Regenerative Cell Therapy for Hearing Loss: Rincell-1 from Rinri Therapeutics

Brian Taylor: Hello, and welcome to another episode of This Week in Hearing. I’m your host, Brian Taylor, and our topic today is regenerative cell therapies for sensorineural hearing loss. And with me to discuss this topic, I’m pleased to have Simon Chandler, who’s the chief executive officer of Rinri Therapeutics. Simon, welcome to This Week in Hearing. so pleased to have you.

Simon Chandler: Thank you very much for the invite. It’s a pleasure to talk to you.

Brian Taylor: Well, before we kind of get into the topic at hand of regenerative cell therapy, I thought we could have you share a little bit about your background and a little bit about the company, RinrRi Therapeutics.

Simon Chandler: Yes So Rinri as it was originally a spin out from the University of Sheffield, and we formed back in, in 2019 off the back of some of the amazing work that had been done in the lab of Professor Marcelo Rivolta, who’s a professor of sensory stem cell biology at, at the university. So Rinri’s really been based on, on decades of, of his work in auditory neuroscience and stem cell biology, and particularly it crystallized from his 2012 Nature paper showing the preclinical efficacy potential of, of a cell therapy approach for, for hearing loss. My kind of entry into this is from a completely different route, from a non-scientific route. I was working in venture capital and evaluating new technologies from universities around the UK and, and further afield. And this was one of the technologies that I saw and thought was exceptional had potential to be translated and, and ultimately commercialized to, to derive kind of benefit for, for patients. So that was my immediate entry into that. But I do have a scientific background. I come from following my PhD in, in molecular and, and cell biology, worked in the biotech industry, particularly in instrumentation and the CRO business in, in biotech. But that was my kind of entry into this. But you also might be quite interested to know about where we came up with the name RinrRi Therapeutics. This the word RinrRi is a a, a Quechua word. So Quechua is a indigenous language of South America particularly in, in the high Andes. And Marcelo is originally from Argentina and RinrRi means to hear or, or or hearing in, in that, in that language. So it had a connection back to Marcelo’s kind of roots in Argentina, and obviously was a, a unique word that not, not used in, in other kind of companies in, in this space. So kind of a nice resonance there.

Brian Taylor: Yeah. Well, that’s an interesting backstory. Thanks for sharing that. I wanted to jump into our topic at hand here, which is your first product that’s about to enter clinical trials Rinzel1Rincell-1. Could you maybe describe it a little bit and talk about how it’s intended to work?

Simon Chandler: Absolutely. So our hypothesis at RinrRi Therapeutics is that sensorineural hearing loss is ultimately a, a cellular problem. So it derives from the death or the damage to the, the sensory cells within the cochlea. So either the auditory hair cells or the auditory neurons. And therefore, the, I suppose the most elegant, the most simple way in which one could restore hearing in patients with sensorineural hearing loss is to replace those cells with functional cells and therefore restore or regenerate the cochlea and therefore elicit hearing or improved hearing in these patients. So the core concept is to, you know, our cell therapy is to transplant functional cells back into the cochlea, and therefore restore the cytoarchitecture that should, should be there. Our cell therapy specifically are progenitors of the sensory cells that should, should be there in, in the cochlea. So the progenitors, the precursors of the say sensory auditory hair cells or auditory neurons. And we are focusing initially on on auditory neuropathy. So we are, we are generating human otic neural progenitors from pluripotent stem cells, and it is these progenitors of the auditory neurons which we are transplanting into the cochlea. And once they’re in the cochlea, they’re able to engraft into the cochlea and mature into functional auditory neurons, and they are able to reconnect to the hair cells and also back to the brainstem and, and restore the, the circuitry that should be there. And therefore because that those neurons are replaced, you restore the capability of hearing. And that’s, that’s the central concept of, of what we’re, of what we’re doing.

Brian Taylor: Well, that’s… We’ll, we’ll maybe into a little more detail in a second, but I wanted to ask you, how do you envision Rinzel Rincell-1 fitting into the existing treatment paradigms that are out there? Do you, do you see it as a standalone solution or as a complementary therapy?

Simon Chandler: So I think I think first of all, if we look at the current standard of care, we have your, the hearing loss space is really dominated by devices, medical devices. So you have hearing aids for those with more mild to moderate hearing loss, and you have cochlear implants for those with, you know, severe to profound hearing loss. I think it’s important to understand that both these devices really serve to overcome problems with the auditory hair cells by, you know, either optimizing the sound going into the ear in, in relation to hearing aids or bypassing the damage completely and, and directly stimulating the auditory neurons in the case of cochlear implants. So they’re, not really, uh…focusing or, or, tackling the, the entire problem in sensorineural hearing loss and, and looking at the auditory neurons, which is where we are we are focusing with, with RINSE1Rincell-1, our, our lead product. And I think that is one differentiator to our approach. We, we really truly believe that auditory neuropathy or, or loss of auditory neurons is a key component of, of loss of hearing in, in, in people with sensorineural hearing loss, and something that we definitely needs to be addressed to, to be able to restore natural hearing. To your original question where do we see ourselves fitting? I think there’s two places where we can fit in the current paradigm of, of, of treatment of hearing loss. So for cochlear implantation we believe that we can work as an adjunct, so alongside cochlear implants, and actually improve the performance of cochlear implants by restoring the auditory neurons of patients. We know now from number of studies that come out in the last few years, that patients with, let’s say age-related hearing loss, presbycusis, all have a, a a large degree of auditory neuropathy, and we know that the cochlear implants are, are therefore not treating this. And the performance of these cochlear implants is being limited by, by the lack of innervation of the cochlear. So we can help restore that neuralization, that innervation of the cochlea and help improve the hearing of, of age-related hearing loss patients. So a secondary use of, of our therapy will be to be able to address those with more pure auditory neuropathy, so what we call auditory neuropathy spectrum disorder patients. And these patients have relatively well-functioning hair cells but really poor innervation of their cochlear. So they often are missed by current diagnostic pathways which rely on, on PTAs and do not really uncover significant auditory neuron loss. And these patients are given standard care, but they often still have real, significant problems in hearing speech in, in, in kind of complex noisy backgrounds, and that’s, we, we would argue, due to the the lack of innervation of the cochlear of these patients. So for these patients, they don’t really benefit from cochlear implants or, or hearing aids if they have kind of mild, milder issues. So we could use Rincell-INSE1 as a monotherapy in in these patients and, and just restore the neural components and therefore restore hearing in these patients. And that’s really where we see the, the kind of two-pronged benefit of our, of our therapy in the current paradigm. So.

Brian Taylor: I see. Well, the way I understand it Rinne’s Rinri’s approach is a novel procedure for cell delivery through the inner ear’s round window which I would guess is a less invasive approach. Could you maybe elaborate on the benefits and challenges with this delivery approach, and maybe compare it to alternative approaches that are out there?

Simon Chandler: Yeah. I mean, one of the reasons that we’ve adopted this approach for delivery, as you say, we are, we are going through the round window. We’re, we’re doing a surgical technique which is very analogous, very similar to that of a cochlear implant surgeon would use. But we are needing to go in this direction to access the internal auditory meatus, so the, the space at the base of the, of the cochlea where the the spiral ganglion neuron comes into the cochlea to, to innervate it. And I suppose the advantages of this technique is we can access this route readily using almost all of the cochlear implant procedure, and, and basing our procedure on this gives us kind of high degree of safety and, and, and confidence in the, in the procedure to be able to deliver to this space, which is important to, for the efficacy of our, of our therapy. And I think by adopting this route we have something which is potentially much safer than going by other kind of more destructive routes, and we can preserve more residual hearing, and it’s clearly more familiar to surgeons that, … are, performing cochlear implant procedures kind of day in, day out. So it’s a, it’s a much more familiar environment for them. I think in terms of challenges delivery of cells is always a, a challenge. There are … We, we are obviously cutting edge in terms of being the first regenerative or any any kind of cell therapy for, for the ear. So there are few delivery devices kind of developed for this application. So in terms of the precision of, of cell placement, we’ve done a lot of work to ensure that when we do deliver, we’re delivering to the correct space and the, the cells are kind of retained in that space and cannot escape from that space. And then I suppose the other challenges are to ensure that following delivery this surgical technique allows us to ensure cell survival, the integration, and ultimately the function of these cells once they’ve kind of integrated with, the cochlea.

Brian Taylor: Lets move to talk your themore about RINN Cell OneRincell-1. It’s the first in-human clinical trial that Rinne Rinri is about to embark on as far as I can … as I understand it. It’s expected to begin in the next couple of months. Could you talk a little bit about the specific the specifics of it? What patient populations are you studying? Maybe a little bit about the design what you’re hoping to gather from this clinical trial?

Simon Chandler: Yes. So absolutely correct. This is a first in human first-in-class cell self therapy clinical trial for this therapy, RINN Cell OneRincell-1. We are looking to obviously derive safety and establish safety of, of the of the cells in patients. But also demonstrate early signs of efficacy. So we’re doing a phase I-IIA IIa combined trial, which so we Eenables, enables us to look at both of these aspects. In terms of who we want to recruit into this study, we are looking at both patients with age-related hearing loss, so presbycusis, and those with auditory neuropathy spectrum disorders, so we want to be able to try and capture both those populations. Back to my previous comment about the use of it as an adjunct but also as a monotherapy we want to be able to explore both of those populations. And what we are going to be doing is delivering ourselves our cells alongside a cochlear implant as an adjunct for both of these patient populations in the first instance. And the reason we want to do that is that we are going to leverage cochlear implant as a, as a analytical tool, as a measurement tool for this first in-human trial, to enable us to gather objective measures of cochlear health on these patients. So we don’t have to rely solely on audiological real-world measures for demonstrating the efficacy of our, of our therapy. And this will enable us to gather things like neural response indicators, particularly things like eCAPS, so electrically evoked compound action potentials from from these patients, enable us to really power this study to be able to show early signs of efficacy as, as rapidly as possible. We will be also looking at look real-world benefits in our kind of secondary and tertiary outcomes as well. So looking for improved speech perception, and particularly speech in noise particularly in the AANSD populations, and, and looking at things like hearing thresholds, as well as other patient-reported outcomes and quality of life kind of measures as well. I suppose clearly what we want to show is safety as primary outcome that we, we’re looking at, and that obviously we’re monitoring for any adverse events. And, and we don’t really expect to see any. We have a, a a, a very thorough kind of pre-clinical safety background in, in, in models of, of these conditions, which really do not indicate any kind of safety concerns. But we are obviously going to be monitoring that in the, in the first in-human clinical trial. But really what this structure of this study enables us to do is look for kind of significant improvement of eCAP measurements in, in patients to indicate that the neural populations are being restored. And then hopefully in, in certain particularly AANSD patient population, we may be able to see some early signs of real-world improvement as well. So we’re kind of leveraging ourselves to, to be able to demonstrate these two elements to take us into later stage trials.

Brian Taylor: Can you tell us a little bit about how long you think the study might take, and when the results might become available?

Simon Chandler: Yeah, very good question. So we are looking to once we dose patients, follow them up for 13 months. The the way in which the study is designed is going to be an open-label study. So we are going to be able to monitor the the outcome measures that we were interested in, particularly the, the eCAP measurements from almost kind of from day one. So we’re gonna be able to pick up early signs of efficacy once, once they once they appear. And one of the, I suppose, the biggest unknowns we’ve got at the moment is this translation from pre-clinical models to humans. We know it takes about four to five weeks to show significant improvements in our pre-clinical models in the, in the Waibene-Gerbelouabain gerbil model. But we obviously don’t know about the difference to to, to in human patients. So the 13 months allows us to identify if it happens quicker, but also gives us time to, for, for longer acting kind of efficacy to be detected as well. But the trial is looking at recruiting 20 patients from in total 10 patients from each group where we’re gonna be dosing six patients and having four as controls. And we think the whole study itself with the staggering that we have to do for safety purposes will take about two years in total to to, to to complete. However, because it’s open label and we’re gonna be monitoring patients in almost real time if we see early signs of efficacy, we can kind of accelerate the study as well and, and reduce the time and move on to later stage clinical trials if it’s, yeah, if it’s significantly positive.

Brian Taylor: Well, we, we hope to have you on in a, in a couple of years, and you can talk more about those results.

Simon Chandler: That’d be great. Yeah.

Brian Taylor: So in addition to the clinical trials involving RINcell OneRincell-1, are there any other future therapies on the on your roadmap that you can talk about?

Simon Chandler: Yes. I think that, yes, RINcell OneRincell-1 is our lead product for auditory neuropathy, as, as I’ve, as we’ve explained. This product is an allogenic cell therapy and therefore requires short-term immune suppression of the patients bef- whilst the initial kind of immune response kind of dampens down after administration. We have a pipeline project called RINcell TwoRincell-2 which is looking at developing hypoimmune versions of this, of this product which would not require any immune suppression, even, even short-term after delivery. And then, I suppose, our core technology also enables us to generate the precursors of, the auditory hair cells otic epithelial progenitors, and we are also in the early stages of pre-clinical development of OEPs, so human otic epithelial progenitor cells, which could be have the potential to replace the auditory hair cells. And obviously that’s the other side of the sensorineural hearing loss problem. So I suppose our vision is that, you know, ultimately we could have a, a, a solution for all of sensorineural hearing loss in the future, and that’s where we’re working towards. But clearly at the moment, we’re focused on RINcell OneRincell-1 and, and demonstrating kind of clinical proof of concept of that first before we move on to, onto the secondary product lines.

Brian Taylor: Excellent. My guest this week is Simon Chandler, who’s the chief executive officer at RINRI Rinri Therapeutics. As we conclude Simon, and I wanna thank you for your time, any final thoughts around regenerative cell therapies that you wanna share with our audience today?

Simon Chandler: Absolutely. I think, I mean, hearing loss has no, you know, disease-modifying therapeutics at the moment, and I think that the recent positive data coming from the gene therapy trials is, is incredibly exciting. But these therapies will never treat the bigger problems in, in, in hearing loss in the bigger populations. They are very specific and, and have relatively limited patient populations. So regenerative approaches are going to be needed to tackle the, the, the bigger problems in hearing loss in the bigger populations. And really regenerative medicines like we are developing at, at RINRI Rinri Therapeutics could really shift the way in which hearing loss is, is treated from the compensation kind of approach, the, the dealing with the symptoms of hearing loss, to, to the restoration of, of hearing, and, and really be transformative to the way in which kind of patients are treated and their outcomes in, in future years. And I think that’s the really exciting bit about the potential of, of cell therapies for, for hearing loss.

Brian Taylor: And if people wanna learn more about what your company is doing do you have a website you could share?

Simon Chandler: Absolutely. If you’d like to learn more, we have quite a a good website with all the detail about what we’re doing, our technology, our clinical trials both for clinicians but also for patients as well. We’re very keen on engaging with, with patients on you know with lived experience of hearing loss, and just go to www.rinri-therapeutics.com and you can see all the information there.

Brian Taylor: Excellent. Simon thanks again for your time. Really appreciate it.

Simon Chandler: Thank you very much, Brian.