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spk00: preclinical programs, and expectations regarding operating expenses for 2020, cash runway, and autonomy's ability and resources to support its product pipeline and development activities. Please refer to autonomy's filings with the SEC, which are available from the SEC or on the autonomy website for information concerning the risk factors that could affect the company. I will now turn the call over to Dave Weber, President and CEO of Otonomy.
spk01: Thank you, Robert. Good afternoon, everyone, and thank you for joining us all to discuss Otonomy's business updates as well as financial results for the third quarter of 2020. We continue to execute on our business plan during the third quarter, including achievement of the following milestones. We completed patient enrollment in the Phase III trial of Otividex in Meniere's disease and are on track for announcing results in the first quarter of 2021. We announced positive Phase I-II clinical results for our OTO 313 program in tinnitus and are now moving into full Phase II development. We completed patient enrollment in our OTO 413 Phase I-II trial in hearing loss and expect to announce results by end of year. We also advanced our multiple preclinical programs that extend our efforts across additional hearing loss pathologies and patient populations. And we completed a successful financing that attracted new top-tier biotech investors to the company and significantly extended our cash runway to support continued advancement of our product pipeline. the broadest and most advanced in the neurotology field. In short, we are doing the things we need to do to drive value creation, and I am very excited about the Otividex and OTO413 clinical catalysts we have coming up. During this call, I'll provide a brief update on our programs and highlight the financial results from the quarter. We can then open up the line for any questions. Beginning with the OTIVID-X phase III trial in Meniere's disease, we completed patient enrollment at the beginning of October and expect results in the first quarter of 2021. We enrolled a total of 149 patients from the United States and Europe, exceeding our target of 142 patients. We appreciate the continued effort by investigators in support of our study completion activities as well as by the final randomized patients working through their three-month observation period following treatment. In July, we provided an update on the statistical analysis plan for this trial. In response to questions received from the FDA regarding use of the generalized Poisson model to analyze the daily vertigo count data reported by patients, we submitted a revised statistical analysis plan that uses a statistical test called the Negative Binomial Model for the primary analysis. After an extensive review, we selected the Negative Binomial Model because we believe it provides the best fit of the OTIVIDEX clinical data based on the Phase IIb trial, the successful AVERTS2 trial, and the integrated data set from both trials. Assuming positive results from this additional Phase III trial, we plan to submit a new drug application to the FDA in the third quarter of 2021. Turning to OTO 313 for tinnitus, we announced positive results from a Phase I-II trial in July. The exploratory efficacy cohort of this trial included 31 evaluable patients with persistent tinnitus of at least moderate severity based on the Tinnitus Functional Index, or TFI, a clinically validated instrument Patients also reported the loudness and annoyance of their tinnitus using daily phone diaries and completed the patient global impression of change, or PGIC. Following a two-week lead-in period, subjects were randomized to a single intratympanic injection of Oto313 or placebo in a one-to-one randomization and then followed for eight weeks. This trial achieved its objectives by demonstrating a positive clinical signal for OTO313 using a TFI responder analysis, good correlation with other endpoint metrics, and a favorable safety profile versus placebo. In particular, 43% of OTO313 patients were responders at both day 29 and day 57, compared to only 13% of placebo patients with statistical significance at p-value of less than 0.05. Furthermore, OTO 313 patients who were TFI responders reported improvements in tinnitus loudness and annoyance levels based on the daily diaries, as well as improvement in the PGIC, with a high correlation coefficient between these various measures. Finally, the trial demonstrated that a single intratempanic injection of Oto313 was well-tolerated, and the incidence of ear-related adverse events was lower than in the placebo group. Based on these results, we are advancing Oto313 into full Phase II development and have submitted a Type C meeting request to review aspects of the Phase II clinical plan with the FDA. Our third clinical stage program is OTO413, a sustained exposure formulation of brain-derived neurotrophic factor, or BDNF, that we are developing for the repair of cochlear synaptopathy. Recent research has identified damage to synaptic connections as the underlying pathology in noise and age-related hearing loss that manifests as speech and noise hearing deficits. Neurotrophic factors, including BDNF, have potential therapeutic effects in the cochlea by promoting the survival of spiral ganglion neurons, increasing neurite outgrowth, and reconnecting neurons with cochlear hair cells after damage. During the third quarter, we completed enrollment in a Phase I-II ascending dose safety and exploratory efficacy study of OTO413 and that enrolled 39 patients with speech and noise hearing deficit, including 15 patients in the high-dose cohort. Each dose cohort was randomized three to one for a single intratempanic injection of OTO413 or placebo, and then followed for three months. As this is the first clinical evaluation of BDNF delivered to the ear, the primary objective is the assessment of safety and tolerability with multiple assessments of hearing function conducted at baseline and during follow-up to evaluate signs of clinical activity. We expect to announce top line results by end of this year for this trial. A brief update now about our three preclinical programs that are focused on different hearing loss pathologies and patient populations. The first of these is our gene therapy collaboration with AGTC that targets GJB2, the most common cause of congenital hearing loss. Patients born with this mutation can have severe to profound deafness in both ears that is identified in screening tests now performed routinely in newborns. We presented preclinical results at conferences earlier this year demonstrating that a gene of interest can be expressed in support cells of the cochlea which are the relevant target cells for treating GJB2 deficiency using novel and proprietary AAV capsids. Also, consistent gene expression was observed for at least 12 weeks following a single local administration. These results supported selection of the product candidate for further development. We are very excited about this program and will provide additional information about the timeline in the coming months. We also presented data earlier this year related to our OTO 510 program targeting otoprotection for patients at risk for cisplatin-induced hearing loss, or CIHL. Cisplatin is a potent chemotherapeutic agent that is widely used to treat a variety of cancers in adults and children. Unfortunately, it is also commonly associated with severe adverse effects, including chronic Cisplatin-induced hearing loss that is progressive, bilateral, and irreversible. We have identified a novel class of agents that potently bind to cisplatin and provide greater otoprotection in preclinical models than known antioxidant and anti-apoptotic molecules and increased potency relative to other cisplatin-binding molecules currently in clinical development. These results highlight the therapeutic potential of our locally delivered OTO 510 product candidate to provide superior OTO protection without tumor protection. Our third preclinical program, OTO 6XX, targets hair cell regeneration as an approach to treating patients with severe hearing loss. It is well established that damage to cochlear hair cells through aging, excessive noise, or exposure to ototoxic chemical leads to hearing loss, and that these cells do not regenerate naturally. However, we believe it is possible to regenerate new functional hair cells with drug treatment. In July, we entered an exclusive license agreement with Kirin Pharmaceutical Company, providing us with worldwide rights to develop and commercialize a novel Kirin compound for the treatment of sensory neural hearing loss. This is a very interesting program, which is complementary to our OTO 413 program targeting cochlear synaptopathy. One final program update related to our co-promotion partnership with Alcabello that supports the sales and marketing of Otiprio. We initiated this collaboration in June, focused on acute otitis externa, and recently expanded the effort to include use of Otiprio during ear tube surgery. we will continue to record all product revenues and pay Alcabelo a share of proceeds from sales. During the multi-year deal, Autonomy will also receive co-promotion fees and reimbursement for proportion of product support costs. Now, switching gears, let me now provide a brief summary of the financial results for the third quarter, and please refer to our earnings release in 10-Q for the details. The key takeaways are that we are on track with our spending guidance for the year, which is for non-GAAP expenses of $35 to $38 million and GAAP expenses of $45 to $48 million. Importantly, we finished the quarter with $94.5 million in cash, cash equivalents, and short-term investments, thanks to our continued careful spending and the financing we completed in July that raised gross proceeds of approximately $69 million. This cash balance will fund the company for at least two years and enable us to achieve important milestones for our programs. In closing, we are continuing to execute on our business plan that is focused on the advancement of the broadest pipeline in neurotology. We have clinical stage programs targeting the largest patient populations and market opportunities in the field, including hearing loss, tinnitus, and balance disorders. We look forward to the completion of our Otividex Phase III trial in Meniere's disease next quarter and are ready to move to an NDA filing in the third quarter of 2021 following a successful result. In tinnitus, we are building off the positive Phase I-II results for OTO 313 and advancing the program into full Phase II development. And in hearing loss, we are finishing a Phase I-II trial for OTO 413 the first of our several programs to address multiple hearing loss pathologies and patient populations. I am very excited about the transformational opportunity our clinical catalysts provide for the company over the next few months and look forward to keeping you updated on our progress. Operator, we are now ready for questions.
spk05: Thank you, sir. Ladies and gentlemen, if you have a question at this time, please press the star and then the number one key on your touchstone telephone. If your question has been answered or you wish to remove yourself from the queue, press the pound key. We have a question from the line of Tara Bancroft from Piper Sandler. Your line is open.
spk06: Hi, guys. Thanks for taking the question. So for the OTO 413 data that's coming this quarter, can we talk about what we can expect to see both for the global impression range and the electrophysiology measurements and what KOLs believe are meaningful changes for these patients?
spk01: Hi, Tara. Yes. Thanks for the question. For the 413 data, there is numerous auditory measures that are being done for safety since it is first and foremost a safety study. In addition, we will be looking at those to determine if there are any measures with regards to changes in hearing loss. But given that these patients would typically be expected to have almost normal hearing in terms of standard audiometric tests, like, for example, the pure tone average, what we're really focused on to look for signs of activity are the speech and noise hearing deficit tests. So these are the ones that are word recognition or number recognition tests. in the background of sound because that's the real pathology for these patients is the inability to hear in the background of noise. So we believe these word-in-noise tests are really going to be the primary focus for looking for signals of activity as composed to the more safety-related audiometric measures.
spk06: Thank you so much.
spk01: You also asked about the patient global impression of change. Sorry. The PGIC is obviously one that also just gives from the patient perspective, do they observe and feel that they have made changes in basically the impression of their hearing ability? And there what we really look for is exactly like what we saw with 313, where there was a very high consistency between the patient global impression of change and and actual improvements as measured by, in that case for tinnitus, the tinnitus functional index, obviously we'd be looking here more again to the word and recognition tests, word and noise recognition tests connected with those PGIC outcomes.
spk06: Perfect. Thank you so much.
spk05: Thank you. We do have another question from the line of Georgie Yardanoff from Cohen & Company. Your line is open. Please ask your question.
spk02: Hey, guys. Thank you so much for taking my question, and congratulations on all the progress. So, just a couple from us. So, first, Natividex, with the enrollment in the trial exceeding your initial target of 142 patients, could you remind us of your powering assumptions, and where would this get you in terms of statistical power? Do you have any early sense of patient compliance and dropout rates? And then I'll have one more follow-up.
spk01: Yeah, thank you, Georgie. Thank you for participating here. Yeah, for the Tibidex trial, 142 was our target, and that 142 was based on a powering of well over 90%. So with the 149, we obviously feel very good about our powering. You know, we would expect to have a few dropouts. It's just natural in the course of these types of studies with longer follow-up. But that said, this is well within, you know, even the 142 incorporated our assumptions with regards to any patient drop-off, which, again, is usually low in these studies. We've always seen very high compliance and high participation with minimal drop-out. So the 149 really gives us a very strong number as it's well above the 142. The other part in terms of powering, so that basically would tell us that we're well into the 90% plus power range. In terms of compliance, I'm very happy and very delighted with the efforts of the patients, the investigators, and our staff and CRO with regard to patient compliance throughout not only the trial, but obviously more recently this year, the COVID pandemic. And compliance has remained extremely high, again, very consistent with what we've seen in prior studies with Meniere's. These patients are highly motivated, given the lack of any therapy, and therefore are highly compliant. And that's exactly what we've continued to see, even despite COVID.
spk02: Thank you. And on 313, I was just wondering, have you received a response regarding the timing of the type – of the Type C meeting for the Phase 2 trial from the FDA. Do you have any idea for the initiation of the Phase 2 program? And I guess just if you could talk about the option to pursue a higher dose or slightly change the clinical trial enrollment criteria, if you could just talk about your, I guess, decision-making process in this and what would you be expecting from the FDA?
spk01: Yeah, thank you there. So once we submitted the Type C meeting request, the FDA has 75 days in which to respond for that meeting request. So we do have a date that will be coming up, but we have not reached that yet. So we have not heard a response from them. The primary purpose of that Type C meeting request was with the question of dose. As you know, The 313 results that we observed, we saw very strong safety for Oto313. In fact, there were fewer AEs, including specifically ear-related adverse events, with the treatment group relative to the placebo. And as a result of that, plus coupled with the strong clinical efficacy signals that we saw both in the TFI and the loudness and annoyance and patient global impression of change measures, it really made sense to us to try a higher dose given that good safety profile. So that's the primary question that we've asked for the agency to respond to. We think it still meets our levels that we observed in the preclinical animals, so we're still well within a good safety margin there, and we do expect to have a favorable outcome in response to the option to go to a higher dose. Now, I will say, Georgie, that importantly, we will continue to look at the current dose as well. The current dose is clearly showing very good activity. And so as we look at our clinical trial design for Phase 2, we will definitely include the current dose. It will just be a matter of adding an additional dose at a higher level. With regards to initiation and more details in terms of the inclusion-exclusion criteria, We're going to be talking about that more in the coming months. We are trying, as soon as we hear from the agency, that we are working very quickly to be ready to initiate a trial in the early part of 2021. And as part of that, we're currently going through a very rigorous analysis, both with our statisticians as well as with KOLs, to talk about potential changes to our inclusion-exclusion criteria, basically refinements based on the data that we have. I think there will be a number that we will be looking at, such things, for example, as the level of disease entering into the study, what level of TFI would we require, as well as the duration of the tinnitus is something that we want to look at, and expanding out the duration from within six months of onset, probably to nine months, possibly up to one year. So we'll be looking at those things and talking about them more in the months to come here shortly.
spk02: This is great. Thank you so much.
spk01: Thank you, Georgie.
spk05: Thank you. Our next question is from the line of Oren Levinat from HC Wainwright. Your line is open. Please ask your question.
spk04: Thanks. I have a couple of questions. Just quickly, regarding the 413 program, I'm sorry if you already mentioned it. Can you just remind us, is it just primarily the higher dose in 15 patients that you're focused on for the upcoming efficacy readouts? And just do you have any more color on the efficacy endpoints you're using in terms of what sort of variability one would tend to even see across these? You know, how robust a result do you think you'll get out of this small sample? And do you think the FDA has a view already in this field as to what the right sort of tests are in this area? And I have a follow-up. Thanks.
spk01: Okay. Thanks, Oren. Yeah, we can take this and then tackle your next question. So with regard to the 413 program, again, Really, we're looking at all the cohorts. Clearly, we started off very low for safety reasons. We started off at a very low exposure. But we will be looking and contrasting all the different cohorts to look for the activity, given that it is a dose ranging both for safety, but we are going to higher doses. So I think we would expect potentially to see some changes as we go through the dose levels. With regards to the variability, that's exactly one of the things that we are looking at. I mean, to be fair, and I think this is where it's different than the TENATIS 313 program where we had a very established clinically validated clinical instrument with the TFI that was clearly our primary. Here, this is really the first kind of study of its kind using these word recognition measures which we have multiples in order to answer those very questions, which kind of variability would we expect to see in clinical trials and what kind of changes could we detect. So the important part about this trial, it will also allow us to not only understand the variability of the measures but also be able to compare them and understand how they relate to one another. So I think these will be very important as we continue to move on, not only for this program but for hearing loss programs in general because word recognition is another important measure of hearing function. With regard to the FDA, I don't think the FDA at this point is really familiar with these different measures. Again, this is the first study of its kind. And there's other work going on in the field as well that's very early stage. And so the FDA has not, to our knowledge, really seen this kind of data. And that is one of the things of why we're doing the work we're doing, that we can also share with them our learnings and show the data that support what we're viewing as being important measures to understand both cochlear synaptopathy as well as overall hearing loss changes.
spk04: Okay. And I guess you kind of segued into my next question. I'm sure you don't want to comment too much about anyone else's programs. But you did mention there is some other work going on out there, and it's not lost to me that there's another public company with an $800 million market cap in an early stage, maybe phase 2A hearing loss program, with a mechanism not totally unlike one of yours. And I'm just wondering, that's Frequency Therapeutics, and I'm just wondering if you can comment just to what extent, in your knowledge, is there anything different that you're doing? Is there any difference in the endpoints or thresholds that you've studied to date and are looking at going forward that you think will differentiate your program and based on what the data you've seen to date from theirs?
spk01: Yeah, I mean, I think from what I know, obviously, of their program publicly, I mean, I think one of the things that we can say is we have an extensive amount of testing going on here, both for classic audiometric type tests as well as word and noise hearing tests. We have multiple, as I've talked about, multiple word and noise study testing that we're doing here which I think others are more focused on a very narrow set. So I think that will obviously be a very important learning that we will have, understanding how these different measures compare. I think one of the things that's important to remember is our drug delivery technology, which we've now shown not only with Otividex, previously with Otiprio, but now even with Oto313, a single administration that's improving tinnitus in those patients. 43% of patients at the high dose for eight weeks. That delivery technology, the ability to deliver high concentrations of a drug for an extended period, the hallmark of that, why that is so important to us, is the ability to drive efficacy, that you're getting enough drug in. And I think this is one of the things you're seeing about our program that compares differently to other companies in the field. And I mean multiple companies that have been working in the otology space. The need to retreat and undergo multiple retreatments as opposed to our practice of doing a single tympanic injection to cover a broad patch of time is inherent to our technology and strong IP position around drug delivery to the ear. And that really, we believe, drives efficacy. So while it's very convenient for the physician and for the patient and will aid in the commercialization of a product, importantly, we think it's an important determinant of efficacy. And so I think that's probably the most important. And then I think the final comparison, obviously, of us to others in the field is our broad pipeline. We have a program addressing every aspect that is currently in work amongst any other company in hearing loss. But in addition to hearing loss, we have tinnitus and Meniere's as well. The extensive both clinical and preclinical program obviously sets us apart from others. All right. Thanks. I appreciate the call. Thank you, Oren. Thank you, Oren.
spk05: Thank you, sir. Again, everyone, if you would like to ask a question, you will need to press star 1, then the number 1 on your touchtone telephone. We do have another question from the line of Francois Bryce from Oppenheimer. Your line is open. Please ask your question.
spk03: Hi, thanks for taking the question. Just quickly here, in terms of the type C meeting, you talked about upping the dose, talked about maybe the duration, the patients that may be up to nine months that have had tinnitus. But I was wondering, anything in terms of repeat dose? And also, in terms of the endpoint on the TFI, which seems to be very clear, the 13-point is a responder, is the FDA okay with, do you expect them to be okay in terms of primary endpoint with responders only, or is this all patients put together that they might want to see?
spk01: Yeah, thanks, Francois. With regard to the type C, in addition to the upper dose and the duration, we did consider, you know, really our approach on repeat dosing is more from a safety aspect of if patients need to be retreated. I think that is still something we're trying to understand in this condition with tinnitus because if you look at the patients who improved, those 43% of patients, they were still improving at the end of this eight-week study. So one of the things that we will be looking at in our Phase II program is extending the observation period out. We'll keep the eight weeks as primary, but we are planning to extend out for a longer period of time to look to understand whether those patients continue to improve. Some of them have actually improved to the point that they are now very mild tinnitus. And so... The question is, do they even need another administration? And so that's something that may vary by patient and where they start off in tinnitus, and that's something we'll be able to look at in our Phase II, as we will ultimately show with the design of the trial and these additional observation periods. So I think the question really with repeat, it's really how we've tried to handle it in Meniere's disease, which is a chronic condition where patients – wax and wane in terms of their vertigo episodes is to look at repeat dosing more from a safety aspect than a therapeutic need. And so that is possible, what we'll be looking at here with tinnitus. But again, I think what we need to do is look at the longer observation period, see how these patients do, and whether there is any need to do any long duration of treatment But I can't tell that yet based on the great results we had from the Phase 1-2 trial here where every one of those patients was better at the end of the study and was their best outcome. So clearly it's suggesting that at least in those patients that they are continuing to improve over the full duration. In regard to the TFI and the 13-point responder, We have had discussions. It's one of the reasons we chose the TFI is preliminary discussions with the agency, both in the pre-IND for 313, but also in connection with our MNIRS program because tinnitus is a symptom of MNIRS. And as a result of that, we feel good about the TFI. Clearly, again, this is really some of the most data the FDA will have seen as they look at our TFI data. And so it is something that as we're conducting our phase two trial, part of what we're doing is collecting data that I think we can even see in our phase one, two trial that support the TFI as an outcome. And that is really looking at those correlations to other endpoints like loudness and annoyance, as well as the patient global impression of change. And I think that's what really for me is very important is that correlation really helps establish the TFI as a very practical and effective measure of not only the hearing function for these patients, but their overall quality of life changes and impression of change. And so I think that's a very important piece that will be very helpful with us as we ultimately talk to the FDA in the end of Phase II meetings.
spk03: I just, in terms of responders, because that 43% versus 13% that you saw with the p-value lower than 0.05 was for just the responders, but I'm wondering, any discussions, is that a primary endpoint, just responders, that you think you can go forward with in the next trials, or are they going to be looking at all patients?
spk01: We've not had those discussions since this is not a registration trial at this point, and we've not had the interface to media. We haven't had a full discussion about statistical analysis plans and what would be the ultimate primary endpoint. I will say that as our statisticians and KOLs and regulatory people look at potential endpoints, this is one that we think could be a potential endpoint based on looking at other programs in other areas. that have been approved based on a responder-type analysis. So that is something that we will look at. I think importantly, as you know from the data we've more recently shown from that study, is we were actually seeing overall changes in the population as well. So at the eight-week time, patients, the overall population treated with OTO313 was almost, almost achieved that 13-point change. even on that small subset, a small set of patients. So I think from the standpoint of is it very possible for us to do a full patient analysis, yes. From what I've seen of this data, we could definitely size for that, but I think the responder analysis is very powerful here, and it is something that we would end up talking with the FDA.
spk03: Great. Thank you for clarifying that, and I think, yeah, that was, the two new slides in the deck are very helpful to get a feel for that. And it is trending the same way. And then just lastly, there's so much data in that 313 that I'm sure you're going through. And I think the daily diaries is extremely interesting to see every day because it does seem like it's working more and more as time goes on. But for the data we've talked about in the past, conferences aren't quite at the level in neurotology as they might be in ophthalmology. Is there any thoughts about getting all this data and to what extent would you show details of this potentially at a conference upcoming, or is that still just a lot of work to be done before that?
spk01: No, we have plans to present. We have submitted for potential presentation upcoming meetings. Unfortunately, as you know, many of those are virtual at this time, and some of them have even been planned and then subsequently canceled. But we do have plans to present this data in upcoming meetings, and hopefully we'll be doing that in the early part of next year.
spk03: Excellent. That's it for me. Thank you, and congrats on the progress.
spk01: Thank you, Francois.
spk05: Thank you, sir. There are no further questions at this time. I will now turn back the call to Mr. Dave Weber, President and CEO of Autonomy, sir.
spk01: Thank you, everyone, for participating in our call today. We will be attending the Piper Sandler and the Evercore ISI virtual healthcare conferences in December and hope to speak with many of you then. Have a good evening, everyone. Thank you.
spk05: Ladies and gentlemen, this concludes today's conference call. You may now disconnect. Thank you for participating. you Thank you. Thank you. Thank you. music music you
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