The Latest Advances in Otoprotective Agents with Ting Therapeutics CEO, Dr. Jian Zuo

Hi, everybody, and welcome back to another episode of This Week in Hearing. I’m your host, Brian Taylor, and this week we’re going to be discussing otoprotective agents and other applications of drugs used to treat hearing loss. And with me to discuss this topic is Jian Zuo, co huh, founder and CEO of Ting Therapeutics. I understand that we can call you JZ, is that right? Yes. I can guarantee you I have nothing to do with Beyonce’s children. Well, that’s good to know. Thanks and welcome to the broadcast, JZ, we’re glad to have you here. Thank you. I wanted to dive in and start the conversation by having you maybe elaborate a little bit on the origins of Ting Therapeutics what your founding vision is, and sort of what the mission of the company might be. Yeah. Thank you for this opportunity. I’m very happy to tell you a little bit about our company. So I have been long interested in hearing loss therapeutics. As a key opinion leader in this space. I have been trying to make some realistic contribution to the people in society. So after some 25 years of studies of hearing loss mechanisms and so on, I feel I strongly need to make some therapeutics feasible. So about 15 years ago, we started doing some hair cell regeneration studies, and after some long studies, I feel it’s very difficult to achieve this ambitious goal to restore hearing after damage in the mammalian cochlea. Actually I still do not understand the mechanisms. Instead, I believe that the lowest hanging fruit in the inner ear therapeutic space are the acquired induced hearing loss therapeutics, which I believe are actually very feasible to tackle from that angle. About ten years ago, we started to start to screening and characterizing some of the drugs that would prevent and treat the cisplatin-induced hearing loss, noise induced hearing loss, as well as aminoglycoside induced hearing loss. We hope that this kind of approach will be very effective. Simply I think it’s because of the. There is really no FDA approved drugs for this large, unmet medical need, except there recently, there’s a sodium thiosulfate as the drug that has been approved for treatment of pediatric solid tumors with local non metastatic tumors. So, I think it’s feasible, and it’s important. So our goal is to identify drugs that have greater potency and efficacy, that have safer profiles and can be utilized in the various means. Easy, convenient deliveries for this, as well as it’s treated, can be used to treat diverse range of tumors, not just pediatric, but also adult tumors and so on. And also can be applied to healthy individual populations with noise induced hearing loss. As even in an age related hearing loss, there are bigger markets like that. So those are our goals. Our first step is actually to screen drugs with in-vitro methods or with silicon methods, and plus the in-vivo platforms. After screening of a large number of drugs that are out there, we’ve identified a large number of over 150 or so different drugs that have very potent efficacy in terms of protecting against various insults. We actually identify some of the top drugs that have shown more than hundred times or even 1000 times higher potency under identical conditions, in this case cochlear explant, than many of the existing benchmark compounds. This really raised the feasibility, our hope that we could further develop them into effective therapeutics. In the last five years or so, we have been working on characterizing some of those good top compounds. And in this recent publications and the grants award so long, we have been able to demonstrate those drugs actually worked in preclinical models in both zebrafish and mouse models with various induced hearing loss conditions. We believe that this really provides preclinical models, preclinical proven concept for the future clinical studies. This is our hope. This is really the history and our strategy, our vision. In 2018, we first established this company called Ting Therapeutics, which ‘ting’ stands for hearing in Chinese. That’s why we believe that this is a good sort of a team therapeutic or in therapeutic space. So since then, we have characterized a large number of those drugs in preclinical models. We have applied for patents and also we have obtained SBIR grants as well as DoD grants. This really laid the foundation for our company. We recently, actually, a year ago moved our company to San Diego. Of course, San Diego is a hub of a biotech industry with a great potential and a good environment for that. So we’re very happy about this. This is pretty much the sort of a simple history of our company. Well, thank you for that. I appreciate it. You mentioned some grants and some studies phase 2 grants. Maybe we could talk about some of those individually. The first one I’d like to ask you about is the phase 2 NIH grant that you received, and maybe a subset, and maybe talk a little bit about any subsequent study on this, but a drug aimed at preventing antibiotic induced hearing loss. Can you tell us a little bit about the significance of that project? Thank you. Yeah. So this has been a long journey. For the last five years or so, have been conducting a large amount of in-silico and in-vivo screens for medical exercise induced hearing loss, otoprotectants. So we actually first utilized the zebrafish strains to identify the TT003, or pipelactin. This was the drug we discovered in the zebrafish screen. And now we later characterize them in the mouse models. And these results provide, as I said, the proof of concept for our future clinical studies, or in particular in this SBIR phase II grant. We aim to accomplish the subsequent studies for this TT003. For IND enabling standard ind enabling is a step that will that is required before we go on to the clinical trials. So you must get IND FDA approval. We can conduct clinical trials. So this is the sort of a necessary step. And in this particular grant, we propose to do, trying to conduct some experiments to prove that our drugs has a very good efficacy at the different doses in multiple species, including mice and guinea pigs. And furthermore, we would like to determine that the pharmacokinetic properties are perfect for clinical trials in this preclinical models. And finally, we want to prove that it actually does not interfere with the antibiotic bacterial killing ability in-vivo. Those are all important necessary questions for IND approval. Therefore, I think we propose to do that. We are very fortunate that the NIH reviewing panels are very enthusiastic about our results and very supportive about this. The most important, I think the study is that we were the first group to actually identify the in vivo mouse models where the drug can be used to treat the amyinoglycoside induced hearing loss in-vivo in mice. This has been traditionally very difficult task to accomplish. So I think this is why our studies are significant. And building on this grand support, we would be able to not only get those and the enabling results, but also we would be able to further commercialize and discuss and prepare for the clinical trials with physicians who are very keen about treating patients such as cisplatin, such as cystic fibrosis, patients who have been treated with antibiotics for their lung infections and so on. Those are life saving medications. And unfortunately they have they will, many of them will develop aminoglycoside induced hearing loss with permanent hearing loss. This is a significant problem among many of those patients who received aminoglycoside treatment. What you just mentioned was the drug TT003, correct? Correct. Yes. And I believe I read somewhere that there’s two other drugs, TT001 and TT002 which are used for, I believe, noise induced hearing loss. Could you tell us a little bit more about those projects? Yeah. So, actually, they’re both effective in treating the noise induced hearing loss as well as cisplatin induced hearing loss. So those are also a top drugs that we identified during our screens. And we further chose those top drugs to characterize them in vivo in zebrafish, as well as in mice. So those are the, again, the proof of concept experiments and the results that are promising. And that also led us to get two additional SBIR phase 2 grants. Recently we published a paper in Science Advances that also addresses the two EGFR inhibitors that are effective in protecting against noise induced hearing loss. These two EGFR inhibitors, one is fatinib, another one is zorofetinib, are very effective anticancer drugs against EGFR mutation mediated lung cancers and other cancers. Those cancer patients do develop cisplatin induced hearing loss. Many of them. In fact, there are about half a million cancer patients in the United States each year that receive chemotherapy. And more than half of them develop cisplatin or other chemotherapy induced hearing loss. It’s a huge market. Most important is that these individuals must receive the chemotherapy, cisplatin chemotherapy. Therefore, they must have to endure those kinds of treatment and with the risk of developing hearing loss, permanent hearing loss. So these are one hand is a very unfortunate but mathematical need, on the other provides a significant opportunity for us to develop the drugs against this condition, against cisplatin use hearing. Those are the individuals. We can actually treat them and test our drugs and provide them with. With the time window and necessity for necessity for developing, testing. Drugs to be effective or not in the clinical trials. So those are quite important for inner ear therapeutics field because those are necessary conditions that you can actually test your drugs on. Unlike many other conditions that are basically, for example, noise induced hearing is very complex, but also very difficult to test because in most cases in most professions, noise induced hearing loss actually is if untreated, is illegal, or if unprevented, is it illegal in the United States and in modern societies that are really present, that present a very difficult scenario to test all of the other drugs therapies. So I believe that cisplatin and induced hearing loss are probably the lowest hanging fruits for us to test. This is why I believe this is not only bigger mathematical needs, bigger market, but also lowest hanging fruit for us to have significant impact to the society and to individuals. So I hope this will help to reach that goal by further characterizing our TT001, and TT002 drugs Those are the ones that are really important. We hope to further develop collaborations with oncologists who are interested in preventing their cancer patients with the potential cistplatin induced hearing loss. So in aminoglycoside induced hearing loss populations, we hope to work with cystic fibrosis community and the doctors who will have more interest as well as the expertise to collaborate with us to carry out some of the clinical trials in the future. Yeah, that’s excellent information. I think many of our viewers see patients in their clinic on a routine basis that have noise induced hearing loss, given the prevalence of that condition in audiology clinics around the country, around the world for that matter. I was wondering if you could give us your perspective on how one of your otoprotective agents could work, theoretically, maybe hypothetically, in a clinic as far as preventing noise induced hearing loss or minimizing the effects of it. Yeah, so this is a really big challenge. The noise induced hearing loss is very prevalent, as you notice, right. And it’s particularly prevalent in the military settings. For example, our military service members many, many of them have experienced no easy induced hearing loss. So they must have incentive to participate in those studies. The complexity of this noise induced hearing loss is that it is very difficult to control the noise environment. In fact, as I mentioned in my previous statements, that the many situations where the noise induced hearing loss is not prevented, not treated is illegal. So therefore you have to treat the population with noise induced hearing loss ethically. So, for that major problem is very difficult to tackle. So what we hope is in the future, somehow we have collected enough evidence that our otoprotective agents would be useful for cisplatin and aminoglycoside induced hearing loss. So then we will have gathered enough momentum to start tackling some of those problems of noise induced hearing loss. So, for example, it has been widely studied. Many drugs have been tested in the noise induced hearing loss. Clinical trials, there were about 30 or some or so in the United States, registered in the United States. However none of them have succeeded so far, as far as I know. So it’s been very challenging. There are multiple other issues. For example, the complexity of the genetic backgrounds, genetic contributions, predispositions that could contribute to the various responses of noise induced hearing loss. And also the history of the noise exposure would also contribute significantly to the variation in the clinical settings, plus all of the other legal, ethical issues. So it’s been very difficult to test. And more important, I think what we hope is that the better drugs may provide a better chance to prevent such conditions. We actually had started by screening better drugs. We actually compared our drugs with many other benchmark compounds under identical conditions, such as cochlea explants, against platinum induced hair cell loss. In the explant conditions, we found our potency is much better. So our hope is that we don’t have to use some of the low, potent drugs. We should stick to good, potent drugs first. And it is also very difficult to get good drugs to be in the market. It’s almost impossible to get a bad drug to be good in the market. We hope that we should establish a perfect, a good, potent drug first in other conditions, and then we hope to apply in the future to noise induced hearing loss, or even to the age related hearings. Those are the two most difficult market difficult conditions to tackle therapeutically. History, as I mentioned, multiple problems there. It sounds like an incredibly complex challenge, a lot of different components to it. Looking into the horizon what are some of the future plans that you have at Ting Therapeutics? Yeah, as I outlined in the beginning our vision is to really start providing some proof of concept, preclinical drug candidates, and then hope that we can get the IND approval by FDA and apply to the clinical studies. So eventually we will be able to get NDA then FDA approval for commercialization in the future. So that’s our long term plan. And to achieve such a goal, our major focus right now is to focus on cisplatin induced hearing loss, as well as aminoglycoside induced hearing loss. Those are the two trackable and easiest and lowest hanging fruit for us. So I believe our first goal is to accomplish those studies and to get IND approval. And next step will be to collaborate with the clinician with the help of either federal government grants from NIDCD, or from private investors who will sponsor such an expensive, large number of patient trials. So I think those are the most difficult step. And we hope in five or six years, we will have some drugs for both cisplatin induced hearing loss for adult and many other types of tumors without much of the side effects, and safe and potent and efficacious. And hopefully, we should also provide the first drugs that would be in the aminoglycoside induced hearing loss space. And of course, our company is aware of many other companies that also are doing very similar studies with their strong drug candidates. And we are very much on to collaborate with different companies to cover different areas of those unmet medical needs. And we believe all our companies should work together and to work together with the government agency as well as the venture capital, private investor, investing companies to support our effort. I believe, and we also believe that, again, this induced hearing loss is a very important, lowest hanging fruit feasible market to tackle and it will have significant payback. This I think, is a very attractive market you can compare to many other inner ear therapeutic space research area. I believe based on my experience of 25 years of research in the hearing loss space. I think those two are the biggest market with the lowest hanging fruits, and will have biggest payoff. So this is what I think our field should all sort of put more emphasis on this induced hearing loss space. That’s my sort of the message. I want to lay out I kind of have a general question about the broader topic of otoprotective agents. I think I’m asking this on the behalf of a lot of the clinicians that watch this for, you know, getting information from researchers such as yourself. How should clinicians think about otoprotective agents and how might that impact their clinical practice down the road? Yeah. So our goal, obviously, is to co-treat our drug with chemotherapy and aminoglycosides at the same time. So what we hope is that our drug would not only provide therapeutic effects for it, but also we would combine with some other additional methods. We will identify the risk of those people who are, those patients who will develop hearing loss associated with those treatments, such as chemo treatment, as well as aminoglycoside treatment. So we believe we need to have done, we should do two different areas, two different approaches. One is to test the effective drugs, and the second is to probably determine those individuals who are at high risk. So if we can develop genetic testing or some other biomarker testing to identify those individuals at risk and further treat those individuals together with our therapeutics, those are the two areas that clinicians could help us to identify those kinds of individuals and tailor the therapeutic approaches for the benefits of the patients. Those are the two areas, of course, in the noise, as well as the age related hearing loss. Those are much far down the road, much bigger market, and they will have different challenges for clinicians to tackle those kind of bigger diseases. Right. Thats excellent information. I appreciate your time on this. One last question. Where can people get more information about Ting Therapeutics? Yeah, so we have, as you found in our website, is tingtherapeutics.com. and so we have outlined our vision, our current top compounds, top drugs, as well as our recent publications and some of the grant information. So you could contact us if you have some interest in carrying out some of the clinical studies or have some interest in investing into our company for this ambitious approaches. Great. We will if you’re okay with it, we will put your email in the show notes. Sure. As I said, you know, I always said I got 99 problems hearing loss on them Yeah. So hopefully that will be the message. I’ll make that happen for you. Yeah Thanks to Jay Z. Yeah. JZ. Thank you. Co founder, CEO of Ting Therapeutics. Thanks for your time. Really appreciate it. Thank you. Appreciate it.