GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - SCYNEXIS INC

I'm Vamil Devan, one of the biopharma analysts here at Guggenheim. Pleased to join us now. Next in this room, we have the team from Synexis, David Angulo up here, the CEO of the company. We do have a few slides we're going to kind of show throughout the course of the discussion. But, David, maybe I'll just have you start by just for people less familiar with Synexus and the story, a little bit of an overview. It's been a sort of transformative year for you. So where do things stand now? And then we'll look forward from there. Thank you. Thank you for the invitation. BAMIL in CS, certainly to tell you a little bit about the company, the ones that you're not familiar with. So we're focusing really advancing innovative solutions for rare diseases spaces. And what you, BAMil, mentioned about really the developments over the past year, what we did is that in the past, we were focusing development of antifungal products for many years. We have our own platform of antufungal drugs that we were developing in basic fungal disease infections, and we recently acquired an asset that we are developing in the ADPKD space. Primary reason for really expanding our indications into the ADpKD space was obviously this is an area still in the rare disease space that we were quite interested on, has an area of significant attractive market, a lot of development opportunities. It's an area that is substantially underserved by current therapeutic options, and obviously it was a way to really provide a potential shareholder value creation opportunity within the space. So at this point, really, we have evolved the company. Right now, we're having two programs, one in ADPKD and one in invasive fungal disease infections. And we have already developed a product in the past that we partnered with GSK, which is called BrexFM. At this point it's fully out-licensed to them, for which we are eligible to receive some sales milestones about it. Okay, great. So maybe we can talk more about 770 and the potential there in ADPKD. And just maybe you can give a little more background on the product itself, this mechanism, and why you think this has your potential in ADpKD? Yeah, thank you. And yes, we selected this particular product for acquisition, really, because we were very much attracted by the mechanism of action in this particular disease. I don't know if you are familiar, but in the ADPKD space, there is only one therapeutic alternative right now that it is, I would say, that not very much used because the fact that it has a very significant safety connotations and lack of tolerability, beside of that, is a very substantial market opportunity. And this particular product that we license in has a novel mechanism of action that is very well validated by a scientific community to have the opportunity to really deliver a clinically meaningful effect in ADPKD patients. It's a product that has already been administered in around 300 individuals in different stages of clinical trials. It's ready for real initiation of phase two that we're planning to initiate by the end of this year and really has a very clear path of, or really a really clear path for regulatory approval. It has a good IP protection. So those were kind of elements that really drove too much into our decision to really bring this product into the company. And more specifically, addressing your question regarding the mechanism of action. ADPKD is a disease that it is generated by the mutation of one or two genes that are responsible for the production of certain proteins, polycystin-1 proteins that are needed or essential for the adequate functioning of the tubular epithelial cells. And when these two proteins are not present, There is a cascade of events in which they start really forming cysts, and those cysts start taking over the entire kidney architecture, and they ended up causing kidney dysfunction. It is very known, it is well known that AMPK activation is reduced during this physiopathological pathway, and by reactivating this enzyme that is responsible for multiple metabolic aspects in the cells, by reactivating this enzyme via a direct AMPK activator, we are able to modify critical pathways like the mTOR, cyclic AMP that are responsible for the CIS proliferation. We are also able to really reduce the fluid secretion into the cells by the chloride channels, and also reduce inflammation, which are, I would say, three of the key hallmarks of this particular disease and what we are also very excited about this AMPK activator is that it has a very high selectivity so it binds preferentially into the versions of this enzyme that are more common in the kidney space rather than binding into other versions of that inside that may be more common another type of organs with that really with that type of selectivity really allows you to have a better safety profile okay great then you did have some phase phase one data that you've shared also, maybe you can review that. That's right. So we actually, we conducted a phase one study in order to evaluate additional doses that had not been evaluated with this particular molecule in the past. So we recently announced the completion of that particular study. And with that data from that study, the doses that we evaluated were higher than doses previously evaluated, had allowed us to really conduct a population PK modeling in order to inform us properly about the doses that we are proposing for the Phase II study that we are planning to initiate by the end of this year. So the positive data is that all those doses were well tolerated. We were able to further characterize the pharmacokinetic profile of those doses. We're in the process of discussing with the FDA our final study design for Phase II and really trying to move it into initiation towards the end of the year. Okay, great. I know you're still in discussions in finalizing, but maybe you can give us a sense of what you're hoping and what you're expecting to show in terms of the design for the phase two program. Yeah, the design, the outline of the designer for the specifics of the designers, as I mentioned to you, we'll probably share them once we do have a reach agreement with the agency. But the outline is a full one-year treatment period. So we're aiming to really have three groups of patients, two of them receiving two different doses of 7-7-0 and one receiving placebo is going to be a full year treatment duration. We are aiming to have an interim readout towards the end of next year. And that particular interim readout will give us an indication of the progression or the impact in the progression of total kidney volume, which is one key relevant, I would say, endpoint to really understand the potential efficacy of a product in this particular condition, we are aiming to enroll patients that are rapid progressors, that are defined as rapid progressos based on certain categories, and that will allow us to really see the magnitude of effect in a much more shorter period of time. The design is not so different to what is typically evaluated and seen in this particular type of studies, and we will be happy to disclose soon what are the doses that we're going to be integrating into that particular study. And then maybe just on that total kidney volume measures, what would you be hoping to see when you look at sort of the interim data next year? Sure. So really the best benchmark information that we have about how TKV evolves when you do have an effective therapy on board is really the data that exists for the current product that is approved, which is Tolvaptim, because it's the only product that has been evaluated in a long term that has shown efficacy, that has shown efficacy. And what has been observed is that patients not receiving therapy, let's say patients receiving placebo over a year period of time, they typically have a progression of their total kidney volume of about 5%. That's a group of patients that are typically enrolled in these studies. About 5% increase in total kidney value in a year. And Tolvaptan showed that it was able to reduce that 5% by half. So it had a 50% relative reduction. We believe that that particular trend that demonstrated to be, I would say, a good signal to obtain Tolbaptan approval, but also to really prevent or delay the progression to end-stage kidney disease, could be a good target for us. So if we are able to really show a 50% relative reduction in TKV, it will definitely be a good signal of evidence of efficacy for this particular problem. Okay, and then obviously TKB is now well-established as a potential surrogate endpoint. What else would you need to do beyond that if you showed that surrogacy benefited in the interim to kind of move into phase three? What's the path to market, essentially? Yeah, TKV, total kidney volume, has been recognized as a reasonable surrogates or likely surrogated market of the disease itself. At the end, in order to get approval for an indication like this one, you also need to demonstrate evidence of activity in reducing the decline of GFR, which is actually the reflection of the function of the kidneys. And so you need to be tracking both. But TKB has been identified as a surrogate endpoint because you are able to really see the changes in TKV, typically sooner than you are able to really identify the changes in GFR. Both programs, phase two and phase three, will be evaluating both, but certainly there is the opportunity to get an accelerated approval based on TKv data only initially at one year in your phase three program, and then eventually you will need to also show the evidence of efficacy in the GFR endpoint as well. The outline of the development program at this point is thinking about one phase two study and one single phase three study. And both studies will be evaluating these two endpoints in the way that the phase two study will give us a good indicator about what is the magnitude of effect in these both of these endpoints to properly plan the phase three. Okay. And maybe you can talk about, you talked a little bit about ADPKD as a condition and obviously limited options available right now in the market. Maybe just the commercial sort of landscape as you see it, it seems like there's a lot a lot more activity now, companies looking at ADPKD as a potential space to move into, so just how do you view the landscape would be helpful? Yeah, it's certainly an area that has attracted a lot of attention, for sure. And number one, because there is a very significant unmet medical need. Number two, because the biology and many of the pathophysiological aspects of the disease probably are better understood now at this point, so it has really allowed many other to be progressed to. So I was mentioning that there is only one product in the market, Tolvapt, and at this point, despite the fact of the limitations in terms of safety and tolerability, they reported sales of $1.5 billion in 2024, so it's clearly an important commercial opportunity. And right now, there are different treatment modalities. To the best of our knowledge, we are the only ones exploring an AMPK activator as a treatment modality for ADPKD in the clinical stages. There are other treatment modalities that are being explored. There is a product being developed by Farabusten, Farabuesten being developed Novartis that really has another mechanism of action, which is inhibiting microRNA inhibitor that is intended to increase the production of polycystin-1. There are others that are really trying to really modify the genetic mechanisms to which some of the mutations are resulting in lack of production of polycystin-1 as well. Most of them have either are in phase 1, many of them are in Phase 1, completed Phase 1b. One of them, the most potentially advanced in the development program is probably the Faragustin product that is right now about to enter Phase 3 to the best of our understanding. So there is great interest, great interest in the novel mechanism of actions, and that's fantastic to really see, because there is a fantastic opportunity to really demonstrate a significant impact in patients through one or two modalities, treatment by themselves or in a combination therapy, to really being able to potentially finally impact the life of these patients that are in substantial and medical need. And is this, do you see 770 as something that would be able to be used on top of tovaptin or on top of fair-person and combination approaches, or is there some reason that wouldn't? In theory, yes. I think that everyone is going to be developing their product to demonstrate efficacy of the product by itself. However, the fact that, as you can see here in this particular cascade that is shown here, the 770 is a product that will be agnostic of any type of genetic mutation. It will be Agnostic if this is a problem that it is following, or the disease is following PKD1 or PKD2 type of mutations, if this is a missing mutation, a truncated mutation, it will be agnostic to all that because it's downstream to that. So in theory, it could potentially be considered as a good partner to many of the other products that are being developed at this point. It's not the primary intention that this product will be developed for being used in combination. But however, as it has evolved with many chronic diseases, at the end, you end up having potentially two different treatment modalities to really try to maximize the beneficial effects in the patients. That is foreseeable in this particular disease as well. Okay. So why don't we switch gears to 247 and just kind of talk about that program as well, since you've had some good progress and developments there as well? You had the contract recently. Maybe you can just highlight where that stands and how you're developing that program? Yeah, let me tell you a little bit about the BARDA program probably first. Let me tell this. So we recently announced in our other development path that we have is an antifungal program that is intended to address very significant and medical needs in the treatment of invasive candidiasis. And invasive candidias is a deathly fungal disease that is typically impacting patients that are immunocompromised because of many reasons. For instance, patients that are receiving cancer therapies or that are receive bone marrow transplants, solid organ transplants. Once you have these invasive fungal conditions, you have really a very high mortality rate. There are not too many treatment options and there is increasing the rate of resistance pathogens that are not responding to the currently available therapy options. Considering this particular significant and unmet medical need, BARDA has a program in which they really incentivize or partner with companies in order to make sure that there is good products being developed in order address this particular, I would say, that public health threat that will represent the risk of having infections by multidrug resistant strains. So we were lucky that they decided to partner with us. And that provides up to $240 million in potential, If all options are exercised by BARDA towards the development of SEY247, in the initial tranche, which is the initial option that they opted in, they are committed to provide us $18.5 million for that particular tranche. And then subsequently, there are different stages according to what you are, if you are meeting certain milestones of development, then they can, you can maybe keep unlocking in different stages and different tranches of funding through this particular program. So this is a fantastic opportunity because, obviously, allow us to, in a non-diluted funding, allow us really to, non- diluted funding additional input into our development programs allow us to really continue progressing this development with really a very limited impact in our actual cash ad flows from our standpoint. Okay. And you've completed some phase one work with 247, looking to move into phase two. Maybe just walk through what you've seen so far in phase one and your plans going forward. Absolutely. So that is quite interesting. We selected this particular molecule, CY247, among a broad selection of fungus that we own the full platform of. And this particular analog we selected because we wanted to demonstrate some characteristics in terms of potentially enhanced oral viability versus our prior analog that we developed by Brexifunga. And we also wanted to really see a very significant tissue penetration to those organs that are typically affected by invasive fungal diseases. We also wanted an intravenous and oral formulation that for the previous analog developing the IV formulation was a little bit more challenging. So in this particular case, we have already completed all full phase one assessment activities enabled with the oral formulation and we recently completed as well that with the IV formulation. So the next stage of development for this molecule is a phase two study in patients with invasive candidiasis. It has a broader spectrum of activity. It not only impacts candida, it also may be appropriate to really treat other fungal diseases like aspergillus, pneumocystis, et cetera. The initial focus is going to be in the treatment of invasive candidiasis because there is a very substantial unmet medical need, however, because of the properties of this molecule to have low risk for drug-drug interactions and favorable safety profile, it can also play very well in other indications like prophylaxis, prevention of invasive fungal diseases. This is the overall picture in regards to what we are planning for the overall development program, so a phase 2 study in invasive candidiasis and potentially two phase 3 studies, one in invasive candidiases and one in prophylaxis of invasive fungal diseases, in the way that we can get a very broad label at the end that really is able to really support the treatment and prevention of these diseases in patients in need. So that's really, we're very happy that we were able to progress it right now with the aim to initiate the phase 2 studies by next year. And how are you looking just in terms of developing that further than the face? So it would be both the IV and the oral, and then it would, like you're saying, sort of an easy step down for patients if you can get both of them available? That is right. So at this point, among the antifungal for systemic invasive fungal disease offerings that exist right now in the market, there is only one family of compounds that you can start with IV therapy and step down to the same family of compounds oral therapy. Everything else, echinocannins, for instance, they are only available intravenously. Polyenes that are only available intraveaneously. So having a product that has a very highly potent compound that you are able to reinitiate intraveniously and being able to move orally once the time is right is really a great, great advancement into the current treatment and momentarium. We need to keep in mind that invasive fungal diseases typically require several weeks of therapy. sometimes months of therapy. So having the option to really start IV when those patients are in a very, I would say, critical condition and being able to step them down to oral and continue therapy to oral is a critical success factor, in our opinion, for a product in this case and also is one of the significant unmet needs. Okay. All right, great. So now in the last few minutes, a couple of other things to touch on. One, BrexFM, obviously you mentioned that's outlicensed. It's not GSK, just the latest that you can share in terms of the progress on getting that back to the market? Sure. We developed Brexafen. We obtained two indications for that particular molecule for the treatment of vulvovaginal candidiasis and also for reduction of the incidence in patients with recurrent VVC. We had at that time other products under development. There were some other studies conducted in terms OF treatment of refractory fungal diseases. GSK indicated to us that they were planning to really focus their commercialization efforts in the VVC indications, and they are in the process of relaunching the product. They have not indicated publicly when is their time freely to relaunch. We know that they are progressing in that particular process, and we are all very eagerly awaiting to the news from GSK announcing that Brexafem will be available to the patients in need. Brexfem really fulfills a very significant need in the market because as an oral available medications to treat BBC only fluconazole is available in those patients that are not responding to fluconasol because they are either resistant or cannot tolerate the drug there is no other treatment available for them. So Brexofem was really aiming to really fill that particular significant need. It's still extraordinarily relevant in the market. There is nothing else that come out that really has, I would say, that is supplying to those patients in that sense. So we are eagerly awaiting for GSK to bring it back to the market, we believe that soon we know that they're making progress towards that, but they have not disclosed a specific timing for that. Okay, and then maybe now you mentioned the BARDA funding as a nice way to bring in some resources. What's now the cash position for the company and your runway looking forward? Yeah, our cash position, we reported $63.2 million by the end of September. And that really provide us a cash runway until into 2029. So that is sufficient cash for us to be able to really complete or phase two studying that we are planning with the 770, which is the ADPKD program. And certainly, adding the development program for a CY247, we don't anticipate that that will impact in any way your cash runway, because most of that program is somehow subsidized through the VAR contract. So we right now have cash into 2029, allowing us really past really the completion of the phase to study 4770. GARY GENSLER. And then maybe just to wrap it up here, going to lay out the catalyst events here coming up, So obviously, starting the phase twos, but maybe just talk through the details then. So really, some news flows that we're anticipating in the near future, certainly we just released, as you mentioned, the phase one data 4770 that really provide us additional information to put together the design for the phase two study. We are anticipating to really start the phase three phase two studies before the year ends with an interim analysis by the Q4 of 2027 for that particular program, and the completion should be in 2028. For the antifungal, we just released the phase one data, and we certainly are planning for the initiation of the phase two study sometime mid-2027. At this point, for that program, we're in the process of discussing with the regulators what's going to be the design of the study, also with our partners, manufacturing clinical trial material, and being ready to really start that particular problem. Those are, I would say, the key milestones in the progression of our programs in terms of development. Okay, great. Thanks again for joining us. Congrats on the transformation of the company over the last 12 months and look forward to seeing the progress over the next 12. Thank you, Damil. Thank you for the continued support. Thank you all for your attendance.