Hi, everyone. I'm Gary Nachman, a Senior Biotech BioPharma Analyst at Canaccord Genuity, and we're very excited to have Miranda Toledano, CEO of Entera Bio, with us to discuss some recent exciting developments at the company. Miranda's been with Entera on the board since 2018 and as CEO since 2022, and it's been a labor of love, I think it's fair to characterize that, to progress EB613 for osteoporosis through development. You're certainly in a much better place now, including with the recent $275 million financing. So congrats on that, and thank you so much for joining us, Miranda. Thanks for being here. Thank you so much for having me. Pleasure. Okay. If anyone has a question during the chat, please raise your hand, and we'll make sure to get to you. So maybe for those not familiar with Entera, you could just start with a few minute overview of the company's proprietary N-Tab technology, what's so unique about it with respect to developing oral peptides. Then a quick background on why you decided to pursue osteoporosis as your lead indication with 613, where I know you believe there's still such a huge unmet need. Thank you. So Entera leverages on our N-Tab platform, which stands for Entera Tablets. Basically, what that enables us to do is develop simple tablet formats of native peptides, which really is a huge technological challenge, and that's due to three main reasons. Peptides, even though they're the smallest of proteins, are still large molecules, and we specifically focus our efforts on large hydrophilic linear peptides like PTH, GLP-1, GLP-2, and the like. They have polarity limitations, which even if stabilized in the GI tract, do not enable them to permeate into the bloodstream for systemic absorption and bioavailability. Of course, the proteolytic environment in the gastrointestinal tract readily degrades anything we ingest. What N-Tab does is it has two main mechanisms of action. One of them is to stabilize the peptide, and we use specific excipients to deactivate proteolytic enzymes in the stomach and the intestines, such as pepsin and chymotrypsin and trypsin locally around the tablet. Our tablets are not encapsulated. They look like an off-white, white baby aspirin size. The second mode of action is we use SNAC, which is a transcellular permeation enhancer, which basically increases epithelial cell permeability so that once the peptide is stabilized, goes through the GI tract, can enter the bloodstream at therapeutically relevant levels. I would just mention that every candidate in the Entera pipeline is a pure peptide. What we are talking about is pure amino acid sequences. This is not a medicinal chemistry approach. This is really just the pure kind of native peptides. The only modification, and this is not in relation to 613, but in relation to our other pipeline, is in certain situations where we need to, for example, seek a specific PK profile, which requires us to extend the half-life of that sequence, then we will acylate. Quite similar to what Novo Nordisk has with semaglutide, which is an acylated GLP-1, and of course, is marketed as both Ozempic and Wegovy tablets today for diabetes and obesity a nd osteoporosis. Osteoporosis. I know we could spend a lot of time on that. Osteoporosis specifically, teriparatide, which is the API in EB613, which is our lead clinical candidate, which we plan to move into phase III imminently, pursuant to our alignment with FDA, which we announced on June 22, 2026. Teriparatide is a 34 amino acid sequence of the parathyroid hormone. It's the functional region of the native peptide. It's a very short acting analog. It has a half-life in blood of about five, six minutes. And it has the ideal profile to engender, in an unmodified way, bone formation and an anabolic effect. If you're looking to engender bone formation, which is the mode of action of EB613, what you're really looking to do is produce a very short pulsatile PK and kind of get that osteoblast, osteoclast mechanism going, and of course, induce rapid gains in bone mass and bone strength. Entera, our scientific capabilities are in developing the oral peptide, so it was quite reasonable almost a decade ago when this labor of love began to focus on a native peptide that had, with no modification, the correct PK for osteoporosis. If you look across our pipeline, the rest of the candidates are acylated, and their half-life has been increased to basically provide a protein replacement therapy for EB612 for hypoparathyroidism and to provide a long-acting peptide for metabolic syndrome. Osteoporosis as a therapeutic indication, though more importantly, is the most common metabolic bone disease globally. It is also probably the most under-treated yet diagnosed chronic progressive disease. There is a persistent treatment chasm in osteoporosis, and that doesn't necessarily stem from lack of available treatments. But there are certain limitations to current treatments and an enormous challenge in relation to the three anabolic or bone-forming treatments for osteoporosis, which consists of FORTEO, a daily subcutaneous injection, abaloparatide-Tymlos, daily subcutaneous injection, and EVENITY, an anti-sclerostin monoclonal antibody. Patient acceptance of these when they start to progress is quite limited. And so what we're trying to do with EB613 is really democratize anabolic therapy and develop a viable anabolic in a tablet, really so we can address patients across the clinical ecosystem for osteoporosis, which really range from primary care, gynecology, endocrinology, rheumatology, and orthopedic surgery. Okay. No, that was a great overview. Thank you. So maybe just describe a little bit what the process was like working with FDA to finally get alignment on the phase III. It took such a long time. And where you ended up with them in terms of the design of this study, is it exactly what you had hoped for? And then also just based on what you saw in the phase II study for 613, what gives you confidence that you're going to be able to hit the primary endpoint that you agreed upon with FDA? So in relation to question one, we were at FDA every year since the end-of-phase-II meeting. So I took the CEO. Just tell people when that was, the phase II meeting. The end-of-phase II meeting minutes came in February of 2022. Yep. Prior management had thought to conduct a traditional bioequivalent study with a permissible endpoint of a 12-month lumbar spine BMD, using FORTEO, our listed drug, as an active control in that potential registrational format. If you look at the phase II data for 613, we are certainly pursuing and able to pursue a 505(b)(2) application with FDA based on comparability of PK, specifically in relation to AUC. EB613 is not a bio. Referencing FORTEO. Exactly. Which is an injectable form. Which is the daily injection of the anabolic. Yep. Of teriparatide. Yeah. EB613 is not a bioidentical. There are certain nuances when you change the mode of administration of a peptide. There are changes to kinetics, to the PK. If you look at the PK curve of EB613 tablet versus FORTEO, we have a much shorter duration of exposure, much shorter elimination phase. It is a very quick pulse. Basically, the same Tmax. We have a slightly higher Cmax. We believe that those changes in the pharmacokinetic profile are lending to differences in bone turnover mechanistic responses, and these are proteins that you can measure in the blood, which basically look at activity of the drug on osteoblast bone forming and osteoclast cells. And if you look at what is called anabolic window, which is the balance of what the drug may be doing based on the measurement of these proteins in the blood, EB613 seems to be, at least in the phase II, engendering a dual mechanism whereby it is preferentially activating osteoblast, meaning bone-forming cells, and also suppressing osteoclast. It has the bone formation and a dual mild bone resorption with a reduction in CTX. That was nuance number one. What FDA came back, at the time when company received the end of phase II minutes in about February of 2022, came back and said, "Because of these differences, this is not a bioidentical. Doing a head-to-head in a statistical non-inferiority may not be the best way to get potentially the drug approved into patients." At that time, the FDA was looking to qualify total hip BMD as a surrogate efficacy endpoint for fracture, given the lack of new developments in osteoporosis for the past over a decade. The last approved drug was approved in 2019. That is EVENITY. That drug required about 11,200 women to get approved. The feedback was this pathway of being able to use total hip BMD versus placebo may become available. In 2022, it was supposed to get qualified in 2023. It ultimately got qualified on December 19, 2025. In 2022, 2023, 2024, 2025, I was at the FDA every year, and what we were trying to do in every one of those interactions was ascertain what is the non-clinical and clinical package required for 613 to actually be able to submit an NDA. We made very good progress across those years, but we were also the only company with positive phase II data awaiting an endpoint change. Right. The culmination of that was July 2025. We filed a type A meeting and received an unprecedented alignment from FDA that we could use this total hip BMD versus placebo in a 24-month, two year registrational study, which was, at the time, a big win. However, when the FDA institutionally qualified BMD in December of 2025, we saw room to streamline, potentially, this phase III, which is what we did. We filed a clinical amendment in Q1 of 2026. On June of 2022, we received agreement from FDA that we could indeed carry out a 12-month placebo-controlled, not 24-month as our double-blind registrational study, which, to answer your question, is a huge win for us and i s the ideal way to get 613 expeditiously now through this program, and hopefully in a successful way to patients. Yeah. Just in terms of your ability to hit that endpoint at 12 months, how much are you going to need to power the phase III study based on what you saw in the phase II? It's probably also important to note that there's an open label extension going out to 24 months. That was the agreement with the FDA, because they do want to see two-year data. You don't think that should hold up the application once you have the 12-month data, correct? Yeah. The registrational package for the potential NDA filing will consist of the 12-month safety and efficacy double-blind placebo-controlled study. We have alignment to initiate that study in about 750 post-menopausal women at risk of fracture with osteoporosis. The way that we're thinking to power the study and size the study was to produce effects on total hip BMD at 12 months, which are comparable to what have been reported for our listed drug, FORTEO, at 12 months, which is about 1.7% based on its summary basis of approval, and 2% based on the active study, which was a 2016 phase III publication. FORTEO was used as an active control in the abaloparatide phase III registrational study. So FORTEO, in a phase III placebo-controlled format, produces about 1.7% to 2% increase in total hip BMD at 12 months. That is associated with 64% to 80% vertebral fracture reduction at 18 and 19 months. That's our position for clinical effectiveness in relation to what 613 did in our phase II study. Our phase II study was a six-month dose-escalating placebo-controlled study. At the top dose of 2.5 mg, EB613 in a non-titrated and titrated fashion produced between 1.34% and 1.57% at six months. So we're quite highly powered to meet the 1.7% to 2%, which is our goal. For the 12-month outcome measure for the phase III. In addition to the safety and efficacy outcomes from that study, we also will be providing FDA with our scientific bridge analysis with FORTEO. Right. Which is predicated on a population PK and PK sub-study, where we're looking at PK exposure analysis for comparability. We also will be providing outcomes from a transiliac crest biopsy sub-study in a very small number of women, which is required. We also will continue to look at our bone turnover markers, P1NP and CTX, which is not required, but of course, we have this really compelling dual mechanism, and we want to continue to look at that. In the extension study, which you alluded to, what our plan is for the women that will have received EB613 in the base study, we will randomize half of them to continue on 613 through 24 months. FDA has told us that they would like to see 18-month safety data while the extension is ongoing, and they do want to see the 24-month outcome of the monotherapy to look at safety and durability of response. The second half of women that will have started on the base study on 613 will be sequenced to an anti-resorptive standard of care, which frankly is the way we think the drug should be used. So an anabolic boost with a consolidation with an antiresorptive drug, so 12 plus 12, then the placebo patients will be, in the extension, rolled over to most likely EB613. Okay. I think it's safe to say this was extremely well thought out, the whole clinical program, which is great, and now you have the capital to start the phase III later this year. So it's amazing. Let's take it up a little bit to the market. You just alluded to it in the beginning. Just talk about the drugs that are currently available. So you have the oral bisphosphonates, the injectable anabolics, the antiresorptive meds. What portion of the market still isn't doing well? Where would this fit in? What types of patients? Then from a payer standpoint, assuming you hit the data the way you hope, how you think they're going to view it, just given that it's a highly genericized category, at least with portions of the market already. Yeah. The numbers for osteoporosis, as you know, are staggering. So there's about 200 million across major geographies. In the U.S., there's about 10 million-12 million diagnosed with osteoporosis. This is a woman-centric condition, and most commonly afflicts women of post-menopausal age, as estrogen starts to decline during the menopausal transition. So it's about 80% women. There's about 54 million Americans with low bone mass, which are most likely going to go into a progression into osteoporosis. But in terms of the treatment paradigm today, which pretty much has been static for many years. The two main mechanisms of action used to treat patients are the antiresorptive drugs and the anabolic drugs. We estimate, based on different clinician surveys, quant surveys, patient surveys, and discussions with the ecosystem, that out of the about 13 million diagnosed with osteoporosis, I'm referring to the U.S., less than 40% receive any treatment or are willing to take any of the available drugs. So there's diagnosed untreated, and that's persistent. Is it because of the tolerability with the drugs, or they just. It's a number of issues, and I'll try to. It's a silent disease maybe, so they don't see. Well, they're diagnosed, but there's an entire group which is simply unwilling, and I'll maybe try to go through it drug by drug to explain our, at least our understanding of the situation. The antiresorptive drugs are drugs that slow down bone resorption or bone degradation. They do not rebuild bone, and they do not ameliorate, improve the skeletal microarchitecture, which actually mechanistically is what patients with osteoporosis need. But they are the most commonly used drugs. In our estimation, about 80% of prescriptions are within this antiresorptive camp, and there are two main drugs which are used. One are the bisphosphonates. We estimate about 60% of prescriptions are bisphosphonates, and this is not unusual given bisphosphonates are oral. In a silent, asymptomatic disease, it is easier to agree to take an oral drug. That's like Fosamax. Exactly. That has been around for. [Alendronate]. Forever. Forever. Yeah. Right. These have been generic for over a decade, 15 years, and they are cheap, and they're oral. About 60% of patients first start on a bisphosphonate. But we also know that about half of those will discontinue a bisphosphonate within 12 months because bisphosphonates have very high rates of acid reflux and are intolerable to most patients. So there's a very, very rapid second line, post-bisphosphonate intolerance. The second most commonly used drug is Prolia, which is Amgen's anti-RANKL monoclonal antibody, which has undergone genericization in the past couple of years, denosumab. And this is a very good drug, highly effective, and also much more acceptable to patients because it only requires an injection every six months, and it also has a higher access profile because even a primary care clinician can send his or her patient to potentially an infusion center every six months to get that denosumab subcutaneous injection. And so that became, as you know, a $5 billion franchise. Now, there are limitations to Prolia. It is a drug that is quite difficult to get off of, and if it's not taken at the appropriate time, can lead to potential rebound with very rapid kind of vertebral fractures. So this is stable. We don't anticipate that kind of 20% to change. There's a lot of biosimilars that are vying to get that $5 billion place. So we kind of see, in my mind at least, I see Prolia and the denosumab group as an island. Maybe just because we're a little short on time. Yeah. Just jump into where is this going to fit in. Yeah. Lines of therapy. I wanted to ask you one quick other question. Very briefly, anabolics, the three approved anabolics are FORTEO, our listed drug. daily subcutaneous injection, abaloparatide daily subcutaneous injection. The last drug approved, EVENITY, is an anti-sclerostin antibody, requires two injections every month at the physician's office and has a black box warning. Those three highly efficacious anabolic injectables treat less than 10% or 15% of patients. There's this huge, what I call white space between the kind of 80%- and the 15%. What we're trying to do with EB613 is provide a viable anabolic tablet, so not the minority, but the majority of women can better protect their bones and improve their skeletal microarchitecture. That's our thesis for EB613 is really to intercept the treatment paradigm and close that treatment gap. Do you think payers would be amenable, really, just quick answer, just given all the generic alternatives that are available? Well, the generic equivalents for. Yeah. Teriparatide are not that cheap. These are injectable peptides, and there's a drug device involved. Yeah. What I would say is that our COGS profile for 613 enables us to price in line with the anabolics, including the generic equivalents, which again are not cheap. We have flexibility. I think, we have a strong pharmacoeconomic argument for providing a viable bone forming agent to a much larger amount of patients to deter the progression of the disease and these fractures, which rates are not going down. There's about 2 million fractures in the U.S. They cost about $54 billion annually, so there's a huge economic incentive. Excellent. Okay. We're up on time. There are other programs in the pipeline earlier. We'll save that for another chat. But thank you. Good luck with everything, starting with phase III. Thanks for being here. Thank you, Gary. Thanks, everyone.