply “recycled” theories from years ago, or a lazy, unoriginal review. It is the exact opposite!)
A unified explanation of tinnitus development… worthy of the community’s spotlight?
It is now up to the tinnitus community to decide if they wish to discuss stochastic resonance and highlight the work of Schilling et al to make sure high-quality research like this gets the attention it deserves. (Remember, if promising research gets ignored… if promising research does not get attention… the funding dollars will either dry up, or – if history is any indication – be swallowed by “mainstream” studies involving TRT, etc. So, do your part and share original research! The community’s attention can be a remarkably powerful force in steering the direction of future research.)
Acknowledgements: A special thank you to the team of authors responsible for this noteworthy research: Achim Schilling, Konstantin Tziridis, Holger Schulze, Patrick Krauss.
The Stochastic Resonance model of auditory perception: A unified explanation of tinnitus development, Zwicker tone illusion, and residual inhibition
Achim Schilling, Konstantin Tziridis, Holger Schulze, Patrick Krauss
bioRxiv 2020.03.27.011163; doi: https://doi.org/10.1101/2020.03.27.011163
Some new research that brings in to question how cortical plasticity relates to tinnitus.
Is cortical plasticity a cause of tinnitus or the key to reversing it?
Some interesting developments from the paper, Cortical Tonotopic Map Changes in Humans are Larger in Hearing Loss than in additional Tinnitus:
This observation suggests a connection between tinnitus and an incomplete form of central compensation to hearing loss, rather than excessive adaptation. One implication of this may be that treatments for tinnitus shift their focus towards enhancing the cortical plasticity on track, instead of reversing it.[…]
Tinnitus, a common and potentially devastating condition, is the presence of a ‘phantom’ sound that often accompanies hearing loss. Hearing loss is known to induce plastic changes in cortical and sub-cortical areas. Although plasticity is a valuable trait that allows the human brain to rewire and recover from injury and sensory deprivation, it can lead to tinnitus as an unwanted side effect. In this large fMRI study, we provide evidence that tinnitus is related to a more conservative form of reorganization than in hearing loss without tinnitus. This result contrasts with the previous notion that tinnitus is related to excessive reorganization. As a consequence, treatments for tinnitus may need to enhance the cortical plasticity, rather than reversing it.
Here is a sneak preview “summary” of the most recent Lenire (Neuromod) device clinical trial results.
It is an abstract.
It is from the Association for Research in Otolaryngology’s 43rd Annual MidWinter Meeting’s Abstract Book: Abstracts 488 Volume 43, 2020 (PS 767).
It is exciting.
But remember to keep a few important points in mind while reading:
Here it is:
Safety and Efficacy of Combined Sound and Trigeminal Nerve (Tongue) Stimulation to Treat Tinnitus: Effects of Different Stimulation Settings over Time
Hubert H. Lim, Caroline Hamilton, Stephen Hughes, Emma Meade, Martin Schecklmann, Thavakumar Subramaniam, Sven Vanneste, Deborah Hall, Berthold Langguth, Brendan Conlon
University of Minnesota, Minneapolis, USA, St. James’s Hospital/Trinity College Dublin, Neuromod Devices Limited, University of Regensburg, The University of Texas at Dallas, University of Nottingham
Tinnitus affects 10-15% of the population. Unfortunately, there are limited treatment options. Recent animal and pilot human research has demonstrated the ability to drive extensive auditory plasticity and potentially treat tinnitus by pairing sound with trigeminal or somatosensory nerve activation, such as with tongue stimulation. A non-invasive device (Lenire) using auditory and tongue (bimodal) stimulation was evaluated in two large randomized and blinded clinical trials in over 500 participants with tinnitus in Ireland and Germany. The first study (TENT-A1) investigated three stimulation settings (PS1, PS2, PS3) presented for 12 weeks (60 minutes recommended per day) and evaluated during treatment and up to 12 months post-treatment (326 enrolled participants). Primary outcome measures included the Tinnitus Handicap Inventory (THI) and Tinnitus Functional Index (TFI). The second study (TENT-A2) investigated different stimulation settings over time across four treatment arms (191 enrolled participants). The first treatment arm consisted of the most effective stimulation setting from TENT-A1 during the first 6-weeks (PS1) followed by a new bimodal stimulation setting during the second 6-weeks (PS4). The second and third arms consisted of different bimodal settings than the first arm, while the fourth arm consisted of an acoustic only condition during the first 6-weeks followed by a bimodal condition during the second 6-weeks. All three stimulation settings in TENT-A1 resulted in statistically significant improvements in tinnitus for THI (p< 0.0001) and TFI (p< 0.0001) that were also clinically significant ( >7 THI points, >13 TFI points). Post-treatment, PS1 resulted in persistent improvements lasting 12 months after treatment ceased (p< 0.0001). The treatment was safe and well-tolerated with a high compliance rate (84%; >36 hours of usage). The largest therapeutic effects occurred within the first 6-weeks. In TENT-A2, similar results were observed for PS1 during the first 6-weeks as in TENT-A1. Changing the stimulation setting from PS1 to PS4 led to a greater improvement (p< 0.001) than observed in TENT-A1 that also persisted for 12 months post-treatment, as well as reaching a higher compliance rate of 91%. Post-hoc analyses showed that different bimodal stimulation settings over time could be as effective as the PS1-to-PS4 condition and that specific bimodal stimuli consistently outperformed the acoustic only condition for both THI and TFI. Overall, these findings demonstrate that the Lenire treatment provides safe, fast-acting (within 6 weeks) and reproducible therapeutic effects that can last at least 12 months. Furthermore, adjusting the stimulation settings time can drive greater therapeutic effects.
The complete results and supporting data will probably only be available (published in a peer-reviewed journal) in Q1 2021 or Q2 2021.
This information is presented without further comment.
What do you think of this Lenire update? Discuss it in the Tinnitus Talk forums, on Reddit (r/tinnitus and r/tinnitusresearch), in Facebook groups, and on Twitter. Ask lots of questions. Or send an email to email@example.com with your opinion and commentary.
To get more exclusive tinnitus treatment-related updates delivered to your inbox, subscribe to the Tinnitus Treatment Report email updates list. It is a free once-weekly link roundup and newsletter that will be sending out its first issue very soon.
Toward Tinnitus Subtyping: or Finding a Key for Each Keylock
Toward Tinnitus Subtyping: or Finding a Specific Personalized Treatment for Each Patient
Why Tinnitus Needs Citizen Science: A Researcher’s Perspective
Developing effective treatments or even a cure for tinnitus
Published on February 3, 2020, added to TinnitusTreatmentReport.com manually on September 7, 2020
Resaphene Suisse AG: Charité Ethics Committee in Berlin Approves Study on Tinniwell Tinnitus Therapy
Published: Jan 21, 2020
Cognosetta, Inc receives funding to test whether treatment with BMS-191011, a calcium-activated potassium (BK) channel opener, can reduce behavioral and neurophysiological manifestations of chronic tinnitus. The project started on December 15, 2019 and is expected to continue until June 30, 2020.
Project Number: 1R43DC018487-01
Contact PI / Project Leader: SCOTT, LUISA L
Title: DEVELOPING A NOVEL THERAPEUTIC FOR TREATING TINNITUS Awardee Organization: COGNOSETTA, INC.
Tinnitus or “ringing in the ears” is a hearing disorder that disproportionately impacts those who are or have served in the military. There is currently no effective cure for tinnitus. Patients with tinnitus exhibit broad changes in brain activity in the auditory system and elsewhere. One of the fundamental characteristics of tinnitus is a dysregulation in the excitatory/inhibitory balance in the central auditory system (CAS) leading to neuronal hyperexcitability and synchrony. The large conductance calcium-activated potassium (BK) channel is implicated in other neuronal excitability disorders like temporal lobe epilepsy, tonic-clonic seizures and alcohol withdrawal seizures. Gated by both voltage and intracellular calcium, and expressed throughout the peripheral and central auditory system, the BK channel is able to modulate auditory neuronal signaling across a wide variety of conditions. Recently, Lobarinas et al. found that two BK channel openers, Maxipost and its enantiomer, reduced behavioral evidence of salicylate-induced tinnitus in rats. Though Maxipost was originally developed as a BK channel opener, in fact it is a more potent KCNQ channel opener. Nonetheless, these findings provided the impetus for our preliminary studies showing that BMS-191011, a more specific BK channel opener, reduces behavioral manifestations of tinnitus in two mouse models. Consistent with a mechanistic aim of counteracting hyperactivity in the CAS, our preliminary data and other’s shows that BK channel openers reduce neuronal activity in the auditory midbrain. The overall aim of the proposed studies is to test whether treatment with a class of BK channel openers, exemplified by BMS-191011, can reduce behavioral and neurophysiological manifestations of chronic tinnitus. Behavioral assays will probe whether treatment with the BK channel opener modifies responses that can be linked to CAS function. Both invasive and non-invasive neurophysiological recordings in vivo will characterize treatment effects on neural correlates of tinnitus in the CAS to 1) provide cross-methodological confirmation for the behavioral effects, 2) facilitate preclinical target validation and engagement studies, and 3) allow translation to clinically-measurable markers of tinnitus. The studies will employ a mouse model of acoustic trauma-induced tinnitus that matches the etiology of a substantial portion of the patient population. The use of mice will enable a longitudinal study design in which treatment begins ~2-3 months after acoustic trauma. Many mammals preclude long duration studies or higher usage rates, but the CBA/CaJ mouse is both affordable and now considered a reliable model of tinnitus following noise trauma. Together, the proposed preclinical studies will explore whether administration of a class of BK channel openers exemplified by BMS-191011 is a valid strategy to counteract maladaptive CAS function underlying stable tinnitus. This therapeutic approach clinically would allow a lapse in time following noise trauma before treatment onset, in line with the practical needs of at-risk members of the Armed Forces who may develop tinnitus while deployed, and the many patients who already have acoustic trauma-related tinnitus.
Ion channels regulate neural processing; and, changes in ion channel function can underlie central nervous system disorders. tinnitus or “ringing in the ears”, which is characterized by hyperexcitability in the central auditory system, may be relieved by modulating the function of specific ion channels. This project will explore whether a specific class of potassium channel modulators can reduce the neural and behavioral manifestations of chronic tinnitus.
SOURCE: National Institutes of Health – NIH Research Portfolio Online Reporting Tool (RePORT)
Free email updates:
For the latest tinnitus treatment-related news and updates, sign up for the Tinnitus Treatment Report newsletter.
One email per week. No spam. (New issue to be sent very soon.)
New ‘fast-track’ system for tinnitus and hearing loss
Auris Medical Announces Notice of Allowance for European Patent Application
Auris Medical Receives “Intention to Grant” notice from European Patent Office for New Oral NKCC1 inhibitor Treatment for Tinnitus
European Patent Office (EPO) issues notice of “Intention to Grant” for Auris Medical’s “Treatment of Tinnitus Through Modulation of Chloride Co-Transporter NKCC1 in the Auditory System”
Email Print Friendly Share
January 10, 2020 08:30 ET | Source: Auris Medical AG
Application covers invention of oral treatment for tinnitus
Hamilton, Bermuda, January 10, 2020 – Auris Medical Holding Ltd. (NASDAQ: EARS), a clinical-stage company dedicated to developing therapeutics that address important unmet medical needs in neurotology and central nervous system disorders, today announced that the European Patent Office (EPO) has issued a notice of “Intention to Grant” for its patent application entitled “Treatment of Tinnitus Through Modulation of Chloride Co-Transporter NKCC1 in the Auditory System” (European Patent Application 11 894 529.3).
The allowed claims cover compounds modulating the sodium potassium chloride co-transporter 1 (NKCC1) for use in the oral treatment or prevention of tinnitus. As demonstrated in an animal model of acute noise trauma, administration of an NKCC1 inhibitor resulted in a significant reduction of a biomarker for the presence of tinnitus (p<0.02). Inhibition of NKCC1 reduces trauma-induced excessive intracellular chloride ion levels in inner hair cells and the resulting neural hyperexcitability in the auditory system, which underlies the perception of tinnitus. The communication from the EPO concludes substantive examination of the patent application, which is now expected to issue as a patent once the issue fees are paid and the patent office concludes its respective administrative procedures. A corresponding patent application is currently pending before the US Patent and Trademark Office (USPTO) and was already granted in Japan. “We are very pleased with this new addition to our patent estate in tinnitus, which remains an area of great unmet medical need“, commented Thomas Meyer, Auris Medical’s founder, Chairman and CEO. “NKCC1 represents a new and promising target for tinnitus therapy, particularly because it may allow for oral treatment and thus complement Keyzilen®, our investigational tinnitus drug for intratympanic administration. We intend to develop a proprietary NKCC1 inhibitor through our new subsidiary, Zilentin Ltd., which we recently established in order to bundle our activities and assets within the therapeutic areas of tinnitus and hearing loss.” About Auris Medical Auris Medical is a biopharmaceutical company dedicated to developing therapeutics that address important unmet medical needs in neurotology and central nervous system disorders. The company is focused on the development of intranasal betahistine for the treatment of vertigo (AM-125) and for the treatment of antipsychotic-induced weight gain and somnolence (AM-201). These projects have gone through two Phase 1 trials and entered into proof-of-concept studies in 2019. In addition, Auris Medical has two Phase 3 programs under development: Sonsuvi® (AM-111) for acute inner ear hearing loss and Keyzilen® (AM-101) for acute inner ear tinnitus. The Company was founded in 2003 and is headquartered in Hamilton, Bermuda. The shares of Auris Medical Holding Ltd. trade on the NASDAQ Capital Market under the symbol “EARS.” Forward-looking Statements
Auris Medical Announces Formation of New Subsidiary for Development Projects in Tinnitus and Hearing Loss
American Tinnitus Association and British Tinnitus Association Partner to Spark Innovations in Tinnitus Treatments and Advance Global Discussion About Potential Tinnitus Breakthroughs
Sufficient proof of concept to support future investigation of MDMA as a treatment for tinnitus?
Frequency Therapeutics Provides Business Updates and Reports Third Quarter 2019 Financial Results
Initiated FX-322 Phase 2a clinical study for sensorineural hearing loss
Granted FDA Fast Track designation for FX-322
Completed an $88.6 million initial public offering in October 2019, providing Company runway into 2022
“This has been a tremendously productive period for Frequency as we commenced our Phase 2a study, received Fast Track designation for FX-322, and completed key financings that we believe will enable us to advance our hearing program and further diversify our portfolio as we apply our progenitor cell activation platform in numerous disease areas,” said Frequency Therapeutics Chief Executive Officer David Lucchino. “We have opened all U.S. sites for our Phase 2a study of FX-322 and remain on track to report top-line data in the second half of next year. We believe FX-322 has the potential to be a restorative, disease-modifying treatment for the millions of patients with hearing loss, with the aim of improving hearing function, including speech intelligibility. We also continue to advance our multiple sclerosis development efforts and remain focused on moving our remyelination program into the clinic in the second half of 2021.”
Neuromodulation for Tinnitus Relief: Interview with Neuromod Devices CEO Dr. Ross O’Neill
The cortisol awakening response: could this be an effective measure of tinnitus distress?
Frequency Therapeutics Commences Dosing in its Phase 2a Study of FX-322 for Sensorineural Hearing Loss; FDA Grants FX-322 Fast Track Designation
VIDEO: Susan Shore on Bimodal Stimulation for Tinnitus – #TRI2019 (via TinnitusHub)
When will Neuromod publish the results of their latest clinical trial, Treatment Evaluation of Neuromodulation for Tinnitus – Stage A2 (TENT-A2)?
It looks like we now have an answer…
The data collection and database lock are expected to be completed by February 2020, and the data analysis and manuscript submission are expected to be conducted in autumn of 2020.
The findings of this study will be disseminated to relevant research, clinical, and health services and patient communities through publications in peer-reviewed journals and presentations at scientific and clinical conferences.
The source of this information, published on September 27, 2019:
Conlon B, Hamilton C, Hughes S, Meade E, Hall DA, Vanneste S, Langguth B, Lim HH
Noninvasive Bimodal Neuromodulation for the Treatment of Tinnitus: Protocol for a Second Large-Scale Double-Blind Randomized Clinical Trial to Optimize Stimulation Parameters
JMIR Res Protoc 2019;8(9):e13176
Why the long wait?
The time between manuscript submission and publication is usually a matter of months.
For example, The Proceedings of the National Academy of Sciences (PNAS) website mentions that the average time from submission to online publication for their journal is 5.5 months and the average time from submission to issue publication is 6 months.
The wait time varies depending on the publication, but you get the idea…
Even if Neuromod submits their manuscript in late 2020 – as currently planned – that still means we probably won’t see the actual findings and published article until Q1 2021 or Q2 2021… or maybe later…
So despite all those exciting Hubert Lim videos and teasers, it seems like we are not going to get the TENT-A2 results for another year or more.
(Prove us wrong, Neuromod, prove us wrong!)
Meanwhile, the company continues to prepare for global commercialisation of their Lenire tinnitus treatment.
What do you think? Head on over to TinnitusTalk, r/tinnitus, r/tinnitusresearch, or your favorite tinnitus forum and/or Facebook group and discuss this update.
And remember to subscribe to TinnitusTreatmentReport.com email updates for more exclusive tinnitus treatment-related updates and the latest research. (First newsletter issue coming soon.)
Questions? Comments? Corrections? Email firstname.lastname@example.org and say hello.
Neuromod Successfully Closes €8 Million Capital Raise: proceedswill be used to accelerate ongoing commercialisation of the Company’s Lenire® tinnitus treatment device
A Breakthrough in Understanding Tinnitus: The Entire Hearing System Studied
Possible Link Between Marijuana Use, Tinnitus
Study added to conflicting information on the issue
Some more information about the upcoming presentation and study, Phase 1/2 Hearing Loss Trial of Intratympanic FX322, a Progenitor Cell Activator, has been posted on the AAO-HNSF 2019 conference website.
This information was previously embargoed (fully), but this abstract/preview has just been made public:
Background: Study Objectives: Although most species can regenerate hair cells, hair cell loss in mammals is permanent because the subset of supporting cells that serve as hair cell progenitors during development fail to divide and differentiate on their own. This work showed that two small molecules that now comprise FX322 restore the regenerative potential of mouse and human progenitor cells in vitro and regenerate hair cells when applied to ototoxin damaged mouse tissue. Importantly, a single intratympanic injection of FX322 restores hair cells and auditory function in mice with trauma within one month after treatment. Utilizing small molecules to regenerate hair cells could provide a therapeutic advantage over the complexities and challenges associated with gene and cell therapies. This preclinical body of data supported the start of the first clinical trial of FX322 in patients with sensorineural hearing loss. Methods: The trial was conducted at three private US otolaryngology practices to assess the systemic safety, plasma PK, and effects on otoscopy, audiometry, and word testing of locally-delivered FX322. The trial was double-blinded, placebo-controlled and enrolled 23 patients with medical histories consistent with either noise-induced hearing loss or sudden sensorineural hearing loss which was considered stable (no change ≥10dB at any frequency, ≥6 months, PTA ≤70dB). Patients were randomized to either placebo or FX322 at two different dose volumes, and treatment was given as a single intratympanic dose. Patients were monitored overnight for safety and PK, and returned at months 0.5, 1, 2 and 3 for otoscopy, audiometry and word testing. Results: As of the date of this writing the study remains blinded and final results will be presented at the annual AAO-HNS meeting.
Expect more information on the day of the presentation: September 17, 2019.
For more tinnitus treatment/cure updates, subscribe to the weekly digest/newsletter (first issue will be sent out soon). Also check out Hearing Loss Treatment Report for more treatment-related updates. Questions/Comments/Suggestions – email email@example.com and say hello.
Thank you to Reddit user /u/pandoira for finding this update and bringing it to the attention of the tinnitus and hearing loss community!
The image below shows delivery of FX-322 that turns to a gel in the middle ear. The drug diffuses into the cochlea and is expected to create the greatest concentration of drug in the high frequency region of the cochlea.
Phase 1/2 clinical trial
We conducted a Phase 1/2 clinical trial of FX-322 in which we enrolled 23 adult patients aged 33 to 64 with an established diagnosis of mild to moderately severe stable SNHL, defined as the average pure tone value of 26 to 70 dB at the 500, 1000, 2000 and 4000 Hz frequencies, who had no change of 10 db or more at any frequency for more than six months. Fourteen patients had mild SNHL and nine patients had moderate to moderately severe SNHL. Of the nine moderate to moderately severe patients, six were randomized to FX-322 and three to placebo. In this trial, 15 patients were treated with a single injection of FX-322 and eight patients received placebo. Each patient had a documented medical history consistent with either noise-induced hearing loss, or NIHL, typically from noise exposure at work, or sudden SNHL, or SSNHL, which is characterized as a loss of 30 dB at three adjacent frequencies occurring over a 72-hour period. All patients had stable SNHL, meaning their hearing function at study entry was not significantly different based on a documented audiogram from at least six months prior to the study. Hearing function, specifically speech intelligibility, was assessed using WR and WIN. Hearing loudness was also measured using pure tone audiometry. Patients were randomized to a single injection of FX-322 or placebo administered at one of two different dose volumes (0.05 mL and 0.2 mL) to assess the safety of FX-322 administration and systemic exposure to FX-322. Follow-up visits occurred at 15, 30, 60, and 90 days after injection.
The objectives of the trial were to assess:
the systemic safety of FX-322;
the plasma pharmacokinetic profile to determine the systemic exposure to FX-322; and
the effect of FX-322 on measures of ear health and hearing function.
FX-322 was observed to be well-tolerated in this trial. No serious adverse events were observed, and all treatment-related adverse events were mild, procedure-related, and generally resolved within minutes after dosing. We also observed limited concentrations of the FX-322 components in systemic circulation.
We also performed a post hoc analysis that showed a statistically significant improvement in WR by all FX-322-treated patients versus all placebo patients (p=0.01). A p value, as expressed in the data above, is the probability that the difference between two data sets was due to chance. The smaller the p value, the more likely the differences are not due to chance alone. In general, if the p value is less than or equal to 0.05, the outcome is statistically significant. The data are presented as adjusted mean relative percent change from baseline in the figure below. FX-322 treated patients saw improvements as early as 15 days after treatment that were sustained over 90 days.
We performed an additional post hoc analysis on WIN data. As shown in the figure below, the adjusted mean relative percent change from baseline was assessed at 15, 30, 60, and 90 days after injection, and a trend in improvement was seen in FX-322-treated patients versus placebo. Also, there were non-statistically significant trends in improved WIN scores at Day 90 in the four FX-322, treated patients that had statistically significant and clinically meaningful improvements in WR in the prospective statistical analysis.
We assessed audiometric changes from 250 Hz to 8000 Hz for all patients. Since drug enters closest to the high frequency region, the greatest drug exposure is expected to occur in the high frequency region. While no statistical differences were observed at any frequency when comparing pooled treatment groups, four of the moderate to moderately severe FX-322 patients showed a 10 dB threshold improvement at 8000 Hz at Day 90.
Planned Phase 2a clinical trial
Based on our analysis of the data from our Phase 1/2 clinical trial, we intend to initiate a randomized, double-blind, placebo-controlled, single- and repeat-dose Phase 2a clinical trial of FX-322 at approximately 12 sites in the United States in the fourth quarter of 2019. We plan to enroll approximately 96 adults aged 18 to 65 with stable SNHL. As in the Phase 1/2 clinical trial, patients must have a documented medical history consistent with either stable NIHL or stable SSNHL, with an average range of 26 to 70 dB loss measured by pure tone audiometry across four frequencies.
To explore how a single dose compares to multiple doses of FX-322, we plan to randomize patients to one of four groups, each of which will receive four injections, once per week at weekly intervals starting at the initial visit. Group 1 will receive one injection of FX-322 and three injections of placebo. Group two will receive two injections of FX-322 and two injections of placebo. Group three will receive four injections of FX-322. Group four will receive four injections of placebo. Patients will have follow-up visits two weeks after dosing and then monthly for seven months. The efficacy endpoints of this trial are expected to be WR, WIN, and pure tone audiometry in the range of 250 to 8000 Hz. The exploratory efficacy endpoints are expected to be the Tinnitus Functional Index, the Hearing Handicap Inventory for Adults, and pure tone audiometry in the range of 9000 to 16000 Hz. The selection of the efficacy endpoints in this study build on the learnings from the Phase 1/2 trial,
and we believe will add to our knowledge on the potential ways in which FX-322 may improve hearing function. We expect to report top-line data from this trial in the second half of 2020. We may also conduct clinical research in presbycusis.
Prior to commencing clinical trials, we tested FX-322 in multiple preclinical studies, including in human cells ex vivo and functional hearing tests in mice in vivo. In in vitro testing of isolated human inner ear progenitor cells with the compounds comprising FX-322, we observed the formation of new progenitor cells and their subsequent conversion into hair cells. We also observed translation across species in our in vitro studies of the inner ear progenitor cells from rhesus macaques in which a similar expansion of cell numbers were observed as in the in vitro studies of human cells.
We also conducted ex vivo testing in intact cochlea isolated from mice. To cause hair cell loss, we exposed the cochlea for 16 hours to an aminoglycoside antibiotic that is toxic to hair cells. We then treated the cochlea for 72 hours with the compounds comprising the active agents in FX-322. Aminoglycoside treatment (left panel in the figure below) killed more than 80% of the hair cells in the cochlea (shown in green). By contrast, cochlea treated with the compounds in FX-322 (shown in the middle panel) regenerated hair cells to a near native level, as shown graphically in the right panel.
Restoration of Hair Cells in Mouse Cochlea
We also tested FX-322 in a mouse model of severe noise-induced hearing loss. Following noise exposure, 47 mice were treated with FX-322 and 37 were treated with placebo. Hearing function was measured using auditory brainstem response, or ABR, in which the signal generated by the auditory nerve upon sensing sound is detected by electrodes on the scalp. We performed ABR testing after 24 hours, and measured hearing recovery after 30 days. The figure below shows the percentage of mice treated with FX-322 (shown in orange) or with placebo (shown in blue) that achieved a hearing recovery of at least 10 dB at 20000 Hz, a mid-range
frequency for mice. The improvement observed in the placebo-treated mice was due to recovery of temporary effects not related to hair cell death, which is typical following acute hearing loss.
Hearing Recovery in Mice Treated with FX-322
We have also conducted pharmacokinetic tests in multiple species in which we observed that FX-322 administration achieved therapeutic levels of the active pharmaceutical ingredients in the cochlea.
Auris Medical Announces Formation of Scientific Advisory Board for Tinnitus Programs
Brain Inflammation Identified as Potential Target to Treat Tinnitus
The discovery by UA associate professor of physiology Shaowen Bao and his colleagues could lead to new treatments to silence tinnitus for millions of sufferers.
Frequency will use the proceeds to support the clinical development of FX-322, a regenerative therapeutic for the treatment of sensorineural hearing loss that is moving into a Phase 2a study, and to advance discovery programs in other therapeutic areas using its proprietary Progenitor Cell Activation (PCA) platform.
FACT #1: Some people habituate to their tinnitus.
FACT #2: Some people do not habituate to their tinnitus.
FACT #3: Some people believe that EVERYONE can habituate to their tinnitus.
FACT #4: Some people believe that IT IS YOUR FAULT if you are unable to habituate to your tinnitus… that you CHOOSE not to habituate… and the reason you have not habituated like the others, is because there is a problem with your personality… because you are unwilling to habituate… because you are pretending you cannot habituate… because you are trying to not habituate… because you are lying about your habituation… or because you are depressed or have psychological “issues”…
Yes, it sounds crazy… but some people really do hold these disturbing beliefs. Sadly, you don’t even need to look very far to find evidence of this attitude within the tinnitus community. People arguing over habituation, as if they have all the answers. Alas…
We might not have to worry about these habituation-pushers (enemy NPCs) for much longer. Because more and more researchers are starting to find clues that could soon confirm what many “non-habituated” people in the tinnitus community already know from personal experience: NOT EVERYONE CAN HABITUATE TO THEIR TINNITUS – and, importantly… the cause of this “habituation-proof subtype” of tinnitus (or patient) has nothing to do with the “reasons” mentioned above (which are not only unscientific and lazy, but insulting and destructive).
The real reasons some people do not habituate are almost certainly physiological (i.e. they can be traced back to a physical process, outside of your control and/or independent of your thoughts). What, exactly? We do not know yet. But… it appears that the science is starting to support the obvious: that people who do not habituate are NOT just stubborn or self-sabotaging or defective.
So, if YOU can’t habituate, don’t worry. The science is finally starting to confirm what you already knew. It is NOT your fault and it is NOT “all in your head” or imaginary.
Instead, there is probably a physiological cause. At least, that seems to be the big picture that is emerging from the newest studies. And the most recent of these studies, exploring the cause of habituation-proof tinnitus and/or patients, is from July 12, 2019. The title of the study is Toward An Exploration of Habituating to Tinnitus: Perspectives on Sensory Gating and it is from the the American Academy of Audiology.
Here is a link to this latest habituation-related study on PubMed:
You can read the abstract. The full paper is not yet available (the link to the journal site is appears to be broken or is not yet active).
Here is an excerpt:
The purpose of this study was to compare behavioral aspects of sensory gating in normal and tinnitus participants to search for the reason why some tinnitus participants habituate to their tinnitus but some others do not.[…]
These results suggested that tinnitus associated with behavioral aspects of sensory gating and decompensated tinnitus may be a result of deficient sensory gating.
PMID: 31304914 DOI: 10.3766/jaaa.18038
The next time someone argues about habituation or gives you a hard time, politely refer them to this recent study which explores deficient sensory gating as the reason why some people cannot habituate… or… you can also refer them to another recent study, previously mentioned on this website, which examines The potential role of auditory prediction error in preventing habituation to tinnitus.
And remember… if scientists can prove not all tinnitus patients can habituate… then groups/organizations such as the VA will be “forced” to seek other solutions – for all those patients who cannot be helped by habituation – and this could lead to more resources being put toward finding an ACTUAL cure. You never know!
Astellas picks up Frequency’s regenerative hearing loss med outside U.S. for $80M
Tinnitus experts Susan Shore and Calvin Wu discuss the future of tinnitus research and the approaches that are most likely to provide reliable therapies…
The new paper, titled “Mechanisms of Noise-Induced Tinnitus: Insights from Cellular Studies,” was published in Neuron on July 3, 2019. It is a thorough review of 161 different scientific papers… and the concluding remarks provided by authors Susan Shore and Calvin Wu are insightful and exciting.
Here is a link to the full text:
Studies of single neurons and how ensembles of neurons produce population responses are likely to be the most effective route to unraveling the mechanisms of this elusive disease. To enable us to develop methods to alleviate the bothersome or debilitating symptoms of tinnitus, we need to understand the cellular underlying mechanisms.
Here is the abstract:
Tinnitus, sound perception in the absence of physical stimuli, occurs in 15% of the population and is the top-reported disability for soldiers after combat. Noise overexposure is a major factor associated with tinnitus but does not always lead to tinnitus. Furthermore, people with normal audiograms can get tinnitus. In animal models, equivalent cochlear damage occurs in animals with and without behavioral evidence of tinnitus. But cochlear-nerve-recipient neurons in the brainstem demonstrate distinct, synchronized spontaneous firing patterns only in animals that develop tinnitus, driving activity in central brain regions and ultimately giving rise to phantom perception. Examining tinnitus-specific changes in single-cell populations enables us to begin to distinguish neural changes due to tinnitus from those that are due to hearing loss.
NOTE: The article has a delayed release embargo on PMC until July 2020. However, the full text is now public and online. It was tracked down by TinnitusTreatmentReport.com’s automated research gathering system. To get the latest tinnitus research – without waiting months and months for it to become “public” (or easily found) – remember to sign up for our free weekly email updates. You will receive these weekly email summaries every Saturday, which will be sent out in the coming weeks.
Evolution, Revolution, Stagnation? – Exclusive Insights from #TRI2019
Research Roundup: 20+ field reports from the Tinnitus Research Initiative (TRI) 2019 Conference in Taipei
This new model of tinnitus is NOT directly linked to hearing loss and primary auditory cortex abnormalities… but with a simultaneous premotor ear-eye disturbance…
Could this “disturbed crosstalk between the ear and eye systems” also explain why so many tinnitus patients also suffer from visual snow? Hmmmm…
Here is a link to the full pre-print paper (not yet peer-reviewed):
Tinnitus mechanisms remain poorly understood. Our previous functional MRI (fMRI) studies demonstrated an abnormal hyperactivity in the right parietal operculum 3 (OP3) in acoustic trauma tinnitus and during provoked phantom sound perceptions without hearing loss, which lead us to propose a new model of tinnitus. This new model is not directly linked with hearing loss and primary auditory cortex abnormalities, but with a proprioceptive disturbance related to middle-ear muscles. In the present study, a seed-based resting-state functional MRI method was used to explore the potential abnormal connectivity of this opercular region between an acoustic trauma tinnitus group presenting slight to mild tinnitus and a control group. Primary auditory cortex seeds were also explored because they were thought to be directly involved in tinnitus in most current models. In such a model, hearing loss and tinnitus handicap were confounding factors and were therefore regressed in our analysis. Between-groups comparisons showed a significant specific connectivity between the right OP3 seeds and the potential human homologue of the premotor ear-eye field (H-PEEF) bilaterally and the inferior parietal lobule (IPL) in the tinnitus group. Our findings suggest the existence of a simultaneous premotor ear-eye disturbance in tinnitus that could lift the veil on unexplained subclinical abnormalities in oculomotor tests found in tinnitus patients with normal vestibular responses. The present work confirms the involvement of the OP3 subregion in acoustic trauma tinnitus and provides some new clues to explain its putative mechanisms.
New research from Susan Shore presented at last month’s 4th International Hearing Loss Conference…
Cochlear damage may be necessary but not sufficient to induce tinnitus
While hearing loss is associated with tinnitus, the relationship is not causal as people without audiometric hearing loss can develop tinnitus and not all people with audiometric hearing loss develop tinnitus.
Likewise, in animal models, noise exposures that produce only temporary threshold shifts result in behavioral evidence of tinnitus only in about half of the exposed animals. Following tinnitus-induction using narrow band noise exposures, we have demonstrated that dorsal cochlear nucleus fusiform cells show BF-specific alterations in stimulus-timing dependent plasticity, increased spontaneous synchronization, and increased spontaneous firing rates (SFR) in animals with behavioral evidence of tinnitus [1, 2].
Conversely, animals without plasticity-induced changes in fusiform cells, but equivalent degrees of cochlear damage, did not show evidence of tinnitus. Similarly, bushy cells in ventral cochlear nucleus showed BF-restricted increased SFR and cross-unit synchrony in animals with behavioral evidence of tinnitus but not in those without such behavioral evidence, even though ABR thresholds and suprathreshold wave-1 amplitudes were equivalent , suggesting similar cochlear damage in the two groups. Changes in glutamatergic and cholinergic transmission were also changed in these animals in a tinnitus-specific manner [4, 5].
Conclusions: These results suggest that hearing loss, whether visible or ‘hidden’, is insufficient by itself to produce a tinnitus phenotype. Changes in cochlear output after noise exposure require accompanying plastic changes in recipient neurons in the CNS in order to result in the physiological and behavioral signatures of tinnitus.
References:  C. Wu, D.T. Martel, S.E. Shore, Increased Synchrony and Bursting of Dorsal Cochlear Nucleus Fusiform Cells Correlate with Tinnitus, J Neurosci, 36 (2016) 2068-2073.  K.L. Marks, D.T. Martel, C. Wu, G.J. Basura, L.E. Roberts, K.C. Schvartz-Leyzac, S.E. Shore, Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans, Sci Transl Med, 10 (2018).  D. Martel, S. Shore, Ventral cochlear nucleus bushy cells contribute to enhanced auditory brainstem response amplitudes in tinnitus., ARO, 2019, DOI (2019).  A.N. Heeringa, C. Wu, C. Chung, M. West, D. Martel, L. Liberman, M.C. Liberman, S.E. Shore, Glutamatergic Projections to the Cochlear Nucleus are Redistributed in Tinnitus, Neuroscience, DOI 10.1016/j.neuroscience.2018.09.008(2018).  L. Zhang, C. Wu, D.T. Martel, M. West, M.A. Sutton, S.E. Shore, Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs, Hippocampus, DOI 10.1002/hipo.23058(2018).
This information is from page 17 of the [PDF] International Hearing Loss Conference 2019 Program.
Drug to reduce brain inflammation CURED tinnitus in mice – paving the way towards a pill for humans
Reducing brain inflammation could treat tinnitus and other hearing loss-related disorders