Okay, let's get started. Welcome, everybody, to our second day of our conference here in Miami. With us today, I have the pleasure of hosting Entera Bio. With me is Miranda Toledano, CEO of Entera Bio. Miranda, welcome. Thanks so much for making time for us. We'd love to dig into in terms of Q&A, but before we do so, we'd love to kind of give a state of the union of the business from you and what we could look forward to in maybe the next six to 12 months.
First of all, thank you so much for having me again. In terms of Entera, for those not as familiar with the company, we develop first-in-class oral peptides. These are pure peptides. This is not a medicinal chemistry approach. This is actually taking the amino acid sequence of peptides and creating a simple tablet treatment. We've got four main programs. Our lead clinical candidate, we had groundbreaking news at the end of the summer. This is EB613, the first and only osteoanabolic bone-building tablet treatment for postmenopausal women with osteoporosis. We just came out of a very successful Type A meeting with the FDA, which provided us a green light and a de-risked pathway to our registrational phase three study. We also have programs across hyperparathyroidism, also using different long-acting PTH variants.
And we're hoping to read out some preclinical validating data from at least two of those variants by the end of 2025. We also have dual agonist GLP-1 glucagon tablet treatment, which we're currently in IND enabling toxicology and CMC activities with an intention to file an IND in the first half of 2026 for metabolic diseases. And we have a GLP-2 tablet that we developed through PKPD and large animal models. And that really was positioned for short bowel syndrome, but we're starting to understand from some strategic discussions that GLP-2 has actually a lot more potential indications that we could look at. So we're trying to evaluate what to do and how to move that program forward. It's preclinical.
Excellent. Excellent. So just focusing on EB613, obviously the old fracture-focused trial requirements held the field back, especially in terms of innovation and anabolics. But now the FDA has accepted total hip bone mineral density as a surrogate endpoint. So obviously EB613 is kind of poised to kind of hit the ground running out of the gate. Any thoughts on that? And I know it's been kind of a long road.
It's been a mission.
Yeah.
Yeah, it's been a mission. For us, this was my fifth Type meeting with the FDA since June 16th, 2022. And what I would say is those Type C and D meetings that we had in 2022 through 2024 were very productive in the sense that we understood clearly what the non-clinical and clinical package requirements would be to support an NDA for EB613. Of course, we didn't get the clear black and white minutes on the endpoint and the approach that we're taking until July 28th, 2025. In terms of what you said, it's exactly right. The entire field, not just anabolics of osteoporosis, has not had much innovation in the last decades. The last approved drug, as you know, is Evanity, Amgen's anti-sclerostin monoclonal antibody, which was approved in 2019, which took close to a decade to develop and required 7,200 patients in a fracture.
That totaled over $1 billion in terms of development capital that needed to get that drug. In relation to EB613, I think this is a very big step in terms of opening the floodgate to innovation in a disease that has a pervasive treatment chasm that I think because investors are less focused on this space for the past decade, are less knowledgeable about. But we're talking about a disease that is lethal. We're talking about a disease where less than 25% of women at least have access to treatment after a fracture, which is monumental.
So what we're trying to do is really, with EB613, it's not just about the endpoint, but it's about providing a validated osteoanabolic mechanism in a simple tablet treatment to address patients in a chronic symptomatic, asymptomatic progressive disease where the very highly efficacious injectables are just not moving, have not been able to move upstream.
Got it. Got it. So it's fair to say that EB613 is arguably the first drug candidate to kind of take advantage of this evolution in the FDA's thinking in terms of surrogate endpoints.
FDA actually initiated in 2012 this work, which was started as a public-private partnership between the agency and every company at the time, all the sponsors that had historically developed osteoporosis drugs, whether that was Merck or Amgen, Pfizer, Novartis, et cetera. They pooled and contributed 177,000 patient data, which led to a meta-analysis with which the SABRE group has been leading. As you may remember, when I sat here in December of 2024, what we were waiting for at Entera, because we are still the only company that has placebo-controlled positive phase two data, we were waiting for the qualification of the SABRE endpoint. That was scheduled or expected to happen in January, around January 6th, 2025. That date came and went. What happened was I made the decision that we need another strategy.
We need to find a way to gain alignment on our program and not have this dependence on the potential qualification of the SABRE endpoint, and that's what we reached finally in July of 2025.
Got it. Just focusing on the phase two data and how it may de-risk phase three.
Yeah.
Just given, I guess, the six-month phase two gains across spine, hip, and femoral neck improvements, the same 2.5 mg dose is being carried into phase three, correct?
Yes.
Okay.
The titrated regimen.
Okay. So in terms of the phase two data, to what extent do you see this 24-month, I guess, phase three trial as de-risked versus the typical osteoporosis pivotal trial?
In reality, it's not that different. If you look at our program, we had 161 placebo-controlled dose-ranging studies for EB613. That was our phase two. At our 2.5 mg dose, we had 21 patients, and we still look at 1.5 mg as a viable. We have a very statistically significant dose response, but our starting dose is 1.5 mg, so if we look at the 1.5 mg and the 2.5 mg cohorts collectively, we have an N of 43. If you look at the studies that were phase two studies for the most recent approvals in osteoporosis, Evanity, Romosozumab in its phase two study had about 42 patients at the dose they moved forward with, I believe, into a 7,200 patient fracture study, and phase two studies are BMD. They don't have fracture endpoints.
Likewise, if you look back at Radius's phase 2 study for abaloparatide, which was approved in 2018 on the basis of a 2,400-patient fracture endpoint study, it, like us, had a six-month bone mineral density study dose ranging similar to ours, similar patient population, and 33 patients at that selected phase 3 dose. So this leap, again, I think it seems kind of it's not consistent with other therapeutic categories, but it's not unusual. I think the difference is that Radius was a more established company. Obviously, Amgen had the wherewithal to take on a 7,200-patient study after their validating phase 2 study. But the numbers in terms of graduating to a potentially larger study or a longer study, I should say, are not unusual. Abaloparatide was 18 months, and romosozumab had two-year data in phase 2 and ultimately had a 12-month phase 3.
We have been mandated by FDA to have this 24-month, and the reason also is because, at least stated to us, because I did petition to have a shorter duration study over the past couple of years and take that in our label. The reason is the agency truly believes that EB613, if approved, will be widely used, and as you know, the black box warning for carcinogenicity for the PTH agonist, whether it's Forteo or Abaloparatide, was removed in 2018 and 2019. So there is kind of this safety stigma has been removed, and so they do expect the drug to be used for at least a couple of years.
Got it. Just going back to the phase 2 data, but you had a great graph on the anabolic window where the bone formation biomarker, I think it was P1NP, stayed above baseline.
Yeah.
And the bone resorption biomarker, which is CTX, remained suppressed through six months. So does this suggest to you about how strongly and how long EB613 can drive bone formation over the two-year treatment window in phase three?
Yeah. So this is a very common question. I think the field historically kind of looked at P1NP as a hallmark biomarker of bone formation. The notion of drugs' ability and anabolic drugs' ability to create increased bone mass density and ameliorate the skeletal microarchitecture, which really distinguishes anabolics from anti-resorptive drugs, is not just based on looking at one metric, P1NP. It really is the balance between the duality of looking at what the drug does to the bone formation, in this case, P1NP or osteocalcin, to the bone degradation or resorption marker, in our case, CTX. We seem to be seeing in our mechanism, which is distinct to Forteo, and we do believe this may be PK-driven, a preferential activation of osteoblasts. So increase of P1NP, and we actually have no cortical porosity, meaning there is no continuous increase in CTX. If you look, we actually suppress CTX.
So we have, in our mechanism, both our anabolic window looks a little bit closer to Romosozumab, which is the only uncoupled anabolic window that's been seen to date. So in terms of, I think your question is lending to, well, we have six-month data, our P1NP went back to baseline. What does this say about 24-month data? We're very comfortable with our anabolic window. In fact, the benefit of having this minimal cortical porosity is that that is what lends a drug's quicker onset of action and higher increases in the short term at cortical sites like hip and femoral neck. And you see that with Romo, you see that with abaloparatide, which has less of that increase in CTX than subcutaneous teriparatide Forteo. And you see it also with our quicker onset of action at cortical sites.
In terms of how does that translate to 24-month data, all anabolic drugs, if you look at the three approved or you look at Teribone in Japan, which is a high dose, 56 microgram once-a-week injection, they all have a distinct anabolic profile. And these proteins, P1NP and CTX, are proteins that you measure in the blood to look at kind of global skeletal mechanistic action, but it's not actually telling you what's happening at the tissue level. And so it's not providing the whole picture. And so we saw from our non-human primate, even though safety was our primary objective for our non-clinical studies, but in our TUG studies, we see continuous increases in bone mass, both trabecular in those studies over nine months.
And we see also in this 3D Shaper analysis that we did. We see this early onset of both at what is programmed to look at potential changes at the tissue level, cortical and trabecular site formation. And so, like all anabolic drugs, there's a waning effect. And you see that with the BMD curves of all three. So the way that we project our effect size for what is our effect size at 24 months on BMD, the bulk of our slope, like any anabolic, we expect to happen within the first 12 months. And then an increased slope, like other anabolic drugs, but I actually put a zero slope increase between 18 and 24. The way we model our effect size is actually quite conservative.
Got it. Got it. Excellent. So as we think about phase three, it's a 24-month multinational with at least 20% of patients in the U.S., the rest of the sites, 80% rest of the world. I mean, how should we read into that geographic mix? Is that designed to kind of further any regulatory priorities, or is it just, why is it designed that way, only 20% U.S. studies?
20% U.S. is quite high, and it's deliberate. I think, you know, I mean, in my background, you know, companies, sponsors used to get away with 10% or less U.S. and still gain FDA approval. I think that in recent years, debates, and that hasn't been as well received by the agencies. We deliberately are trying to get 20% U.S. representation. U.S. enrollment is the most expensive, but we just actually completed a, we're trying to front-end as much as possible for this phase three study. We just completed a multi-regional feasibility study looking at sites across Europe, the U.S., and Hong Kong and Latin America. We have multiple centers of excellence in the U.S. that are very excited about joining our study. In Europe, it's typically, if you look at recent osteoporosis studies, it's just easier to enroll.
Eastern Europe, in terms of market, economic value proposition, Europe is actually the most difficult. There are countries in Europe, Western Europe, where, for example, Prolia isn't reimbursed, definitely not Evenity. France, for example, doesn't. Forteo is the only approved anabolic or what I would say reimbursed, so from an economic standpoint, market standpoint, the two biggest markets for osteoporosis are the US and Japan, and then Europe, we will have also representation. Hong Kong is a center of excellence with an amazing investigator that really believes and has bought into our thesis of democratizing anabolic therapy and making it available to younger women, and she really wants to change the paradigm, so.
I see. So phase three is geared up, it's locked and loaded to start. When might this trial start?
We're still planning and aiming to be able to start the study in the first half of 2026.
Okay. In the interest of time, I want to maybe just pivot to your GLP-1 glucagon oxyntomodulin analog. I guess what milestone should we look forward to in this next year, or will the sole focus just be osteoporosis for 2026?
In 2026, obviously, a lot of the focus hopefully will be on EB613 and starting the study. We will also have phase one data that we're currently testing next generation 613, probably in Q1 of 2026. We also plan to file the IND for oxyntomodulin and GLP-1 glucagon tablet in H1 2026, and potentially, we're aiming to start the SAD phase one study, which we could have data by, depending on enrollment, end of 2026 or beginning of 2027, and we also will be reporting potentially on, we're testing a third variant of the long-acting PTH for hypo preclinically, and so we'll have data on that one as well, and then we'll have to find a path to get the hypo tablet program back into clinic because that's a very high priority program for us and also has a lot of interest.
I see. Final question, Ranj, just in the interest of time, why should folks invest in Entera now? Maybe what's a nuance or something that you think the street isn't fully appreciating at this point?
I think we've made a lot of progress. We have a platform. We're consistently validating these oral tablets, which are not cumbersome to take. It's baby, basically their tablets are not even coated. They look like a baby aspirin, homeopathic medicine. The GLP-1 glucagon might be a bit bigger. But I think at least with 613, we are really, our aspiration is to change the treatment paradigm. And I think with that comes a lot of responsibility and a lot of, it's an aspiration, it's a mission. We're not trying to move the needle. We're trying to actually change the way osteoporosis is treated and close a gap. And so I think it's a very exciting time. I think the company remains at a very, how should I put this, easy to invest in valuation.
I think as we progress through our programs, I think all eyes, a lot of eyes have been on 613 in the last, I would say, 12 months. I think as the other programs continue to evolve and that news flow comes out, I think people are probably going to appreciate the value of our NTAB platform across different therapeutic indications.
Excellent. Well, that's all we have time for. Miranda, this has been extremely helpful. Thanks again for your time.
Thank you.
Okay.